RU2838188C2 - Pharmaceutical compositions containing dextromethorphan compound and quinidine for treatment of agitation in dementia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: disclosed is a method of treating agitation and/or aggression, and/or associated symptoms in a patient with dementia, comprising administering deuterated dextromethorphan and quinidine to a patient in need thereof, where deuterated dextromethorphan is orally administered in amount of 10 mg to 200 mg per day and quinidine is orally administered in amount of 0.05 mg to 50 mg per day, and deuterated dextromethorphan and quinidine are administered in amounts sufficient to reduce a subject's score according to a modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS - CGIC) in relation to excitation of at least 0.5 times compared to subjects without treatment or subjects with the introduction of placebo, and/or to reduce the patient’s overall clinical assessment of changes (PGI-C) in relation to arousal by at least 0.6 times compared to untreated subjects or subjects when administered with placebo. Also disclosed is the use of deuterated dextromethorphan and quinidine for treating arousal and/or aggression and/or associated symptoms in a patient with dementia and using deuterated dextromethorphan and quinidine for preparing a drug for treating agitation and/or aggression, and/or related symptoms in a patient with dementia.

EFFECT: group of inventions provides treating excitement and/or aggression, and/or related symptoms in a patient with Alzheimer's disease, and said method has no increased risk of developing serious undesirable effects.

10 cl, 10 dwg, 16 tbl, 6 ex

Description

[001] This application claims priority from the following U.S. Provisional Applications: No. 62/050,170, filed September 14, 2014, No. 62/061,451, filed October 8, 2014, No. 62/063,122, filed October 13, 2014, No. 62/063,861, filed October 14, 2014, No. 62/068,742, filed October 26, 2014, No. 62/111,053, filed February 2, 2015, No. 62/111,590, filed February 3, 2015, No. 62/128,446, filed March 4, 2014, 2015, No. 62/162140, filed May 15, 2015, No. 62/165535, filed May 22, 2015, No. 62/169997, filed June 2, 2015, No. 62/180026, filed June 15, 2015, No. 62/193347, filed July 16, 2015, No. and 62/205061, filed August 14, 2015, No. 62/216636, filed September 10, 2015, No. 62/217142, filed September 11, 2015, and No. 62/217,470, filed September 11, 2015, and the contents of all such applications are incorporated herein by reference.

FIELD OF INVENTION

[002] The present invention relates to the treatment of behavioral disorders such as agitation and/or aggression and/or associated symptoms associated with central nervous system (CNS) disorders, such as Alzheimer's disease. Methods related to the present invention include administering a dextromethorphan compound, alone or in combination with a CYP2D6 inhibitor such as quinidine (Q), to a subject suffering from agitation and/or aggression and/or having symptoms associated with central nervous system (CNS) disorders, such as Alzheimer's disease. The invention also relates to pharmaceutical combinations comprising a dextromethorphan compound, alone or in combination with a CYP2D6 inhibitor such as quinidine (Q).

STAGE OF INVENTION

[003] Alzheimer's disease is a progressive neurodegenerative disorder that ultimately results in death. An estimated 5.4 million Americans have Alzheimer's disease. The number of people with Alzheimer's disease has doubled since 1980 and is expected to exceed 16 million by 2050 (Brookmeyer et al., AlzheimersDement. 2011; 7(1):61-73). Among American adults over 65 years of age, the prevalence of dementia ranges from 5% to 15%, with Alzheimer's disease being the most common type of dementia (Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences, 1998; Evanset et al., JAMA. 1989;262(18):2551-6; Losonczye et al., Public Health Reports., 1998;113:273-80).

[004] Agitation is well recognized as a common and important clinical feature of Alzheimer's disease (AD) and other forms of dementia (Ballard C. G. et al., Nat. Rev. Neurol. 2009; 5 (5):245-255). Despite the ease of recognition of this symptom by clinicians and caregivers, only recently has a consensus definition of agitation in dementia been developed by the Agitation Definition Working Group (ADWG) of the International Psychogeriatric Association (IPA). This definition uses the following criteria: "1) occurs in patients with cognitive impairment or a dementia syndrome; 2) the patient exhibits behavior consistent with emotional distress; 3) there is excessive motor activity, verbal or physical aggression; and 4) patterns of behavior that cause excessive, disabling impairment in relationships and/or daily functioning are endorsed and that are not the sole cause of other disorders (psychiatric, clinical, or substance-related)" (Cummings J. et al., Int. Psychogeriatr. 2014:1-11). According to experts, agitation and/or aggression are observed in approximately 80% of patients with dementia (Ryu S-Hetal., Am. J. Geriatr. Psychiatry. 2005; 13(11):976-983; Tractenberg R. E. et al., J. Geriatr. psychiatry. Neurol. 2003; 16(2):94-99), with its prevalence increasing as the disease progresses.

[005] Agitation in patients with dementia is the cause of increasing functional impairment (Rabins P. V. et al., Alzheimer's Dement. 2013; 9(2):204-207), deterioration in quality of life (González-Salvador T. et al., Int. J. Geriatr. Psychiatry. 2000; 15(2):181-189), early institutionalization (Steele C. et al., Am. J. Psychiatry. 1990; 147(8):1049-1051), increased burden on caregivers and the patient (Rabins P. V. et al., Alzheimer's Dement. 2013; 9(2):204-207), and increased costs of medical services (Murman D. L. et al., Neurology. 2002; 59(11):1721–1729), shortening the time to onset of symptoms of severe dementia (Peters M.E. et al., Am. J. Geriatr. Psychiatry. 2014; 22(3):S65–S66), and hastening mortality (Peters M.E. et al., Am. J. Geriatr. Psychiatry. 2014; 22(3):S65–S66). For these reasons, agitation and aggression in patients with Alzheimer's disease are the neuropsychiatric symptoms most likely to require pharmacological intervention (Ballard C.G. et al., Nat. Rev. Neurol. 2009; 5(5):245–255).

[006] However, there are currently no FDA-approved pharmacologic treatments for agitation in AD, and physicians end up using antipsychotics, sedative/hypnotics, tranquilizers, and antidepressants off-label in an attempt to treat these symptoms (Maher A.R. et al. JAMA, 2011; 306 (12): 1359-1369). Unfortunately, these drugs have limited applicability and, consequently, low efficacy, which is offset by relatively poor compliance, safety and tolerability indicators (Ballard C. G. et al., Nat. Rev. Neurol. 2009; 5(5):245-255; Schneider L. S. et al., N. Engl. J. Med. 2006; 355(15):1525-1538; Huybrechts K. F. et al., BMJ 2012; 344:e977). Thus, there is a clear need to develop a safe and effective pharmacological intervention for the treatment of agitation in dementia. Such treatment could profoundly impact patient care, reduce the burden on caregivers and potentially improve the overall prognosis of the disease.

[007] Because there is no FDA-approved treatment for the behavioral symptoms associated with Alzheimer's disease, off-label prescription of antipsychotics is widely used to treat symptoms such as aggression and agitation (Salzman et al., J. Clin. Psychiatry. 2008; 69(6):889-98; Levenson and Crecelius, AMDA: Publications - Caring for the Ages., 2003; 4(6):31,34-35). Atypical antipsychotics have modest efficacy in the short-term treatment of aggression (6–12 weeks) but are of limited benefit in the long-term because their potential efficacy is usually outweighed by adverse effects (Scheide et al., N. Engl. J. Med. 2006; 355(15):1525–38). Benefits for other symptoms, such as agitation, are less well established (Sultzer et al., Am. J. Psychiatry. 2008; 165(7):844–54). Additionally, there is considerable concern about the potential for serious adverse outcomes with antipsychotics, including stroke and increased mortality (Hybrechts et al. BMJ, 2012; 344:e977). Also, non-antipsychotic psychotropic drugs have been studied without much result in terms of their use both for symptom relief and for their secondary prevention (Tariot et al., Arch. Gen. Psychiatry. 2011; 68 (8):853-61). In this regard, there is a need for a thorough study of other pharmacological and non-pharmacological approaches to the treatment of agitation and aggression in patients with Alzheimer's disease (Ballard et al., Curr. Opin. Psychiatry. 2009; 22 (6): 532-40; Lyketsose et al., The Journal of Alzheimer's Association. 2011; 7 (5): 532-9).

[008] Dextromethorphan is the international nonproprietary name for (+)-3-methoxy-N-methylmorphinan. It is one of a class of molecules that belong to the dextrorotatory analogues of morphine-like opiates. Dextromethorphan is known to have at least three different receptor actions that affect the central neurons of the nervous system. Although the pharmacological profile of dextromethorphan indicates its clinical efficacy for several indications, the efficacy of dextromethorphan when administered as is is disappointing compared to placebo.

[009] It has long been known that in most humans (estimated to include approximately 90% of the total population of the United States), dextromethorphan is extensively converted in the liver to dextrorphan by O-demethylation catalyzed by CYP2D6 and is rapidly eliminated from the body (Ramachander et al., J. Pharm. Sci. 1977; 66(7):1047-8, and Vetticaden et al., Pharm. Res. 1989; 6(1):13-9). The CYP2D6 enzyme is a member of a class of oxidative enzymes that are present in high concentrations in the liver and are called cytochrome P450 enzymes (Kronbach et al., Anal. Biochem. 1987; 162(1):24-32, and Dayer et al., Clin. Pharmacol. Ther. 1989; 45(1):34-40).

[010] In addition to the metabolism of dextromethorphan, CYP2D6 is also responsible for the hydroxylation of the polymorphic debrisoquine in humans (Schmid et al., Clin. Pharmacol. Ther. 1985; 38:618-624). The alternative pathway is mediated primarily by CYP3A4 and N-demethylation to form 3-methoxymorphinan (Von Moltke et al., J. Pharm. Pharmacol, 1998; 50:997-1004). Both dextrorphan and 3-methoxymorphinan can be further demethylated to 3-hydroxymorphinan, which then undergoes glucuronidation. The metabolic pathway by which dextromethorphan is converted to dextrorphan is the predominant one in the population and is the principle underlying the use of dextromethorphan as a model for distinct phenotypes, such as CYP2D6 extensive and poor metabolizers (Kupfer et al., Lancet. 1984; 2:517-518; Guttendorf et al., Ther. DrugMonit. 1988; 10:490-498). Approximately 7% of Caucasians have a poor metabolizer phenotype, and the incidence of the poor metabolizer phenotype is even lower in Chinese and black African populations (Droll et al., Pharmacogenetics. 1998; 8:325-333). In a study examining the ability of dextromethorphan to elevate pain thresholds in poor and extensive metabolizers, the antinociceptive effects of dextromethorphan were found to be more pronounced in poor metabolizers than in extensive metabolizers (Desmeuies et al., J. Pharmacol. Exp. Ther. 1999; 288:607-612). These results are consistent with direct neuromodulatory effects mediated by the parent compound dextromethorphan, as opposed to the dextrorphan metabolite.

The essence of the invention

[011] As described above, there remains a pressing need for additional or improved forms of treatment for agitation, aggression, and/or related symptoms in patients with Alzheimer's disease. The present invention relates to methods for treating agitation and/or aggression and/or related symptoms in patients with Alzheimer's disease, and said methods do not have an increased risk of developing serious adverse effects.

[012] The first aspect of the present invention relates to a method of treating agitation and/or aggression and/or related symptoms in patients suffering from dementia by administering a dextromethorphan compound in combination with a CYP2D6 inhibitor such as quinidine (Q). The invention also encompasses the use of pharmaceutically acceptable salts of the dextromethorphan compound alone or also salts of quinidine in the described methods. The methods described in the invention may also use an analog or derivative of quinidine. In one embodiment, the dementia is dementia of the Alzheimer's type.

[013] A second aspect of the present invention relates to a combination of a dextromethorphan compound and a CYP2D6 inhibitor such as quinidine. The invention also encompasses the use of pharmaceutically acceptable salts of one or both of the dextromethorphan compound and quinidine in the described combination. Such a combination can be used to treat agitation and/or aggression and/or related symptoms in a subject with dementia. A quinidine analog or derivative can also be used in this combination. In one embodiment, the dementia is Alzheimer's type dementia.

[014] In some embodiments, according to the first and second aspects of the present disclosure, the dextromethorphan compound is administered or used in an amount in the range of about 10 mg per day to about 200 mg per day, and quinidine is administered or used in an amount of about 0.05 mg per day to less than about 50 mg per day.

[015] In some embodiments, quinidine is administered or used in an amount in the range of about 4.75 mg per day to about 20 mg per day. In some embodiments, the dextromethorphan compound is administered or used in an amount in the range of about 10 mg per day to about 90 mg per day.

[016] In some embodiments, one or both of the quinidine and dextromethorphan compounds are in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts according to the present invention include alkali metal salts, lithium salts, sodium salts, potassium salts, alkaline earth metal salts, calcium salts, magnesium salts, lysine salts, N,N`dibenzylethylenediamine salts, chloroprocaine salts, choline salts, diethanolamine salts, ethylenediamine salts, meglumine salts, procaine salts, tris salts, free acid salts, free base salts, inorganic salts, sulfate salts, hydrochloride salts, and hydrobromide salts. In some embodiments, the dextromethorphan compound is in the form of dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide. In some embodiments, the quinidine is in the form of quinidine sulfate.

[017] In some embodiments of the present invention, the dextromethorphan compound and quinidine are administered or used in a unit dosage form. In some embodiments, the unit dosage form comprises about 4.75 mg, 4.9 mg, 9 mg, or 10 mg of quinidine (e.g., as quinidine sulfate) and about 45 mg, 34 mg, 30 mg, 28 mg, 24 mg, 23 mg, 20 mg, 18 mg, 15 mg, or 10 mg of the dextromethorphan compound (e.g., as deuterated dextromethorphan hydrobromide or dextromethorphan hydrobromide). In one embodiment, the unit dosage form comprises about 10 mg of quinidine (e.g., quinidine sulfate) and about 20 mg or 30 mg of a dextromethorphan compound (e.g., dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide). In another embodiment, the unit dosage form comprises about 9 mg of quinidine (e.g., quinidine sulfate) and about 15 mg or 23 mg of a dextromethorphan compound (e.g., dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide). In another embodiment, the unit dosage form comprises about 4.9 mg of quinidine (e.g., quinidine sulfate) and about 18 mg, 24 mg, 28 mg, 30 mg, or 34 mg of a dextromethorphan compound (e.g., dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide). In yet another embodiment, the unit dosage form comprises about 4.75 mg of quinidine (e.g., quinidine sulfate) and about 18 mg, 24 mg, 28 mg, 30 mg, or 34 mg of a dextromethorphan compound (e.g., dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide). In some embodiments, the unit dosage forms of the dextromethorphan and quinidine compound are provided as a tablet or capsule.

[018] In some embodiments, the dextromethorphan compound and quinidine are administered or used in a combined dose or in separate doses in a weight ratio of dextromethorphan compound to quinidine that is about 1:1 or less. In some embodiments, the weight ratio is about 1:1, 1:0.95, 1:0.9, 1:0.85, 1:0.8, 1:0.75, 1:0.7, 1:0.65, 1:0.6, 1:0.55, or 1:0.5 or less. Furthermore, in some embodiments, the weight ratio of the dose of dextromethorphan compound to quinidine is less than about 1:0.5, such as about 1:0.45, 1:0.4, 1:0.35, 1:0.3, 1:0.25, 1:0.2, 1:0.15, or 1:0.1, 1:0.09, 1:0.08, 1:0.07, 1:0.06, 1:0.05, 1:0.04, 1:0.03, 1:0.02, or 1:0.01, or less. The weight ratios can be, for example, about 1:0.75, about 1:0.68, about 1:0.6, about 1:0.56, about 1:0.5, about 1:0.44, about 1:0.39, about 1:0.38, about 1:0.31, about 1:0.30, about 1:0.29, about 1:0.28, about 1:0.27, about 1:0.26, about 1:0.25, about 1:0.24, about 1:0.23, about 1:0.22, about 1:0.21, about 1:0.20, about 1:0.19, about 1:0.18, about 1:0.17, about 1:0.16, about 1:0.15, about 1:0.14, about 1:0.13, about 1:0.12, about 1:0.11, and about 1:0.10. In some embodiments, the weight ratios of dextromethorphan free base to quinidine free base are about 1:0.68, about 1:0.56, about 1:0.44, about 1:0.38. In some other embodiments, the weight ratios of d6-deuterated dextromethorphan free base to quinidine free base are about 1:0.30, about 1:0.22, about 1:0.19, about 1:0.18, about 1:0.16, and about 1:0.15.

[019] The dextromethorphan compound and quinidine may be administered or used as one combination dose per day or at least two combination doses per day. In one embodiment, the dextromethorphan compound and quinidine are administered together.

[020] In some embodiments, the improvement due to the use of a dextromethorphan compound in combination with quinidine for the treatment of agitation and/or aggression and/or related symptoms in patients with Alzheimer's disease can be measured by an improvement in one or more of the following:

- arousal/aggression domain according to the Neuropsychiatric Inventory (NPI);

- overall NPI score;

- a combination of NPI scores for the domains of arousal/aggression, irritability/lability, aberrant motor behavior, and anxiety (NPI4A);

- a combination of NPI scores for the domains of arousal/aggression, irritability/lability, aberrant motor behavior, and disinhibition (NPI4D)

- NPI caregiver distress - arousal/aggression domain;

- modified Alzheimer's Disease Cohort Study - Global Clinical Assessment of Change (ADCS-CGIC) for agitation; and/or

- Patient Global Assessment of Changes in Clinical Change (PGI-C) in relation to arousal.

[021] In one embodiment, the subject's NPI score for arousal/aggression is reduced by at least 1.5-fold compared to untreated subjects or subjects receiving placebo.

[022] In one embodiment, the subject's NPI4A score is reduced by at least 2.4-fold compared to untreated subjects or subjects when administered a placebo.

[023] In one embodiment, the subject's NPI4D score is reduced by at least 3.0-fold, compared to untreated subjects or subjects when administered a placebo.

[024] In one embodiment, the subject's ADCS-CGIC score for agitation is improved by at least 0.5-fold compared to untreated subjects or subjects when administered placebo.

[025] In one embodiment, the subject's PGI-C score for arousal is improved by at least 0.6-fold compared to untreated subjects or subjects when administered a placebo.

[026] The pharmaceutical compositions described in the invention may optionally include pharmaceutically acceptable carriers, adjuvants, excipients, or other pharmaceutical compositions, and may be administered in any of a variety of dosage forms or by any of a variety of routes of administration known in the art.

[027] The methods disclosed in the invention may optionally also include administering a dextromethorphan compound and a CYP2D6 inhibitor, such as quinidine, in combination with other therapeutic agents, such as, for example, one or more therapeutic agents known or discovered for the treatment of Alzheimer's disease.

[028] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide a further, non-restrictive explanation of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

[029] Figure 1 shows the chemical structure of an embodiment of the dextromethorphan compound of the present invention, namely, d6-deuterium modified dextromethorphan.

[030] Figure 2 shows the study design for the clinical trial of agitation in Alzheimer's disease. The legend "dextromethorphan/quinidine 20/10" refers to a dose of 20 mg dextromethorphan and 10 mg quinidine. The QD and BID doses refer to once daily and twice daily administration, respectively. An asterisk (*) indicates study participants who withdrew prior to the Week 1 visit and therefore did not have any post-baseline data available for the primary efficacy endpoint.

[031] Figure 3 is a Consolidated Standards of Reporting Trials (CONSORT) design for patients used in the clinical trial of agitation in Alzheimer's disease described in the invention. Populations denoted by ‡ represent populations included in the sequential parallel comparison design (SPCD).

[032] Figure 4 shows the mean NPI Agitation/Aggression scores at Time 1 for patients enrolled in the Alzheimer's Disease Agitation Clinical Trial described in the invention, which utilized a sequential parallel comparison design (or SPCD). For each visit, P-values are shown, calculated from an analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline as a covariate. ^a = observed cases.

[033] Figure 5 shows the mean NPI Agitation/Aggression scores at Time 2 for subjects enrolled in the Alzheimer's Disease Agitation Clinical Study described in the invention (which utilized the SPCD design). For each visit, the P-values are calculated from an analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline as a covariate. ^a = observed cases.

[034] Figure 6 shows the mean NPI agitation/aggression scores in a 10-week secondary analysis of the Alzheimer's disease agitation clinical trial described herein. Only subjects who remained in the same treatment group during the trial, i.e., were randomized to dextromethorphan/quinidine alone or placebo alone for the sake of completeness of the trial, were included in the 10-week secondary analysis, thus simulating a parallel trial design. P-values are reported for each visit, calculated from an analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline as a covariate. ^a = observed cases.

[035] Figure 7 shows mean plasma concentrations over time during treatment with paroxetine and AVP-786 - Group 1.

[036] Figure 8 shows mean plasma concentrations over time during treatment with paroxetine and AVP-786 - Group 2.

[037] Figure 9 shows mean plasma concentrations over time during treatment with duloxetine and AVP-786 - Group 3.

[038] Figure 10 shows mean plasma concentrations over time during treatment with duloxetine and AVP-786 - Group 4.

DETAILED DESCRIPTION

[039] The following is a detailed description and examples illustrating some embodiments of the present invention. It will be apparent to those skilled in the art that there are numerous variations and modifications of the present disclosure that are within its scope. Therefore, the description of specific embodiments should not be construed as limiting the scope of the present invention.

[040] All references cited herein, including without limitation published and unpublished applications, patents, and literature references, are hereby incorporated by reference in their entirety and are hereby incorporated into this disclosure.

Definitions

[041] The terms "improving" and "treating" are used interchangeably and include therapeutic treatment. Both terms mean improving, reducing, suppressing, attenuating, reducing, stopping, or stabilizing the development or progression of a disease (e.g., a disease or disorder described in the invention) or the symptoms of a disease, individually or collectively (e.g., a syndrome). The term "treating" is used in the invention to mean reducing or alleviating at least one symptom of a disease in a patient. For example, the term "treating" with respect to behavioral disorders may mean removing or alleviating agitation and/or aggression and/or related symptoms and any combination of their manifestations (e.g., hitting, fighting, swearing, pacing, stubbornness, etc.) and related behavior patterns (e.g., irritability, anxiety, etc.). In the context of the present description, the term “treatment” also means stopping, delaying the onset of a disease (i.e. the period before clinical manifestation of the disease), and/or reducing the risk of developing or worsening the disease.

[042] "Disease/Malaise" means any condition or disorder that damages or impairs the normal functioning of a cell, tissue, organ, or organism.

[043] The term "dementia" refers to a general mental deterioration caused by organic or psychological factors. Dementia is characterized by disorientation, memory impairment, judgment and intellect, and mild affective instability. Types of dementia, according to the invention, include vascular dementia, ischemic vascular dementia (IVD), frontotemporal dementia (FTD), dementia with Lewy bodies, Alzheimer's dementia, and the like. The most common form of dementia is caused by Alzheimer's disease (AD).

[044] The term "Alzheimer's disease (AD)" refers to a progressive mental deterioration characterized by memory loss, confusion, and disorientation. AD typically begins in late adulthood and often results in death within 5 to 10 years. A diagnosis of Alzheimer's disease can be made by an experienced neurologist or physician. In one embodiment, a patient with AD meets the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for determining the likelihood of having AD.

[045] The terms "analog" or "derivative" are used herein in their generally accepted pharmaceutical sense to refer to a molecule having structural similarity to a reference molecule (e.g., a dextromethorphan, deuterated dextromethorphan, or quinidine molecule) that has been modified in a targeted and controlled manner to replace one or more specific substituents in the reference molecule with alternative substituents, thereby creating a molecule having structural similarity to the reference molecule. A well-known approach to drug development in the art of pharmaceutical chemistry is the synthesis and screening of analogs (e.g., by structural and/or biochemical analysis) to identify minimally modified versions of a known compound that may have improved or altered attributes (e.g., greater potency and/or selectivity for a particular type of target receptor, increased ability to penetrate the blood-brain barrier in mammals, reduced side effects, etc.). Additionally, using methods known to those skilled in the art, it is possible to create analogs and derivatives of the compounds of the invention that have improved therapeutic efficacy, i.e., higher efficacy and/or selectivity with respect to a particular type of target receptors, and greater or lesser ability to penetrate the blood-brain barrier in mammals (e.g., higher or lower rate of penetration through the blood-brain barrier), less pronounced side effects, longer existence in the patient's body, etc.

[046] The term "agitation" as used herein is an umbrella term that can refer to a variety of behavioral disorders or disturbances including aggression, aggressiveness, and hyperactivity. For purposes of the present disclosure, this definition includes agitation as described by Cummings et al. International Psychogeriatrics; Volume 27; Issue 01; January 2015, pp. 7-17. Broadly, according to the definition of agitation by Cummings et al., it is considered that: 1) it occurs in patients with cognitive impairment or dementia syndrome; 2) the behavior displayed is consistent with emotional distress; 3) excessive motor activity, verbal aggression, or physical aggression is displayed; and 4) patterns of behavior are endorsed that cause additional disability and are not exclusively related to another disorder (psychiatric, clinical, or substance use disorder). The term agitation also includes:

1) excessive motor activity associated with a feeling of internal tension. The activity is usually unproductive and repetitive and consists of such behavioral features as the inability to sit still, pacing, wringing hands, and tugging at clothes;

2) inappropriate verbal, vocal, or motor activity that cannot be explained by the needs, or confusion itself. This includes behavior patterns such as aimless wandering, pacing, cursing, yelling, biting, and hitting;

3) vocal or motor behavior that is either disruptive to social behavior or is unsafe or interferes with treatment in a particular environment. It includes four behavioral domains, such as vocalization, motor disturbances, aggression, and resistance to treatment;

4) behavior patterns that are transmitted to others, that is, the patient experiences an unpleasant state of arousal, and which remain after interventions aimed at reducing internal or external stimuli by regulating resistance, alleviating aversive physical symptoms, and reducing sources of accumulated stress; and

5) behavior in which the patient refuses to cooperate, does not allow people to help, or makes it difficult to treat him/herself.

[047] The term "associated symptoms" as used herein refers to symptoms associated with a patient that meet the criteria for cognitive impairment or a dementia syndrome (e.g., Alzheimer's disease, FTD, DLB, vascular dementia, other types of dementia, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment, or other cognitive disorders). Associated symptoms include, for example, behavior patterns that are associated with observed or inferred evidence of emotional distress (e.g., rapid mood swings, irritability, emotional outbursts). In some cases, such behavior is persistent or frequently repeated over a period of at least two weeks, and represents a change from the patient's usual behavior. The term "associated symptoms" also includes excessive motor activity (e.g., pacing, rocking, gesturing, pointing, fidgeting, making repetitive mannered movements), verbal aggression (e.g., yelling, speaking in an excessively loud voice, using foul language, screaming, shouting), and physical aggression (e.g., the patient may grab, push, shove, push, hit others, kick objects or people, scratch or bite, throw objects, hit oneself, slam doors, tear things, and destroy property).

[048] The term "combination" with respect to the active ingredients used in the invention means a single pharmaceutical composition (formulation) containing both medicinal substances of the present invention (i.e., the dextromethorphan compound and quinidine), or two separate pharmaceutical compositions (formulations), each containing one medicinal substance of the invention (i.e., the dextromethorphan compound or quinidine), which are intended to be administered together.

[049] As used herein, the term "co-administration" is used to mean the administration of the dextromethorphan compound and quinidine simultaneously in a single composition, or simultaneously in different compositions, or means their sequential administration. In order for the sequential administration to be considered "co-administered," the dextromethorphan compound and quinidine are administered separately with a time interval, thereby achieving a beneficial effect in treating, preventing, stopping, delaying the onset of, and/or reducing the risk of a patient developing a behavioral disorder associated with the central nervous system (CNS). For example, in some embodiments, the dextromethorphan compound and quinidine are administered on the same day (e.g., each of these drugs is administered once a day or twice a day).

[050] According to the invention, the overall NPI score is the sum of the scores for 12 standard NPI domains. The NPI questionnaire is a validated clinical instrument for psychopathological assessment in various clinical situations, including dementia. The NPI questionnaire results in a retrospective patient assessment scale by a caregiver, which covers 12 domains of neuropsychiatric symptoms: delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elevation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior patterns, nocturnal behavior disorders, and appetite/eating disorders. The NPI script questionnaire includes general screening questions for each symptom domain, followed by a list of questions about behavior patterns from a specific domain, which is used if the corresponding screening question is answered positively. The neuropsychiatric manifestations within a domain are collectively ranked, according to the caregiver, in terms of their frequency (0 to 4) and severity (1 to 3), resulting in a composite domain symptom score of 1 to 12 (frequency x severity) for each positively rated domain. The frequency and severity rating scales are used to determine anchor points to improve the reliability of the caregiver's responses. The caregiver's distress is assessed for each positive domain of neuropsychiatric symptoms on a scale with anchor points ranging from 0 (no distress at all) to 5 (extreme distress). According to the invention, the NPI4A score is a composite score containing the NPI domains of arousal/aggression, aberrant motor behavior, irritability/lability, and anxiety. According to the invention, the NPI4D scores represent a composite score containing the NPI domains of arousal/aggression, aberrant motor behavior, irritability/lability, and disinhibition.

[051] The term "therapeutically effective" with respect to a dose or amount means an amount of a compound or pharmaceutical composition that is sufficient to achieve a desired effect when administered to a subject in need thereof. As used herein, the term "therapeutically effective amount/dose" with respect to pharmaceutical compositions containing a dextromethorphan compound is referred to interchangeably with the term "neurologically effective amount/dose" and refers to an amount/dose of a compound or pharmaceutical composition that is sufficient to achieve an effective neurological response, i.e., to relieve a behavioral disturbance associated with a CNS disorder, when administered to a subject.

[052] The term "pharmaceutically acceptable" as applied to the compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not generally produce adverse reactions when administered to a subject (e.g., a human). In some embodiments, the term "pharmaceutically acceptable" means that the substance is approved by a regulatory agency of the federal or state government, or is listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in mammals, and more particularly, in humans.

[053] The term "carrier" as applied to the pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which the active compound (e.g., the dextromethorphan compound or quinidine) is administered. Such pharmaceutical carriers can be sterile liquids, for example, water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Suitable pharmaceutical carriers are described in E. W. Martin's Remington's Pharmaceutical Sciences, 18th edition.

[054] As used herein, the term "subject" includes mammals (e.g., rodents such as mice or rats). In some embodiments, the term refers to a human with an identified behavioral disorder associated with a CNS disorder, such as agitation and/or aggression. The term "subject" also includes humans exhibiting neuropsychiatric symptoms or behavioral symptoms of dementia.

[055] It should be understood that during the synthesis of a compound, some variations in the natural isotopic composition occur, which are due to the origin of the chemical materials used in the synthesis. Thus, the drug dextromethorphan will naturally contain a small amount of deuterated and/or ^13C -containing isotopologues. The concentration of commonly occurring stable isotopes of hydrogen and carbon, despite these variations, is low and insignificant compared to the degree of substitution of stable isotopes in the compounds of the invention. See, for example, Wada E. et al., Seikagaku 1994, 66:15; Ganes L. Z. et al., Comp. Biochem. Physiol. A Mol. Integr. Physiol . 1998, 119:725. With respect to a compound of the invention, if a particular position indicates the presence of deuterium, it is understood that the deuterium content of that position is substantially greater than the natural abundance of deuterium, which is typically about 0.015%. The position with the indicated presence of deuterium is typically characterized by a minimum isotopic enrichment factor that is at least 3000 (45% of the deuterium incorporated) for each atom designated as deuterium in the said compound.

[056] The term "isotopic enrichment factor" as used in the invention means the ratio between the abundance of an isotope and the natural abundance of a particular isotope.

[057] In other embodiments, a compound of the invention has an isotopic enrichment factor for each said deuterium atom that is at least 3500 (52.5% incorporation of deuterium in each said deuterium atom), at least 4000 (60% incorporation of deuterium), at least 4500 (67.5% incorporation of deuterium), at least 5000 (75% incorporation of deuterium), at least 5500 (82.5% incorporation of deuterium), at least 6000 (90% incorporation of deuterium), at least 6333.3 (95% incorporation of deuterium), at least 6466.7 (97% incorporation of deuterium), at least 6600 (99% incorporation of deuterium), or at least 6633.3 (99.5% incorporation of deuterium).

[058] In the compounds of the invention, any atom for which a specific isotope type is not specifically defined is any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", it is understood that hydrogen is naturally present at that position in its isotopic composition.

[059] The term "isotopologue" refers to a species that has the same chemical structure and formula as a particular compound of the present invention, except for the isotopic composition at one or more positions, for example, H versus D. Thus, an isotopologue differs from a particular compound of the present invention in its isotopic composition.

[060] The term "compound" as used in the invention also includes any salts, solvates or hydrates. The term "dextromethorphan compound" is used in this application for ease of use and includes the following terms: dextromethorphan, or deuterated dextromethorphan, or an analog thereof, or a derivative of dextromethorphan, or an analog or derivative of deuterated dextromethorphan.

[061] In general, the dextromethorphan compound of the present invention has four molecular rings in a configuration called the “morphinan” structure, which is represented as follows:

[062] In this structural diagram, the carbon atoms are numbered in the conventional manner as shown. The wedge-shaped bonds connecting carbon atoms 9 and 13 indicate that these bonds arise from the plane formed by the other three rings in the morphinan structure.

[063] A salt of a compound of the invention is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[064] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, and related inorganic and organic acids. Said pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include salts formed with mineral acids such as hydrochloric acid and hydrobromic acid, and salts formed with organic acids such as maleic acid.

[065] In some embodiments, pharmaceutically acceptable salts include alkali metal salts, lithium salts, sodium salts, potassium salts, alkaline earth metal salts, calcium salts, magnesium salts, lysine salts, N,N'dibenzylethylenediamine salts, chloroprocaine salts, choline salts, diethanolamine salts, ethylenediamine salts, meglumine salts, procaine salts, tris salts, free acid salts, free base salts, inorganic salts, sulfate salts, hydrochloride salts, and hydrobromide salts.

[066] Unless otherwise stated, the dosages described in the invention refer to the hydrobromide and sulfate salt forms of the dextromethorphan compound and quinidine, respectively. Based on this information, one skilled in the art can calculate appropriate dosages for the corresponding active ingredients in the form of free acids or free bases. One skilled in the art can calculate the molecular weight for the dextromethorphan salt and the molecular weight for the dextromethorphan free base, and use this ratio to calculate appropriate dosages for the free base as well as for the salt. For example, a dose of 15 mg dextromethorphan hydrobromide (with the molecular formula C ₁₈ H ₂₅ ΝΟ ΗΒr Η ₂ O) and a dose of 9 mg quinidine sulfate (with the molecular formula (C ₂₀ H ₂₄ N ₂ O ₂ ) ₂ H ₂ SO ₄ 2H ₂ O) (corresponding to approximately 11 mg dextromethorphan and 7.5 mg quinidine) may be administered or used. Other doses include, for example, 23 mg dextromethorphan hydrobromide and 9 mg quinidine sulfate (corresponding to approximately 17 mg dextromethorphan and approximately 7.5 mg quinidine); 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (equivalent to approximately 15 mg dextromethorphan and 8.3 mg quinidine); 30 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (equivalent to approximately 22 mg dextromethorphan and 8.3 mg quinidine).

[067] d6-deuterated dextromethorphan hydrobromide (with the molecular formula C ₁₈ H ₁₉ D ₈ NO HBr H ₂ O) may be administered at a dose of 24 mg and quinidine sulfate (with the molecular formula (C ₂₀ H ₂₄ N ₂ O ₂ ) ₂ H ₂ SO ₄ 2H ₂ O) at a dose of 4.75 mg (corresponding to approximately 18 mg dextromethorphan and 3.96 mg quinidine). Other doses of d6-deuterated dextromethorphan include, for example, 34 mg d6-dextromethorphan hydrobromide and 4.75 mg quinidine sulfate (corresponding to approximately 25.18 mg d6-dextromethorphan and approximately 3.96 mg quinidine); 18 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 13.33 mg d6-dextromethorphan and 4.08 mg quinidine); 24 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 17.78 mg d6-dextromethorphan and 4.08 mg quinidine); 28 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 20.74 mg d6-dextromethorphan and 4.08 mg quinidine); 30 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 22.22 mg d6-dextromethorphan and 4.08 mg quinidine); 34 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 25.18 mg d6-dextromethorphan and 4.08 mg quinidine).

[068] As used herein, the term "hydrate" means a compound that further comprises a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[069] As used herein, the term "solvate" means a compound that further comprises a stoichiometric or non-stoichiometric amount of a solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol or the like, bound by non-covalent intermolecular forces.

[070] A compound of the present invention (e.g., a compound of Formula I, described below) may contain an asymmetric carbon atom, such as by substitution of deuterium or otherwise. Thus, the compounds of the present invention may exist as separate enantiomers or as a mixture of two enantiomers. Accordingly, a compound of the present invention will include both racemic mixtures and individual corresponding stereoisomers that are substantially free of other possible stereoisomers. As used herein, the term "substantially free of other stereoisomers" means the presence of other stereoisomers in an amount of less than 25%, in some embodiments less than 10% other stereoisomers, in some embodiments less than 5% other stereoisomers, and in some embodiments less than 2% other stereoisomers, or in an amount of less than "X"% other stereoisomers (where X is a number in the range from 0 to 100, inclusive). Methods for preparing or synthesizing a particular enantiomer of a given compound are well known in the art and may be applied, where practicable, to final compounds or starting material or intermediates.

[071] The term "stable compounds" as used in the invention refers to compounds that are stable enough to permit their manufacture and that maintain the integrity of the compound for a sufficient period of time while remaining useful for the purposes described in the invention (e.g., for formulating drug products, for intermediates for the manufacture of drug compounds, for isolable or storable intermediates, for treating a disease or condition that is responsive to drugs).

[072] "D" stands for deuterium.

[073] "Stereoisomer" refers to both enantiomers and diastereomers.

[074] In the text of the present invention, variables may refer to general concepts (e.g., "each R") or may refer to specific elements (e.g., R ¹ or R ² ). Unless otherwise indicated and a variable refers to general concepts, such a variable includes all specific embodiments of that particular variable.

[075] The term "comprising" as used in the invention is synonymous with the terms "including", "consisting of" or "characterized by the presence of", and is inclusive or open-ended and does not exclude additional unspecified elements or method steps.

[076] All numbers expressing quantities of ingredients, reaction conditions, etc., used in this application are to be considered as modified whenever the term "about" is used. Accordingly, unless otherwise indicated, numerical parameters set forth in the invention are approximate and may vary depending on the desired properties. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claim in any of the applications to which priority is claimed by this application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding practices.

Therapeutic compounds

[077] Dextromethorphan (DM) is a non-opioid d-isomer of the codeine analogue levorphanol and has been widely used as an over-the-counter (OTC) antitussive for approximately 50 years. Dextromethorphan has complex pharmacological properties, exhibits binding affinity for a number of different receptors, and exerts its primary action in the central nervous system (CNS). DM is well known to act as a weak, non-competitive N-methyl-D-aspartate receptor (NMDA) antagonist (K _i = 1500 nM) (Tortella et al. Trends Pharmacol. Sci. 1989; 10(12):501-7; Chou YC et al., Brain Res. 1999; 821(2):516-9; Netzer R et al., Eur. J. Pharmacol. 1993; 238(2-3):209-16; Jaffe DB et al., Neurosci. Lett. 1989; 105(1-2):227-32) with corresponding possible action as an excitatory glutamate receptor antagonist. DM is also a potent sigma-1 agonist (Zhou GZ et al., Eur. J. Pharmacol. 1991; 206(4):261-9; Maurice T et al., Brain Res. Brain Res. Rev. 2001; 37(1-3):116-32; Cobos EJ et al., Curr. Neuropharmacol. 2008; 6(4):344-66) (K _i = 200 nM) and binds with high affinity to the serotonin transporter (SERT, K _i = 40 nM). DM has moderate affinity for the norepinephrine transporter (K _i = 13 μM), but DM is a potent inhibitor of norepinephrine uptake (K _i = 240 nM) (Codd EE et al., J. Pharmacol. Exp. Ther. 1995; 274(3):1263-70). DM is an α3β4 nicotinic acetylcholine receptor antagonist, and the reported IC50 (concentration producing 50% inhibition) value of DM is 0.7 μM (Damaj et al., J. Pharmacol. Exp. Ther. 2005; 312(2):780-5).

[078] As a result of one or more of these interactions, DM decreases potassium-mediated glutamate release (Annels SJ et al., Brain Res. 1991; 564(2):341-3) and modulates monoamine (serotonin, norepinephrine, and dopamine) neurotransmission (Codd EE et al., J. Pharmacol. Exp. Ther. 1995; 274(3):1263-70; Maurice T et al., Pharmacol. Ther. 2009; 124(2):195-206; Maurice T et al., Prog. Neuropsychopharmacol. Biol. Psychiatry. 1997; 21(1):69-102). The antagonism of DM at α3β4 nicotinic acetylcholine receptors (Damaj MI et al., J. Pharmacol. Exp. Ther. 2005; 312(2):780-5) may have an impact on some CNS movement disorders and drug dependence (Silver AA et al., J. Am. Acad. Child Adolesc. Psychiatry. 2001; 40(9):1103-10). When administered as a single agent, DM is rapidly metabolized in the liver primarily to dextrorphan (DX), which results in its extremely low bioavailability and thus limits the CNS effects of DM. Although DX interacts with some of the same receptors as DM, its affinity for the major receptors differs. DX also undergoes rapid conjugation with glucuronides, which significantly prevents its passage through the blood-brain barrier, and thus reduces its CNS effects at prescribed doses (Church J. et al., Eur. J. Pharmacol. 1985; 111(2):185-90; Franklin P.H. et al., Mol. Pharmacol. 1992;41(1):134-46).

[079] The present invention relates to a compound of formula I, including pharmaceutically acceptable salts, solvates and hydrates thereof:

where R ¹ is selected from CH ₃ , CH ₂ D, CHD ₂ and CD ₃ ; and R ² is selected from CH ₃ , CH ₂ D, CHD ₂ and CD ₃ .

[080] All compounds of formula I that have at least one deuterium are referred to as deuterated dextromethorphan. In one embodiment, both R ¹ and R ² groups are CD ₃ . This compound is also referred to as d6-dextromethorphan or d6-DM. In another embodiment, only one of R ¹ and R ² is CD ₃ .

[081] In another embodiment, the compound is selected from any one of the compounds listed in Table 1.

Table 1: Examples of compounds of formula I

Connection No. R ¹ R ² 100 CD ₃ CD ₃ 101 CD ₃ CD ₃ 102 CH ₂ D CD ₃ 103 CD ₃ CH ₂ D 104 CD ₃ CD ₃ 105 CH ₂ D CH ₂ D 106 CH ₂ D CD ₃ 107 CD ₃ CH ₂ D 108 CD ₃ CD ₃

[082] In another set of embodiments, any atom not designated as deuterium in any of the embodiments set forth above or below is present in its natural isotopic abundance.

[083] In another set of embodiments, the compound of Formula I is isolated or purified, such that the purity of the compound of Formula I is at least 50% by weight (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, or 99.9%) of the total amount of isotopologues of Formula I present, respectively. Thus, in some embodiments, a composition comprising a compound of Formula I may comprise a distribution of isotopologues of the compound, so long as at least 50% of the isotopologues by weight are the compound in question.

[084] In some embodiments, at any position in a compound of Formula I designated as having D, the minimum content of deuterium incorporated is at least 45% (such as at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 99%, or at least 99.5%) at the designated position(s) in the compound of Formula I. Thus, in some embodiments, a composition comprising a compound of Formula I can comprise a distribution of isotopologues of the compound, so long as at least 45% of the isotopologues include D at the designated position(s).

[085] In some embodiments, the compound of Formula I is “substantially free” of other isotopologues of the compound, such as the other isotopologues being present in the compound in an amount of less than 50%, less than 25%, less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5%.

[086] Compounds of formula I can be readily synthesized by those skilled in chemical synthesis. Suitable procedures and intermediates are disclosed, for example, in Kim HC et al., Bioorg. Med. Chem. Lett . 2001, 11:1651 and Newman AH et al., J. Med. Chem . 1992, 35:4135.

[087] Methods for synthesizing the compounds mentioned in the invention can be carried out using the appropriate deuterated reagent and, optionally, other isotopically containing reagents and/or intermediates, or using standard synthetic protocols known in the art to introduce isotopic atoms into the chemical structure.

[088] Deuterated (d6)-DM (d6-DM) (Figure 1) is the deuterated isotope of DM in which deuterium replaces 6 hydrogen atoms at specific positions. Deuterium is a stable, non-radioactive isotope of hydrogen that is ubiquitous in the environment, including water. Stable isotopes have a long and widespread use in medical research, in humans of all ages from neonates to adults. Deuterium is most commonly used to study pharmacokinetics (PK) and trace metabolism. It is also anticipated that the expected exposure levels from chronic administration of deuterated drugs should be quite small compared to daily exposure to deuterium from natural sources such as water. For example, the exposure obtained from a 30 mg dose of d6-DM is expected to be approximately equivalent to the exposure to 20 mL (0.7 oz) of water. This calculation is based on the natural deuterium content of water being 0.0156% and on the assumption that the total ingested dose of d6-DM (MW=277.43) will be metabolized to d3-dextrorphan (d3-DX), releasing deuterated water (MW=20.03). The latter assumption overestimates the amount of deuterated water released, but gives an indication of the relative amount of deuterium consumed.

[089] Pharmacology studies performed by the present inventors with deuterated DM have shown that deuteration does not affect the basic pharmacological properties of DM. PK and metabolism studies of this drug indicate that d6-DM is metabolized via the same metabolic pathways as DM. Metabolism via CYP2D6 is most affected by inhibition by deuterium substitution. In vitro metabolism studies also indicate that d6-DM and DM (in different species, including humans) are metabolized to the same metabolites, i.e., no unique metabolites of d6-DM were identified compared to DM. A tissue distribution study revealed similar radiolabel distributions of ^14C -labeled d6-DM ( ^14C -d6-DM) and ^14C -labeled DM ( ^14C -DM). Toxicology studies of d6-DM have shown that the dose-limiting toxicities (DLTs) of d6-DM and DM are comparable at comparable exposures and are dependent on adverse clinical signs due to CNS effects. A 13-week toxicity study of d6-DM/Q was conducted, which included a high dose of DM/Q for comparison, and analysis of toxicity values showed similar results for d6-DM/Q and for non-deuterated DM/Q.

Examples of synthesis

[090] A convenient method for synthesizing compounds of formula I is to substitute the appropriate deuterated intermediates and reagents from the synthetic methods used to prepare dextromethorphan. These methods are described, for example, in U.S. Patent No. 7,973,049, which is incorporated herein by reference in its entirety. Compounds of formula I can be prepared from one of the known intermediates X, XI, and XII shown below, and from related intermediates that can be readily prepared by known procedures.

Scheme 1 shows the general route to compounds of formula I.

[092] Scheme 1 shows a general route to compounds of formula I wherein R ¹ is not CH ₃ . The HBr salt (10) is treated with NH ₄ OH and N-demethylated to give compound 11. Acylation of amine 11 with ethyl chloroformate gives carbamate 12, which is then O-demethylated with BBR ₃ to give alcohol 13. Compound 13 is treated with iodomethane, which is suitably deuterated, in the presence of base to give ester 14, which is reduced with either lithium aluminum deuteride (LAD) to give compounds of formula I where R ² = CD ₃ or lithium aluminum hydride (LAH) to give a compound where R ² = CH ₃ . For those compounds in which R ¹ is CH ₃ , carbamate 12 is directly treated with LAD to give the compound in which R ² is CD ₃ .

[093] The specific approaches and compounds shown above are not intended to be limiting. The chemical structural formulas and schemes of the present invention depict variables whose definitions are given in accordance with the definitions of chemical groups (functional groups, atoms, etc.) from the corresponding position in the formula of the compound of the invention, regardless of whether they have the same variable names (i.e., R ¹ or R ² ) or not. One of ordinary skill in the art will know whether a chemical group in the structural formula of a compound is suitable for use in the synthesis of another compound.

[094] Additional methods for synthesizing compounds of formula I and their synthetic precursors, including compounds with synthetic routes not explicitly provided herein, are within the skill of the art. Synthetic, transformation, and protecting group (protection and deprotection) techniques useful for synthesizing useful compounds are known in the art and include, for example, those described in the following textbooks: Larock R., Comprehensive Organic Transformations, VCH Publishers (1989); Greene TW et al., Protective Groups in Organic Synthesis, ^3rd edition, John Wiley and Sons (1999); Fieser L. et al., Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette L., ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and in subsequent editions of these textbooks.

[095] The combinations of substituents and variables of the invention are those that result in the formation of stable compounds.

Analogues or derivatives of deuterated dextromethorphan and dextromethorphan.

[096] It should be understood that the dextromethorphan compounds used in the methods and combinations of the invention include analogs or derivatives of both dextromethorphan and deuterated dextromethorphan. For example, in one embodiment, the combinations or methods of the invention include deuterated dextromethorphan, and in another embodiment, the combinations and methods include analogs or derivatives of deuterated dextromethorphan. Similarly, in another embodiment, the combinations or methods of the invention include dextromethorphan, and in another embodiment, the combinations or methods include analogs or derivatives of dextromethorphan.

[097] As used herein, the term "alkyl" means any straight or branched, substituted or unsubstituted saturated hydrocarbon. The alkyl moiety may be a branched or straight chain. The alkyl group may have from 1 to 10 carbon atoms (whenever a numerical range is mentioned herein, such as "from 1 to 10", it is understood that each integer in the range is considered, such as "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, and this definition also covers the term "alkyl" mentioned without indicating a numerical range).

[098] The term "substituted" has its generally accepted meaning, which can be found in numerous contemporary patents from the prior art. See, for example, U.S. Patent Nos. 6,509,331, 6,506,787, 6,500,825, 5,922,683, 5,886,210, 5,874,443, and 6,350,759, all of which are incorporated herein by reference in their entireties. In particular, the definition of substitution is as broad as that set forth in U.S. Patent No. 6,509,331, in which the term "substituted alkyl" refers to an alkyl group. In some embodiments, the term "substituted alkyl" refers to a group of 1 to 10 carbon atoms having 1 to 5 substituents, and in some embodiments 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxyalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic substituent, heterocyclooxy, hydroxyamine, alkoxyamine, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -aryl and -SO ₂ -heteroaryl. The remaining patents listed above also provide standard definitions of the term "substituted" that are well understood by those skilled in the art.

[099] The term "cycloalkyl" refers to any non-aromatic hydrocarbon ring that, in some embodiments, has from five to twelve atoms comprising the ring. The term "heterocycle" or "heterocyclic" refers to any non-aromatic hydrocarbon ring in which at least one heteroatom, such as an oxygen, sulfur, or nitrogen atom, is in a ring with at least one carbon atom.

[0100] The term "alkenyl" as used in the invention means any straight or branched, substituted or unsubstituted, unsaturated hydrocarbon having a double bond between two carbon atoms. The term "alkynyl" as used in the invention means any straight or branched, substituted or unsubstituted, unsaturated hydrocarbon having a triple bond between two carbon atoms.

[0101] As used herein, the terms "aryl" and "heteroaryl" refer to aromatic hydrocarbon rings that in some embodiments have five, six, or seven atoms, and in other embodiments have six atoms, comprising the ring. "Heteroaryl" refers to aromatic hydrocarbon rings in which at least one heteroatom, such as an oxygen, sulfur, or nitrogen atom, is in a ring with at least one carbon atom. The term "heterocycle" or "heterocyclic" refers to any cyclic compound containing one or more heteroatoms. Such aryls, heterocycles, and heteroaryls may be substituted with any substituent, including those described above and substituents known in the art.

[0102] The substituent "R", mentioned by itself and without a numerical designation, refers to a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a carbon atom in a ring) and heteroalicyclyl (attached through a carbon atom in a ring).

[0103] The term "aminoalkyl" refers to a substituent selected from the group consisting of -RNR'R", -RNHR' and -RNH ₂ , wherein R, R' and R" are independently R, as defined herein.

[0104] The term "halogen atom" as used in the invention means any one of the radiostable atoms of Group 7 of the Periodic Table of Elements, such as fluorine, chlorine, bromine or iodine.

[0105] The term "alkoxy" refers to any straight or branched, substituted or unsubstituted, saturated or unsaturated ether, for example, C ₁ -C ₆ straight, saturated, unsubstituted ethers, methoxy and dimethyl, diethyl, methyl isobutyl and methyl tert-butyl ethers.

[0106] A number of dextromethorphan analogs have been identified that have the ability to slow or prevent the metabolism of dextromethorphan. In some embodiments, the hydrogen at the 2-position of the aryl ring, R ₁ , may be replaced by a bulky group.

[0107] As used herein, the term "bulky" refers to a substituent with a cone angle greater than that of hydrogen. Suitable substituents include, but are not limited to, _C1 - _C10 alkyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl, _C6 - _C12 aryl, _C7 - _C13 arylalkyl, _C3 - _C10 cycloalkyl, _C2 - _C10 heterocycle, _C3 - _C10 heterocycloalkyl, _C3 - _C12 heteroaryl, _C4 - _C12 heteroarylalkyl, alkylamino, and dialkylamino, and wherein each hydrogen is optionally substituted with lower alkyl, alkoxy, or halogen.

[0108] Without wishing to be bound by any particular theory, it is believed that the introduction of a bulky group may block CYP2D6 by interfering with the initiation of the catalytic mechanism by which the dextromethorphan compound is converted to dextrorphan and other metabolites. As a result, the rapid metabolism of dextromethorphan analogs, including deuterated analogs, may be prevented or dramatically reduced. For example, a tert-butyl alkyl group with a relatively large cone angle may protect the methyl group attached to the oxygen atom and prevent O-demethylation of dextromethorphan or deuterated dextromethorphan. Alternatively, if the bulky group contains a basic nitrogen, the presence of such a nitrogen atom within 5 to 7 angstroms of the methoxy group may prevent oxidation by inhibiting CYP2D6.

[0109] Suitable analogues with bulky groups at position 2 include compounds (1-1) and (1-2) below.

(1-1)

(1-2)

[0110] In other embodiments, the methoxy group at the 3-position may be substituted with a bulky OR ₂ group.

[0111] Suitable substituents include, but are not limited to, the following: R ₁ is selected from the group consisting of: hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₁₂ aryl, C ₇ -C ₁₃ arylalkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ heterocycle, C ₃ -C ₁₀ heterocycloalkyl, C ₃ -C ₁₂ heteroaryl, C ₄ -C ₁₂ heteroarylalkyl, alkylamino, and dialkylamino, wherein each hydrogen is optionally substituted with lower alkyl, alkoxy, or halogen; and R ₂ is selected from the group consisting of C ₂ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₁₂ aryl, C ₇ -C ₁₃ arylalkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ heterocycle, C ₄ -C ₁₀ heterocycloalkyl, C ₃ -C ₁₂ heteroaryl, C ₄ -C ₁₂ heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with lower alkyl, alkoxy or halogen. If R ₁ is hydrogen, R ₂ cannot be either hydrogen or methyl, so as to exclude dextromethorphan and dextrorphan.

[0112] Suitable analogs with bulky -OR ₂ groups in the 3-position include compounds (II-1) to (II-4) listed below.

(II - 1)

(II - 2)

(II - 3)

(II - 4)

[0113] In other embodiments, the methoxy group at the 3-position may be substituted with a bulky group that includes a sulfur atom.

[0114] Suitable substituents include, but are not limited to, the following: each R ₁ is independently selected from the group consisting of hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₁₂ aryl, C ₇ -C ₁₃ arylalkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ heterocycle, C ₃ -C ₁₀ heterocycloalkyl, C ₃ -C ₁₂ heteroaryl, C ₄ -C ₁₂ heteroarylalkyl, alkylamino, and dialkylamino, wherein each hydrogen is optionally substituted with lower alkyl, alkoxy, or halogen; and R ₂ is selected from the group consisting of -SR ₁ .

[0115] Suitable analogs with a sulfur-containing bulky group at the 3-position include compounds (III-1) to (III-3) below.

(III-1)

(III-2)

(III-3)

[0116] Without wishing to be bound by any particular theory, it is believed that the introduction of a bulky group that contains either an oxygen atom or a sulfur atom at the 3-position can increase the half-life (T _1/2 ) of dextromethorphan or deuterated dextromethorphan. By increasing the half-life, it is possible to maintain an increased concentration of dextromethorphan analogs in the blood for a longer period of time before it is converted to dextrorphan. Alternative substituents and substitutions are also within the scope of the present invention. In particular, substituents and substitutions that include one or more deuterium atoms, such as d6DM, are within the scope of the present invention. One skilled in the art will recognize methods for modifying the dextromethorphan analogs of the invention to produce deuterated dextromethorphan analogs.

[0117] Also included within the scope of the present invention are compounds described by Newman et al. in J. Med. Chem. 1992 Oct. 30;35(22):4135-42. Newman found that these compounds exhibit anticonvulsant activity in various in vitro and in vivo models of seizure activity.

CYP2D6 inhibitors

[0118] According to the invention, it is contemplated to use a dextromethorphan compound together with a CYP2D6 inhibitor, such as quinidine. Quinidine is most often used for co-administration with other antioxidants, such as those described in Inaba et al., Drug Metabolism and Disposition. 1985;13:443-447, Forme-Pfister et al., Biochem. Pharmacol. 1988;37:3829-3835, and Broly et al., Biochem. Pharmacol. 1990;39:1045-1053. Quinidine can also be co-administered with the dextromethorphan compound to reduce its transformation. According to Inaba et al., CYP2D6 inhibitors with a K _i value of 50 μM or less (the inhibition index according to the Michaelis-Menton equation) include nortriptyline, chlorpromazine, domperidone, haloperidol, pipamperone, labetalol, metoprolol, oxprenolol, propranolol, timolol, mexiletine, quinine, diphenhydramine, ajmaline, lobeline, papaverine, and yohimbine. Compounds with particularly potent inhibitory activity include yohimbine, haloperidol, ajmaline, lobeline, and pipamperone, and the K _i value of these compounds ranges from 4 to 0.33 μM. In addition to the antioxidants mentioned above, fluoxetine, a drug supplied by Eli Lilly and Co., has also been found to be an inhibitor of CYP2D6. under the trade name Prozac ^® , has the effect of increasing blood levels of dextromethorphan in some individuals. Additionally, any of the following compounds may be used to inhibit CYP2D6: terbinafine, cinacalcet, buprenorphine, imipramine, bupropion, ritonavir, sertraline, duloxetine, thioridazine, metoclopramide, paroxetine, or fluvoxamine. Doses of other antioxidants may vary depending on the antioxidant and may be determined on an individual basis.

[0119] It has been unexpectedly discovered that agitation and/or aggression in patients with Alzheimer's disease can be treated with the dextromethorphan compound in combination with an amount of quinidine that is significantly lower than the minimum amount previously considered necessary to achieve a significant therapeutic effect.

[0120] Additionally, the metabolism of dextromethorphan or its deuterated form can be avoided by co-administering a CYP2D6 inhibitor with dextromethorphan. Quinidine is a potent CYP2D6 inhibitor and has been specifically studied for use as such (US Patent No. 5,206,248, Smith). The chemical structure of quinidine is as follows:

[0121] Co-administration of quinidine has at least two distinct beneficial effects. First, it significantly increases the amount of dextromethorphan compounds circulating in the blood. Additionally, co-administration also achieves a more stable and predictable concentration of dextromethorphan. Studies involving the study of dextromethorphan or co-administration of quinidine and dextromethorphan, as well as the effect of quinidine on plasma concentrations, are described in the patent literature (see, e.g., U.S. Patent No. 5,166,207, U.S. Patent No. 5,863,927, U.S. Patent No. 5,366,980, U.S. Patent No. 5,206,248, U.S. Patent No. 5,350,756, and U.S. Patent No. 7,973,049).

[0122] Quinidine administration can convert subjects from a extensive metabolizer phenotype to a poor metabolizer phenotype (Inaba et al., Br, J. Clin. Pharmacol. 1986; 22: 199-200). Blood dextromethorphan levels increase linearly with the dextromethorphan dose when coadministered with quinidine, but most patients receiving dextromethorphan alone, even at high doses, have undetectable blood levels (Zhang et al., Clin. Pharmac. &Therap. 1992; 51:647-55). Thus, the plasma levels observed in patients with the rapid metabolizer phenotype after coadministration of dextromethorphan with quinidine are similar to those found in patients with poor metabolizers. Accordingly, physicians should exercise caution when administering quinidine to patients who may have a poor metabolizer phenotype.

Pharmaceutical compositions

[0123] One of the properties of the described methods and combinations is the effect of reducing agitation and/or aggression in patients with Alzheimer's disease. In some cases, this reduction is achieved without the use of tranquilizers or other serious interference with consciousness or awareness, and/or without increasing the risk of serious adverse events. As used in the invention, the term "serious interference" refers to adverse events that could become pronounced or manifest at a clinical level (e.g., cause a specific concern to a physician or psychologist), or at a personal or social level (e.g., cause sufficiently pronounced drowsiness, as a result of which the ability to drive a car may be reduced). In contrast, certain types of very minor side effects that can be caused by an over-the-counter drug, such as dextromethorphan-containing cough syrup, when used in recommended doses, are not considered a serious interference.

[0124] The therapeutic dose of dextromethorphan compound in combination with quinidine for acute or chronic treatment of agitation and/or aggression in patients with Alzheimer's disease may vary depending on a number of factors, such as the specific cause of the condition, the severity of the condition, and the route of administration. Dosages and/or frequency of administration may also vary depending on the age, body weight, and response of the individual patient.

[0125] In one embodiment, the dextromethorphan compound and quinidine are administered in a combined dose or in separate doses. The separate doses can be administered substantially simultaneously. In one embodiment, the weight ratio of the dextromethorphan compound to the weight of quinidine is about 1:1 or less. In some embodiments, the weight ratio of these drugs is about 1:1, 1:0.95, 1:0.9, 1:0.85, 1:0.8, 1:0.75, 1:0.7, 1:0.65, 1:0.6, 1:0.55, or 1:0.5 or less. Furthermore, in some embodiments, the weight ratio of the dextromethorphan compound to the weight of quinidine is less than about 1:0.5, such as about 1:0.45, 1:0.4, 1:0.35, 1:0.3, 1:0.25, 1:0.2, 1:0.15, or 1:0.1, 1:0.09, 1:0.08, 1:0.07, 1:0.06, 1:0.05, 1:0.04, 1:0.03, 1:0.02, or 1:0.01 or less. This ratio by weight can be, for example, about 1:0.75, about 1:0.68, about 1:0.6, about 1:0.56, about 1:0.5, about 1:0.44, about 1:0.39, about 1:0.38, about 1:0.31, about 1:0.30, about 1:0.29, about 1:0.28, about 1:0.27, about 1:0.26, about 1:0.25, about 1:0.24, about 1:0.23, about 1:0.22, about 1:0.21, about 1:0.20, about 1:0.19, about 1:0.18, about 1:0.17, about 1:0.16, about 1:0.15, about 1:0.14, about 1:0.13, about 1:0.12, about 1:0.11, and about 1:0.10. In some embodiments, the weight ratio of dextromethorphan free base to quinidine free base is about 1:0.68, about 1:0.56, about 1:0.44, about 1:0.38. In some other embodiments, the weight ratio of d6-deuterated dextromethorphan free base to quinidine free base is about 1:0.30, about 1:0.22, about 1:0.19, about 1:0.18, about 1:0.16, and about 1:0.15.

[0126] In some embodiments, when the dextromethorphan compound and quinidine are administered in a weight ratio of 1:1 or less, the amount of quinidine administered at any one time is less than 50 mg. For example, in some embodiments, quinidine is administered in an amount of about 30, 25, or 20 mg or less. In other embodiments, quinidine is administered in an amount of about 15, 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.0, or less. In other embodiments, quinidine is administered in an amount of about 5.00, 4.95, 4.90, 4.85, 4.80, 4.75, 4.70, 4.65, 4.60, 4.55, 4.50, 4.45, 4.40, 4.35, 4.30, 4.25, 4.20, 4.15 4.10, 4.05, 4.00, 3.95, 3.90, 3.85, 3.80, 3.75, 3.70, 3.65, 3.60 3.55, 3.50, 3.45 3.40, 3.35, 3.30, 3.25, 3.20, 3.15, 3.10, 3.05, 3.00, 2.95, 2.90, 2.85, 2.80, 2.75 2.70, 2.65, 2.60 2.55, 2.50, 2.45, 2.40, 2.35, 2.30, 2.25, 2.20, 2.15, 2.10, 2.05, 2.00, 1.95, 1.90 1.85, 1.80, 1.75 1.70, 1.65, 1.60, 1.55, 1.50, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10, 1.05 1.00, 0.95, 0.90 0.85, 0.80, 0.75, 0.70 0.65 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or 0.05, or less.

[0127] In some embodiments, the combination dose (or the separate doses administered simultaneously) at a weight ratio of 1:1 or less is administered once daily, twice daily, three times daily, four times daily, or more frequently to achieve a certain daily dose level in a patient, such as: 60 mg of quinidine and 60 mg of the dextromethorphan compound per day, when administered in two doses, wherein each dose will contain 30 mg of quinidine and 30 mg of the dextromethorphan compound; 50 mg of quinidine and 50 mg of the dextromethorphan compound per day, when administered in two doses, wherein each dose will contain 25 mg of quinidine and 25 mg of the dextromethorphan compound; 40 mg quinidine and 40 mg dextromethorphan compound per day, given in two doses, each dose containing 20 mg quinidine and 20 mg dextromethorphan compound; 30 mg quinidine and 30 mg dextromethorphan compound per day, given in two doses, each dose containing 15 mg quinidine and 15 mg dextromethorphan compound; or 20 mg quinidine and 20 mg dextromethorphan compound per day, given in two doses, each dose containing 10 mg quinidine (i.e., approximately 9 mg quinidine free base) and 10 mg dextromethorphan compound. In some embodiments, the total amount of dextromethorphan compound and quinidine in the combination dose may be adjusted depending on the number of doses prescribed for daily administration such that the patient achieves an appropriate total daily dose while maintaining a weight ratio of 1:1 or less.

[0128] In some embodiments, the total daily dose of a dextromethorphan compound in combination with quinidine for treating agitation and/or aggression in patients with Alzheimer's disease is: about 10 mg or less to about 200 mg or more of a dextromethorphan compound in combination with quinidine in an amount of about 0.05 mg or less to about 60 mg or more. In some embodiments, the daily dose for treating agitation and/or aggression in patients with Alzheimer's disease is about 10 mg to about 90 mg of a dextromethorphan compound in combination with quinidine in an amount of about 2.5 mg to about 60 mg of quinidine, in monolithic or divided doses. In some embodiments, the total daily dose of the dextromethorphan compound is about 15, 16, 17, 18, 19, or 20 mg in combination with quinidine in an amount of about 15, 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.00, 4.95, 4.90, 4.85, 4.80, 4.75, 4.70, 4.65, 4.60, 4.55, 4.50, 4.45, 4.40, 4.35, 4.30, 4.25, 4.20, 4.15, 4.10, 4.05, 4.00, 3.95, 3.90, 3.85, 3.80, 3.75, 3.70, 3.65, 3.60, 3.55, 3.50, 3.45, 3.40, 3.35, 3.30, 3.25, 3.20, 3.15, 3.10, 3.05, 3.00, 2.95, 2.90, 2.85, 2.80, 2.75, 2.70, 2.65, 2.60, 2.55, 2.50, 2.45, 2.40, 2.35, 2.30, 2.25, 2.20, 2.15, 2.10, 2.05, 2.00, 1.95, 1.90, 1.85, 1.80, 1.75, 1.70, 1.65, 1.60, 1.55, 1.50, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10, 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or 0.05 mg or less.

[0129] In some embodiments, the daily dose for treating agitation and/or aggression in patients with Alzheimer's disease is: about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg of a dextromethorphan compound in combination with quinidine in an amount of about 15, 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.00, 4.95, 4.90, 4.85, 4.80, 4.75, 4.70, 4.65, 4.60, 4.55, 4.50, 4.45, 4.40, 4.35, 4.30, 4.25, 4.20, 4.15, 4.10, 4.05, 4.00, 3.95, 3.90, 3.85, 3.80, 3.75, 3.70, 3.65, 3.60, 3.55, 3.50, 3.45, 3.40, 3.35, 3.30, 3.25, 3.20, 3.15, 3.10, 3.05, 3.00, 2.95, 2.90, 2.85, 2.80, 2.75, 2.70, 2.65, 2.60, 2.55, 2.50, 2.45, 2.40, 2.35, 2.30, 2.25, 2.20, 2.15, 2.10, 2.05, 2.00, 1.95, 1.90, 1.85, 1.80, 1.75, 1.70, 1.65, 1.60, 1.55, 1.50, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10, 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10 or 0.05 mg or less; or approximately 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 mg of dextromethorphan compound in combination with quinidine in an amount of 15, 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.00, 4.95, 4.90, 4.85, 4.80, 4.75, 4.70, 4.65, 4.60, 4.55, 4.50, 4.45, 4.40, 4.35, 4.30, 4.25, 4.20, 4.15, 4.10, 4.05, 4.00, 3.95, 3.90, 3.85, 3.80, 3.75, 3.70, 3.65, 3.60, 3.55, 3.50, 3.45, 3.40, 3.35, 3.30, 3.25, 3.20, 3.15, 3.10, 3.05, 3.00, 2.95, 2.90, 2.85, 2.80, 2.75, 2.70, 2.65, 2.60, 2.55, 2.50, 2.45, 2.40, 2.35, 2.30, 2.25, 2.20, 2.15, 2.10, 2.05, 2.00, 1.95, 1.90, 1.85, 1.80, 1.75, 1.70, 1.65, 1.60, 1.55, 1.50, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10, 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or 0.05 mg or less; or approximately 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg of dextromethorphan compound in combination with quinidine in an amount of approximately 15, 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.00; 4.95, 4.90, 4.85, 4.80, 4.75, 4.70, 4.65, 4.60, 4.55, 4.50, 4.45, 4.40, 4.35, 4.30, 4.25, 4.20, 4.15, 4.10, 4.05, 4.00, 3.95, 3.90, 3.85, 3.80, 3.75, 3.70, 3.65, 3.60, 3.55, 3.50, 3.45, 3.40, 3.35, 3.30, 3.25, 3.20, 3.15, 3.10, 3.05, 3.00, 2.95, 2.90, 2.85, 2.80, 2.75, 2.70, 2.65, 2.60, 2.55, 2.50, 2.45, 2.40, 2.35, 2.30, 2.25, 2.20, 2.15, 2.10, 2.05, 2.00, 1.95, 1.90, 1.85, 1.80, 1.75, 1.70, 1.65, 1.60, 1.55, 1.50, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10, 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or 0.05 mg or less; or about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 mg of the dextromethorphan compound in combination with quinidine in an amount of about 15, 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.00, 4.95, 4.90, 4.85, 4.80, 4.75, 4.70, 4.65, 4.60, 4.55, 4.50, 4.45, 4.40, 4.35, 4.30, 4.25, 4.20, 4.15, 4.10, 4.05, 4.00, 3.95, 3.90, 3.85, 3.80, 3.75, 3.70, 3.65, 3.60, 3.55, 3.50, 3.45, 3.40, 3.35, 3.30, 3.25, 3.20, 3.15, 3.10, 3.05, 3.00, 2.95, 2.90, 2.85, 2.80, 2.75, 2.70, 2.65, 2.60, 2.55, 2.50, 2.45, 2.40, 2.35, 2.30, 2.25, 2.20, 2.15, 2.10, 2.05, 2.00, 1.95, 1.90, 1.85, 1.80, 1.75, 1.70, 1.65, 1.60, 1.55, 1.50, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10, 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or 0.05 mg or less; or about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70 mg of dextromethorphan compound in combination with quinidine in an amount of about 15, 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.00, 4.95, 4.90, 4.85, 4.80, 4.75, 4.70, 4.65, 4.60, 4.55, 4.50, 4.45, 4.40, 4.35, 4.30, 4.25, 4.20, 4.15, 4.10, 4.05, 4.00, 3.95, 3.90, 3.85, 3.80, 3.75, 3.70, 3.65, 3.60, 3.55, 3.50, 3.45, 3.40, 3.35, 3.30, 3.25, 3.20, 3.15, 3.10, 3.05, 3.00, 2.95, 2.90, 2.85, 2.80, 2.75, 2.70, 2.65, 2.60, 2.55, 2.50, 2.45, 2.40, 2.35, 2.30, 2.25, 2.20, 2.15, 2.10, 2.05, 2.00, 1.95, 1.90, 1.85, 1.80, 1.75, 1.70, 1.65, 1.60, 1.55, 1.50, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10, 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or 0.05 mg or less; or about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80 mg of the dextromethorphan compound in combination with quinidine in an amount of about 15, 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.00, 4.95, 4.90, 4.85, 4.80, 4.75, 4.70, 4.65, 4.60, 4.55, 4.50, 4.45, 4.40, 4.35, 4.30, 4.25, 4.20, 4.15, 4.10, 4.05, 4.00, 3.95, 3.90, 3.85, 3.80, 3.75, 3.70, 3.65, 3.60, 3.55, 3.50, 3.45, 3.40, 3.35, 3.30, 3.25, 3.20, 3.15, 3.10, 3.05, 3.00, 2.95, 2.90, 2.85, 2.80, 2.75, 2.70, 2.65, 2.60, 2.55, 2.50, 2.45, 2.40, 2.35, 2.30, 2.25, 2.20, 2.15, 2.10, 2.05, 2.00, 1.95, 1.90, 1.85, 1.80, 1.75, 1.70, 1.65, 1.60, 1.55, 1.50, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10, 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or 0.05 mg or less; or approximately 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 mg of dextromethorphan compound in combination with quinidine in an amount of approximately 15, 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.00, 4.95, 4.90, 4.85, 4.80, 4.75, 4.70, 4.65, 4.60, 4.55, 4.50, 4.45, 4.40, 4.35, 4.30, 4.25, 4.20, 4.15, 4.10, 4.05, 4.00, 3.95, 3.90, 3.85, 3.80, 3.75, 3.70, 3.65, 3.60, 3.55, 3.50, 3.45, 3.40, 3.35, 3.30, 3.25, 3.20, 3.15, 3.10, 3.05, 3.00, 2.95, 2.90, 2.85, 2.80, 2.75, 2.70, 2.65, 2.60, 2.55, 2.50, 2.45, 2.40, 2.35, 2.30, 2.25, 2.20, 2.15, 2.10, 2.05, 2.00, 1.95, 1.90, 1.85, 1.80, 1.75, 1.70, 1.65, 1.60, 1.55, 1.50, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10, 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or 0.05 mg or less; and the doses indicated are monolithic or divided doses.

[0130] In some embodiments, the daily dose of the dextromethorphan compound and quinidine is 30 mg dextromethorphan hydrobromide and 30 mg quinidine sulfate. Other doses include, for example, 15 mg dextromethorphan hydrobromide and 9 mg quinidine sulfate (corresponding to about 11 mg dextromethorphan and about 7.5 mg quinidine); 23 mg dextromethorphan hydrobromide and 9 mg quinidine sulfate (corresponding to about 17 mg dextromethorphan and about 7.5 mg quinidine); 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (corresponding to about 15 mg dextromethorphan and 8.3 mg quinidine); 30 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (equivalent to approximately 22 mg dextromethorphan and 8.3 mg quinidine).

[0131] A dose of 30 mg d6-dextromethorphan hydrobromide (molecular formula C ₁₈ H ₁₉ D ₆ NO HBr H ₂ O) and 30 mg quinidine sulfate (molecular formula (C ₂₀ H ₂₄ N ₂ O ₂ ) ₂ H ₂ SO ₄ 2H ₂ O) (corresponding to approximately 22.22 mg dextromethorphan and 25 mg quinidine) may be administered or used. Other doses for d6-deuterated dextromethorphan include, for example, 24 mg d6-dextromethorphan hydrobromide and 4.75 mg quinidine sulfate (corresponding to approximately 18 mg d6-dextromethorphan and approximately 3.96 mg quinidine); 4 mg d6-dextromethorphan hydrobromide and 4.75 mg quinidine sulfate (equivalent to approximately 25.18 mg d6-dextromethorphan and approximately 3.96 mg quinidine); 18 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 13.33 mg d6-dextromethorphan and 4.08 mg quinidine); 24 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 17.78 mg d6-dextromethorphan and 4.08 mg quinidine); 28 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 20.74 mg d6-dextromethorphan and 4.08 mg quinidine); 30 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 22.22 mg d6-dextromethorphan and 4.08 mg quinidine); 34 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 25.18 mg d6-dextromethorphan and 4.08 mg quinidine).

[0132] In some embodiments, treatment is initiated at a lower daily dose, such as about 18 or 30 mg of the dextromethorphan compound in combination with quinidine in an amount of about 2.5 to 10 mg of quinidine per day, and is increased to about 90 mg of the dextromethorphan compound in combination with quinidine in an amount of about 10 to 20 mg of quinidine, or at a higher dose, depending on the overall response of the patient. In some embodiments, in neonates, children, individuals over 65 years of age, and in patients with impaired renal or hepatic function, administration is initiated at low doses that can be adjusted based on the individual response(s) and blood level(s). Typically, a daily dose of 18 to 90 mg of the dextromethorphan compound and 4.75 to 20 mg of quinidine is well tolerated by most patients.

[0133] It will be apparent to those skilled in the art that in some cases dosages outside the ranges mentioned in the invention may be used. Additionally, it should be noted that the average clinician or treating physician is aware of how and when to interrupt, adjust, or discontinue treatment based on individual response.

[0134] Any suitable route of administration may be used to deliver to a patient an effective dose of a dextromethorphan compound in combination with quinidine for the treatment of agitation and/or aggression associated with Alzheimer's disease. For example, oral, rectal, transdermal, parenteral (subcutaneous, intramuscular, intravenous), intrathecal, topical, inhalation and the like routes of administration may be used. Suitable dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, patches and the like. Administration of medicaments prepared from the compounds described herein may be accomplished by any suitable route that delivers said compounds into the bloodstream. In some embodiments, the compositions may comprise a mixture of the active compounds with pharmaceutically acceptable carriers or diluents known to those skilled in the art.

[0135] The pharmaceutical compositions described in the invention comprise as active ingredients a dextromethorphan compound in combination with a CYP2D6 inhibitor such as quinidine, or pharmaceutically acceptable salts of the dextromethorphan compound and/or quinidine, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.

[0136] The terms "pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases. Suitable pharmaceutically acceptable salts include metal salts, such as aluminum salts, zinc salts; alkali metal salts, such as lithium, sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts, organic salts, such as lysine salts, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine and Tris compounds; salts of free acids and bases; inorganic salts, such as sulfate, hydrochloride and hydrobromide; and other salts that are now widely used pharmaceutically and are listed in sources well known to those skilled in the art, such as The Merck Index.

[0137] Any suitable component for preparing a salt of the active drug described in the invention may be selected, provided that the component is non-toxic and does not significantly affect the desired effect. In addition to the salt, pharmaceutically acceptable precursor compounds and derivatives of these compounds may be used. Pharmaceutically acceptable amides, lower alkyl esters, and protected derivatives of deuterated dextromethorphan and/or quinidine may also be suitable for use in the compositions and methods of the invention. In some embodiments, deuterated dextromethorphan is used as deuterated dextromethorphan hydrobromide, dextromethorphan is used as dextromethorphan hydrobromide, and quinidine is used as quinidine sulfate.

[0138] The compositions can be prepared in any desired form, for example, tablets, powders, capsules, injections, suspensions, sachets, wafers, patches, solutions, elixirs, and aerosols. In oral solid dosage forms, carriers such as starches, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used. In some embodiments, the compositions are prepared as oral solid forms (such as powders, capsules, and tablets). In some embodiments, the compositions are prepared as oral liquid forms. In some embodiments, the oral solid forms are tablets. If desired, the tablets can be coated using standard aqueous or non-aqueous coating techniques.

[0139] In addition to the above-described dosage forms, the compounds of the invention can also be administered in sustained-release, delayed-release, or controlled-release compositions and/or via delivery devices, such as those described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, and 4,008,719.

[0140] Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage forms such as capsules, sachets, wafers, patches, injections, tablets and aerosol sprays, each of said dosage forms containing predetermined amounts of the active ingredients. Said pharmaceutical compositions may also be presented as a powder or granules, or as a solution or suspension in an aqueous liquid, a non-aqueous liquid, as an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the conventional methods of pharmacy, but most of the methods typically include the step of bringing into association the active ingredients with a carrier that consists of one or more ingredients. In general, such compositions are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product to impart the desired appearance.

[0141] For example, a tablet can be made by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be made in a suitable machine by compressing the active ingredient in a free-flowing form, for example, as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface-active or dispersing agent. Molded tablets can be made in a suitable machine by molding a mixture of a powdered compound moistened with an inert liquid diluent.

[0142] In some embodiments, each tablet comprises about 30 mg of dextromethorphan hydrobromide and 30 mg of quinidine sulfate. The tablet may include, for example, 15 mg of dextromethorphan hydrobromide and 9 mg of quinidine sulfate (corresponding to about 11 mg of dextromethorphan and about 7.5 mg of quinidine); 23 mg of dextromethorphan hydrobromide and 9 mg of quinidine sulfate (corresponding to about 17 mg of dextromethorphan and about 7.5 mg of quinidine); 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate (corresponding to about 15 mg of dextromethorphan and 8.3 mg of quinidine); 30 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (equivalent to approximately 22 mg dextromethorphan and 8.3 mg quinidine).

[0143] The tablet may comprise 30 mg d6-dextromethorphan hydrobromide (molecular formula C ₁₈ H ₁₉ D ₆ NO HBr H ₂ O) and 30 mg quinidine sulfate (molecular formula (C ₂₀ H ₂₄ N ₂ O ₂ ) ₂ H ₂ SO ₄ 2H ₂ O) (corresponding to approximately 22.22 mg dextromethorphan and 25 mg quinidine). The tablet may contain other dosages, such as 24 mg d6-dextromethorphan hydrobromide and 4.75 mg quinidine sulfate (corresponding to approximately 18 mg d6-dextromethorphan and approximately 3.96 mg quinidine); 34 mg d6-dextromethorphan hydrobromide and 4.75 mg quinidine sulfate (equivalent to approximately 25.18 mg d6-dextromethorphan and approximately 3.96 mg quinidine); 18 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 13.33 mg d6-dextromethorphan and 4.08 mg quinidine); 24 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to 17.78 mg d6-dextromethorphan and 4.08 mg quinidine); 28 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 20.74 mg d6-dextromethorphan and 4.08 mg quinidine); 30 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 22.22 mg d6-dextromethorphan and 4.08 mg quinidine); 34 mg d6-dextromethorphan hydrobromide and 4.9 mg quinidine sulfate (equivalent to approximately 25.18 mg d6-dextromethorphan and 4.08 mg quinidine).

[0144] As used herein, the term "minimum therapeutically effective amount" means an amount that satisfactorily inhibits the rapid elimination of the dextromethorphan compound from the body, while not causing any adverse effect or causing adverse effects only to an acceptable degree and with acceptable characteristics. More specifically, in some embodiments, the therapeutically effective amount of the dextromethorphan compound is in the range of about 9, 10, 18, 20, 25 or 30 mg to about 90 mg per day, and the therapeutically effective amount of quinidine is less than about 50 mg per day. In some embodiments, the therapeutically effective amount of the dextromethorphan compound is in the range of about 20 or 30 mg to about 90 mg per day, and about 0.5 mg to about 30 mg of quinidine per day. In some embodiments, the amount is administered in a dose divided based on the plasma half-life of the dextromethorphan compound. For example, in one embodiment, deuterated dextromethorphan and quinidine are administered in specific mg increments to achieve a target plasma concentration of deuterated dextromethorphan at a given pg/mL level, with the maximum specific dose of deuterated dextromethorphan and quinidine determined based on body weight. In some embodiments, the target dose is administered every 12 hours. In some embodiments, the target dose is administered once daily. In some embodiments, the quinidine level is minimized and the side effects observed with high doses of quinidine are minimized or eliminated, which provides a significant advantage over compositions containing a dextromethorphan compound in combination with quinidine at a higher content.

[0145] In some embodiments, other therapeutic agents are administered in combination with the dextromethorphan compound and quinidine. For example, the dextromethorphan compound and quinidine can be administered in combination with a compound for treating depression and anxiety.

[0146] In some embodiments, the dextromethorphan compound and quinidine are used as an adjuvant to known therapeutic agents intended for treating the symptoms of Alzheimer's disease. Agents for treating the symptoms of Alzheimer's disease include, but are not limited to, cholinesterase inhibitors such as donepezil, rivastigmine, galantamine and tacrine, memantine, and vitamin E.

EXAMPLES

Example 1: Clinical study of agitation and aggression in Alzheimer's disease

[0147] A clinical study was conducted to determine the effectiveness of a combination of dextromethorphan and quinidine in reducing agitation and/or aggression in patients with Alzheimer's disease.

[0148] This 10-week study was a randomized, double-blind, placebo-controlled, multicenter trial of the efficacy of oral dextromethorphan/quinidine in patients with suspected Alzheimer's disease and clinically significant symptoms of agitation. The study was conducted at 42 U.S. sites, including Alzheimer's disease outpatient clinics, nursing facilities, and assisted living facilities.

[0149] Participants aged 50 to 90 years with probable Alzheimer's disease (National Institute on Aging-Alzheimer Association 2011 criteria) and clinically significant agitation symptoms, defined as a state of poorly organized and purposeless psychomotor activity characterized by at least one of the following behaviors: verbal aggression (e.g., yelling, swearing); physical aggression (e.g., destroying objects, grabbing, being physical); and nonaggressive physical activity (e.g., pacing, restlessness) were eligible for the study. Eligible participants had been agitated (intermittently or persistently) for 7 days prior to screening, and agitation symptoms had to be severe enough to interfere with daily functioning and require medication. Eligible participants were also assessed for agitation level ≥4 (moderate illness) on the Clinical Global Impression of Illness Scale (CGIS) and a Mini Mental State Examination (MMSE) score of 8–28. Anti-Alzheimer's disease medications at stable doses (≥2 months, memantine and/or acetylcholinesterase inhibitors) and antidepressants, antipsychotics, or hypnotics (≥1 month, including benzodiazepines and short-acting non-benzodiazepines) were allowed; doses had to remain stable throughout the study. Oral lorazepam (maximum dose of 1.5 mg/day for no more than 3 days in a 7-day period) was allowed during the study as a rescue medication for agitation if deemed necessary by the supervising investigator.

[0150] The following exclusion criteria were used: non-Alzheimer's disease dementia, agitation not secondary to Alzheimer's disease, psychiatric hospitalization, severe depression (≥10 on the Cornell Depression Scale in Dementia [CSDD]), schizophrenia, schizoaffective or bipolar disorder, myasthenia gravis (since quinidine is contraindicated), or clinically significant/unstable systemic illness; history of complete heart block, corrected reversal of QT prolongation (QTc), or torsades de pointes ; family history of congenital long QT; history of postural or unexplained syncope within the past year; or alcohol/chemical dependence within 3 years. The use of first-generation antipsychotic drugs, tricyclic antidepressants and monoamine oxidase inhibitors was not permitted.

[0151] The 10-week study consisted of 2 sequential, double-blind, 5-week stages (Stage 1 and Stage 2) (Figure 2). In Stage 1, participants were randomized in a 3:4 ratio (active: placebo). Randomization in Stage 1 was stratified by baseline cognitive function (MMSE > 15 vs ≥15) and severity of agitation (CGIS score 4-5 vs 6-7); block randomization ensured equality of treatment within each stratum. For the first 7 days of Stage 1 (days 1-7), the active treatment group received AVP-923-20 (20 mg dextromethorphan and 10 mg quinidine) in the morning and placebo in the evening, and the placebo group received placebo twice daily. For the next 2 weeks of Phase 1 (Days 8–21), the AVP-923 group received AVP-923-20 twice daily and the placebo group received placebo twice daily. On Day 22, the dose was increased for the AVP group, with AVP-923-30 (30 mg dextromethorphan and 10 mg quinidine) administered twice daily. The AVP group continued to receive AVP-923-30 twice daily for the remaining 2 weeks of Phase 1 (Days 22–35). Participants receiving placebo continued to receive placebo twice daily.

[0152] In Phase 2, participants who received AVP-923 in Phase 1 continued to receive AVP-923 twice daily for the entire 5-week period. Participants who received placebo in Phase 1 were divided into two subgroups based on their clinical response, as assessed by their Clinical Impression of Illness Severity (CGIS) score and the Neuropsychiatric Inventory (NPI) Arousal/Aggression domain, based on arousal scores at the end of Phase 1 (Visit 4). Participants were considered to be treatment responders if their CGIS Arousal score was less than 3 (moderate illness) and their NPI Arousal/Aggression domain score decreased by 25% or more compared to baseline. Participants who did not meet these criteria were classified as non-responders, i.e., individuals who did not respond to treatment. Thereafter, each placebo subgroup (responders and nonresponders) was rerandomized in a 1:1 ratio to receive either AVP-923 or matching placebo. Participants who received placebo during Phase 1 and were rerandomized to AVP-923 in Phase 2 received AVP-923-20 in the morning and placebo in the evening for the first 7 days of the study (Phase 2, days 36–42). Beginning on Day 43, participants received AVP-923-20 twice daily for 2 consecutive weeks (Phase 2, days 43–56), then beginning on Day 57, participants received AVP-923-30 twice daily for the remaining 2 weeks (Phase 2, days 57–70) until study completion.

[0153] Participants visited the study center for a screening examination, baseline (Day 1), and days 8, 22, 36, 43, 57, and 70 (Visits 2-7). The duration of participation of each patient in this study was approximately 14 weeks, including the screening phase. Blood samples for measurement of plasma drug levels were collected on Day 36 (Visit 4) and Day 70 (Visit 7). Blood samples for determination of cytochrome P450-2D6 (CYP2D6) genotype were collected on Day 1 (baseline visit).

[0154] The investigator or study sponsor had the option to withdraw a participant from the study in the event of an intercurrent illness, adverse event, other reasons concerning the health or well-being of the participant, or in the event of lack of cooperation, non-compliance, protocol violation, or other administrative reasons. Additionally, participants who had a QTc interval (Bazett QT correction (QTcB) or Fridericia QT correction (QTcF)) > 500 msec (excluding ventricular pacing) or a change in QTc interval from screening electrocardiographic (ECG) data > 60 msec at any time after randomization were excluded from the study. The clinical significance of QTc values were assessed and recorded. Participants who withdrew before study completion were asked to return to the study center for a final visit 7 (end of study) assessment. If a participant was withdrawn or discontinued from the study before study completion, every effort was made to record the participant's values. If a participant withdrew from the study and the participant's caregiver and/or representative withdrew consent for future disclosure of information, no further assessments were conducted and no additional data were collected.

[0155] Participants and caregivers were instructed that the participant should take the study drug approximately every 12 hours ±4 hours orally with water (morning and evening). AVP-923 and placebo were provided as identical capsules and packaged in white, 85 ^cc plastic bottles with child-resistant caps (one bottle with a white label for morning administration and one bottle with a blue label for evening administration). The compositions of the AVP-923 and placebo capsules are shown in Table 2.

Table 2:

Ingredients
(amount in mg) AVP-923-30 AVP-923-20 Placebo dextromethorphan hydrobromide USP,EP 30,00 20,00 0 Quinidine sulfate dihydrate USP,EP 10.00 10.00 0 sodium croscarmellose NF 7.80 7.80 7.80 microcrystalline cellulose NF 94,00 94,00 94,00 colloidal silicon dioxide NF 0.65 0.65 0.65 lactose monohydrate NF 116.90 126.90 156.90 magnesium stearate NF 0.65 0.65 0.65

EP=European Pharmacopoeia; USP=United States Pharmacopoeia; NF=National Formulary

[0156] Participants and caregivers were instructed to return any unused study medication and empty vials to the study center on Days 8, 22, 36, 43, 57, and 70 (Visits 2-7). For this study, patient compliance was defined as the participant taking at least 80% of the prescribed dose. Caregivers were provided with patient diaries and instructions to record the number of capsules taken and the time of administration each day. Patient diaries were collected on Days 8, 22, 36, 43, 57, and 70 (Visits 2-7) or at the time of early termination of the study.

Efficiency

[0157] The primary efficacy endpoint was improvement in NPI arousal/aggression domain scores. Secondary efficacy endpoints included changes from baseline in NPI total score (range, 1 to 144), individual NPI domain scores, and NPI composite scores covering the arousal/aggression, aberrant motor behavior, and irritability/lability domains plus either anxiety (NPI4A) or disinhibition (NPI4D) scores. The NPI-Caregiver Distress Score (NPI-CDS; 0 (no distress) to 5 (very distressed) was recorded for each positively rated NPI domain. ADCS-CGIC (modified Alzheimer's Disease Collective Study - Clinical Global Assessment of Change, 1 to 7 (very much improved to much worse) and caregiver-reported Patient Global Assessment of Change (PGI-C) scores (1 = very much improved to 7 = very much worse) were collected at weeks 5 and 10 and were intended to measure clinical significance. Additional secondary endpoints included the ADCS - Activities of Daily Living Questionnaire (ADCS-ADL, 0 to 54, higher scores indicating greater activity); the Cornell Depression in Dementia Scale (CSDD, 0 to 38, higher scores indicating more severe depression); caregiver strain index (CSI; 0 to 13, higher scores indicate higher strain); Alzheimer's disease quality of life (QOL-AD, 13 to 52, higher scores indicate better quality of life); and changes in psychotropic medication/use of the rescue drug lorazepam. Cognitive function was assessed using the MMSE (0 to 30, lower scores indicate more cognitive impairment) and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog; 0 to 70, higher scores indicate more cognitive impairment). Safety outcomes included adverse events (AEs), vital signs, clinical laboratory results, and ECG data. QT interval measurements were corrected for heart rate change and QTcF (QT/ ³ √[RR]) calculations were used.

[0158] The efficacy parameters described above were assessed at the following time points during the study: CSI and all domains of the NPI were assessed at baseline and at weeks 1, 3, 5, 6, 8, and 10; ADCS-CGIC agitation, QOL-AD quality of life (caregiver assessment), and ADAS-cog cognitive impairment were assessed at baseline and at weeks 5 and 10; CSDD and MMSE scores were assessed at screening and at weeks 5 and 10; and PGI-C scores were assessed at weeks 5 and 10.

[0159] The primary and secondary efficacy endpoints were analyzed using established methods using a sequential parallel comparison design (SPCD) (Fava et al., Psychother. Psychosom. 2003;72(3):115–127; Chen et al., Contemp. Clin. Trials., 2011;32(4):592–604) with data from both 5-week stages weighted 1:1 using ordinary least squares (OLS) and including all participants from stage 1 and only rerandomized placebo non-responders (Figure 2) from stage 2. The analysis of the primary endpoint of the study was prespecified; no adjustment was made for multiplicity in the secondary endpoints. The dextromethorphan/quinidine group and placebo group were compared using 2-tailed tests with an alpha=0.05 significance level. Additionally, an analysis of covariance (ANCOVA), with treatment as a fixed effect and baseline as a covariate, was performed to compare scores within the treatment group at each time point and at each visit separately. Finally, for the 10-week parallel-group design (as shown in Figure 2), a prespecified comparison was performed of NPI agitation/aggression scores among participants who were randomized to receive dextromethorphan/quinidine alone (n=93) or placebo alone (n=66) for the entire 10 weeks of the study (regardless of treatment response status). All statistical analyses were performed using SAS ^® software version 9.1 or higher (SAS Institute, Cary, NC, USA).

[0160] To ensure the robustness of the primary analysis results and given the use of SPCD methodology, additional exploratory sensitivity analyses of the primary endpoint were conducted. One analysis used the prespecified repeated measures model (MMRM) described by Doros et al. (Doros et al., Stat. Med. 2013; 32(16):2767–2789) to control for the potential impact of missing data and to exclude re-randomized placebo responders in Step 2. This model uses all available data from the NPI Arousal/Aggression domain. Three separate models were used to estimate the treatment effect, and data collected at baseline, end of Step 1, and end of Step 2 were included in the analyses, with a pooled model allowing for inclusion of data from interim visits. Based on FDA recommendation, a second sensitivity analysis of the primary endpoint was performed using the apparently unrelated equations (SUR) method (Doros et al., Stat. Med. 2013; 32(16):2767–2789; Zellner et al., J. Am. Stat. Assoc. 1962; 57(298):348–368; Tamura and Huang, Clin. Trials. 2007; 4(4):309–317) in a sequential parallel comparison design (SPCD) instead of the least squares method, after deblinding, to determine whether missing data could not have been missed by chance. In addition to the above, a pre-specified exploratory analysis of the primary endpoint was conducted using the same SPCD methodology described above for the primary analysis, but in this case both placebo groups, responders and non-responders, who were re-randomised in stage 2 were included in the analysis.

[0161] In published studies of treatment of dementia-related agitation, estimates of the standard deviation (SD) in change scores on NPI agitation/aggression scores ranged from 3.1 to 5.2 units (Herrmann et al., CNS Drugs. 2011; 25(5):425-433; Mintzer et al., Am. J. Geriatr. Psychiatry. 2007; 15(11):918-931; Herrmann et al., Dement. Geriatr. Cogn. Disord. 2007; 23(2):116-1199). An SD of 5.0 units was assumed, and a sample size of 196 participants was calculated based on a 2-sided, 2-sample comparison of means from independent samples at the 5% significance level to provide 90% power to detect a mean difference of 2.5 units. Sample size calculation was based on a parallel design because there had been no previous analysis of SPCD for the treatment of agitation in patients with Alzheimer's disease.

[0162] The safety analysis set included all participants who received at least 1 dose of study drug. The modified intent-to-treat (mITT) efficacy analysis set included all participants assessed by the NPI after baseline for agitation/aggression in Step 1. Missing data were imputed using the last documented value.

[0163] The safety analysis population included all 220 randomized participants (126 women, 94 men); 218 participants comprised the mITT efficacy analysis population, with 194 participants (88.2%) completing the study (Figure 3). The SPCD methods were used and the placebo group was re-randomized at the start of Stage 2. A total of 152 participants received dextromethorphan/quinidine (93 participants started in Stage 1 and an additional 49 re-randomized participants from the placebo group in Stage 2) and 127 participants received placebo, resulting in approximately 26.7% greater exposure in the dextromethorphan/quinidine group (1153 patient-weeks) than in the placebo group (91 patient-weeks). Seventeen participants (11.2%) discontinued the study while receiving dextromethorphan/quinidine and 9 participants (7.1%) discontinued the study while receiving placebo, including 8 participants (5.3%) and 4 participants (3.1%) due to adverse events (AEs), respectively. Participants were proportionally distributed between treatment groups by their outcomes and are presented in Table 3 and Table 4 (mITT efficacy study group). These outcomes were also proportionally distributed in the rerandomized group in Stage 2. mITT data from the rerandomized placebo group, obtained by the SPCD method, are presented in Table 3.

Table 3

Indicators Placebo (n=127) ^a Dextromethorphan/quinidine (n=93) ^a Age (years), mean, standard deviation (SD) 77.8 (7.2) 77.8 (8.0) Age ≥ 75 years, n (%) 86 (67.7) 68 (73.1) Women, n (%) 74 (58.3) 52 (55.9) Race, n (%) Whites 118 (92.9) 84 (90.3) Black or African American 6 (4.7) 5 (5.4) Asians 1 (0.8) 3 (3.2) Native Hawaiians or other Pacific Islanders 0 1 (1,1) Other 2 (1.6) 0 Ethnicity Hispanic or Mexican 13 (10.2) 7 (7.5) Location, n (%) Outpatient 111 (87.4) 82 (88.2) Assisted Living Home 10 (7.9) 5 (5.4) Nursing facility 6 (4.7) 6 (6.5) Concomitant drug treatment, n (%) Acetylcholinesterase inhibitors 95 (74.8) 67 (72.0) Memantine 66 (52.0) 43 (46.2) Antidepressants 65 (51.2) 57 (61.3) Antipsychotic drugs 29 (22.8) 16 (17.2) Benzodiazepines 12 (9.5) 6 (6.5) Benzodiazepine-like derivatives 12 (9.5) 6 (6.5) History of falls, n(%) 16 (12.6) 16 (17.2) Ranking on rating scale ^b , mean (SD) Arousal by CGI-S 4.5 (0.7) 4.4 (0.6) Arousal/Aggression by NPI 7.0 (2.4) 7.1 (2.6) Overall NPI Score 38.0 (18.7) 40.1 (19.6) Aberrant motor behavior according to NPI 3.5 (4.2) 4.3 (4.4) Irritability/lability by NPI 5.4 (3.2) 5.8 (3.7) NPI4A 20.1 (8.3) 20.9 (9.4) NPI4D 18.5 (9.2) 19.8 (9.1) NPI Caregiver Distress (Arousal) 3.0 (1.0) 3.3 (0.9) NPI Caregiver Distress (Total Score) 17.0 (8.3) 17.9 (8.0) CSI 6.8 (3.6) 6.9 (3.2) CSDD 5.8 (2.4) 5.9 (2.4) QOL-AD 37.2 (6.4) 36.5 (7.4) QOL-AD 30.1 (6.0) 30.9 (6.0) MMSE 17.2 (5.8) 17.4 (6.0) ADAS-cog 32.0 (15.2) 30.6 (14.1) ADCS - ADL 34.1 (12.8) 35.8 (11.9) CGIS baseline arousal scores, ^b , n (%) 4 (moderate severity of the disease) 77 (60.6) 61 (65.6) 5 (significant severity of the disease) 40 (31.5) 28 (30.1) 6 or 7 (severe or among the most seriously ill) 10 (7.9) 4 (4.3)

Participant characteristics by treatment group. ^a Safety analysis set at randomization. ^b Modified intent-to-treat (mITT) analysis in the efficacy analysis (placebo, n= 125, dextromethorphan/quinidine (n=93).

Table 4

Indicators Placebo Dextromethorphan/quinidine Floor n 125 93 Women 74 (59.2%) 52 (55.9%) Men 51 (40.8%) 41 (44.1%) Race n 125 93 Whites 116 (92.8%) 84 (90.3%) Black or African American 6 (4.8%) 5 (5.4%) Asians 1 (0.8%) 3 (3.2%) American Indians or Alaska Natives 0 0 Native Hawaiians or other indigenous Pacific Islanders 0 1 (1.1%) Other 2 (1.6%) 0 Ethnicity n 125 93 Hispanic or Mexican 13 (10.4%) 7 (7.5%) Not Hispanic or Mexican 112 (89.6%) 86 (92.5%) Age (years) n 125 93 Average value 77.6 77.8 SD 7.19 8.01 Minimum 56 53 Median 78.0 78.0 Maximum 90 90 Age group 2 (years) n 125 93 < 75 41 (32.8%) 25 (26.9%) ≥ 75 84 (67.2%) 68 (73.1%) Patient's living conditions n 125 93 Outpatient 109 (87.2%) 82 (88.2%) Assisted Living Home 10 (8.0%) 5 (5.4%) Nursing facility 6 (4.8%) 6 (6.5%) CGI-S Arousal Rating n 125 93 Average value 4.5 4.4 SD 0.67 0.57 Minimum 4 4 Median 4.0 4.0 Maximum 7 6 CYP2D6 Metabolism Subgroup n 121 85 Weak metabolism 7 (5.8%) 9 (10.6%) Average metabolism 48 (39.7%) 38 (44.7%) Extended metabolism 65 (53.7%) 35 (41.2%) Super fast metabolism 1 (0.8%) 3 (3.5%)

Population group from the modified intent-to-treat (mITT) analysis in the efficacy analysis based on randomization in stage 1. The “extended” metabolizer group includes patients with “normal” or “normal or intermediate” metabolizers

Table 5

Indicators Placebo Dextromethorphan/quinidine Floor n 45 44 Women 29 (64.4%) 23 (52.3%) Men 16 (35.6%) 21 (47.7%) Race n 45 44 Whites 41 (91.1%) 42 (95.5%) Black or African American 2 (4.4%) 2 (4.5%) American Indians or Alaska Natives 0 0 Other 2 (4.4%) 0 Ethnicity n 45 44 Hispanic or Mexican 6 (13.3%) 2 (4.5%) Not Hispanic or Mexican 39 (86.7%) 42 (95.5%) Age (years) n 45 44 Average value 77.3 78.3 SD 7.02 7.40 Minimum 59 60 Median 78.0 80.0 Maximum 89 90 Age group 2 (years) n 45 44 < 75 17 (37.8%) 13 (29.5%) ≥ 75 28 (62.2%) 31 (70.5%) Patient's living conditions n 45 44 Outpatient 39 (86.7%) 41 (93.2%) Assisted Living Home 4 (8.9%) 2 (4.5%) Nursing facility 2 (4.4%) 1 (2.3%) CGI-S Arousal Rating n 45 44 Average value 4.6 4.6 SD 0.75 0.66 Minimum 4 4 Median 4.0 4.5 Maximum 7 6 CYP2D6 Metabolism Subgroup n 45 41 Weak metabolism 2 (4.4%) 3 (7.3%) Average metabolism 13 (28.9%) 19 (46.3%) Extended metabolism 30 (66.7%) 18 (43.9%) Super fast metabolism 1 (2.4%)

Rerandomized placebo subjects are non-responders from a modified intent-to-treat (mITT) analysis performed using a sequential parallel comparison design (SPCD) in Stage 2. The “extended” metabolizer group includes subjects with “normal” or “normal or average” metabolizers

[0164] Dextromethorphan/quinidine significantly improved NPI arousal/aggression scores compared with placebo in the primary SPCD analysis (OLS least squares Z-statistic: -3.95, P < 0.001) in the population-based mITT group. Results from each step also show a benefit for dextromethorphan/quinidine compared with placebo (Table 6). At Step 1, mean NPI scores (95% Ci) for arousal/aggression decreased from 7.1 (6.6, 7.6) to 3.8 (3.1, 4.5) with dextromethorphan/quinidine and from 7.0 (6.6, 7.4) to 5.3 (4.7, 5.9) with placebo ( P < 0.001), with a least squares (LS) mean treatment difference (95% Ci) of -1.5 (-2.3 -0.7). A differential response was noted at week 1 (-0.8 [-1.5, -0.03], P = 0.04; figure 4). At stage 2 (placebo non-responders re-randomized to either dextromethorphan/quinidine or placebo), mean NPI scores (95% Ci) for agitation/aggression decreased from 5.8 (4.9, 6.7) to 3.8 (2.9, 4.7) with dextromethorphan/quinidine and from 6.7 (5.9, 7.5) to 5.8 (4.7, 6.9) with placebo ( P = 0.02), with a least squares (LS) mean treatment difference (95% Ci) of -1.6 [-2.9, -0.3]; figure 5). Improvements in the NPI arousal/aggression domain were statistically significant at week 1 and at every time point until study completion except week 6 (in phase 2). A prespecified comparison of NPI arousal/aggression scores among participants who were randomized to dextromethorphan/quinidine alone (n=93) or placebo alone (n=66) across the 10 weeks of the trial (regardless of treatment response status (responder or nonresponder) with parallel-group design modeling as shown in Figure 2) also shows an advantage for dextromethorphan/quinidine compared with placebo (LS mean treatment difference (95% Ci) -1.8 [-2.8, -0.7]; Table 6, Figure 6). The response to dextromethorphan/quinidine compared with placebo did not appear to differ by disease stage. Stratified randomization by baseline MMSE score (>15 versus ≤15) and baseline CGIS score (4 or 5 versus 6 or 7) yielded proportionate treatment groups for both agitation and cognitive function. Additional analyses to assess the potential influence of these factors did not suggest differences in response, although some strata in these analyses were small and such observations require confirmation in larger studies.

Table 6

Parameter Stage N/N Dextro-methorphan/
quinidine/
placebo Dextro-methorphan/
Quinidine, Mean Change from Baseline
(95% Ci) P- value at stage ^{a , b} Mean treatment difference by OLS
(95% Ci) P- value of SPCD ^h Arousal/aggression by NPI ^d 1 ^a 93/125 -3.3 (-3.9, -2.6) -1.7 (-2.3, -1.2) <,001 -1.5 (-2.3, -0.7) <,001 2 ^b 44/45 -2.0 (-3.0, -1.0) -0.8 (-1.9, 0.2) ,02 -1.6 (-2.9, -0.3) 10 week ^c 93/66 -3.6 (-4.3, -2.9) -1.9 (-2.8, -1.0) ,001 -1.8 (-2.8, -0.7) N/A Overall NPI score ^d 1 ^a 93/125 -13.5 (-17.1, -9.9) -8.5 (-11.0, -5.9) ,03 -4.1 (-8.0,-0.4) ,01 2 ^b 44/45 -6.0 (-9.7, -2.2) -2.5 (-6.0, 1.1) ,15 -3.8 (-9.0, 1.4) 10 week ^c 93/66 -16.0 (-19.5, -12.5) -10.1 (-14.7, -5.5) ,02 -5.7 (-10.7, -0.7) N/A Aberrant motor behavior according to NPI ^d 1 ^a 93/125 -1.2 (-2.0, -0.4) -0.4 (-1.1, 0.3) ,39 -0.4 (-1.3, 0.5) ,03 2 ^b 44/45 -0.8 (-1.6, -0.1) 0.4 (-0.6, 1.3) ,04 -1.2 (-2.4, -0.1) 10 week ^c 93/66 -1.3 (-2.1, -0.5) 0.1 (-0.7, 0.8) ,03 -1.0 (-1.9, -0.1) N/A Irritability/lability by NPI ^d 1 ^a 93/125 -2.2 (-3.0, -1.4) -1.2 (-1.8, -0.6) ,09 -0.7 (-1.5, 0.1) 0.03 2 ^b 44/45 -1.0 (-2.0, 0.04) -0.7 (-1.8, 0.5) ,14 -0.9 (-2.2, 0.3) 10 week ^c 93/66 -2.4 (-3.3, -1.6) -1.8 (-2.8, -0.7) ,38 -0.4 (-1.4, 0.6) N/A NPI4A ^d 1 ^a 93/125 -7.3 (-9.1, -5.4) -4.5 (-6.0, -3.0) ,03 -2.4 (-4.6, -0.2) ,001 2 ^b 44/45 -4.8 (-6.9, -2.7) -1.4 (-3.8, 1.0) ,01 -3.9 (-7.0, -0.9) 10 week ^c 93/66 -8.5 (-10.4, -6.7) -5.0 (-7.4, -2.5) ,01 -3.4 (-6.1, -0.7) N/A NPI4D ^d 1 ^a 93/125 -7.6 (-9.4, -5.7) -4.0 (-5.5, -2.6) ,006 -3.0 (-5.1, -0.9) <,001 2 ^b 44/45 -4.6 (-6.8, -2.4) -1.9 (-4.2, 0.4) ,02 -3.5 (-6.5,-0.5) 10 week ^c 93/66 -8.3 (-10.1, -6.5) -5.0 (-7.4, -2.6) ,02 -3.0 (-5.5, -0.4) N/A NPI Caregiver Distress (Arousal) ^d 1 ^a 93/125 -1.4 (-1.6, -1.0) -0.6 (-0.8, -0.4) <,001 -0.7 (-1.0, -0.3) ,01 2 ^b 44/45 -0.5 (-0.9, -0.004) -0.7 (-1.2, -0.2) ,49 -0.2 (-0.8, 0.4) 10 week ^c 93/66 N/A N/A N/A N/A N/A Caregiver distress, NPI total score ^d 1 ^a 93/125 -6.6 (-8.2, -5.0) -3.6 (-4.8, -2.5) N/A N/A ,01 2 ^b 44/45 -2.6 (-4.3, -1.0) -2.0 (-3.8, -0.3) N/A N/A 10 week ^c 93/66 N/A N/A N/A N/A N/A CSI ^d 1 ^a 93/125 -1.2 (-1.7, -0.7) -0.6 (-0.9, -0.2) ,03 -0.6 (-1.2, -0.1) ,05 2 ^b 44/45 -0.2 (-0.7, 0.3) 0.1 (-0.5, 0.6) ,42 -0.3 (-1.0, 0.4) 10 week ^c 93/66 -1.2 (-1.7, 0.6) -0.4 (-0.9, 1.3) ,04 -0.8 (-1.6, 0.02) N/A CSDD ^f 1 ^a 88/123 -0.1 (-1.8, -0.3) 0.6 (-0.1, 1.3) ,002 -1.6 (-2.5, -0.6) ,02 2 ^b 43/44 -0.9 (-1.8, -0.004) -0.7 (-1.5, 0.1) ,75 -0.2 (-1.3, 0.9) 10 week ^c 88/64 -1.2 (-2.0, -0.4) 0.4 (-0.6, 1.5) ,03 -1.3 (-2.6, -0.1) N/A Excitation ^e by ADCS - CGIS 1 ^a 88/123 3.0 (2.8, 3.3) 3.6 (3.4, 3.8) <,001 -0.6 (-0.9, -0.3) <,001 2 ^b 42/42 3.3 (2.9, 3.6) 3.7 (3.3, 4.2) ,07 -0.5 (-1.0, 0.1) 10 week ^c 82/59 2.7 (2.3, 3.1) 3.3 (3.0, 3.7) ,02 -0.5 (-0.9, -0.1) N/A PGI-C ^g 1 ^a 88/123 3.1 (2.8, 3.3) 3.6 (3.4, 3.8) ,001 -0.6 (-0.9, -0.2) ,001 2 ^b 43/44 3.2 (2.8, 3.6) 3.8 (3.3, 4.2) ,04 -0.6 (-1.1, -0.1) 10 week ^c 81/59 2.9 (2.7, 3.2) 3.5 (3.2, 3.8) ,007 -0.6 (-1.0, -0.2) N/A QOL-AD (patient) ^e 1 ^a 87/116 1.3 (-0.03, 2.6) 0.0 (-1.0, 0.9) ,14 1.1 (-0.4, 2.6) ,16 2 ^b 40/40 1.5 (-0.1, 3.1) 0.7 (-0.7, 2.0) ,50 0.7 (-1.4, 2.7) 10 week ^c 87/61 0.7 (-0.7, 2.1) 0.5 (-1.1, 2.0) ,96 -0.1 (-2.0, 1.9) N/A QOL-AD (Caregiver) ^e,i 1 ^a 88/123 0.4 (-0.5, 1.3) 0.3 (-0.5, 1.1) ,63 0.3 (-0.9, 1.5) ,47 2 ^b 43/43 -0.3 (-1.5, 0.9) 0.9 (-0.4, 2.2) ,24 1.1 (-2.8, 0.7) 10 week ^c 88/64 1.3 (0.2, 2.4) 0.9 (-0.5, 2.4) ,28 0.9 (-0.7, 2.6) N/A ADCS-ADL ^e 1 ^a 88/123 -0.9 (-1.8,-0.04) -0.8 (-1.5, -0.1) ,90 -0.1 (-1.2, 1.1) ,16 2 ^b 43/44 -2.0 (-3.4, -0.5) -0.6 (-1.7, 0.4) ,12 -1.4 (-3.1, 0.4) 10 week ^from 88/64 -0.8 (-1.8, 0.2) -1.8 (-2.9, 0.7) ,17 1.0 (-0.5, 2.5) N/A Overall MMSE score ^f 1 ^a 88/122 0.2 (-0.4, 0.9) -0.3 (-0.8, 0.20 ,20 0.5 (-0.3, 1.3) ,05 2 42/44 0.3 (-0.5, 1.2) -0.5 (-1.3, 0.2) ,15 0.8 (-0.3, 2.0) 10 week ^a 88/63 0.1 (-0.5, 0.8) -0.6 (-1.5, 0.3) ,21 0.7 (-0.4, 1.8) N/A ADAS-cog ^e 1 ^a 87/121 -0.9 (-2.5, 0.6) 0.3 (-5.7, 1.3) ,11 -1.4 (-3.0, 0.3) ,20 2 ^b 42/43 0.3 (-1.4, 1.9) 0.8 (-0.7, 2.3) ,64 -0.5 (-2.8, 1.7) 10 week ^from 81/58 -0.7 (-1.9, 0.7) 1.2 (-0.2, 2.4) ,07 -1.7 (-3.5, 0.2) N/A

N/A=not assessed

*Treatment difference: dextromethorphan/quinidine vs. placebo; ^a Stage 1: all participants are included in the study and measures change from Stage 1 baseline to week 5 for each outcome; ^b Stage 2: only randomized placebo nonresponders from Stage 1 are included in the study and measures change from Stage 2 baseline (week 5) to week 10 for all outcomes except PGI-C (Stage 1 baseline to week 10); ^c only those participants who remained on their original treatment throughout their study participation (i.e., receiving dextromethorphan/quinidine only or placebo only, thereby creating a parallel comparison design) and measures from Stage 1 baseline to week 10 are included in the 10-week analysis; ^d assessments at baseline, weeks 1, 3, 5, 6, 8, and 10; ^e assessment at baseline, weeks 5 and 10; ^f assessment at screening, weeks 5 and 10; ^g assessment at weeks 5 and 10. ^h SPCD (sequential parallel comparison design) analysis was specified by the protocol for the primary efficacy analysis and pools the results of all patients in stage 1 and from “placebo non-responders” rerandomized in stage 2, based on 50/50 weighting of the NPI arousal/aggression domain for each study phase; ⁱ for QOL-AD (carer assessment), carer rating of patient’s quality of life; P- value across study phases based on analysis of covariates (ANCOVA); P- value for SPCD analysis based on ordinary least squares (OLS).

[0165] In the SPCD analysis of pre-specified secondary outcomes (Table 6), a beneficial effect of dextromethorphan/quinidine was demonstrated, resulting in significant improvements in the total score (PGI-C and CGIC), NPI total score, NPI Aberrant Motor Behavior and Irritability/Lability domain scores, NPI4A and NPI4D composite scores, NPI Caregiver Distress (both Arousal/Aggression domain and total score), CSI, and CSDD. Changes in QOL-AD, ADCS-ADL, MMSE, and ADAS-cog (exploratory outcome) scores were not significant compared with placebo. In a post hoc analysis, improvement in NPI agitation/aggression scores was similar with dextromethorphan/quinidine in participants receiving concomitant acetylcholinesterase inhibitors, memantine, antidepressants, or antipsychotics compared with participants not receiving these medications. Lorazepam rescue treatment was used in 10 of 152 (6.6%) and 13 of 125 (10.4%) participants on dextromethorphan/quinidine and placebo, respectively. At the end of 10 weeks of treatment, 45.1% of participants receiving dextromethorphan/quinidine alone (n=82) were “much improved” or “very much improved” on the ADCS-CGIC score, compared with 27.1% of participants receiving placebo alone (n=59).

Safety and tolerability

[0166] Dextromethorphan/quinidine was generally well tolerated in the population receiving multiple concomitant medications and was not associated with cognitive impairment. Treatment-emergent adverse events (TEAEs) were considered to be related to the treatment being administered at the time of their occurrence. TEAEs were reported by 93 of 152 participants (61.2%) and 55 of 127 participants (43.3%) (safety study population) during treatment with dextromethorphan/quinidine or placebo, respectively. The most common TEAEs (>3%) were falls (8.6% vs 3.9%), diarrhea (5.9% vs 3.1%), urinary tract infection (5.3% vs 3.9%), dizziness (4.6% vs 2.4%), and agitation (3.3% vs 4.7%) with dextromethorphan/quinidine compared with placebo, respectively. Serious adverse events (SAEs) occurred in 12 (7.9%) participants receiving dextromethorphan/quinidine and 6 (4.7%) participants receiving placebo. Serious adverse events in participants receiving dextromethorphan/quinidine included chest pain (n=2), anemia, acute myocardial infarction (occurring 2 days after completion of dosing), bradycardia, kidney infection, femur fracture, dehydration, colon cancer, cerebrovascular accident, aggression, and hematuria (n=1, each). SAEs in participants receiving placebo included idiopathic thrombocytopenic purpura, dizziness, pneumonia, gastroenteritis, contusion, transient ischemic attack, and agitation (n=1, each). Eight participants (5.3%) receiving dextromethorphan/quinidine and 4 participants (3.1%) receiving placebo discontinued treatment due to adverse events (AEs), including 4 participants (2.6%) and 2 participants (1.6%), respectively, due to SAEs. There were no deaths during the study.

[0167] Of the 13 participants who reported falls while receiving dextromethorphan/quinidine, 9 had a history of falls. Three participants fell between 2 and 4 days after study completion, and one participant fell twice within 24 hours of lorazepam rescue medication administration on both occasions; none of the participants who fell while receiving placebo had a history of falls. Two falls were associated with serious AEs (SAEs): a femur fracture with dextromethorphan/quinidine and a contusion with placebo.

[0168] No clinically significant differences were observed between groups in ECG parameters. At the last visit, the mean (SD) QTcF was 5.3 msec (14.06) and -0.3 msec (12.96) in participants receiving dextromethorphan/quinidine (n=138) and placebo (n=60), respectively. Fifteen participants (10.3%) receiving AVP923 and 8 participants (6.7%) receiving placebo had a QTcF change ≥30 msec across all visits; one participant in the placebo group had a QTcF change >60 msec. No participants had a QTcF >500 msec.

[0169] Based on the data presented in Table 6 and Figure 4, Figure 5, and Figure 6, it is evident that the combination of dextromethorphan and quinidine is highly effective in treating agitation and aggression in patients with probable Alzheimer's disease compared to placebo. In addition, the combination is generally well tolerated in this elderly population and does not cause cognitive impairment, sedation, or clinically significant prolongation of the QTc interval.

Example 2: Relevance of studying AVP-786 for the treatment of agitation in Alzheimer's disease.

[0170] AVP-786 is a combination product of deuterated (d6)-dextromethorphan hydrobromide (d6-DM), a central nervous system (CNS) active component, and quinidine sulfate (Q), used as an inhibitor of d6-DM metabolism by the liver isoenzyme cytochrome P450 (CYP) 2D6 (CYP2D6). AVP-786 may have clinical benefit for the treatment of agitation in patients with Alzheimer's disease (AD).

[0171] d6-DM binds to receptors responsible for modulating glutamate, monoamine, sigma-1, and nicotinic cholinergic pathways, which may be key for therapeutic agents acting on the CNS. Pharmacological studies of d6-DM conducted by the present inventors have shown that deuteration does not alter the basic pharmacological properties of DM. Also, pharmacokinetic (PK) and drug metabolism studies have shown that d6-DM is metabolized via the same metabolic pathways as DM, but its deuteration results in a decrease in the rate of CYP2D6 metabolism.

[0172] A recent Phase 2 study by the inventors identified the primary efficacy endpoint and demonstrated a significant reduction in agitation in patients receiving AVP-923 compared to placebo. The study was a 10-week, randomized, double-blind, placebo-controlled, 2-stage, sequential parallel comparison (SPCD) study designed to evaluate the efficacy, safety, and tolerability of AVP-923 for the treatment of agitation in 220 patients with Alzheimer's disease. Patients receiving AVP-923 demonstrated a significant reduction in agitation compared to patients receiving placebo (p < 0.001), as measured by the agitation/aggression domain of the Neuropsychiatric Inventory (NPI). Most of the secondary endpoints studied (eg, NPI total score, NPI arousal/aggression domain, caregiver distress domain, Clinical Global Impression Scale [CGIC] change score for arousal, Clinical Impression of Severity [CGIS] change score for arousal, and Patient Global Impression of Change [PGIC]) were also statistically significant. Both physician and patient/caregiver impressions of change support the clinical significance of the improvements seen in arousal. There was also a nominally favorable response in cognitive function, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog), which did not reach statistical significance.

[0173] Further studies by the inventors showed that the d6-deuterium modification of dextromethorphan (DM) reduces the rate of metabolism by CYP2D6 such that combination with quinidine at a much lower dose (< 50% of the amount of quinidine Q contained in AVP-923) is sufficient for bioequivalence of d6-DM and DM in AVP-786 and AVP-923, respectively. The reduction in the amount of quinidine in AVP-786 helps reduce interactions with other CYP2D6 substrates, limits Q levels even in the presence of CYP3A4 inhibitors, and reduces the effect on myocardial repolarization and the QTc interval.

Example 3: A multicenter, randomized, double-blind, placebo-controlled phase 3 study to evaluate the efficacy, safety, and tolerability of AVP-786 (deuterated [d6]-dextromethorphan hydrobromide [d6- DM]/quinidine sulfate [Q]) for the treatment of agitation in patients with dementia of the Alzheimer's type.

[0174] This study is designed to evaluate the efficacy, safety, and tolerability of AVP-786 for the treatment of agitation in patients with Alzheimer's type dementia.

Rationale for the duration of treatment with AVP-786.

[0175] For efficacy assessment, the optimal duration of treatment is considered to be 12 weeks, based on a review of data from the 12-AVR-131 study of AVP-923 (Papakostas GI et al., Am. J. Psychiatry . 2012; 169(12):1267-1274; Marshall R, Leigh-Pemberton R, Memisoglu A, et al. Opioid modulation: a novel mechanism for the treatment of depression: results of the ALKS 5461 phase 2 study. 2004; 2:5461). For patients who were assigned the same treatment for the entire 12 weeks of the study, the treatment response can also be assessed over time.

Study population

[0176] Number of Patients : The study will enroll approximately 380 patients at approximately 60 centers in the United States.

[0177] Condition/Disease: Patients with agitation secondary to dementia of the Alzheimer's type. The diagnosis of probable Alzheimer's disease will be based on the criteria in the 2011 Diagnostic Guidelines for Alzheimer's Disease issued by the National Institute on Aging (NIA)/Alzheimer's Association (AA) Task Force (McKhann GM et al., Alzheimers Dement. 2011; 7(3):263-269). The diagnosis of agitation will be based on the preliminary consensus definition of agitation in patients with cognitive impairment developed by the International Psychogeriatric Association (IPA) Agitation Definition Task Force (Cummings J et al, Int. Psychogeriatr. 2014:1-11).

[0178] Key inclusion criteria: At screening and for at least 2 weeks prior to randomization, patients have clinically significant, moderate/severe agitation that interferes with daily functioning and warrants prescription medication, in the opinion of the investigator. Eligibility requires a Clinical Global Impression of Illness (CGIS) agitation score ≥4 (moderate illness) at screening and baseline. Eligible patients must have a reliable caregiver who is able and willing to perform study procedures, including not administering any illicit drugs during the study.

[0179] Key exclusion criteria: Patients with dementia that is primarily not of the Alzheimer's type (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, chemical-induced dementia) and patients with agitation that is not secondary to Alzheimer's disease (e.g., dementia due to pain, another psychiatric disorder, or delirium) are not eligible for participation in the study.

Research plan

[0180] Design: Multicenter, randomized, double-blind, placebo-controlled, phase 3 study.

[0181] Duration: Patients will be enrolled in the study for approximately 16 weeks, with a screening period of 4 weeks and a treatment period of 12 weeks.

[0182] Investigational Treatment: The investigational product is AVP-786 (deuterated [d6]-dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]). Two doses of AVP-786 will be studied: d6-DM 28 mg/Q, 4.9 mg and d6-DM 18 mg/Q, 4.9 mg, hereinafter referred to as AVP-786-28/4.9 and AVP-786-18/4.9, respectively.

[0183] Composition of AVP-786: The qualitative and quantitative compositions of the 2 doses of study drug (SD) and placebo are shown in Table 7 below.

Table 7:

Ingredients
(amount in mg) AVP-786-28/4,9 AVP-786-18/4,9 AVP-786 Placebo dextromethorphan hydrobromide 28.00 18:00 0 Quinidine Sulfate USP,EP 4.90 4.90 0 sodium croscarmellose NF 6.60 6.60 6.60 microcrystalline cellulose NF 177.20 187.20 210.10 colloidal silicon dioxide NF 2.20 2.20 2.20 magnesium stearate NF 1.10 1.10 1.10 Total 220,0 220,0 220,0 Blue opaque capsules, size 3 (medium weight) 48.0 48.0 48.0 Total 268,0 268,0 268,0

EP=European Pharmacopoeia; USP=United States Pharmacopoeia; NF=National Formulary

[0184] Control: Placebo capsules identical in appearance to the study drug will be used as a control.

[0185] Randomization/stratification: Eligible patients will be randomized to receive either AVP-786-28/4.9 capsules, AVP-786-18/4.9 capsules, or matching placebo capsules. Randomization will be stratified by Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain score (≤6 vs. >6), falls risk score (normal/moderate vs. moderate/high risk), and concomitant antipsychotic use (YES vs. NO).

[0186] Administration Regimen: Eligible patients will be randomly assigned at Visit 1 (baseline) to receive either AVP-786 capsules or placebo capsules. Patients randomized to AVP-786-28/4.9 will begin receiving AVP-786-18/4.9 once daily in the morning and placebo in the evening for the first 7 days of the study. Beginning on Day 8, patients will receive AVP-786-18/4.9 twice daily for 14 days. Beginning on Day 22, patients will receive AVP-786-28/4.9 twice daily for the remaining 9 weeks of the study.

Patients randomized to AVP-786-18/4.9 will begin receiving AVP-786-18/4.9 once daily in the morning and placebo in the evening for the first 7 days of the study. Beginning on day 8, patients will receive AVP-786-18/4.9 twice daily for the remaining 11 weeks of the study. Patients will have at least a 50% chance of receiving AVP-786 at some point during the study. Study drug will be administered orally twice daily (1 capsule in the morning and 1 capsule in the evening, approximately 12 hours apart) for the duration of the study.

Assessments and visits

[0187] Patients will visit study sites at screening, baseline (day 1), and on days 8 (week 1), 22 (week 3), day 43 (week 6), day 64 (week 9), and day 85 (week 12). Follow-up telephone calls to assess safety will be made on day 29 (week 4) and day 71 (week 10). Study procedures will be performed at each visit as outlined in the Schedule of Visits and Assessments (Table 8). Assessments should be performed by the same assessor, whenever possible, throughout the study.

Table 8: Schedule of visits and assessments

Procedure Visit: Screening baseline visit 2 ¹ visit 3 ¹ phone call ^1,2 visit 4 ¹ visit 5 ¹ phone call ^1,2 visit 6 ¹
/ ET ^3.4 Day of the study: days from -28 to -1 day 1 day 8 day 22 day 29 day 43 day 64 day 71 day 85 Study end week: weeks from -4 to -1 week 1 week 3 week 4 week 6 week 9 week 10 Week 12 Informed Consent Form X Medical history X Eligibility Check ⁵ X X Randomization X Physical and neurological examination X X X Vital signs and body weight ⁶ X X X X X X X CGIS X X X X Fall risk assessment (logbook and TUG test) X X ⁷ X ⁷ ECG X X ⁸ X X ⁸ X X Adverse events (AE) X X X X X X X X Previous and concomitant medications X X X X X X X X X MMSE X X X X GMRHR X X NPI X ⁹ X X X X X X CSDD X X X ZBI Interview X X X X X DEMQOL ¹⁰ X X X EQ-5D-5L ¹⁰ X X X ADAS-cog ¹¹ X X X PGIC ¹² X X X X ADCS-CGIC Baseline Assessment X ADCS-CGIC X X X X RUD X X X S-STS X X X X X X X Dispensing the morning dose of study drug in the clinic X X ¹³ X X X X Biochemical, hematological tests; urine analysis X ¹⁴ X X Urine test for pregnancy ¹⁵ X X X X Blood sample for PK analysis X X Blood sample for CYP2D6 X X X Dispensing of study drug on prescription and patient diary X X X X Checking and returning unused study drug and patient diary X ¹³ X X X X

ADAS-cog - Alzheimer's Disease Rating Scale - cognitive subscale; ADCS-CGIC - Clinical Global Impression of Change; AE - adverse event; CGIS - Clinical Global Impression of Disease; CSDD - Cornell Dementia Depression Scale; DEMQOL - Dementia Quality of Life Scale; ECG - electrocardiogram; EQ-5D-5L - 5 measures of 5 levels of the EuroQol quality of life at baseline; ET - early discontinuation; GMHR - general medical level of health; MMSE - Mini-Mental State Examination; NPI - Neuropsychiatric Questionnaire; PGIC - patient global impression of change as rated by a caregiver; PK - pharmacokinetics; RUD - resource use in dementia; S-STS - Sheehan Suicidality Tracking Scale; TUG - Timed Up and Go test; ZBI interview - interview with Dr. Zarit Burden.

1. Study visits are scheduled at +/- 3 day intervals, except for the Baseline Visit, Visit 2, and phone calls. The Baseline Visit, Visit 2, and phone calls are scheduled at +3 day intervals.

2. A telephone call should be made to the patient/caregiver to collect information on adverse events and to inquire about the use of concomitant medications.

3. An early termination visit is performed by patients who left the study before its completion.

4. Patients who withdraw early from the study or do not enter the extension study (Study 15-AVP-786-303) receive a telephone call regarding the safety of the study drug 30 days after the last dose of study drug.

5. A protocol compliance form is completed for each patient.

6. Body weight should be measured only at the baseline visit.

7. To assess the risk of falls at visits 4 and 6, only the TUG test should be performed.

8. ECG should be recorded before and after administration of the dose.

9. The NPI assessment for the arousal/aggression domain only should be performed at the screening visit. This assessment should be performed prior to the CGIS assessment.

10. The proxy version should be assessed by a caregiver. The non-proxy version should only be assessed by patients who scored ≥10 on the MMSE at baseline.

11. The ADAS-cog assessment is performed only in patients who showed ≥10 points on the MMSE scale at the beginning of the study.

12. The PGIC assessment must be carried out by a carer.

13. The study drug should be taken from the blister pack opened by the patient. The blister pack and patient diary should be returned to the patient/caregiver after compliance has been verified.

14. Thyroid function tests (TSH and T3 and T4 reflex if TSH levels are abnormal) should be performed during the screening visit.

15. Urine pregnancy testing should only be performed on women of childbearing age.

Reaction measurements

[0188] Primary efficacy measurement: Primary efficacy will be assessed using the NPI Arousal/Aggression domain.

[0189] Secondary efficacy measures: Secondary efficacy measures include the Clinical Impression of Change Global Score (CGIC) for agitation, NPI Agitation/Aggression Domain Score for Caregiver Distress, NPI Aberrant Motor Behavior Domain Score, Zarit Burden Interview (ZBI), NPI Irritability/Lability Domain Score, Patient Global Impression of Change (PGIC, carer-rated), Dementia Quality of Life (DEMQOL), Cornell Dementia Depression Scale (CSDD), Resource Use in Dementia (RUD), NPI Total Score, CGIS Agitation, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), General Medical Health Rating (GMHR), and the European 5-Dimensions 5-Level Quality of Life (EQ-5D-5L).

[0190] Pharmacokinetics: Plasma concentrations of d6-DM, its metabolites, and quinidine Q will be measured.

[0191] Safety and Tolerability: The safety and tolerability of AVP-786 will be assessed based on adverse event (AE) reports, physical and neurologic examination, vital signs, clinical laboratory evaluation, 12-lead resting electrocardiogram (ECG), Sheehan Suicidality Tracking Scale (S-STS), Mini-Mental State Examination (MMSE), and Timed Up and Go (TUG) test. Pregnancy testing should be performed in women of childbearing potential.

General statistical methods and types of analysis

[0192] Efficacy Analysis: The primary efficacy endpoint of this study is the change from baseline to week 12 (day 85) in the NPI Arousal/Aggression domain score. Treatment effects will be estimated using a mixed-effects linear repeated measures (MMRM) model based on observed likelihood. A stepwise gatekeeping approach will be used to control for overall type I error with a two-sided α=0.05 test for the 2 primary comparisons: AVP-786-28/4.9 versus placebo and AVP-786-18/4.9 versus placebo. Secondary efficacy endpoints include change from baseline to week 12 (day 85) in the following efficacy measures: CGIC agitation, NPI agitation/aggression domain score, caregiver distress score, NPI aberrant motor behavior domain score, ZBI, NPI irritability/lability domain score, PGIC, DEMQOL, CSDD, RUD, NPI total score, CGIS agitation, ADAS-cog, GMHR, and EQ-5D-5L.

[0193] Safety analysis: Safety outcome measures will be summarized by treatment group.

[0194] Sample Size Calculation: Power calculations were performed assuming a bivariate normal distribution for the primary efficacy endpoint of AVP-786-28/4.9 (high dose) compared to placebo. Based on the results of the Phase 2 study, the estimated treatment difference is -2.1 and the standard deviations are 4.7 (effect size -0.45). The overall attrition rate is 20%. The planned enrollment of 380 patients gives the study approximately 93% power to reject the null hypothesis of AVP-786-28/4.9 versus placebo, with a two-sided Type I error rate of 0.05. To control for the overall Type I error rate at the 0.05 level, the low dose AVP-786-18/4.9 null hypothesis will be tested only if the high dose null hypothesis is rejected.

Example 4: Phase 3 study: A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of AVP-786 (deuterated [d6]-dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for the treatment of agitation in patients with Alzheimer's type dementia.

[0195] The objective of this study is to evaluate the efficacy, safety, and tolerability of AVP-786 compared with placebo for the treatment of agitation in patients with Alzheimer's type dementia.

[0196] It is necessary to demonstrate maintenance of efficacy for a drug being developed to treat a chronic disease. Experts and regulatory authorities generally consider a treatment duration of 12 weeks to be a reasonable time to evaluate the acute and chronic effects and safety of a compound intended for chronic use. To ensure tolerability, patients in the treatment study (AVP-786) will be gradually exposed to a higher dose. The study will begin with once daily administration of a low dose (AVP-786-18/4.9) for one week, followed by twice daily administration of a low dose for 2 weeks, and then twice daily administration of a high dose (AVP-786-28/4.9) for the remainder of the 9-week study. Additionally, a single dose reduction will be allowed only in patients who demonstrate problems tolerating the high dose.

Study population

[0197] Number of Patients : The study will enroll approximately 325 patients at approximately 50 centers in the United States.

[0198] Condition/Disease: Patients with a symptom of agitation secondary to dementia of the Alzheimer's type. The diagnosis of probable Alzheimer's disease will be based on the criteria of the 2011 Diagnostic Guidelines for Alzheimer's Disease issued by the National Institute on Aging (NIA) and the Alzheimer's Association (AA) Working Group (McKhann GM et al., Alzheimers Dement. 2011; 7(3):263-269). The diagnosis of agitation will be based on the preliminary consensus definition of agitation in patients with cognitive impairment developed by the International Psychogeriatric Association (IPA) Agitation Definition Working Group (Cummings J et al, Int. Psychogeriatr. 2014:1-11).

[0199] Key inclusion criteria: At screening and for at least 2 weeks prior to randomization, patients have clinically significant, moderate/severe agitation that interferes with daily functioning and warrants prescription medication, in the opinion of the investigator. Eligibility requires a Clinical Global Impression of Illness (CGIS) agitation score ≥4 (moderate illness) at screening and baseline. Eligible patients must have a reliable caregiver who is able and willing to perform study procedures, including not administering any illicit drugs during the study.

[0200] Key exclusion criteria: Patients with dementia that is primarily not of the Alzheimer's type (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, chemical-induced dementia) and patients with agitation that is not secondary to Alzheimer's disease (e.g., dementia due to pain, another psychiatric disorder, or delirium) are not eligible for participation in the study.

Research plan

[0201] Design: Multicenter, randomized, double-blind, placebo-controlled, phase 3 study.

[0202] Duration: Patients will be enrolled in the study for approximately 16 weeks, with a screening period of 4 weeks and a treatment period of 12 weeks.

[0203] Investigational Treatment: The investigational product is AVP-786 (deuterated [d6]-dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]). Two doses of AVP-786 will be studied: d6-DM 28 mg/Q, 4.9 mg and d6-DM 18 mg/Q, 4.9 mg, hereinafter referred to as AVP-786-28/4.9 and AVP-786-18/4.9, respectively.

[0204] Composition of AVP-786: The qualitative and quantitative compositions of the 2 doses of study drug (SD) and placebo are shown in Table 9 below.

Table 9:

Ingredients
(amount in mg) AVP-786-28/4,9 AVP-786-18/4,9 AVP-786 Placebo dextromethorphan hydrobromide 28.00 18:00 0 Quinidine Sulfate USP,EP 4.90 4.90 0 sodium croscarmellose NF 6.60 6.60 6.60 microcrystalline cellulose NF 177.20 187.20 210.10 colloidal silicon dioxide NF 2.20 2.20 2.20 magnesium stearate NF 1.10 1.10 1.10 Total 220,0 220,0 220,0 Blue opaque capsules, size 3 (medium weight) 48.0 48.0 48.0 Total 268,0 268,0 268,0

EP=European Pharmacopoeia; USP=United States Pharmacopoeia; NF=National Formulary

[0205] Control: Placebo capsules identical in appearance to the study drug will be used as a control.

[0206] Randomization/stratification: Eligible patients will be randomized to receive either AVP-786 capsules or matching placebo capsules. Randomization will be stratified by Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain score (≤6 vs. >6), falls risk score (normal/moderate vs. moderate/high risk), and concomitant antipsychotic use (YES vs. NO).

[0207] Administration Regimen: Eligible patients will be randomly assigned at Visit 1 (baseline) to receive either AVP-786 capsules or matching placebo capsules. Study drug will be administered orally twice daily (1 capsule in the morning and 1 capsule in the evening, approximately 12 hours apart) for the duration of the study. Patients randomized to AVP-786 will begin receiving AVP-786-18/4.9 once daily in the morning and placebo in the evening for the first 7 days of the study. Beginning on Day 8, patients will receive AVP-786-18/4.9 twice daily for 14 days. Beginning on Day 22, patients will receive AVP-786-28/4.9 twice daily for the remaining 9 weeks of the study. If necessary, in the opinion of the investigator, a one-time dose reduction of AVP-786- 18/4.9 will be allowed after Visit 3 through Visit 5 (i.e., between Day 23 and Day 64), and the patient will remain on the lower dose of study drug for the remainder of the study. If a dose adjustment is necessary, patients will have an unscheduled visit for safety assessments. Patients will have at least a 50% chance of receiving AVP-786 at some point during the study.

Assessments and visits

[0208] Patients will visit study sites at screening, baseline (day 1), and on days 8 (week 1), 22 (week 3), day 43 (week 6), day 64 (week 9), and day 85 (week 12). Follow-up telephone calls to assess safety will be made on day 29 (week 4) and day 71 (week 10). Study procedures will be performed at each visit as outlined in the Visit and Assessment Schedule (Table 10).

Table 10: Schedule of visits and assessments

Procedure Visit: screening baseline visit 2 ¹ visit 3 ^1.14 phone call ^1,2,16 visit 4 ^1.16 visit 5 ^1.16 phone call ^1,2 visit 6 ¹
/ ET ^3.4 Day of the study: days from -28 to -1 day 1 day 8 day 22 day 29 day 43 day 64 day 71 day 85 Study end week: weeks from -4 to -1 week 1 week 3 week 4 week 6 week 9 week 10 Week 12 Informed Consent Form X Medical history X Eligibility Check ⁵ X X Randomization X Physical and neurological examination X X X Vital signs and body weight ⁶ X X X X X X X CGIS X X X X Fall risk assessment (logbook and TUG test) X X ⁷ X ⁷ ECG X X ⁸ X X ⁸ X X Adverse events (AE) X X X X X X X X Previous and concomitant medications X X X X X X X X X MMSE X X X X GMRHR X X NPI X ⁹ X X X X X X CSDD X X X ZBI Interview X X X X X DEMQOL ¹⁰ X X X EQ-5D-5L ¹⁰ X X X ADAS-cog ¹¹ X X X PGIC ¹² X X X X ADCS-CGIC Baseline Assessment X ADCS-CGIC X X X X RUD X X X S-STS X X X X X X X Dispensing the morning dose of study drug in the clinic X X ¹³ X X X X Biochemical, hematological tests; urine analysis X ¹⁴ X X Urine test for pregnancy ¹⁵ X X X X Blood sample for PK analysis X X Blood sample for CYP2D6 X Dispensing of study drug on prescription and patient diary X X X X Checking and returning unused study drug and patient diary X ¹³ X X X X

ADAS-cog - Alzheimer's Disease Rating Scale - cognitive subscale; ADCS-CGIC - Clinical Global Impression of Change; AE - adverse event; CGIS - Clinical Global Impression of Disease; CSDD - Cornell Dementia Depression Scale; DEMQOL - Dementia Quality of Life Scale; ECG - electrocardiogram; EQ-5D-5L - 5 dimensions of 5 levels of the EuroQol quality of life; ET - early termination; GMHR - general medical level of health; MMSE - Mini-Mental State Examination; NPI - Neuropsychiatric Questionnaire; PGIC - patient global impression of change rated by caregiver; PK - pharmacokinetics; RUD - resource use in dementia; S-STS - Sheehan Suicidality Tracking Scale; TUG - Timed Up and Go test; ZBI interview - interview with Dr. Zarit Burden.

1. Study visits are scheduled at +/- 3 day intervals, except for the Baseline Visit, Visit 2, and phone calls. The Baseline Visit, Visit 2, and phone calls are scheduled at +3 day intervals.

2. A telephone call should be made to the patient/caregiver to collect information on adverse events and to inquire about the use of concomitant medications.

3. An early termination visit is performed by patients who withdrew from the study before its completion.

4. Patients who withdraw early from the study or do not enter the extension study (Study 15-AVP-786-303) receive a telephone call regarding the safety of the study drug 30 days after the last dose of study drug.

5. A protocol compliance form is completed for each patient.

6. Body weight should be measured only at the baseline visit.

7. To assess the risk of falls at visits 4 and 6, only the TUG test should be performed.

8. ECG should be recorded before and after administration of the dose.

9. The NPI assessment for the arousal/aggression domain only should be performed at the screening visit. This assessment should be performed prior to the CGIS assessment.

10. The proxy version should be assessed by a caregiver. The non-proxy version should only be assessed by patients who scored ≥10 on the MMSE at baseline.

11. ADAS-cog assessment is performed only in patients who scored ≥10 points on the MMSE scale at baseline.

12. The PGIC assessment must be carried out by a carer.

13. The study drug should be taken from the blister pack opened by the patient. The blister pack and patient diary should be returned to the patient/caregiver after compliance has been verified.

14. Thyroid function tests (TSH and T3 and T4 reflex if TSH levels are abnormal) should be performed during the screening visit.

15. Urine pregnancy testing should only be performed on women of childbearing age.

16. A one-time downward dose adjustment is permitted after Visit 3 (Week 3) up to and including Visit 5 (Week 9), i.e., from Day 23 to Day 64. The patient is required to return to the study site for an unscheduled visit for safety assessment.

Reaction measurements

[0209] Primary efficacy measurement: Primary efficacy will be assessed using the NPI Arousal/Aggression domain.

[0210] Secondary efficacy measures: Secondary efficacy measures include the Clinical Impression of Change Global Score (CGIC) for agitation, NPI Agitation/Aggression Domain Score for Caregiver Distress, NPI Aberrant Motor Behavior Domain Score, Zarit Burden Interview (ZBI), NPI Irritability/Lability Domain Score, Patient Global Impression of Change (PGIC, carer-rated), Dementia Quality of Life (DEMQOL), Cornell Dementia Depression Scale (CSDD), Resource Use in Dementia (RUD), NPI Total Score, CGIS Agitation, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), General Medical Health Rating (GMHR), and the European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L).

[0211] Pharmacokinetics: Plasma concentrations of d6-DM, its metabolites, and quinidine Q will be measured.

[0212] Safety and Tolerability: The safety and tolerability of AVP-786 will be assessed based on adverse event (AE) reports, physical and neurologic examination, vital signs, clinical laboratory evaluation, 12-lead resting electrocardiogram (ECG), Sheehan Suicidality Tracking Scale (S-STS), Mini-Mental State Examination (MMSE), and Timed Up and Go (TUG) test. Pregnancy testing should be performed in women of childbearing potential.

General statistical methods and types of analysis

[0213] Population Analysis: Three population analyses will be used: a modified intent-to-treat (mITT) analysis, an intent-to-treat (ITT) analysis, and a safety analysis. The mITT population analysis includes all patients randomized into the study who have had at least one efficacy assessment after baseline and will be used for all efficacy analyses. Patients in the mITT population analysis will be included in the treatment group to which they were randomized, regardless of the treatment they received. The ITT population analysis includes all patients randomized into the study and will be used for the exploratory efficacy analyses. The safety population analysis includes all patients who received the study drug and will be used for all safety analyses. Patients will be assigned to treatment groups based on the treatment they actually received.

[0214] Efficacy analysis: The primary efficacy endpoint of this study is the change from baseline to week 12 (day 85) in the NPI Arousal/Aggression domain score. Treatment comparisons will be conducted using a mixed-effects linear repeated measures (MMRM) model. This model will include fixed effects for treatment, visit, an interaction with the effect of the factor treatment by visit, an interaction with the effect of the factor treatment by baseline condition, and baseline covariates that include baseline value and other randomization stratification factors. An unstructured covariance model will be used. Secondary efficacy endpoints include change from baseline to week 12 (day 85) in the following efficacy measures: CGIC agitation, NPI agitation/aggression domain score, caregiver distress score, NPI aberrant motor behavior domain score, ZBI, NPI irritability/lability domain score, PGIC, DEMQOL, CSDD, RUD, NPI total score, CGIS agitation, ADAS-cog, GMHR, and EQ-5D-5L.

[0215] Safety Analysis: The safety analysis will consist of summarized data on biological parameters and adverse events (AEs). The safety analysis results will be tabulated by treatment group.

[0216] Sample size calculation: Power calculations were performed assuming a bivariate normal distribution for the primary efficacy endpoint. The treatment effect size for the primary efficacy measure in the completed Phase 2 study was -0.51 in Phase 1 and -0.34 in Phase 2. For this single-stage, 12-week study, the treatment effect size (AVP-786 versus placebo) is assumed to be -0.40. The planned overall sample size of 325 patients (~163/group) would result in a study power of 90%, with a type I error rate of 2-sided α=0.05, assuming a 20% attrition rate during the study.

Example 5: A multicenter, long-term, phase 3 extension study of the safety and efficacy of AVP-786 (deuterated [d6] dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for the treatment of agitation in patients with Alzheimer's type dementia.

[0217] The objective of this study is to evaluate the long-term safety and maintenance of efficacy of AVP-786 for the treatment of agitation in patients with Alzheimer's type dementia.

Study population

[0218] Number of Patients : The study will enroll approximately 550 patients at approximately 110 centers in the United States.

[0219] Condition/Disease: Patients with agitation secondary to dementia of the Alzheimer's type. The diagnosis of probable Alzheimer's disease will be based on the criteria in the 2011 Diagnostic Guidelines for Alzheimer's Disease issued by the National Institute on Aging (NIA)/Alzheimer's Association (AA) Task Force (McKhann GM et al., Alzheimers Dement. 2011; 7(3):263-269). The diagnosis of agitation will be based on the preliminary consensus definition of agitation in patients with cognitive impairment developed by the International Psychogeriatric Association (IPA) Agitation Definition Task Force (Cummings J et al, Int. Psychogeriatr. 2014:1-11).

[0220] Primary inclusion criteria: Patient has successfully completed study 15-AVP-786-301, 15-AVP-786-302, or 12-AVR-131. Eligible patients must have a trusted caregiver who is able and willing to comply with all required study procedures, including not administering any prohibited drugs during the study.

[0221] Key exclusion criteria: Patient is currently participating in or has previously participated in another interventional clinical trial (drug or device) since exiting studies 15-AVP-786-301 and 15-AVP-786-302, or within 30 days prior to baseline for patients in study 12-AVR-131. Patients with concomitant, clinically significant, or unstable systemic diseases that may confound the interpretation of safety results from the study.

Research plan

[0222] Design: A Phase 3, multicenter, long-term extension study of Phase 3 Studies 15-AVP-786-301 and 15-AVP-786-302 that may also enroll patients from Phase 2 Study 12-AVR-131. Patients from Studies 15-AVP-786-301 and 15-AVP-786-302 will be enrolled into this study within 3 days of their last visit (Visit 6, Day 85) in the prior study. Although all patients enrolled in the study will receive AVP-786, the treatment dose assignment will be concealed from the patient, investigator, study staff, and sponsor.

[0223] Duration: Patients will be enrolled in the study for approximately 52 weeks.

[0224] Investigational Drug: The investigational product is AVP-786 (deuterated [d6]-dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]). Two doses of AVP-786 will be evaluated in a titration assay: d6-DM 28 mg/Q, 4.9 mg and d6-DM 18 mg/Q, 4.9 mg, hereinafter referred to as AVP-786-28/4.9 and AVP-786-18/4.9, respectively.

[0225] Composition of AVP-786: The qualitative and quantitative composition of the 2 doses of study drug are listed below in Table 11.

Table 11:

Ingredients
(amount in mg) AVP-786-28/4,9 AVP-786-18/4,9 ¹ dextromethorphan hydrobromide 28.00 18:00 Quinidine Sulfate USP,EP 4.90 4.90 sodium croscarmellose NF 6.60 6.60 microcrystalline cellulose NF 177.20 187.20 colloidal silicon dioxide NF 2.20 2.20 magnesium stearate NF 1.10 1.10 Total 220,0 220,0 Blue opaque capsules, size 3 (medium weight) 48.0 48.0 Total 268,0 268,0

EP=European Pharmacopoeia; USP=United States Pharmacopoeia; NF=National Formulary

1 - A blister pack of AVP-786-18 at a dose of 4.9 will contain AVP-786 placebo capsules as the evening dose on days 1 through 7.

[0226] Control: None

[0227] Treatment Allocation: Eligible patients were assigned to receive either AVP-786-28/4.9 capsules or blinded AVP-786-18/4.9 capsules based on their last treatment in the previous study (15-AVP-786-301 and 15-AVP-786-302) and the investigator's assessment of dose adjustment. Study drug will be administered via a web-based interactive response system (IWRS).

[0228] Patients who received placebo in previous studies and patients from Study 12-AVR-131 will receive AVP-786-18/4.9 in this study. Patients previously treated with AVP-786-18/4.9 will be given the same dose if no dose adjustment is required, or AVP-786-28/4.9 if the investigator deems a dose increase necessary. Patients previously treated with AVP-786-28/4.9 will either continue to receive AVP-786-28/4.9 or will be given lower doses of AVP-786-18/4.9 at the discretion of the investigator.

[0229] Administration regimen : Study drug will be administered orally twice daily (1 capsule in the morning and 1 capsule in the evening, approximately 12 hours apart) for the duration of the study. Patients who received placebo in previous studies and patients in Study 12-AVR-131 will be assigned to receive AVP-786 placebo capsules in the evening on Days 1 through 7, and will receive AVP-786-28/4.9 twice daily beginning on Day 22 (Week 3) thereafter unless a dose adjustment is required. At the discretion of the investigator, the dose of study drug may be reduced at any time during the study for safety reasons.

Assessments and visits

[0230] There are 8 scheduled visits in the study. Patients will visit the study site for baseline (day 1), day 15 (week 2), day 43 (week 6), day 85 (week 12), day 169 (week 24), day 253 (week 36), day 337 (week 48), and day 365 (week 52). Follow-up safety assessment telephone calls will be made on day 29 (week 4), day 127 (week 18), day 211 (week 30), and day 295 (week 42). Patients requiring dose adjustments may have unscheduled safety assessment visits at the discretion of the investigator. Study procedures will be performed at each visit as outlined in the Visit and Assessment Schedule (Table 12).

Table 12:

Procedure Visit: baseline visit 2 ¹ phone call ² visit 3 ² visit 4 ² phone call ² visit 5 ¹ phone call ² visit 6 ² phone call ² visit 7 ² visit 8 ²
/ ET ^3.4 Day of research: day 1 day 8 day 29 day 43 day 85 day 127 day 169 day211 day 253 day 295 day 337 day 365 Study end week: week 1 week 4 week 6 week 12 week 18 week 24 week 30 week 36 week 42 week 48 week 52 Informed Consent Form X ⁵ Medical history X ⁶ Eligibility Check ⁵ Fall risk assessment (logbook and TUG test) X ⁶ X ⁷ X ⁷ Eligibility Check ⁸ X ⁶ Allocation to treatment groups ⁹ X Physical and neurological examination X ⁴ X Vital signs and body weight ¹⁰ X ⁶ X X X X X X X CGIS X ⁶ X X X X X ECG ¹¹ X ¹² X X X X X X X Adverse events (AE) X X X X X X X X X X X X Previous and concomitant medications X X X X X X X X X X X X MMSE X ⁶ X X X X X GMRHR X ⁶ X NPI X ⁶ X ¹³ X X ¹³ X ¹³ X CSDD X ⁶ X X ZBI X ⁶ X X X X X EQ-5D-5L ¹⁴ X ⁶ X X DEMQOL ¹⁰ X ⁶ X X ADAS-cog ¹⁵ X ⁶ X X PGIC ¹⁶ X ⁶ X X X X X ADCS-CGIC Baseline Assessment X ⁶ ADCS-CGIC X X X X X RUD X ⁶ X X IAD X X X S-STS X ⁶ X X X X X X X Dispensing the morning dose of study drug in the clinic X X ¹⁹ X X X X X X Biochemical, hematological tests; urine analysis X
^6.17 X X X X X X X Urine test for pregnancy ¹⁸ X ⁶ X X X X X X X Dispensing of study drug on prescription and patient diary X X X X X X X Checking and returning unused study drug and patient diary X ¹⁹ X X X X

ADAS-cog - Alzheimer's Disease Rating Scale - cognitive subscale; ADCS-CGIC - Clinical Global Impression of Change; AE - adverse event; CGIS - Clinical Global Impression of Disease; CSDD - Cornell Dementia Depression Scale; DEMQOL - Dementia Quality of Life Scale; ECG - electrocardiogram; EQ-5D-5L - 5 dimensions of 5 levels of the EuroQol quality of life; ET - early termination; GMHR - general medical level of health; MMSE - Mini-Mental State Examination; NPI - Neuropsychiatric Questionnaire; PGIC - patient global impression of change rated by caregiver; PK - pharmacokinetics; RUD - resource use in dementia; S-STS - Sheehan Suicidality Tracking Scale; TUG - Timed Up and Go test; ZBI interview - interview with Dr. Zarit Burden; IADL - Instrumental Activities of Daily Living Scale.

1. The baseline visit must occur within 3 days of patient exit from study 15-AVP-786-301 or 15-AVP-786-302.

2. Visit 2 (Day 15) and Visit 3 (Day 43) and the phone call on Day 29 are conducted at intervals of +/- 3 days. All other visits and phone calls in the study are at intervals of +/- 7 days.

3. An early termination visit is performed by patients who withdrew from the study before its completion.

4. For patients who discontinue the study early: The patient/caregiver should be contacted by telephone within 5 days of the early discontinuation to inquire about the patient's general well-being. Additionally, a follow-up telephone call will be made to all patients 30 days after the last dose.

5. Informed consent may be signed at the exit visit from studies 15-AVP-786-301 and 15-AVP-786-302, for patients transferring from these studies.

6. Procedures should only be performed on patients from study 12-AVR-131.

7. Only the TUG test should be performed to assess fall risk during visits 5 and 8.

8. For each patient, a protocol eligibility form will be completed, which includes a check of inclusion/exclusion criteria.

9. Patients will be assigned to receive AVP-786 d6DM 28 mg/Q 4.9 mg or d6DM 18 mg/Q 4.9 mg using the IWRS.

10. Body weight should be measured only at the baseline visit.

11. ECG should be performed 2-3 hours after dose administration.

12. For patients in study 12-AVR-131, ECG should be recorded pre- and post-dose.

13. At Visits 4, 6, and 7, the NPI assessment should be conducted for the Arousal/Aggression domain only. This assessment should be completed prior to the CGIS assessment.

14. The proxy version should be assessed by a caregiver. The non-proxy version should only be assessed by patients who scored ≥10 on the MMSE at baseline.

15. ADAS-cog assessment is performed only in patients who scored ≥10 points on the MMSE scale at baseline.

16. The PGIC assessment must be carried out by a carer.

17. Thyroid function tests (TSH and T3 and T4 reflex if TSH values are abnormal) should also be performed at the baseline visit only for patients included in study 12-AVR-131.

18. Urine pregnancy testing should only be performed on women of childbearing age.

19. The study drug should be taken from the blister pack opened by the patient. The blister pack and patient diary should be returned to the patient/carer after compliance has been verified.

Reaction measurements

[0232] Safety and Tolerability: The safety and tolerability of AVP-786 will be assessed based on adverse event (AE) reports, physical and neurologic examination, vital signs, clinical laboratory evaluation, 12-lead resting electrocardiogram (ECG), Sheehan Suicidality Tracking Scale (S-STS), Mini-Mental State Examination (MMSE), and Timed Up and Go (TUG) test. Pregnancy testing should be performed in women of childbearing potential.

[0233] Efficacy: Efficacy will be assessed by the NPI, the Clinical Global Impression of Change (CGIC) for agitation, the Zarith Burden Interview (ZBI), the Patient Global Impression of Change (PGIC, assessed by the caregiver), the Dementia Quality of Life (DEMQOL), the Cornell Depression Scale in Dementia (CSDD), the Resource Use in Dementia (RUD), the General Medical Health Rating (GMHR), the European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L), and the Instrumental Activities of Daily Living (IADL) scale.

General statistical methods and types of analysis

[0234] Population Analysis: A population-based safety analysis will be used, including all patients who received study drug for all efficacy and safety pooled data. Three treatment groups will be included in the safety and efficacy studies: AVP-786-28/4.9, AVP-786-18/4.9, and all patients combined. No treatment comparisons will be performed.

[0235] Safety analysis: Safety and tolerability outcome measures including AE reports, vital signs, clinical laboratory assessments, 12-lead resting ECG, S-STS, MMSE, ADAS-cog, and TUG will be summarized using descriptive statistics and/or frequency tables.

[0236] Efficacy analyses: Summary statistics will be provided for the observed efficacy data obtained at each visit. Observed baseline values and change from baseline will be presented where applicable.

[0237] Sample size calculation: A sample size of 550 patients included in the study will ensure adequate exposure to the study drug to meet regulatory requirements.

Example 6: A single-center, open-label, sequential, phase 1 drug-drug interaction study between AVP-786 (deuterated [d6] dextromethorphan hydrobromide [DM]/quinidine sulfate [Q]) and paroxetine, and between AVP-786 and duloxetine in healthy subjects.

[0238] The primary objectives of this study were to determine the effect of AVP-786 (d6-DM/Q) on the steady-state pharmacokinetics of paroxetine in healthy subjects; to determine the effect of AVP-786 on the steady-state pharmacokinetics of duloxetine in healthy subjects; and to determine the effect of paroxetine and duloxetine on the steady-state pharmacokinetics of AVP-786 in healthy subjects. Secondary objectives of the study were to evaluate the safety and tolerability of AVP-786 administered concomitantly with paroxetine and duloxetine to healthy subjects. Paroxetine and duloxetine are antidepressants that may have potential use in patients with Alzheimer's disease.

[0239] Two studies were conducted to investigate the PK, safety, and tolerability of d6-DM. Study 12-AVR-132 was a randomized, double-blind, single-dose, multiple-dose, Phase 1 study to evaluate the plasma pharmacokinetics of single and multiple oral doses of AVP786, alone and in combination with quinidine (Q), in healthy subjects. Study 13-AVR-134 was a single-center, randomized, open-label, Phase 1 study to evaluate the pharmacokinetics, safety, and tolerability of AVP-786 in healthy subjects.

Research methodology

[0240] This study was a single center, open-label, sequential design to determine the effect of AVP-786 on the PK of paroxetine and duloxetine, and the effect of paroxetine and duloxetine on the PK of AVP-786. Fifty-six subjects were assigned to one of 4 treatment groups in this study:

Group 1: n=14

- paroxetine 20 mg once daily, days 1-20

- AVP-786-30/4.75 (d6-DM 30 mg/Q, 4.75 mg), twice daily, day 13 - until morning of day 20

Group 2: n=14

- AVP-786-30/4.75 (d6-DM 30 mg/Q, 4.75 mg), twice daily, day 1 until morning of day 20.

- paroxetine 20 mg once daily, days 9-20

Group 3: n=14

- duloxetine 20 mg, twice daily, day 1 until morning of day 13

- AVP-786-30/4.75 (d6-DM 30 mg/Q, 4.75 mg), twice daily, day 6 until morning of day 13

Group 4: n=14

- AVP-786-30/4.75 (d6-DM 30 mg/Q, 4.75 mg), twice daily, day 1 until morning of day 13

- Duloxetine 20 mg, twice daily, day 9 until the morning of day 13.

[0241] Volunteers attended the study center for a screening visit during the 14 days prior to dosing (Day 1). If eligible, they were assigned to one of 4 treatment groups on Day 1 (Day 1 occurred on different days for different treatment groups to ensure bed availability on those days). Subjects reported to the clinic daily for outpatient dosing until Day 2 (morning), when PK samples were collected (this day varied among treatment groups). Following Day 2 (morning) PK sample collection, subjects were admitted to the clinic the night before (full) PK sample collection the following day. Subjects remained in the inpatient unit until the final day of PK sample collection (the length of time varied between treatment groups based on the amount of time it took for study drug to reach steady state).

[0242] Samples were collected for PK assessment up to 36 hours after the last dose of study drug. All samples were assayed for d6-DM, d3-dextrorphan (d3-DX), quinidine, paroxetine, and duloxetine, depending on the assay.

[0243] Safety assessments were performed in all subjects throughout the study. These assessments included adverse event (AE) reports, electrocardiograms (ECGs), laboratory data, physical examinations, and vital signs. The Columbia Suicide Severity Rating Scale (C-SSRS) was used to prospectively assess suicidal ideation and behavior throughout the study.

[0244] Patients returned for a follow-up safety visit 7-10 days after the last dose of study drug.

Planned (and analyzed) number of subjects

[0245] Group 1: planned n=14; participants n=14 (safety study group); analyzed n=11 (PK study group).

Group 2: planned n=14; participants n=14 (safety study group); analyzed n=14 (PK study group).

Group 3: planned n=14; participants n=14 (safety study group); analyzed n=14 (PK study group).

Group 4: planned n=14; participants n=14 (safety study group); analyzed n=11 (PK study group).

Diagnosis and inclusion criteria

[0246] Healthy adult men and women aged 18 to 50 years inclusive with a body mass index (BMI) of 18 to 300 kg/ ^m2 who have the CYP2D6 genotype, which is characterized by extensive metabolism.

Investigational drugs

[0247] Test products: AVP-786-30/4.75 capsules (d6-DM 30 mg/Q 4.75 mg). Paroxetine 20 mg tablets. Duloxetine 20 mg capsules. Subjects received study drug according to the study plan described in the Methods paragraph above.

[0248] Each dose (consisting of one capsule/tablet) was taken orally with 240 mL of room temperature water. The morning dose was administered without food (except water) overnight (i.e., for at least 8 hours), and the evening dose was administered at least 2 hours after a meal. After each dose, no food (except water) was consumed for at least 2 hours after dosing.

Evaluation criteria

[0249] Safety. Safety assessments were performed in all subjects throughout the study. These assessments included adverse event (AE) reports, electrocardiograms (ECGs), laboratory data, physical examinations, and vital signs. The Columbia Suicidal Severity Rating Scale (C-SSRS) was used to prospectively assess suicidal ideation and behavior throughout the study as part of the safety assessment in accordance with the FDA's Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials guideline.

[0250] Pharmacokinetics: Blood samples (6 mL for single-drug administration and 12 mL for combination drug administration) for plasma d6-DM, DX-d3, quinidine, paroxetine, and duloxetine determination were collected at the following time points:

[0251] Before and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose on the last day of single-drug administration. For Group 1 only: Because paroxetine was administered once daily, an additional sample was collected 24 hours after the last day of single-drug administration (before the first combination administration).

[0252] Before administration and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 36 hours after administration of the morning dose on the last day of combination administration.

[0253] Before the morning administration on day 4 (for groups 2 and 4 only) and on each of the two days before the last day of single-drug administration and on the last day of combination administration.

[0254] Non-compartmental methods were used to determine pharmacokinetic parameters, including AUC _0-12 , AUC _0-24 , C _max , T _max , kel, t _½ , C _min , and T _min .

Statistical methods

[0255] Safety: Safety variables including adverse event rates, vital signs, ECG parameters, and clinical laboratory data were summarized by treatment. Responses to the C-SSRS questionnaire were reported for each subject. Individual subject profiles are provided to address any questions regarding abnormal response.

[0256] Pharmacokinetics: Descriptive statistics for plasma concentrations of d6-DM, DX-d3, quinidine, and paroxetine or duloxetine (when applicable) were tabulated for each time point by treatment. Mean plasma concentration-time profiles were plotted by treatment on a linear and semi-logarithmic scale. Additionally, non-compartmental PK parameters were derived. Comparisons between combination treatments (Arm 1 vs. Arm 2, AVP-786 and paroxetine, Arm 3 vs. Arm 4, AVP-786 and duloxetine) were presented as geometric mean ratios of C _max and AUC _0-12 (AUC _0-24 for paroxetine) with 90% confidence intervals. Point estimates and confidence limits were determined using log-log data and then back-transformed to the original scale. The analysis was performed using analysis of variance between subjects and treatments.

Results

[0257] Pharmacokinetics:

[0258] Paroxetine and AVP-786 Interaction: Mean plasma concentrations of various analytes after multiple dose administration over time and by treatment group are shown in Figures 7 and 8. Mean values (CV%) by treatment and analyte (# median (range) for T _max ) are presented in Table 13.

Table 13:

Analyte Treatment N
(n for t _1/2 ) C _max (ng/ml) T _max ^# (watch) AUC _0-12
(PAR: AUC _0-24 )
(hours*ng/ml) t _1/2 (watch) d6-DM group 1, day 20 11 (3) 93.5 (21%) 2.00 (2.00-4.00) 943 (22%) 18.5 (4.8%) group 2, day 8 14 (0) 54.6 (30%) 3.00 (2.00-4.00) 467 (36%) NA group 2, day 20 14 (4) 100 (34%) 3.00 (1.00-8.00) 1027 (37%) 17.3 (20%) d3-DX group 1, day 20 11 (0) 87.2 (22%) 1.00 (0.00-4.00) 820 (21%) NA group 2, day 8 14 (0) 117 (22%) 3.00 (0.00-3.00) 1142 (23%) NA group 2, day 20 14 (0) 94.1 (45%) 0.50 (0.00-2.00) 820 (23%) NA Quinidine (Q) group 1, day 20 11 (10) 24.2 (41%) 1.03 (1.00-3.00) 163 (48%) 6.97 (31%) group 2, day 8 14 (13) 23.1 (40%) 1.00 (0.50-2.00) 146 (38%) 4.80 (15%) group 2, day 20 14 (14) 28.3 (34%) 1.00 (0.50-2.00) 191 (34%) 8.47 (31%) Paroxetine (PAR) group 1, day 12 11 (0) 29.5 (39%) 4.00 (3.00-8.00) 452 (42%) NA group 1, day 20 11 (2) 42.8
(32%) 4.00 (2.00-6.00) 712 (35%) 19.2 (8.7%) group 2, day 20 14 (8) 48.0 (36%) 4.00 (3.00-6.00) 768 (40%) 16.8 (16%)

NA=not rated

[0259] Comparison of combination administration with single drug administration using log-transformed ANOVA (Table 14):

Table 14:

Analyte N Parameter LS value ratio CI 90% of the ratio of LS values Paroxetine (PAR) 11
(group 1) C _max (ng/ml) 149.4% [135.5-164.7] AUC _0-24 (hour*ng/ml) 163.7% [141.7-189.2] d6-DM 14
(group 2) C _max (ng/ml) 180.7% [163.0-200.3] AUC _0-24 (hour*ng/ml) 217.9% [193.1-246.0] d3-DX 14
(group 2) C _max (ng/ml) 77.1% [67.1-88.4] AUC _0-24 (hour*ng/ml) 71.6% [66.2-77.5] Quinidine (Q) 14
(group 2) C _max (ng/ml) 125.3% [110.2-142.5] AUC _0-24 (hour*ng/ml) 132.5% [118.7-148.0]

LS - values = root mean square

CI 90% = 90% confidence interval

[0260] Interaction of duloxetine and AVP-786: Mean plasma concentrations of various analytes after multiple dose administration over time and by treatment group are shown in Figures 9 and 10. Mean values (CV%) by treatment and analyte (# median (range) for T _max ) are presented in Table 15.

Table 15:

Analyte Treatment N
(n for t _1/2 ) C _max (ng/ml) T _max ^# (watch) AUC _0-12
(PAR: AUC _0-24 )
(hours*ng/ml) t _1/2 (watch) d6-DM group 3, day 13 14 (13) 72.7 (31%) 4.00 (2.00-8.00) 692 (34%) 13.3 (14%) group 4, day 8 11 (0) 59.0 (36%) 3.00 (2.00-4.00) 540 (46%) NA group 4, day 13 11 (11) 66.8 (31%) 3.00 (2.00-4.00) 605 (34%) 12.6 (24%) d3-DX group 3, day 13 14 (1) 128 (17%) 3.00 (0.00-8.00) 1295 (16%) 21.7
(NA) group 4, day 8 11 (0) 127 (30%) 3.00 (0.00-4.00) 1267 (30%) NA group 4, day 13 11 (3) 121 (27%) 3.00 (0.00-12.00) 1224 (27%) 20.5 (5.2%) Quinidine (Q) group 3, day 13 14 (14) 25.5 (31%) 2.00 (1.00-4.03) 191 (32%) 7.39 (36%) group 4, day 8 11 (11) 24.9 (46%) 1.00 (0.50-3.00) 160 (44%) 5.19 (13%) group 4, day 13 11 (10) 25.5 (43%) 2.00 (0.50-3.08) 168 (43%) 6.59 (39%) Duloxetine (DUL) group 3, day 5 14 (8) 26.1 (46%) 4.00 (3.00-6.00) 194 (46%) 5.04 (14%) group 3, day 13 14 (14) 41.9
(35%) 3.50 (3.00-6.00) 345 (38%) 11.1 (15%) group 4, day 13 11 (11) 51.4 (37%) 4.00 (3.00-6.00) 419 (46%) 11.4 (22%)

NA=not rated

[0261] Comparison of combination administration with single drug administration using log-transformed ANOVA (Table 16):

Table 16:

Analyte N Parameter LS value ratio CI 90% of the LS-value ratio Duloxetine (DUL) 14
(group 3) C _max (ng/ml) 167.6% [151.5-186.1] AUC _0-12 (hour*ng/ml) 184.0% [167.5-202.1] d6-DM 11
(group 4) C _max (ng/ml) 113.9% [106.8-121.4] AUC _0-12 (hour*ng/ml) 114.8% [108.9-121.0] d3-DX 11
(group 4) C _max (ng/ml) 96.3% [90.1-102.9] AUC _0-12 (hour*ng/ml) 97.6% [91.8-103.7] Quinidine (Q) 11
(group 4) C _max (ng/ml) 103.1% [91.0-116.8] AUC _0-12 (hour*ng/ml) 105.4% [99.5-111.6]

LS - values = root mean square

CI 90% = 90% confidence interval

[0262] Security:

[0263] There were no deaths. One subject (subject R112, paroxetine/AVP-786) experienced 2 concomitant serious adverse events (SAEs): hypokalemia and hypochloremia following administration of paroxetine 20 mg once daily (days 1-16) and AVP-786-30/4.75 twice daily (days 13-16). Both events are considered moderate AEs. The subject reported dizziness associated with orthostatic hypotension on day 15 and bilateral leg weakness with tingling on day 16. To further evaluate clinical symptoms, blood tests and an ECG were obtained on day 17 and revealed hypokalemia, metabolic alkalosis, and QTc prolongation. Symptoms were completely resolved with fluid and electrolyte replacement. Based on the clinical review of the details of these SAEs by the applicant and an independent assessment by a cardiologist, it is concluded that the clinical picture is not consistent with the known drug effects of either paroxetine or AVP-786.

[0264] There were 4 early withdrawals from the study among subjects due to AEs including suicidal ideation (subject R107, after 8 doses of paroxetine), hypokalemia and hypochloremia (subject R112, see above), urinary tract infection (subject R411, after 12 doses of AVP-786), and vomiting (subject R412, after 9 doses of AVP-786).

[0265] Interaction between paroxetine and AVP-786:

[0266] In Cohorts 1 and 2, treatment-emergent adverse events were reported in 7 of 14 patients (50%) following paroxetine (within 12 days of administration), 9 of 14 patients (64%) following AVP-786 (within 8 days of administration), 10 of 12 patients (83%) following paroxetine/AVP-786 combination (within 8 days of administration), and 13 of 14 patients (93%) following AVP-786/paroxetine combination (within 12 days of administration).

[0267] The majority of AEs (104 of 115 AEs, 90%) were considered possibly or probably related to study treatment. The most common treatment-emergent adverse events were dizziness and postural dizziness, headache, diarrhea, nausea, nightmares, and attention disturbances. Nightmares and attention disturbances were reported only by patients receiving the combination of paroxetine and AVP-786. Dizziness was reported more frequently with the combination treatment compared with paroxetine or AVP-786 alone. Of note, headache and nausea were reported only in patients receiving paroxetine or the combination of paroxetine and AVP-786, but not in patients receiving AVP-786 alone.

[0268] Most AEs were classified as minor in severity and no serious adverse events (SAEs) were identified. Moderate adverse events considered related to study treatment were suicidal ideation, hypokalemia and hypochloremia, and depression.

[0269] Interaction between duloxetine and AVP-786:

[0270] In Cohorts 3 and 4, treatment-emergent adverse events were reported in 6 of 14 patients (43%) following duloxetine (within 5 days of administration), 7 of 14 patients (50%) following AVP-786 (within 8 days of administration), 7 of 14 patients (50%) following duloxetine/AVP-786 combination (within 8 days of administration), and 5 of 11 patients (45%) following AVP-786/duloxetine combination (within 5 days of administration).

[0271] The majority of AEs (40 of 50 AEs, 80%) were considered to be related (possibly or probably related) to study treatment. The most common treatment-related adverse events were weakness and muscle stiffness. No common, frequently occurring AEs were observed in subjects following the combination of AVP-786 and duloxetine compared to duloxetine or AVP-786 alone. Of note, weakness was observed only in subjects following AVP-786 administration as a single agent in Cohort 4, but was not observed following AVP-786 administration in Cohort 2.

[0272] Most AEs were classified as minor in severity, with one serious adverse event (SAE). The moderate serious adverse event that was considered related to study treatment was vomiting (1 subject, AVP-786). Moderate adverse events considered related to study treatment were vomiting, cold sweat, headache, dizziness, and lower abdominal pain.

[0273] In the pooled AE data, there were no differences in severity between treatment groups for each treatment group. There were no apparent differences in safety as assessed by clinical laboratory tests, vital signs, or ECG results between treatments.

Conclusions

[0274] There are no clinically significant differences in safety assessments for multiple-dose combinations of AVP-786 with paroxetine or duloxetine compared to multiple-dose combinations of either drug alone.

[0275] Steady-state systemic exposure to paroxetine was significantly increased (up to approximately 150%) when co-administered with AVP-786, compared to paroxetine alone. Significant changes in steady-state systemic exposure to the AVP-786 analytes were observed when co-administered with paroxetine, compared to AVP-786 administered alone, with an approximately two-fold increase in systemic exposure to d6-DM and a significant decrease in d3-DX (up to approximately 75%), suggesting a decreased rate of conversion of d6-DM to d3-DX when AVP-786 was administered in combination with paroxetine. A moderate increase (up to approximately 130%) in systemic exposure to quinidine was observed.

[0276] Steady-state systemic exposure to duloxetine was significantly increased (approximately 180%) when co-administered with AVP-786, compared to duloxetine administered alone.

No significant changes in steady-state systemic exposure to AVP-786 analytes were observed when co-administered with duloxetine compared to AVP-786 administered alone.

Claims (10)

1. A method for treating agitation and/or aggression and/or related symptoms in a patient with dementia, comprising administering to a patient in need thereof deuterated dextromethorphan and quinidine, wherein deuterated dextromethorphan is administered orally in an amount of 10 mg to 200 mg per day and quinidine is administered orally in an amount of 0.05 mg to 50 mg per day, and deuterated dextromethorphan and quinidine are administered in amounts sufficient to reduce the subject's Modified Alzheimer's Disease Collective Study - Clinical Global Assessment of Change (ADCS - CGIC) score for agitation by at least 0.5-fold compared to untreated subjects or subjects when administered a placebo, and/or to reduce the Patient Global Assessment of Change (PGI-C) score for agitation by at least 0.6-fold compared to untreated subjects or subjects when administered a placebo. introduction of placebo. 2. The method according to claim 1, wherein the type of dementia is Alzheimer's disease. 3. The method according to claim 1 or 2, comprising administering deuterated dextromethorphan in an amount of 18 mg and administering quinidine in an amount of 4.9 mg. 4. The method according to claim 1 or 2, comprising administering deuterated dextromethorphan in an amount of 28 mg and administering quinidine in an amount of 4.9 mg. 5. The method according to claim 1 or 2, comprising administering deuterated dextromethorphan in an amount of 42 mg and administering quinidine in an amount of 4.9 mg. 6. The method according to claim 1 or 2, comprising administering deuterated dextromethorphan in an amount of 43 mg and administering quinidine in an amount of 4.9 mg. 7. The use of deuterated dextromethorphan and quinidine for the treatment of agitation and/or aggression and/or related symptoms in a patient with dementia, wherein deuterated dextromethorphan is administered orally in an amount of 10 to 200 mg per day and quinidine is administered orally in an amount of 0.05 to 50 mg per day, and deuterated dextromethorphan and quinidine are administered in amounts sufficient to reduce the subject's Modified Alzheimer's Disease Collective Study - Clinical Global Assessment of Change (ADCS - CGIC) score for agitation by at least 0.5-fold compared to untreated subjects or subjects on placebo, and/or to reduce the Patient Global Assessment of Change (PGI-C) score for agitation by at least 0.6-fold compared to untreated subjects or subjects on placebo. 8. The use according to claim 7, wherein the type of dementia is Alzheimer's disease. 9. The use of deuterated dextromethorphan and quinidine for the preparation of a medicament for the treatment of agitation and/or aggression and/or related symptoms in a patient with dementia, wherein deuterated dextromethorphan is administered orally in an amount of 10 to 200 mg per day and quinidine is administered orally in an amount of 0.05 to 50 mg per day, and deuterated dextromethorphan and quinidine are administered in amounts sufficient to reduce the subject's Modified Alzheimer's Disease Collective Study - Clinical Global Assessment of Change (ADCS - CGIC) score for agitation by at least 0.5-fold compared to untreated subjects or subjects when administered placebo, and/or to reduce the Patient Global Assessment of Change (PGI-C) score for agitation by at least 0.6-fold compared to untreated subjects or subjects when administered placebo. 10. The use according to claim 9, wherein the type of dementia is Alzheimer's disease.