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WO2018189671A1 - Utilisation de lik066 chez les patients souffrant d'insuffisance cardiaque - Google Patents

Utilisation de lik066 chez les patients souffrant d'insuffisance cardiaque Download PDF

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Publication number
WO2018189671A1
WO2018189671A1 PCT/IB2018/052497 IB2018052497W WO2018189671A1 WO 2018189671 A1 WO2018189671 A1 WO 2018189671A1 IB 2018052497 W IB2018052497 W IB 2018052497W WO 2018189671 A1 WO2018189671 A1 WO 2018189671A1
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Prior art keywords
lik066
treatment
study
patients
week
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Inventor
Deborah Lynn KEEFE
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Novartis AG
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Novartis AG
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Priority to JP2018559339A priority Critical patent/JP2019517459A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to pharmaceutical uses of LIK066, their pharmaceutically acceptable salts, and prodrugs thereof specifically for the treatment of heart failure.
  • Type 2 diabetes is a serious condition associated with high risk of cardio -vascular disease (CVD), and its complications, such as heart failure (HF).
  • CVD cardio -vascular disease
  • HF heart failure
  • both the incidence rate of HF and hospitalizations/mortality are higher than in patients without diabetes (Nichols et al, 2004; Kazsnicki et al, 2014).
  • the poor prognosis in patients with T2DM and HF has been attributed to increased myocardial hypertrophy, myocardial fibrosis and abnormal cardiac metabolism (Kazsnicki et al, 2014), which may contribute to the development of myocardial ischemia, worsening of ventricular dysfunction, and arrhythmias (Taegtmeyer et al, 2002).
  • HF HF is associated with recurrent hospitalizations and increased mortality rates (Chun et al, 2012).
  • MRAs mineralocorticoid receptor antagonists
  • ACEi angiotensin converting enzyme- inhibitors
  • ARBs angiotensin II receptor blockers
  • SGLT 2 inhibitors Sodium-glucose co-transporter (SGLT) 2 inhibitors are approved for the treatment of type 2 diabetes.
  • long-term treatment with the SGLT2 inhibitor empagliflozin in the EMPA
  • LIK066 is an inhibitor of SGLT1 and SGLT2. Via inhibition of both SGLT1 and SGLT2 in the proximal renal tubule, the drug may further enhance the effects on renal sodium and glucose handling compared with the selective SGLT2 inhibitors.
  • SGLT1 is expressed in the small intestine where it is required for glucose and galactose absorption. Inhibition of enteric SGLT1 results in glucose and galactose malabsorption (Turk et al, 1991 ) which leads to calorie wasting and other potential endocrine-based weight loss mechanisms.
  • LIK066 is planned for investigation in obese and overweight patients as a weight loss drug (calorie-loss enhancer).
  • BMI body-mass index
  • SGLT1 receptors are expressed in the heart, and it is believed that administration of LIK066 may ameliorate, treat or improve the symptoms associated with those individuals which exhibit comprised cardiac function.
  • a method for the treatment or prevention of heart failure in a subject in need of such treatment which comprises administering to said subject a therapeutically effective amount of an a inhibitor of SGLT1 and SGLT2, e.g. LIK066, or a pharmaceutically acceptable salt thereof.
  • the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.
  • the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.
  • the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of heart failure.
  • a method for the treatment or prevention of heart failure in a subject with Type 2 Diabetes which comprises administering to said subject a therapeutically effective amount of LIK066, or a
  • the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure in a patient with Type 2 diabetes.
  • the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure in a patient with Type 2 diabetes.
  • the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of heart failure in a patient with Type 2 Diabetes.
  • FIG. 1 depicts the study design.
  • FIG. 2 depicts the assessment schedule.
  • FIG. 3 depicts the assessment schedule.
  • FIG. 4 depicts the assessment schedule.
  • FIG. 5 depicts the assessment schedule.
  • the invention is a method for the treatment or prevention of heart failure, including heart failure with preserved ejection fraction and heart failure with reduced ejection fraction in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of LIK066, or a pharmaceutically acceptable salt thereof.
  • the invention is the method according to the first embodiment, wherein about 2.5 mg of LIK066 is administered. In a third embodiment, the invention is the method according to the first embodiment, wherein 10 mg of LIK066 is administered.
  • the invention is the method according to the first embodiment, wherein 50 mg of LIK066 is administered.
  • the invention is the method according to any one of the first through fourth embodiments, wherein LIK066 is administered once a day.
  • the invention is the method according to any one of the first through fifth embodiments, wherein LIK066 is administered at bedtime.
  • the invention is the method according to any one of the first through sixth embodiments, wherein the subject is at least 18 years old. In an eighth embodiment, the invention is the method according to any one of the first through seventh embodiments, wherein the subject has a BMI > 22kg/m 2 .
  • the invention is the method according to any of first through eighth embodiments, wherein the subject has Type 2 diabetes with HbA1 c between 7.0% and 10.0%.
  • the invention is the method according to any of the first through ninth embodiments, wherein the subject has documented symptomatic chronic heart failure (NYHA ll-IV) with at least one of following symptoms selected from, Dyspnea on exertion, Orthopnea, Paroxysmal nocturnal dyspnea and Peripheral edema.
  • the invention is the method according to any one of the first through tenth embodiments, wherein the subject has plasma NT-proBNP > 400 pg/ml.
  • the invention is the method according to any one of the first through eleventh embodiments, wherein the subject is concurrently receiving a medication selected from, ACEi, ARBs, MRAs, ARNi and/or ⁇ -blockers and is on a stable dose of said medication.
  • the invention is the method according to any one of the first through twelfth embodiments, wherein the subject is on diuretic therapy.
  • the invention is the method according to any one of the first through thirteenth embodiments, wherein the subject has controlled systolic BP of less than 140mmHG.
  • the invention is the method according to any one of the first through fourteenth embodiments, wherein the subject has an eGFR > 45ml/min/1 .73m 2 . In a sixteenth embodiment, the invention is the method according to any one of the first through fifteenth embodiments, wherein the subject has serum potassium ⁇ 5.2mM.
  • the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.
  • the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.
  • the invention is the pharmaceutical composition according to the eighteenth embodiment, wherein the compositions comprises 2.5 mg, 10mg, or 50 mg of LIK066.
  • the invention is the pharmaceutical composition according to the eighteenth or nineteenth embodiment, wherein the pharmaceutical composition is administered once a day.
  • the invention is the pharmaceutical composition according to any one of the nineteenth or twentieth embodiments, wherein the subject has a BMI > 22kg/m 2 .
  • the invention is the pharmaceutical composition of any of eighteenth through twenty-first embodiments, wherein the subject has Type 2 diabetes, particularly to any individual with an HbA1 c between 7.0% and 10.0%.
  • the invention is the pharmaceutical composition of any of the eighteenth through the twenty-second embodiments, wherein the subject has documented symptomatic chronic heart failure (NYHA ll-IV) with at least one of following symptoms selected from, Dyspnea on exertion, Orthopnea, Paroxysmal nocturnal dyspnea and Peripheral edema.
  • NYHA ll-IV documented symptomatic chronic heart failure
  • the invention is the pharmaceutical composition of any one of the eighteenth through twenty-third embodiments, wherein the subject is concurrently receiving a medication selected from, ACEi, ARBs, MRAs, diuretics, ARNi and/or ⁇ -blockers, or combinations therefo and is on a stable dose of said medication.
  • the invention is the pharmaceutical composition of any one of the eighteenth through twenty-fourth embodiments, wherein the subject has controlled systolic BP of less than 140mmHG.
  • the invention is the pharmaceutical composition of any one of the eighteenth through twenty-fifth embodiments, wherein the subject has an eGFR > 45ml/min/1 .73m 2 .
  • the invention is the pharmaceutical composition of any one of the eighteenth through twenty-sixth embodiments, wherein the subject has serum potassium ⁇ 5.2mM.
  • the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of heart failure.
  • the invention is the medicament according to the twenty- eighth embodiment, wherein the compositions comprises 2.5 mg, 10mg, or 50 mg of LIK066.
  • the invention is the medicament is for use in the treatment of heart failure in a subject with Type 2 diabetes, particularly to any individual with an HbAl c between 7.0% and 10.0%.
  • the invention comprises LIK066 for use in the treatment of heart failure.
  • the invention comprises LIK066 for use in the treatment of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • the invention comprises LIK066 for use in the treatment of heart failure with reduced ejection fraction (HFrEF).
  • HFrEF reduced ejection fraction
  • the invention comprises LIK066 for use in the treatment of heart failure in a subject with T2D, particularly to any individual with an HbAl c between 7.0% and 10.0%.
  • the invention comprises LIK066 for use in the treatment of heart failure with preserved ejection fraction (HFpEF) in a subject with T2D, particularly to any individual with an HbAl c between 7.0% and 10.0%.
  • HFpEF preserved ejection fraction
  • the invention comprises LIK066 for use in the treatment of heart failure with reduced ejection fraction (HFrEF) in a subject with T2D, particularly to any individual with an HbAl c between 7.0% and 10.0%.
  • HFrEF reduced ejection fraction
  • the invention is the use according to any of the thirty-first through thirty-sixth embodiemtns, wherein the compositions comprises 2.5 mg, 10mg, or 50 mg of l_IK066.
  • the invention is a pharmaceutical unit dose comprising 2.5 mg, 10mg, or 50 mg of LIK066.
  • a "pharmaceutically acceptable salt” is intended to mean a salt of a free base/free acid of a compound represented by formula (I) that is not toxic, biologically intolerable, or otherwise biologically undesirable.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
  • LIK066 is an inhibitor of the sodium-glucose co-transporter-1 (SGLT1 ) and sodium-glucose has the following chemical structure:
  • LIK066 has the following lUPAC name: (2S,3R,4R,5S,6R)-2-(3-((2,3- dihydrobenzo[b][1 ,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol.
  • LIK066 for use in the present invention is either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof.
  • LIK066 including its salts can also be obtained in the form of its hydrates, or include other solvents used for its crystallization. LIK066 may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • LIK066, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
  • the higher oral bioavailability of LIK066 may give rise to the following beneficial effects relating to less bioavailable compounds: (i) an enhanced biological effect may be achieved after oral administration; (ii) an earlier onset of action may be observed following oral administration; (iii) a lower dose may be needed to achieve the same effect; (iv) a higher effect may be achieved by the same dose or (v) a prolonged action may be observed at the same dose.
  • subject typically refers to a human, especially to a human patient diagnosed with heart failure or to a human patient suffering from heart failure associated with Type 2 diabeted.
  • treatment refers to any type of treatment that imparts a benefit to a subject affected with heart failure.
  • Heart failure often referred to as congestive heart failure (CHF) occurs when the heart is unable to pump sufficiently to maintain blood flow to meet the body's needs. Signs and symptoms commonly include shortness of breath, excessive tiredness, and leg swelling. The shortness of breath is usually worse with exercise, while lying down, and may wake the person at night. A limited ability to exercise is also a common feature. Chest pain, including angina, does not typically occur due to heart failure.
  • CHF congestive heart failure
  • heart failure due to left ventricular pressure
  • Heart failure is not the same as myocardial infarction (in which part of the heart muscle dies) or cardiac arrest (in which blood flow stops altogether).
  • Other diseases that may have symptoms similar to heart failure include obesity, kidney failure, liver problems, anemia, and thyroid disease.
  • the condition is diagnosed based on the history of the symptoms and a physical
  • the appropriate dosage will vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in are indicated to be obtained at a daily dosage of from about 0.01 to about 100 mg/kg body weight, preferably from about 1 to about 30 mg/kg body weight, e.g. 10 mg/kg.
  • An indicated daily dosage is in the range from about 0.1 to about 1000 mg, preferably from about 1 to about 100 mg, most preferably from about 1 to about 75 mg of LIK066 conveniently administered, for example, in a single dose once a day. In one embodiment, about 2.5mg of LIK066 is administered once a day. In another embodiment, about 10mg of LIK066 is administered once a day. In yet another embodiment, about 50mg of LIK066 is administered once a day.
  • LIK066 may be administered in any usual manner, e.g. orally, for example in the form of tablets, capsules or drinking solutions; rectally, for example in the form of suppositories; intravenously, for example in the form of injection solutions or suspensions; or transdermal, for example in the form of a patch.
  • the manner of administration is oral administration, for example in the form of a tablet, capsule or drinking solution. In one embodiment, the manner of
  • administration is rectal administration, for example in the form of a suppository.
  • the manner of administration is transdermal administration, for example in the form of a patch.
  • the manner of administration is oral administration.
  • Preferred pharmaceutical compositions comprise LIK066 in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner.
  • Unit dosage forms may contain LIK066 in an amount greater than or equal to 2.5mg, for example greater than or equal to 10mg, such as for example greater than or equal to 50mg.
  • Unit dosage forms may also contain LIK066 in an amount of greater than or equal to 2.5mg, 10mg, 40mg, 50mg, 75mg or 10Omg or greater than or equal to 150mg or 200mg.
  • Unit dosage forms may contain LIK066 in an amount less than or equal to 100mg, for example less than or equal to 100mg, such as for example less than or equal to 50 mg or for example less than or equal to 10mg or for example less than or equal to 2.5mg.
  • Unit dosage forms may also contain LIK066 in an amount in the range from 1 -100mg, e.g. 1 -75mg or 1 - 60mg such as 2-55mg.
  • compositions according to the invention are compositions for enteral administration, such as oral or rectal administration; or parenteral administration, such as intramuscular, intravenous, and nasal or transdermal administration, to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier.
  • the dose of the active ingredient depends on the species of warmblooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • compositions comprise from approximately 1 % to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
  • compositions for transdermal administration are described in Remington's Pharmaceutical Sciences 16 th Edition Mack; Sucker, Fuchs and Spieser, Pharmazeutician Technologie, 1 st Edition, Springer.
  • Control drug Drugs(s) used as a comparator to reduce assessment bias, preserve blinding of investigational drug, assess internal study validity, and/or evaluate comparative effects of the investigational drug.
  • Dosage Dose of the study treatment given to the patient in a time unit (e.g. 100 mg once a day, 75 mg twice a day).
  • Epoch A portion of the study which serves a specific purpose. Typical epochs are:
  • Patient ID A unique number assigned to each patient upon signing the informed consent Randomization number A unique identifier assigned to each randomized patient,
  • Study drug/ treatment Any single drug or combination of drugs administered to the patient as part of the required study procedures; includes investigational drug
  • Study Treatment Discontinuation When the patient permanently stops taking study treatment prior to the defined study treatment completion date.
  • Variable A measured value or assessed response that is determined in specific
  • Wthdrawal of consent Wthdrawal of consent from the study is defined as when a
  • Epoch 2 Placebo run-in
  • Epoch 2 Patients meeting the eligibility criteria enter the placebo run-in (Epoch 2). During the 2 weeks duration of Epoch 2, patients receive single-blind placebo run-in medication. At Visit 101 , the patients' volume status is assessed based on physical examination and laboratory values and, if hypovolemic, corrected during the run-in.
  • eligible patients are randomized in a 1 :1 :2:2:2 ratio to one of the following regimens at Visit 201 (randomization): LIK066 2.5mg qd at bedtime; LIK066 10mg qd at bedtime; LIK066 50mg qd at bedtime; Empagliflozin (up-titrated from 10mg qd to 25mg qd after 2 weeks) in the morning; and Placebo LIK066 at bedtime/Placebo Empagliflozin in the morning.
  • patients are stratified based on geographical region and the left ventricular ejection fraction (LVEF) measurement at Visit 101 : ⁇ 45% versus > 45%.
  • LVEF left ventricular ejection fraction
  • Rationale for study design The study is designed as a standard randomized, controlled, parallel-group study.
  • a single- blind placebo run-in epoch (Epoch 2) is included to familiarize patients with the study drug intake schedule and correct hypovolemia (if diagnosed at Visit 101 ).
  • the effect on NT- proBNP is evaluated after 12 weeks of treatment in Epoch 3, as well as after 36 weeks of the study (Epoch 4) to provide information about the longer-term effect of LIK066 on NT- proBNP, and on clinical and echocardiography parameters. Glycemic control is assessed after 12 and 36 weeks of treatment
  • LIK066 has been studied in multiple clinical trials with a variety of dosing regimens using either single or multiple daily doses at durations of up to 12 week in healthy subjects, patients with T2DM and obese patients.
  • pharmacodynamic effects such as 24 hour urinary glucose excretion (UGE24) and body weight have been observed in these populations.
  • Pharmacodynamic data from phase I studies in patients with T2DM showed that the minimal tested dose, 2.5mg qd, resulted in 24 hour urinary glucose excretion (glucosuria) of approximately 37g, and is considered appropriate as the minimally effective dose in this study.
  • LIK066 50mg qd is selected as the highest dose for this study.
  • the 50mg dose represents a dose potentially at the maximal end of the UGE dose-response curve in patients with T2DM and would be suitable to be tested in this vulnerable population.
  • Gastrointestinal (Gl) tolerability was better with LIK066 30mg qd than with 150 mg qd.
  • the 10mg dose is selected between the low and top dose in the study and to enable exploration of the shape of the dose-response curve.
  • sacubitril/valsartan with valsartan e.g. LCZ696B2214; Solomon et al, 2012
  • treatment with LIK066 for a duration of 12 weeks would be expected to be sufficient in order to reveal a significant change in NT-proBNP. Twelve weeks after introducing an anti-diabetic treatment is an accepted time point for initial evaluation of drugs' effect on glycemic control
  • a placebo group is included to obtain efficacy, tolerability and safety data in an unbiased manner and to determine the dose-response characteristics of the investigational drug.
  • An active comparator empagliflozin which is approved in the treatment of T2DM to improve glycemic control, is included as a reference drug (Zinman et al, 2015). Empagliflozin has also shown CV benefit in T2DM patients in the EMPA-REG Outcome study. Considering that the mechanism leading to the CV benefit with empagliflozin currently remains unclear, the higher of the two approved doses in patients with T2DM, empagliflozin 25mg qd, was chosen as a comparator to potentially achieve a maximum effect on NT-proBNP.
  • the study population consists of male and female patients (>18 years old) with type 2 diabetes and heart failure (heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF)).
  • HFpEF heart failure with preserved ejection fraction
  • HFrEF heart failure with reduced ejection fraction
  • Patients eligible for inclusion in this study must fulfill all of the following criteria: 1 .
  • Written informed consent must be obtained before any assessment is performed; 2.
  • Male or female outpatients > 18 years of age at Visit 1 ; 3.
  • BMI > 22kg/m2 at Visit 1 ; 4.
  • Type 2 diabetes with HbA1 c between 7.0% and 10.0% at Visit 1 ; 5.
  • Documented symptomatic chronic heart failure (NYHA ll-IV) with at least one of the following symptoms at the time of Visit 1 :( Dyspnea on exertion; Orthopnea; Paroxysmal nocturnal dyspnea; and Peripheral edema); 6.
  • Plasma NT-proBNP > 400pg/ml at Visit 1 ; 7.
  • Controlled systolic BP defined as a target systolic BP less than 140mmHg; systolic BP up to and including 160mmHg if patient is on three or more medications to control BP, at randomization (Visit 201); 10. eGFR > 45ml/min/1 .73m2 at Visit 1 (calculated by the Modification of Diet in Renal Disease formula (MDRD)); and 1 1 . Serum potassium ⁇ 5.2mM at Visit 1 .
  • ECG electrocardiogram
  • Concomitant clinically significant cardiac arrhythmias e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV -block without a pacemaker; History of familial long QT syndrome or known family history of torsades de pointes; and Atrial fibrillation with a resting heart rate >100 beats per minute (bpm).
  • Basic contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug.
  • Type 1 diabetes monogenic diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes (e.g. Cushing's syndrome or acromegaly-associated diabetes).
  • Ketoacidosis, lactic acidosis, or hyperosmolar coma within 6 months of Visit 1 , or between Visit 1 and Visit 201 (randomization).
  • Ml Myocardial infarction
  • PCI percutaneous coronary intervention
  • Dyspnea and/or edema from non-cardiac causes, such as lung disease, anemia, or severe obesity.
  • cardiomyopathy such as restrictive cardiomyopathy or infiltrative cardiomyopathy (e.g., amyloid disease).
  • ICD cardioverter defibrillator
  • liver steatosis except liver steatosis, such as hepatitis, cirrhosis or portal hypertension at Visit 1 or Visit 201 (randomization).
  • CYP3A4 inhibitors e.g. clarithromycin, telithromycin,
  • TSH thyroid stimulation hormone
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Platelet count ⁇ 100,000/ ⁇ and/or white blood cell (WBC) count ⁇ 4000/ ⁇ at Visit 1 (screening).
  • WBC white blood cell
  • patients eligible for randomization are assigned to one of the following 5 treatment arms in Epoch 3 (treatment) in a ratio of 1 :1 :2:2:2.5mg qd LIK066; 10mg qd LIK066; 50mg qd LIK066; 10mg qd empagliflozin up-titrated to 25mg qd after 2 weeks; and Placebo qd.
  • Epoch 4 Epoch 4 (treatment)
  • patients continue to receive the treatment they were assigned to in Epoch 3.
  • Treatment assignment and randomization At Visit 201 all eligible patients are randomized via Interactive Response Technology (IRT) to one of the treatment arms.
  • IRT Interactive Response Technology
  • the investigator or his/her delegate contacts the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria.
  • the IRT assigns a randomization number to the patient, which is used to link the patient to a treatment arm and will specify a unique medication number for the first package of study drug to be dispensed to the patient.
  • the randomization number is not communicated to the user of the IRT system.
  • the randomization numbers are generated using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff.
  • a patient randomization list is produced by the IRT provider using a validated system that automates the random assignment of patient numbers to randomization numbers. These randomization numbers are linked to the different treatment arms, which in turn are linked to medication numbers.
  • a separate medication list is produced by or under the
  • Randomization is stratified according to geographical region and LVEF ( ⁇ 45% versus > 45% at Visit 101)).
  • Randomization data are kept strictly confidential until the time of unblinding, and are not accessible by anyone else involved in the study with the following exceptions: the randomization codes associated with patients from whom PK samples are taken will be disclosed to PK analysts who will keep the PK results confidential until database lock and 2.
  • the identity of the treatments will be concealed by the use of study drug that are all identical in packaging, labeling, schedule of administration, appearance, taste and odor. A double dummy design will be used as the identity of the study drugs cannot be disguised due to their different forms.
  • Unmasking will only occur in the case of patient emergencies, at the time of the Week 12 analysis and at the conclusion of the study.
  • the analysis group (statisticians/programmers), who are unmasked to perform the Week 12 analysis, are not involved in any study conduct activities related to the study Week 12 to Week 36 period (Epoch 4) after the unmasking.
  • a separate analysis group who does not have access to the analysis results and the identity of treatments at Week 12 analysis, performs the pre-planned final analysis at the end of the study.
  • the core study team (including the study leader(s), study physician and data manager), who are directly involved in study conduct activities during the study Week 12 to Week 36 period (Epoch 4), do not have access to the patient level data with identity of treatments such as patient listings at Week 12 analysis.
  • Each patient is uniquely identified in the study by a combination of his/her center number and patient number.
  • the center number is assigned by Novartis to the investigative site.
  • the patient is assigned a patient number by the investigator.
  • the first patient is assigned patient number 1
  • subsequent patients/subjects are assigned consecutive numbers (e.g. the second patient is assigned patient number 2; the third patient is assigned patient number 3).
  • the investigator or his/her staff contacts the IRT and provide the requested identifying information for the patient to register them into the IRT.
  • the assigned patient number must be entered in the field labeled "Patient ID" on the EDC data entry screen (e.g. enter , '2', etc.).
  • the patient number is not reused. If the patient fails to be randomized for any reason, the IRT must be notified within 2 days that the patient was not randomized. The reason for not being randomized will be entered on the Screening Log, and the Demography eCRF is completed. Dispensing the study drug
  • Each study site is supplied with study drug in packaging of identical appearance.
  • the study drug packaging has a 2-part label. A unique randomization number is printed on each part of this label which corresponds to one of the treatment arms.
  • Investigator staff identify the study drug package(s) to dispense to the patient by contacting the IRT and obtaining the medication number(s). Immediately before dispensing the package to the patient, investigator staff detach the outer part of the label from the packaging and affix it to the source document (Drug Label Form) for that patient's unique patient number.
  • Study treatment must be received by a designated person at the study site, handled and stored safely and properly, and kept in a secured location to which only the investigator and designees have access. Upon receipt, all study treatment must be stored according to the instructions specified on the labels. Clinical supplies are dispensed only in accordance with the protocol. Technical complaints are reported to the respective Novartis CPO Quality Assurance. Medication labels are in the local language and comply with the legal requirements of each country. They include storage conditions for the study treatment but no information about the patient except for the medication number. The investigator maintains an accurate record of the shipment and dispensing of study treatment in a drug accountability log. Monitoring of drug accountability is performed by monitors during site visits or remotely and at the completion of the trial. Patients are asked to return all unused study treatment and packaging at each study visit and where applicable, at the time of discontinuation of study treatment.
  • the investigator returns all unused study treatment, packaging, drug labels, and a copy of the completed drug accountability log to the Novartis monitor or to the Novartis address provided in the investigator folder at each site.
  • the patients have to take study medication, 1 capsule in the morning, with or without food, and 1 tablet at bedtime. All prescribed dosages and all dose changes during the study are recorded on the appropriate study drug Dosage Administration Record eCRF. All kits of study treatment assigned by the IRT are recorded/databased in the IRT.
  • the investigator should encourage compliance with study medication by instructing the patient to take the study drug exactly as prescribed to maintain the validity of the study and to optimize any potential effect of the study drug regimen.
  • the patient is instructed to contact the investigator if he/she is unable for any reason to take the study drug regimen as prescribed. Permitted dose adjustments and interruptions of study treatment Investigational dose adjustments and/or interruptions are not permitted, unless done for safety reasons.
  • rescue medication may be used in addition to ongoing study medication for those patients whose glycemic control is deteriorating.
  • the patient must come in for an unscheduled visit to have a sample drawn for FPG & HbA1 c measurement performed by the central laboratory if: Self-measured FPG on three consecutive occasions exceeds the limits in Table 5-1 ; and The FPG result from a blood sample analyzed at the central laboratory exceeds the limits described in Table 1 .
  • the background OAD should be initially escalated to the maximal approved dose, followed by addition of rescue medication.
  • Rescue medication preferably insulin, should be used according to the local label and must be provided locally. Rescued patients will continue to participate in the study to allow for assessment of exposure and safety of LIK066. Use of rescue medication must be recorded on the Rescue Medication eCRF.
  • the investigator must instruct the patient to notify the study site about any new medications he/she takes after the patient was enrolled into the study. All medications, procedures and significant non-drug therapies (including physical therapy and blood transfusions) administered after the patient was enrolled into the study must be recorded in the
  • Concomitant Medications/Surgical and Medical Procedures eCRF Every effort should be made by the Investigator to keep the dose level of each patient's allowed background heart failure medications stable throughout the entire study duration. However; if the clinical condition of the patient warrants a change in any of these medications, it is allowed at the discretion of the study Investigator. Each concomitant drug must be individually assessed against all exclusion criteria/prohibited medication. If in doubt the investigator should contact the Novartis medical monitor before randomizing a patient or allowing a new medication to be started.
  • Emergency code breaks are only undertaken when it is required to in order to treat the patient safely. Most often, study treatment discontinuation and knowledge of the possible treatment assignments are sufficient to treat a study patient who presents with an emergency condition.
  • Emergency treatment code breaks are performed using the IRT.
  • the investigator contacts the system to break a treatment code for a patient, he/she must provide the requested patient identifying information and confirm the necessity to break the treatment code for the patient.
  • the investigator then receives receive details of the investigational drug treatment for the specified patient and communication confirming this information.
  • the system automatically informs the Novartis monitor for the site and the Study Team that the code has been broken. It is the investigator's responsibility to ensure that there is a dependable procedure in place to allow access to the IRT system at any time in case of emergency.
  • the investigator provides the protocol number, the study drug name (if available) and the patient number.
  • oral and written information to the patient is provided on how to contact the investigator ' s backup in cases of emergency, or when the investigator is unavailable, to ensure that un-blinding can be performed at any time. Patients whose treatment has been unmasked must be discontinued from study treatment.
  • a patient is considered to have completed the study when the patient has completed the last planned visit (see Figures 2-5).
  • the study as a whole is considered completed when all randomized subjects have completed the last visit planned in the protocol or have discontinued the study prematurely.
  • the investigator must provide follow-up medical care for all subjects who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care.
  • Figures 2-5 list all of the study visits and assessments and indicates with an "X" when the assessments are performed. Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely discontinue the study for any reason should be scheduled for a visit as soon as possible, at which time all of the assessments listed for the final visit will be performed. At this final visit, all dispensed investigational product should be reconciled and the adverse event and concomitant medications reconciled on the eCRF. Patients will be contacted for safety evaluations during the 30 days following the last administration of study treatment.
  • Demographic and BL characteristics data collected on all randomized patients include: year of birth, age, sex, race, ethnicity, relevant medical history/current medical conditions present before signing informed consent including smoking and alcohol history. Where possible, diagnoses and notable symptoms are recorded. Investigators have the discretion to record abnormal test findings on the medical history eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent form (ICF) signature.
  • ICF informed consent form
  • Compliance is assessed by the investigator and/or study personnel at each visit using pill counts and information provided by the patient. This information is captured in the source documents at each visit. All study treatment dispensed and returned must be recorded in the Drug Accountability Log. The site is also required to complete the appropriate Dosage Administration Record eCRF to record any study drug regimen changes or interruptions.
  • Body weight is measured to the nearest 0.1 kg at visits indicated in Figures 2-5 on a calibrated scale. The measurement is performed with the study patient in underwear and without shoes. Voiding before weight measurement is required. Height is measured at Visit 1 and is used to automatically calculate BMI.
  • NT-proBNP N-proBNP
  • NT-proBNP is measured from a blood sample obtained after an overnight fast (at least 8 hours after last evening food intake) at visits indicated in Figures 2-5 and analyzed at a central laboratory. NT-proBNP measured at Visit 1 is used for assessing an inclusion criterion and will not be masked. The results of all other NT-proBNP measurements remain masked until final database lock, except that they are extracted to a restricted area for the statistical/programming team to perform the analysis at the Week 12 database lock.
  • Body composition is measured in all patients using bio-impedance, except in patients where it is contra-indicated, e.g. those using an implantable cardioverter-defibrillator, at visits indicated in Figure 2.
  • a DXA scan ise performed at visits indicated in Figures 2-5.
  • a whole body DXA scan is acquired to assess body composition (lean body mass, fat mass, visceral fat mass, body water (calculated); in addition bone mineral density (BMD) is assessed.
  • BMD bone mineral density
  • the exam takes approximately 10-15 minutes and is non-invasive. In order to assure quality throughout the study, the DXA instrument manufacturer and model should remain consistent at a site and its calibration should be monitored.
  • DXA is performed according to the procedures described in the Imaging Manual. Prior to the examination, the patient is checked for absence of removable metal objects on his/her body, such as snaps, belts, underwire bras, jewelry, and so on. The patient is then positioned so that his/her body is straight on the mat and the site personnel must ensure that the positioning is consistent from scan to scan. A whole body array scan is then initiated on the patient. Immediately after the whole body scan, a DXA scan is acquired to measure lumbar spine, hip and/or distal forearm bone mineral density. DXA data is transferred to a central reading vendor for independent review and analysis.
  • HF signs and symptoms are reviewed at visits indicated in Figures 2-5.
  • the signs and symptoms evaluation may include paroxysmal nocturnal dyspnea, fatigue, edema, dyspnea at rest, dyspnea upon effort, orthopnea, rales, jugular venous distention, presence of a third heart sound.
  • NYHA classification will be assessed and scored at each visit, and the results are entered in the appropriate eCRF.
  • Echocardiography is performed at visits indicated in Figures 2-5. A subset of a standard echocardiographic two-dimensional and Doppler examination are performed. The images are sent to a central reading vendor for independent review and analysis.
  • Echocardiography Manual with detailed instructions and data transfer procedures is provided to the study sites.
  • the following echocardiographic assessments are performed: Left ventricular ejection fraction (LVEF); Left ventricular end systolic volume (LESV); Left ventricular end diastolic volume (LEDV); Left atrial size and volume; Tricuspid regurgitation (TR) velocity; Left ventricular mass (LVM); Mitral inflow pulsed wave Doppler (E wave, A wave); and Isovolumetric relaxation time (IVRT).
  • LVEF Left ventricular ejection fraction
  • LESV Left ventricular end systolic volume
  • LEDV Left ventricular end diastolic volume
  • TR Tricuspid regurgitation
  • RVM Left ventricular mass
  • E wave, A wave Mitral inflow pulsed wave Doppler
  • IVRT Isovolumetric relaxation time
  • HbA1 c is measured from a blood sample obtained at visits indicated in Figures 2-5 and analyzed using a National Glycohemoglobin Standardization Program (NGSP) certified method at a central laboratory.
  • NGSP National Glycohemoglobin Standardization Program
  • FPG is measured from a blood sample obtained after an overnight fast (at least 8h after last evening food intake) at visits indicated in Figures 2-5 and analyzed at a central laboratory.
  • BP measurements and one standing BP measurement are performed at visits indicated in Figures 2-5. Every effort should be made to have the same staff member obtain BP measurements for a given patient, at the same time of day, using the same equipment, at each visit. Sitting BP and standing measurements must be performed prior to any procedure (e.g. blood draw) or medication intake. At Visit 1 (screening) BP must be measured at both arms. The arm with the higher SBP reading must be used for the BP measurements at Visit 1 and the same arm must be used at all subsequent visits. The arm used at each visit must be documented in the source documentation. The patient should be in a relaxed setting and measurements should not be taken immediately after exertion or the consumption of coffee.
  • SBP and DBP are measured three times using the automatic BP monitor and an appropriate size cuff.
  • the bladder of the cuff should be large enough to encircle 80% of the arm.
  • the cuff should be placed so its bottom is 1 to 2cm above the elbow and the arm should be supported so that the bottom of the cuff is at the level of the heart.
  • the tube should run down the center of the arm, approximately in line with the middle finger. The patient is asked to relax his/her arm and turn the palm upward. The patient should not speak or move their arm during the measurement deflation of the cuff.
  • Three separate sitting BP should be obtained with a full two-minute interval between measurements and with the cuff fully deflated between measurements.
  • the patient then stands, and after standing for two minutes, one BP measurement is taken. All 3 sitting BP measurements and the single standing measurement are recorded and documented in the eCRF and in the patient's source documents. All 3 sitting BP readings are used for evaluation of sitting BP.
  • UGE, albumin, creatinine and sodium excretion are measured from a 24h urinary collection from about 25% of randomized patients at visits indicated in Figures 2-5 and analyzed at a central laboratory. UGE results after the baseline assessment are kept blinded until the final analysis, except that they are extracted to a restricted area for the statistical/programming team to perform the analysis at the Week 12 database lock.
  • Bone biomarkers urinary calcium and phosphate excretion
  • renal biomarkers cystatin
  • C/creatinine ratio are measured from the same urine collection. Detailed instructions for urine collection is provided to patients, and handling of the urine sample is described in the laboratory manual. 24h urine collection is done by the patients at home; therefore no overnight stay at the site is required.
  • N-terminal pro-brain natriuretic peptide is a stable, biologically inert fragment cleaved from proBNP along with BNP.
  • NT-proBNP is a marker of left ventricular wall stress. Elevated NT-proBNP levels are associated with adverse outcomes and reductions in NT- proBNP levels have been associated with better outcomes in patients with HF (Masson et al 2006; Komajda et al 201 1).
  • Echocardiography, weight and body composition, BP and fasting lipids are standard measures to assess the efficacy of a drug used in HF patients.
  • HbA1 c and FPG inform about the glucose lowering effect of the drug.
  • UGE measurement allows for evaluation of LIK066's primary mode of action's contribution to potential improvement in glycemic control and HF parameters.
  • Novartis staff (or CRO working on behalf of Novartis) review the data entered into the eCRFs by investigational staff for completeness and accuracy and instruct the site personnel to make any required corrections or additions. Queries are sent to the investigational site using an electronic data query. Designated investigator site staff is required to respond to the query and confirm or correct the data. If the electronic query system is not used, a paper Data Query Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff that will make the correction to the database. The signed copy of the Data Query Form is kept at the investigator site.
  • ATC Chemical (ATC) classification system. Concomitant procedures, non-drug therapies and adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) terminology. Laboratory samples are processed centrally and the results will be sent electronically to Novartis (or a designated CRO). ECG, echocardiography and DXA assessments are processed centrally and the results are sent electronically to Novartis (or a designated CRO).
  • Patients using electronic PROs fill in their PRO data in a site based tablet.
  • the system is supplied by a vendor, who also manages the database.
  • the database is sent electronically to Novartis personnel (or designated CRO). Where no electronic PROs are available, patients complete paper PROs.
  • Randomization codes and data about all study drug(s) dispensed to the patient and all dosage changes are tracked using an Interactive Response Technology (IRT).
  • IRT Interactive Response Technology
  • the system is supplied by a vendor, who also manages the database. The database is sent
  • the main analysis is performed at the end of Epoch 3 when all patients complete their treatment and assessments for Epoch 3, and data collected up to and including week 12 (Visit 301) are cleaned (referred as "Week 12 analysis” in sections below).
  • the study remains blinded.
  • Data collected during Epoch 4 is analyzed based on the secondary objectives requiring data collection beyond Week 12 and complements the results from the Week 12 analysis.
  • the analysis performed after study end is referred as "End of study analysis” in sections below.
  • treatment group refers to LIK066 2.5mg qd, LIK066 10gm qd, LIK066 50mg qd, Empagliflozin 25mg qd and Placebo qd unless specified otherwise.
  • Analysis sets The following analysis populations is defined for statistical analysis. These analysis sets are subsets of the patients who signed the informed consent at Visit 1 .
  • SCR Screened set
  • Randomized set (RAN) - All patients who received a randomization number, regardless of receiving trial medication.
  • Safety set (SAF) (double-blind phase) - All patients who received at least one dose of double- blind study drug. Patients are analyzed according to treatment received. Treatment received is considered identical to the randomized treatment if the patient has received at least one dose of the randomized treatment.
  • FAS Full analysis set
  • ITT intent-to-treat
  • mis-randomized patients are those who have not been qualified for randomization and who have been inadvertently randomized into the study, but have not received double-blind study drug.
  • Mis-randomized patients are defined as cases where IRT contacts were made by the site either prematurely or inappropriately prior to confirmation of the patient's final randomization eligibility and double-blind medication was not administered to the patient. These patients were subsequently discontinued from the study.
  • PPS Per protocol set
  • Major protocol deviations are those ones affecting the primary endpoint analyses, and are pre-specified prior to un-blinding treatment codes for analyses. A list is provided in the Clinical Study Report Statistical Analysis Plan.
  • Summary statistics are provided by treatment group for demographics and baseline characteristics, including sex, age, race, weight, height, body mass index (BMI), systolic blood pressure, diastolic blood pressure, eGFR, LVEF, LVEF group ( ⁇ 45% versus > 45%), geographical region, NYHA class and medical history. These summaries are performed for the FAS. Continuous variables are summarized using n, mean, standard deviation (SD), median, Q1 (25th percentile), Q3 (75th percentile), minimum, and maximum. Categorical variables are summarized using frequency and percentage.
  • the duration of double-blind treatment exposure in Epoch 3 is summarized descriptively by treatment group (using n, mean, standard deviation, median, Q1 , Q3, minimum and maximum) for the SAF.
  • the number and percentage of patients is summarized by treatment group for duration category.
  • Concomitant medications and prior significant non-drug therapies are summarized in separate tables by therapeutic class, preferred term and treatment group for the safety population.
  • the number and percentage of patients meeting rescue criteria and taking rescue medication, and duration of exposure to rescue medication during Epoch 3 are summarized by treatment group for the SAF.
  • the use of prohibited medication, if any, is also summarized.
  • the analyses for End of study analysis is similar to the analyses performed for Week 12 analysis as described above, except that the summaries of treatments are provided for the overall study treatment duration: Epoch 3+Epoch 4.
  • NT-proBNP data follows a log-normal distribution. Therefore a log-transformation on the NT-proBNP data is performed before all statistical analyses are carried out. The analysis results are then be back-transformed and displayed as percentages for ease of data interpretation.
  • the primary efficacy variable is log-transformed ratio of NT-proBNP (pg/mL) collected at Week 12 to BL (i.e., change from BL in log-transformed NT-proBNP at Week 12). Missing Week 12 values are imputed using a multiple imputation approach.
  • null hypothesis of a flat dose-response relationship for the reduction in NT-proBNP compared to placebo is tested at a one-sided significance level of 2.5% against the alternative hypothesis of a dose-response relationship leading to a significant decrease in NT- proBNP after 12 weeks of treatment.
  • H01 there is no dose- response relationship or a dose response in the wrong direction for LIK066 after 12 weeks of treatment (i.e. the dose response relationship is flat, or as dose increases, there is less reduction in NT-proBNP from baseline); and H1 1 : there is a dose-response relationship in the right direction for LIK066 after 12 weeks of treatment (i.e. as dose increases, there is more reduction in NT-proBNP from baseline).
  • Model 1 Emax with ED50 at 3mg
  • Model 2 Emax with ED50 at 10mg
  • Model 3 Emax with ED50 at 25mg
  • Model 4 linear
  • the analysis to derive the test statistics is based on an analysis of covariance (ANCOVA) model with the log-transformed ratio of NT-proBNP (pg/mL) at Week 12 to baseline as a response variable, treatment (placebo and all LIK066 doses), stratification variables geographical region and LVEF ( ⁇ 45% versus > 45% at Visit 101) as factors, and the baseline in log-transformed NT-proBNP as a covariate. As needed, centers are pooled according to country and region for the purpose of analysis.
  • ANCOVA analysis of covariance
  • the response variable of log-transformed ratio of NT-proBNP (pg/mL) at Week 12 to baseline used in the above ANCOVA is from an imputed dataset, where the missing Week 12 NT- proBNP is imputed using the multiple imputation method.
  • this ANCOVA model is repeated for each imputed dataset, which results in a set of least squares (LS) mean estimates for all dose groups and the related covariance matrices.
  • LS least squares
  • Rubin's rule will be used to combine the multiple sets of LS mean estimates and the related covariance matrices to a single set of LS mean estimates of log- transformed ratio of NT-proBNP (pg/mL) at Week 12 to baseline for all dose groups and the related covariance matrix.
  • CO.025 is the common critical value derived from the reference multivariate t-distribution with the 6x6 correlation matrix induced by testing the candidate dose response models with respect to comparing all LIK doses to placebo group.
  • the H01 will be rejected and the statistical significance of dose-response in NT-proBNP reduction is established if the max (t1 , t2, t3... t6) > C0.025.
  • the response data in each imputed data set is used to fit the models in the candidate set.
  • the estimated dose-response is derived by using model averaging methods on a subset of candidate models, for which the associated contrast tests are statistically significant. If there are more than three candidate models that are statistically significant, the top three models with largest t-statistics as calculated above are selected as basis for the model averaging.
  • Model averaging is carried out for each imputed data set, and the resulting mean efficacy estimates and confidence intervals are derived using the combination variance that accounts for the uncertainty of the imputed data using Rubin's combination rules. Comparisons between LIK066 doses and placebo are simultaneously derived for the model averaged estimates together with confidence intervals reflecting the imputation procedure applied. The model- averaging-based estimates of mean changes in log-transformed NT-proBNP within each dose group mean differences between LIK066 and placebo and their confidence intervals are then back-transformed and displayed as ratios of NT-proBNP geometric mean at Week 12 to baseline within dose group, and relative rate of these ratios between LIK066 and placebo.
  • Target dose selection is based on the model averaged dose response estimates of mean NT-proBNP reduction efficacy of LIK066 over the dose range studied in the study. Handling of missing values/censoring/discontinuations Missing data for the primary endpoint is imputed using a multiple imputation approach assuming that the missingness mechanism is retrieved from observed data (missing at random (MAR)).
  • the imputation model includes the longitudinal sequence of NT-proBNP data collected at baseline, Week 4 and Week 12 visits, stratification factors geographical region and LVEF at Visit 101 ( ⁇ 45% versus > 45%), and other baseline covariates (e.g. NYHA class, age, gender, race).
  • NT-proBNP Summary statistics for NT-proBNP are presented by visit (up to and including week 12 visit) and treatment for observed and imputed values.
  • the summary statistics (n, mean, standard deviation (SD), and median, Q1 , Q3, minimum and maximum) are presented by visit and treatment for NT- proBNP and change from BL in NT-proBNP.
  • Figures are produced to visually show the raw and the imputed mean changes by visit over 12 weeks of Epoch 3 for each treatment group, for all patients and by LVEF group ( ⁇ 45% vs. > 45% at V101 ).
  • NT-proBNP summary statistics for the NT-proBNP are presented by visit (up to and including week 12 visit) and treatment for observed and imputed values, by the following subgroups: LVEF at Visit 101 ⁇ 45% vs. > 45%; NYHA class at baseline: II vs. III&IV; HbA1 c at baseline: ⁇ 8% vs. >8%; and NT-proBNP at baseline: ⁇ median vs. > median.
  • LIK066 doses vs. placebo and LIK066 doses vs. empagliflozin (EMPA) at Week 12 and Week 36 Change from BL in HbA1 c; Change from BL in FPG; Change from BL in SBP and DBP; Change from BL in weight; Change from BL in body composition (assessed by bio-impedance); Change from BL in body composition (assessed by DXA in a subset of patients); Percentage change from BL in fasting lipid profile (TG, total cholesterol, HDL cholesterol, LDL cholesterol, calculated VLDL cholesterol and non- HDL cholesterol, lipoproteins (apolipoprotein A-l, apolipoprotein B)); Change from BL in log- transformed hs-CRP; Change from BL in 24h urinary glucose and sodium excretion (in a subset of patients); For the comparison of LIK066 doses vs.
  • the following continuous variables are analyzed using the methods described in this section: Change from BL in HbA1 c at Week 12 and Week 36; Change from BL in FPG at Week 12 and Week 36; Change from BL in SBP and DBP at Week 12 and Week 36; Change from BL in weight at Week 12 and Week 36; Change from BL in body composition (assessed by bio- impedance) at Week 12 and Week 36; Percentage change from BL in fasting lipid profile (TG, total cholesterol, HDL cholesterol, LDL cholesterol, calculated VLDL cholesterol and non-HDL cholesterol, lipoproteins (apolipoprotein A-l, apolipoprotein B)) at Week 12 and Week 36; Change from BL in log-transformed hs-CRP at Week 12 and Week 36; and Change from BL in left atrial size and volume assessed by echocardiography at Week 12 and Week 36.
  • TG total cholesterol, HDL cholesterol, LDL cholesterol, calculated VLDL cholesterol and non-HDL cholesterol, lipoproteins (apolipoprotein
  • the change from baseline in a continuous outcome at Week 12 (or Week 36) is analyzed using a mixed effect model of repeated measures (MMRM) in which the stratification variables (geographical region and LVEF ⁇ 45% vs. > 45% at V101), treatment group, visit, and treatment group- by- vis it interaction are included as fixed-effect factors and baseline outcome variable will be included as a covariate, with a common unstructured covariance matrix for all treatment groups.
  • MMRM mixed effect model of repeated measures
  • the estimates and the 95% confidence intervals are provided for the adjusted means of the change from baseline in the outcome variable at Week 12 (or Week 36) for each treatment group, and for the adjusted mean difference at Week 12 (or Week 36).
  • the treatment effect (mean difference) of LIK066 doses vs. Placebo or LIK066 doses vs. empagliflozin are analyzed using the MMRM model as described above including all treatment groups: LIK066 2.5mg qd, LIK066 10gm qd, LIK066 50mg qd, Empagliflozin 25mg qd and Placebo qd.
  • LIK066 doses vs.
  • Placebo the treatment effects of LIK066 2.5mg qd vs. Placebo qd, LIK066 10mg qd vs. Placebo qd and LIK066 50mg qd vs. Placebo qd will be presented;
  • LIK066 doses vs. EMPA the treatment effects of LIK066 2.5mg qd vs. Empagliflozin 25mg qd, LIK066 10gm qd vs. Empagliflozin 25mg qd and LIK066 50mg qd vs. Empagliflozin 25mg qd are presented.
  • summary statistics n, mean, SD, median, Q1 , Q3, minimum and maximum, and geometric mean for log-transformed variables for these variables are presented by visit and treatment.
  • the change from BL in NYHA class at a given visit is a three-category ordinal variable (improved/unchanged/worsened) with the following definition: 1 . Improved, if NYHA class decreases at least one level from BL; 2. Unchanged, if NYHA class is unchanged from BL; 3. Worsened, if NYHA class increases at least one level from BL.
  • the NYHA class change from BL at Week 12 (or Week 36) is analyzed using a repeated measures proportional odds cumulative logit model in which the stratification factors (geographical region and LVEF ⁇ 45% vs.
  • treatment group, visit, and treatment group- by- vis it interaction are included as fixed-effect factors
  • baseline NYHA class is included as a covariate
  • patient is included as random effects.
  • the analysis is performed based on change from baseline in NYHA class at all post-baseline scheduled visits up to Week 12 (or Week 36) and based on likelihood method with an assumption of MAR for missing data.
  • the estimate and the 95% confidence interval is provided for the adjusted odds ratio at Week 12 (or Week 36) based on the longitudinal proportional odds cumulative logit model.
  • the treatment effect (odds ratio) of LIK066 doses vs. placebo is analyzed using the repeated measures proportional odds cumulative logit model as described above including all treatment groups: LIK066 2.5mg qd, LIK066 10mg qd, LIK066 50mg qd, Empagliflozin 25mg qd and Placebo qd.
  • LIK066 doses vs. Placebo the treatment effects of LIK066 2.5mg qd vs. Placebo qd, LIK066 10gm qd vs. Placebo qd and LIK066 50mg qd vs. Placebo qd are presented.
  • NYHA class will be summarized by visit and treatment group using frequency and percentage.
  • a shift table is provided to summarize the NYHA class shifting from BL to Week 12 (or Week 36) for Week 12 Analysis (or End of Study Analysis).
  • a listing of the PK concentrations is provided. Summary statistics of the PK concentrations are provided if feasible. Concentrations below lower limit of quantification (LLOQ) are treated as zero in summary statistics of concentration data.
  • LLOQ lower limit of quantification
  • the exploratory variables are analyzed in the FAS. Statistical testing of hypotheses on the exploratory endpoints are performed at the two-sided 0.05 significance level without adjustment for multiplicity.
  • LIK066 doses vs. placebo and LIK066 doses vs. EMPA at Week 12 and Week 36 Change from BL in echocardiographic parameters other than left atrial size and volume; Change from BL in quality of life (assessed by the Clinical Summary Score, Total Symptom Score and Overall Summary Score from the KCCQ; descriptive system and VAS from the EQ-5D-5L; SF-36 total score; and PROMIS for physical function and PGIS State).
  • LIK066 doses vs. EMPA at Week 12 and Week 36 Change from BL in log-transformed NT-proBNP; Change from BL in left atrial size and volume assessed by echocardiography; and Change from BL in NYHA class.
  • the exploratory variables are analyzed according to the methods described in the Analysis method.
  • the MMRM model is used for the continuous outcome variables, and the repeated measures proportional odds cumulative logit model is used for the ordinal outcomes.
  • the change from BL in log-transformed NT-proBNP at Week 12 and Week 36 is analyzed using the MMRM method.
  • the MMRM model will include the stratification variables (geographical region and LVEF ⁇ 45% vs. > 45% at V101 ), treatment group, visit, and treatment group-by-visit interaction as fixed-effect factors and baseline log-transformed NT-proBNP as a covariate, with a common unstructured covariance matrix for all treatment groups.
  • the analysis is performed based on change from baseline in log- transformed NT-proBNP at all post-baseline scheduled visits up to Week 12 (or Week 26) and based on likelihood method with an assumption of MAR for missing data.
  • the estimates and the 95% confidence intervals are provided for the adjusted means of the change from baseline in log-transformed NT-proBNP at Week 12 (or Week 36) for each treatment group, and for the adjusted mean difference at Week 12 (or Week 36).
  • the treatment effect (mean difference) of LIK066 doses vs. EMPA is analyzed using the MMRM model as described above including all treatment groups: LIK066 2.5mg qd, LIK066 10gm qd, LIK066 50mg qd, Empagliflozin 25mg qd and Placebo qd.
  • LIK066 doses vs. EMPA the treatment effects of LIK066 2.5mg qd vs. Empagliflozin 25mg qd, LIK066 10gm qd vs. Empagliflozin 25mg qd and LIK066 50mg qd vs. Empagliflozin 25mg qd are presented.
  • the analysis results are back-transformed and displayed as percentages for ease of data interpretation.
  • the change from BL in echocardiographic parameters at Week 12 and Week 36 are analyzed using the MMRM method.
  • the treatment effect (mean difference) of LIK066 doses vs. EMPA or LIK066 vs. placebo is analyzed using the MMRM model as described above including all treatment groups: LIK066 2.5mg qd, LIK066 10gm qd, LIK066 50mg qd, Empagliflozin 25mg qd and Placebo qd.
  • LIK066 doses vs. placebo the treatment effects of LIK066 2.5mg qd vs. Placebo qd, LIK066 10mg qd vs.
  • Placebo qd and LIK066 50mg qd vs. Placebo qd are presented;
  • LIK066 doses vs. EMPA the treatment effects of LIK066 2.5mg qd vs. Empagliflozin 25mg qd, LIK066 10gm qd vs. Empagliflozin 25mg qd and LIK066 50mg qd vs. Empagliflozin 25mg qd are presented.
  • the treatment effect (odds ratio) of LIK066 doses vs. EMPA is analyzed using the same repeated measures proportional odds cumulative logit model, including all treatment groups: LIK066 2.5mg qd, LIK066 10gm qd, LIK066 50mg qd, Empagliflozin 25mg qd and Placebo qd.
  • LIK066 doses vs. EMPA the treatment effects of LIK066 2.5mg qd vs. Empagliflozin 25mg qd, LIK066 10gm qd vs. Empagliflozin 25mg qd and LIK066 50mg qd vs. Empagliflozin 25mg qd are presented. Analysis of change from BL in quality of life at Week 12 and Week 36
  • the following quality of life assessments are continuous variables: Clinical Summary Score, Total Symptom Score and Overall Summary Score from the KCCQ, EQ VAS (from EQ-5D- 5L), PROMIS for physical function and SF-36 total score. Summary statistics (n, mean, standard deviation, median, Q1 , Q3, minimum, and maximum) are provided by visit and treatment group for the measurement at each visit and change from baseline values (up to Week 12 or Week 36) for these continuous variables.
  • Quality of life assessments are continuous variables: Clinical Summary Score, Total Symptom Score and Overall Summary Score from the KCCQ, EQ VAS (from EQ-5D- 5L), PROMIS for physical function and SF-36 total score. Summary statistics (n, mean, standard deviation, median, Q1 , Q3, minimum, and maximum) are provided by visit and treatment group for the measurement at each visit and change from baseline values (up to Week 12 or Week 36) for these continuous variables.
  • Quality of life assessments are continuous variables: Clinical Summary Score, Total Symptom Score and Overall Summary Score from the KCCQ, EQ VAS (from
  • assessments are ordinal variables: PGIS state and EQ-5D-5L descriptive system. These variables are summarized by visit and treatment group using frequency and percentage. Shift tables are also provided to summarize the endpoint shifting from BL to Week 12 (or Week 36) for Week 12 Analysis (or End of Study Analysis).
  • Herdman M, et al (201 1) Development and preliminary testing of the new five-level version of the EQ-5D (EQ-5D-5L). Qual Life Res; 20 (10): 1727-1736.
  • BNP B-Type Natriuertic Peptide
  • Val-HeFT Valsartan Heart Failure
  • Diabetologia 59:1333-1339.
  • Solomon SD Zile M, Pieske B, et al (2012) The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized controlled trial. Lancet; 380: 1387-95.

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Abstract

L'invention concerne l'utilisation de LIK066 chez les patients souffrant d'insuffisance cardiaque et les patients souffrant d'insuffisance cardiaque conjointement avec un diabète de type II.
PCT/IB2018/052497 2017-04-12 2018-04-10 Utilisation de lik066 chez les patients souffrant d'insuffisance cardiaque Ceased WO2018189671A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11185700B2 (en) 2017-06-16 2021-11-30 Cardiac Pacemakers, Inc. Systems and methods for dynamic control of heart failure therapy
US11497918B2 (en) 2017-06-16 2022-11-15 Cardiac Pacemakers, Inc. Systems and methods for dynamic control of heart failure therapy
US11406283B2 (en) 2018-12-11 2022-08-09 Cardiac Pacemakers, Inc. HFpEF detection using exertional heart sounds
US11311731B2 (en) 2019-04-12 2022-04-26 Cardiac Pacemakers, Inc. Cardiac resynchronization therapy heart sound response characterization
US11318313B2 (en) 2019-04-12 2022-05-03 Cardiac Pacemakers, Inc. Response-based cardiac resynchronization therapy parameter determination
WO2021014351A1 (fr) * 2019-07-23 2021-01-28 Novartis Ag Traitement comprenant des inhibiteurs de sglt, par exemple des inhibiteurs de sglt 1/2

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