WO2025215023A1

WO2025215023A1 - Diclofenac for use in the treatment of osteoarthritis symptoms

Info

Publication number: WO2025215023A1
Application number: PCT/EP2025/059605
Authority: WO
Inventors: Deppo JUNEJA
Original assignee: Haleon CH SARL
Current assignee: Haleon CH SARL
Priority date: 2024-04-08
Filing date: 2025-04-08
Publication date: 2025-10-16
Anticipated expiration: 2026-10-08

Abstract

The present invention relates to the use of topical compositions containing diclofenac to treat insomnia and/or other sleep-related disorders and/or fatigue and/or morning stiffness. Preferably, the use is in patients suffering from osteo-arthritis. Particularly, the topical composition is a gel, preferably an emulgel, comprising 1% or 2% of diclofenac or equivalent amount of pharmaceutically acceptable salt thereof.

Description

DICLOFENAC FOR USE IN THE TREATMENT OF OSTEOARTHRITIS SYMPTOMS

FIELD OF THE INVENTION

The present invention relates to the use of topical compositions containing diclofenac to treat insomnia and/or other sleep-related disorders and/or fatigue and/or morning stiffness. Preferably, the use is in patients suffering from osteo-arthritis. Particularly, the topical composition is a gel, preferably an emulgel, comprising 1% or 2% of diclofenac, particularly diclofenac sodium, or equivalent amount of pharmaceutically acceptable salt thereof, such as 1.16% or 2.32% of diclofenac diethylammonium.

BACKGROUND TO THE INVENTION

Topical diclofenac products are well-established globally for the treatment of pain and inflammation due to acute trauma (sprains, strains, muscle aches, sports injuries) as well as for the relief of mild/non-serious osteoarthritis (OA) pain. Topical non-steroidal anti-inflammatory drugs (NSAIDs) applied locally penetrate the skin and permeate deeper tissues to exert a therapeutic effect. Clinical studies of topical NSAIDs in OA of the hand and knee have demonstrated statistically significant and clinically meaningful pain relief.

Regarding osteoarthritis, such as knee osteoarthritis, the primary goal of disease management is to control symptoms, such as pain and impaired function. The use of topical NSAIDs has been recommended in evidence-based treatment guidelines focused on the management of OA. Topical NSAIDs were recommended by the American College of Rheumatology (ACR) and the Osteoarthritis Research Society International (OARSI) for the symptomatic treatment of OA of the knee.

Additionally, the ACR also strongly recommended topical NSAIDs for subjects with knee OA, and notes that topical NSAIDs should be considered prior to the use of oral NSAIDs, to minimize systemic exposure. The OARSI guidelines strongly recommend topical NSAIDs for knee OA subjects with and without gastrointestinal or cardiovascular comorbidities and for subjects with frailty.

Despite the well-established beneficial effects of diclofenac for the treatment of pain and inflammation in OA, the real-life mobility and quality of life (QoL) benefits of using diclofenac for pain relief have not been examined. SUMMARY OF THE INVENTION

In a First Aspect, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in improving functional mobility, physical activity and other quality-of- life parameters such as sleep, fatigue and attention/alertness.

In one embodiment there is provided, a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in improving sleep quality in a subject. Particularly as determined using the Karolinska Sleepiness Scale (KSS) wherein improving refers to an improvement in the respective KSS score over a baseline measurement taken before treatment. More particularly, wherein the subject achieves after at least 3 weeks of application of the topical composition a decrease from baseline in the Karolinska Sleepiness Scale of at least 0.25.

In a second embodiment, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in (a) ameliorating fatigue and/or (b) improving or increasing attention/alertness in a subject. Particularly as determined using the Karolinska Sleepiness Scale (KSS) and wherein amelioration, improving or increasing refers to an improvement in the respective KSS score over the baseline measurement before treatment. More particularly, wherein the subject achieves after up to 3 weeks of application of the topical composition a decrease from baseline in the Karolinska Sleepiness Scale of at least 0.25.

In a third embodiment, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in reducing morning stiffness in a subject. A reduction in morning stiffness may be demonstrated by an increase in levels of activity from 30 to 60 mins post-waking using an accelerometer. A reduction in morning stiffness may be demonstrated by an increase in levels of activity from 30 to 60 minutes post-waking using the WOMAC stiffness subscale.

In a fourth embodiment, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of ameliorating quality of life (QoL) in a subject. Particularly, the QoL is improved in one or more QoL domains, more particularly wherein the one or more QoL domains are dimensions in a QoL questionnaire, optionally where the QoL questionnaire is EuroQol-5 Dimensions-5 Levels (EQ- 5D-5L) quality of life questionnaire. In a fifth embodiment, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of increasing Moderate to Vigorous Physical Activity (MVPA) in a subject. Particularly, wherein an increase in MVPA is determined by an increase in total time spent at or above the MVPA cut point level over the baseline measurement before treatment, for example using an accelerometer.

Particularly, the topical composition comprises at least 1% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof, more particularly from about 1% to about 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof.

In some embodiments the diclofenac is diclofenac sodium, particularly 1% diclofenac sodium. In other embodiments the diclofenac is diclofenac diethylammonium, particularly 1.16% diclofenac diethylammonium or 2.32% diclofenac diethylammonium.

In certain embodiments, the topical composition is a gel, cream, spray or emulgel. Particularly the topical composition is a gel or emulgel.

Preferably the subject is a human subject, particularly a human subject experiencing pain, more preferably a human subject experiencing pain associated with osteoarthritis, yet more preferably a human subject experiencing pain associated with osteoarthritis of the knee, still yet more preferably a human subject experiencing pain associated with mild to moderate osteoarthritis of the knee.

Particularly the human subject is a human adult, more particularly a human adult of at least 40 years of age or older, yet more particularly a human adult of from 40 to 85 years of age.

Preferably the topical composition comprising diclofenac is applied at least once per day, such as at least two to four times per day, for example once per day, two times per day, three times per day or four times per day. Particularly the topical composition is applied at regular intervals, for example at intervals of about at least four hours such as every four hours depending on diclofenac content. A topical composition comprising 1% diclofenac or equivalent amount of pharmaceutically acceptable salt may be applied two to four times per day, particularly three to four times per day with at least four hours between applications. A topical composition comprising 2% diclofenac or equivalent amount of pharmaceutically acceptable salt may be applied two times per day with at least four hours between applications. In certain embodiments, the topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof may be for use in a method. Thus, there is also provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of improving sleep quality in a subject; a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of (a) ameliorating fatigue and/or (b) improving or increasing attention/alertness in a subject; a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of reducing morning stiffness in a subject; a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of ameliorating quality of life (QoL) in a subject and a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of increasing Moderate to Vigorous Physical Activity (MVPA) in a subject.

Particularly, the topical composition for use in a method is a topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof. Particularly, the method comprises applying the topical composition 1 to 4 times per day. The subject may be a human adult of from 40 to 85 years of age experiencing pain associated with mild to moderate osteoarthritis, particularly pain associated with mild to moderate osteoarthritis of the knee.

In some embodiments, the topical composition comprises 1.16% diclofenac diethylammonium. In some embodiments, the topical composition comprises 2.32% diclofenac diethylammonium. Particularly, the topical composition is an emulgel.

DESCRIPTION OF FIGURES

FIGURE 1: Shows the design of the prospective open-label, single-arm, multi-country (US and EU) Real World Evidence (RWE) study with a hybrid low interventional design. The study utilised a clinically validated device (ActiGraph) to objectively measure changes in functional mobility together with the use of subjective assessments such as Numeric Rating Scale (NRS), Visual Analog Scale (VAS), Karolinska Sleepiness Scale, EQ-5D-5L, Quality of Life (QoL) Questionnaire and WOMAC Questionnaire.

FIGURE 2: Shows Change from Baseline in average minutes of MVPA (Moderate and Vigorous Physical Activity.

Figure 3: Shows change in Karolinksa Sleep Scale (KSS) scores from baseline over time.

Figure 4: Shows change in Quality of Life scores from baseline over time measured using EQ-5D- 5L.

Figure 5: Shows change in WOMAC Stiffness Subscale Scores from baseline over time. Figure 6: Shows Indices of Morning Stiffness 30 Mins post wake from baseline over time. Figure 7: Shows Indices of Morning Stiffness 60 Mins post wake from baseline over time. Figure 8: Shows change from baseline over time in the WOMAC Global Score.

DETAILED DESCRIPTION OF THE INVENTION

Whilst diclofenac is known for use in the treatment of pain, the present Inventors have now shown that when applied as a topical composition, diclofenac is capable of improving the physical function and the quality of life of subjects suffering from osteoarthritis.

Topical compositions for use in the Invention comprise diclofenac or equivalent pharmaceutically acceptable salt of diclofenac. Preferably, salts of diclofenac with organic bases of ammonia are used. For example, the ammonium salt, alkylamine salt dimethylamine, diethylamine, trimethylamine and a cyclic amine salt such as epolamine (hydroxyethylpyrrolidine salt) can be used. Preferably, the topical compositions comprise diclofenac sodium, diclofenac diethylammonium or diclofenac diethylamine. More preferably, the topical compositions comprise diclofenac sodium or diclofenac diethylammonium, particularly 1% diclofenac sodium, 1.16% diclofenac diethylammonium or 2.32% diclofenac diethylammonium.

The topical composition may be a gel, cream or emulgel. Particularly the topical composition is a gel or emulgel. More particularly, the topical composition is an emulgel. An "emulgel" is composition that has the characteristics of a gel and an emulsion, for example compositions either of the oil-in- water or water-in-oil type, that are gelled by mixing with a gelling agent. Emulgels are mixtures of two or more liquids that are normally immiscible with one liquid dispersed as globules (dispersed phase) in the other liquid (continuous phase). In some embodiments an emulgel is formulated from a base comprising (i) an oily phase comprising at least one oil, (ii) an aqueous phase comprising water and/or pharmaceutically acceptable water-soluble components, (iii) at least one emulsifier and (iv) at least one gelling agent.

The compositions comprise diclofenac sodium in a concentration of about 1% w/w to about 4% w/w salt or equivalent amount of pharmaceutically acceptable salt of diclofenac. Preferably, the compositions comprise diclofenac diethylammonium in a concentration of about 1.16% to about 2.32% w/w. In some embodiments, the compositions can comprise diclofenac diethylammonium in a concentration of about 1% w/w, 1.01% w/w, 1.02% w/w, 1.03% w.w, 1.04% w/w, 1.05% w/w, 1.06% w/w, 1.07% w/w, 1.08% w/w, 1.09% w/w, 1.10% w/w, 1.11% w/w, 1.12% w/w, 1.13% \N/\N, 1.14% w/w, 1.15% w/w, 1.16% w/w, 1.17% w/w, 1.18% w/w, 1.19% w/w, or 1.2% w/w. Especially preferred is diclofenac diethylammonium in a concentration of about 1.16% w/w or about 2.32% w/w. In instances where a different pharmaceutically acceptable salt of diclofenac is used, one of ordinary skill in the art would understand that the corresponding equivalent amounts are used. For the avoidance of doubt, reference to "% by weight" (%w/w) means by weight of the total composition, the amount of each ingredient being selected so that total ingredients in the composition sum to 100 percent by weight. It is to be understood that the use of the term "equivalent amount" in relation to the pharmaceutically acceptable salt thereof does not necessarily mean an equivalent weight or volume quantity, but represents the quantity or amount of pharmaceutically acceptable salt that offers an equivalent therapeutic effect, particularly an equivalent therapeutic effect compared to diclofenac sodium. For example, 1.16% diclofenac diethylammonium is generally regarded as being equivalent to 1% diclofenac sodium.

By way of non-limiting example, suitable topical compositions of diclofenac are disclosed in US4407824, US4917886 and EP2214642 or marketed under the Voltaren® and Motusol® brands. For example, in certain embodiments, the topical composition of diclofenac comprises (a) 1.2-4 percent (w/w) of diclofenac diethylammonium salt, (b) 0.5-2 percent (w/w) of a saturated or unsaturated C10-C18 fatty alcohol selected from the group consisting of stearyl alcohol, myristyl alcohol, lauryl alcohol and oleyl alcohol, (c) at least 40 percent (w/w) of water, (d) 10-30 percent (w/w) of at least one C2-C4-alkanol, (e) 3-15 percent (w/w) of at least one glycol solvent selected from the group consisting of 1,2-propanediol and polyethylene glycol (200-20000), (f) 0.5-5 percent (w/w) of at least one gelling agent selected from the group consisting of carbomers, (g) 2-8 percent (w/w) of at least one liquid lipid forming the oily phase of the emulsion-gel, (h) 1-3 percent (w/w) of at least one non-ionic surfactant, and (i) a basic agent to adjust the pH of the total composition to 6-9. Particularly wherein the saturated or unsaturated C10-C18 fatty alcohol (b) is oleyl alcohol. For example, a topical composition of diclofenac comprising (a) 1.5-3.5 percent of diclofenac diethylammonium salt, (b) 0.5-2 percent oleyl alcohol, (c) 45-75 percent of water, (d) 10-30 percent of ethanol, isopropanol, or mixtures thereof, (e) 3-12 percent of 1,2-propanediol, (f) 0.7-3 percent of at least one gelling agent selected from the group consisting of carbomers, (g) 3-7 percent of at least one liquid lipid forming the oily phase of the emulsion-gel, (h) 1-3 percent of at least one nonionic surfactant, and (i) 0.5-2 percent of diethylamine to adjust the pH of the total composition to 6.5-8.5. Topical application refers to the application of a composition or formulation externally to the skin of a subject. Thus, a "topical composition" (or synonymously "topical formulation") refers to a composition that can be applied topically, i.e. to the skin of a subject. Preferably the topical composition is applied to an affected area. As used herein, the term "affected area" relates to an area of the subject's body proximate or adjacent to the pain, for example the knee.

Preferably the topical composition comprising diclofenac is applied at least once per day, such as at least two to four times per day, for example once per day, two times per day, three times per day or four times per day. Particularly the topical composition is applied at regular intervals, for example at intervals of about at least four hours such as every four hours depending on diclofenac content. A topical composition comprising 1% diclofenac or equivalent amount of pharmaceutically acceptable salt may be applied two to four times per day, particularly three to four times per day with at least four hours between applications. A topical composition comprising 2% diclofenac or equivalent amount of pharmaceutically acceptable salt may be applied two times per day with at least four hours between applications. From about 2g to about 4g of the topical composition may be applied as a single dose.

Preferably the subject is a human subject, particularly a human subject experiencing pain, more preferably a human subject experiencing pain associated with osteoarthritis, yet more preferably a human subject experiencing pain associated with osteoarthritis of the knee, still yet more preferably a human subject experiencing pain associated with mild to moderate osteoarthritis of the knee. Particularly the human subject is a human adult of at least 18 years of age, more particularly a human adult of at least 40 years of age or older, yet more particularly a human adult of from 40 to 85 years of age. In certain embodiments, the subject is a human adult of from 40 to 85 years of age experiencing pain associated with osteoarthritis, such as pain associated with osteoarthritis of the knee, for example pain associated with mild to moderate osteoarthritis of the knee. In specific embodiments, the subject is a human adult of from 40 to 85 years of age experiencing pain associated with mild to moderate osteoarthritis of the knee. The subject may be male or female.

Mild to moderate osteoarthritis of the knee may be diagnosed by radiological evidence within the last three years or self-reported by the subject as knee pain with a Visual Analogue Scale (VAS) score, a method used to measure a patient's subject experience of pain, of > 40 mm < 70mm. In the context of the present Invention, the term "improve" refers to an improvement in the situation of the treated patient, that is either a subjective improvement (how the patient feels) or an objective improvement (measured parameters). Particularly an improvement is determined by comparison or with regard to a baseline measurement taken before commencement of the treatment or intervention, for example before start of the study. Change can be measured using any of the tests discussed herein on two or more occasions, for example, a first occasion to measure baseline and one or more later occasions, such as a second occasion and/or third occasion, following a period of time (during which time treatment may have been administered). The time points may be at least one week apart, for example, two weeks apart, three weeks apart or four weeks apart.

Sleep Quality

In one embodiment there is provided, a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in improving sleep quality in a subject.

The term "sleep" refers to a prolonged period of rest during which a subject exhibits decreased activity. Typically sleep is a period of rest lasting for 3 or more hours, more typically from about 6 to about 8 hours for most adult humans. The term "wake" refers to the physical condition of arousal from sleeping or resting and is characterised by an increase in the level of physical activity. The period of awakening is generally understood to occur from about 4 or more hours after the commencement of sleep.

Improved sleep quality may arise because of increased sleep efficiency or sleep maintenance, as well as by preventing sleep disturbances in a patient. Particularly, improved sleep quality is determined by improvement of secondary outcomes that may be provided by the present invention, particularly by a decrease in sleepiness and/or increased attention/alertness post-wake.

Particularly improvements in sleep quality may be determined using the Karolinska Sleepiness Scale (KSS) evidenced by an improvement in the respective KSS score over a baseline measurement taken at the beginning of the study prior to treatment with the topical composition. Particularly, an improvement in sleep quality may be inferred when a subject achieves, after up to 3 weeks of application of the topical composition, a decrease from baseline in the Karolinska Sleepiness Scale of at least 0.25. Particularly a second (later) KSS score is improved in comparison to a first (earlier) KSS score, particularly a baseline KSS score taken before treatment. More particularly, up to 3 weeks of application of the topical composition, the second (later) KSS score is decreased by at least 0.25 in comparison to a first (earlier) KSS score, particularly a baseline KSS score taken before treatment.

The Karolinska Sleepiness Scale is a nine- or ten- point scale frequently used for evaluating subjective sleepiness by measuring the subjective level of sleepiness at a particular time during the day. Subjects indicate on the scale the level that best reflects their psycho-physical state.

Fatigue/ Attention/Alertness

In a second embodiment, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in (a) ameliorating fatigue and/or (b) improving or increasing attention/alertness in a subject.

As used herein, the term "fatigue" may refer an overall feeling of tiredness or lack of energy in a healthy subject but also related to some medical condition. The terms "attention" and "alertness" generally refers to a subject's mental awareness and responsiveness. When related to sleep loss or sleep quality, alertness may be considered to be generally equivalent to arousal and opposite to sleepiness, tiredness, fatigue, and drowsiness. Fatigue, attention and alertness can be measured using standard methods known by the person skilled in the art, for example subjective methods such as the Karolinska Sleepiness Scale.

Particularly the level of fatigue, attention and/or alertness may be determined using the Karolinska Sleepiness Scale (KSS), wherein amelioration, improving or increasing refers to an improvement in the respective KSS score over the baseline measurement before treatment. More particularly, wherein the subject achieves after up to 3 weeks of application of the topical composition a decrease from baseline in the Karolinska Sleepiness Scale of at least 0.25. Particularly a second (later) KSS score is improved in comparison to a first (earlier) KSS score, particularly a baseline KSS score taken before treatment. More particularly, after up to 3 weeks of application of the topical composition, the second (later) KSS score is decreased by at least 0.25 in comparison to a first (earlier) KSS score, particularly a baseline KSS score taken before treatment.

Morning Stiffness

In a third embodiment, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in reducing morning stiffness in a subject. The term "morning stiffness" refers to a sensation of loss of free motion or a slowed, "stiff" range of movement, such as difficulty moving joints, encountered on first awakening after sleep often lasting for about 30 minutes or more.

Most humans sleep at night however, some may have alternate sleep schedules. Therefore, for the avoidance of doubt, morning stiffness may relate to the state after awakening from sleep as opposed to the time of day. Individuals whose sleep schedule involves sleeping during the daytime may exhibit symptoms equivalent to morning stiffness in the evening or night when they awaken from sleep.

A reduction in morning stiffness may be demonstrated by an increase in the activity levels of a subject from 30 to 60 mins post-waking using an accelerometer. A reduction in morning stiffness may also be demonstrated by an increase in levels of activity from 30 to 60 minutes post-waking using the WOMAC stiffness subscale.

Quality of Life

In a fourth embodiment, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in ameliorating quality of life (QoL) in a subject.

Quality of Life is based on any aspect that a subject might consider as contributing to one or more domains of their wellbeing, such as, by way of non-limiting example, social performance, family life, job performance, relationships and the like.

Improvement in QoL may be evaluated by patient-reported outcome and/or aided by questionnaires. For example, improvement may be reported by a patient to his/her physician, and/or may be scored by a QoL questionnaire. Quality of life may be measured by subjective means such as the EuroQol-5 Dimensions-5 Levels (EQ- 5D-5L) quality of life questionnaire. The EQ-5D-5L assesses health-related quality of life across five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with five levels of severity (no problems, slight, moderate, severe, and extreme).

Particularly, the QoL is improved in one or more QoL dimensions, more particularly wherein the one or more QoL dimensions are dimensions in a QoL questionnaire, optionally where the QoL questionnaire is EuroQol-5 Dimensions-5 Levels (EQ- 5D-5L) quality of life questionnaire. Particularly, ameliorating quality of life is measured by an improvement in one or more of the EQ- 5D-5L QoL dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).

Moderate to Vigorous Physical Activity

In a fifth embodiment, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in increasing Moderate to Vigorous Physical Activity (MVPA) in a subject.

Moderate to vigorous physical activity (MVPA) is a category of activity intensity that has consistently been shown to benefit and/or reduce the risk of many chronic disease states. MVPA is measured with Metabolic Equivalents (METs). A MET is the ratio of a person's working metabolic rate compared to their resting metabolic rate. A person sitting quietly would be considered 1 MET. Moderate-intensity physical activity is defined as 3 - 6 Metabolic Equivalents (METs) and Vigorous- intensity physical activity is defined as any activity above 6 METs. This means that MVPA is any activity over 3 METs.

To assess physical activity level, data may be obtained from a patient worn accelerometer and converted to number of minutes per day spent in various physical activity intensity categories with the goal of measuring minutes per day of moderate- to vigorous-intensity physical activity (MVPA) in 10-minute bouts.

Particularly, an increase in MVPA is determined by an increase in total time spent at or above the MVPA cut point level over the baseline measurement before treatment, for example using an accelerometer, particularly an ActiGraph accelerometer.

In another embodiment, there is provided a topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in improving mobility in a subject. An improvement in mobility refers to a positive change in the ability of a subject to move. The positive change can be measured using any of the aforementioned tests on at least two or more occasions, for example, a first occasion to measure baseline mobility and a second occasion to measure mobility following a period of time (during which time the topical composition has been administered).

General The term "comprising" encompasses "including" e.g. a composition "comprising" X may include something additional e.g. X + Y. In some implementations, the term "comprising" refers to the inclusion of the indicated active agent, such as recited compounds, as well as inclusion of other active agents, and carriers, excipients, emollients, stabilizers, etc., known in the consumer health industry and generally recognized as safe (GRAS). Use of the transitional phrase "consisting essentially of" means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim, and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. See, In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in the original); see also MPEP § 2111.03. Thus, the term "consisting essentially of" when used in a claim of this invention is not intended to be interpreted to be equivalent to "comprising". The term "consisting of" and variations thereof means including and limited to (for example, the specific recited constituents or steps). In certain territories, the term "comprising an active ingredient consisting of" may be used in place of "consisting essentially". The term "about" in relation to a numerical value x is optional and means, for example, that the numerical value may comprise some variance around the stated number to allow for routine experimental fluctuation, measurement variance or to encompass minor deviations that may achieve substantially the same results as the stated number, such as x±10%, x±5%, x±4%, x±3%, x±2% or x±l%. The word "substantially" does not exclude "completely" e.g. a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention. All percentages and ratios used herein are by weight of total composition, unless otherwise indicated.

All references or patent applications cited within this patent specification are incorporated by reference herein.

Embodiments of the Invention

The following clauses describe certain specific embodiments of the invention:

EMBODIMENT 1: Use of a topical composition containing diclofenac to treat insomnia and/or other sleep-related disorders.

EMBODIMENT 2: Use of a topical composition containing diclofenac to treat morning stiffness. EMBODIMENT 3: Use of a topical composition containing diclofenac to treat insomnia and/or other sleep-related disorders in patients suffering from osteo-arthritis.

EMBODIMENT 4: Use of a topical composition containing diclofenac to treat morning stiffness in patients suffering from osteo-arthritis. EMBODIMENT 5: Use of a topical composition containing diclofenac to treat fatigue.

EMBODIMENT 6: Use of a topical composition containing diclofenac to treat fatigue in patients suffering from osteo-arthritis.

EMBODIMENT 7: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in improving functional mobility, physical activity and other quality-of-life parameters such as sleep quality, fatigue and attention/alertness.

EMBODIMENT 8: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in improving sleep quality in a subject.

EMBODIMENT 9: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in (a) ameliorating fatigue and/or (b) improving or increasing attention/alertness in a subject.

EMBODIMENT 10: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in reducing morning stiffness in a subject.

EMBODIMENT 11: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in ameliorating quality of life (QoL) in a subject.

EMBODIMENT 12: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in increasing Moderate to Vigorous Physical Activity (MVPA) in a subject.

EMBODIMENT 13: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of improving sleep quality in a subject.

EMBODIMENT 14: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of (a) ameliorating fatigue and/or (b) improving or increasing attention/alertness in a subject.

EMBODIMENT 15: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of reducing morning stiffness in a subject.

EMBODIMENT 16: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of ameliorating quality of life (QoL) in a subject.

EMBODIMENT 17: A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of increasing Moderate to Vigorous Physical Activity (MVPA) in a subject.

EMBODIMENT 18: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of improving sleep quality in a subject. EMBODIMENT 19: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of (a) ameliorating fatigue and/or (b) improving or increasing attention/alertness in a subject. EMBODIMENT 20: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of reducing morning stiffness in a subject.

EMBODIMENT 21: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of ameliorating quality of life (QoL) in a subject.

EMBODIMENT 22: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of increasing Moderate to Vigorous Physical Activity (MVPA) in a subject.

EMBODIMENT 23: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of improving sleep quality in a subject wherein the method comprises applying the topical composition 1 to 4 times per day.

EMBODIMENT 24: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of (a) ameliorating fatigue and/or (b) improving or increasing attention/alertness in a subject wherein the method comprises applying the topical composition 1 to 4 times per day.

EMBODIMENT 25: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of reducing morning stiffness in a subject wherein the method comprises applying the topical composition 1 to 4 times per day.

EMBODIMENT 26: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of ameliorating quality of life (QoL) in a subject wherein the method comprises applying the topical composition 1 to 4 times per day.

EMBODIMENT 27: A topical composition comprising 1% to 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof for use in a method of increasing Moderate to Vigorous Physical Activity (MVPA) in a subject wherein the method comprises applying the topical composition 1 to 4 times per day.

EMBODIMENT 28: The topical composition for use of any one of Embodiments 7 to 27, wherein the subject is a human adult of from 40 to 85 years of age experiencing pain associated with mild to moderate osteoarthritis.

EMBODIMENT 29: The topical composition for use of any one of Embodiments 7 to 27, wherein the subject is a human adult of from 40 to 85 years of age experiencing pain associated with mild to moderate osteoarthritis of the knee.

EMBODIMENT 30: The topical composition for use of any one of Embodiments 7 to 29, wherein the topical composition comprises 1.16% diclofenac diethylammonium. EMBODIMENT 31: The topical composition for use of any one of Embodiments 7 to 29, wherein the topical composition comprises 2.32% diclofenac diethylammonium.

EMBODIMENT 32: The topical composition for use of any one of Embodiments 7 to 31, wherein the topical composition is an emulgel.

In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

EXAMPLES

A Prospective Real-World Evidence Study evaluating the effects of Voltaren use on Mobility and Quality of Life in subjects with knee osteoarthritis (OA) pain.

In this study, a prospective Real-world evidence (RWE) design was used to assess the real-life impact of using Voltaren Gel (topical diclofenac) on functional mobility and quality of life (QoL). The RWE studies provided an opportunity to gather information on the real-life effectiveness of a product in a population that was reflective of the consumer base. This was the first Haleon study that went beyond subjective assessment of these benefits, using research-grade wearable devices (ActiGraph) to accurately measure changes in functional mobility and aspects of QoL. Together with objective and subjective assessments of these benefits, this study provided us with first-ever subject-centric data on the real-life benefits of using Voltaren, beyond pain relief.

Topical diclofenac products were well-established globally for the treatment of pain and inflammation due to acute trauma (sprains, strains, muscle aches, sports injuries) as well as for the relief of mild/non-serious osteoarthritis (OA) pain. Topical non-steroidal anti-inflammatory drugs (NSAIDs) which was applied locally to the site of symptoms penetrate the skin and permeates deeper tissues to exert a therapeutic effect . Clinical studies of topical NSAIDs in OA of the hand and knee have demonstrated statistically significant and clinically meaningful pain relief.

With regards to osteoarthritis, the primary goal of disease management was to control symptoms, such as pain and impaired function. A network meta-analysis found that NSAIDs are the most effective individual treatment to improve pain and function in OA. The authors concluded that topical diclofenac, regardless of dose, had the largest effect on pain and physical function compared to other topical treatments including NSAIDs. In a recent meta-analysis of 192 clinical trials, the authors assessed the effectiveness and safety of different preparations and doses of NSAIDs, opioids, and paracetamol to help health care providers manage knee and hip OA pain and physical function.

The use of topical NSAIDs was recommended in evidence-based treatment guidelines focused on the management of OA. Topical NSAIDs were recommended by the American College of Rheumatology (ACR) and the Osteoarthritis Research Society International (OARSI) for the symptomatic treatment of OA of the knee. Additionally, the ACR also strongly recommended topical NSAIDs for subjects with knee OA, and notes that topical NSAIDs should be considered prior to the use of oral NSAIDs, to minimize systemic exposure. The OARSI guidelines strongly recommend topical NSAIDs for knee OA subjects with and without gastrointestinal or cardiovascular comorbidities and for subjects with frailty.

Despite these well-established beneficial effects of diclofenac for the treatment of pain and inflammation in OA, the real-life mobility and QoL benefits of using diclofenac for pain relief have not been examined. Considering the large impact that knee OA pain could have on subject's ability to move, exercise, and perform daily activities, it was highly likely that diclofenac related pain relief can lead to substantial improvement in people's QoL. According to the ACR, exercise was considered a highly effective and recommended intervention in knee OA, thereby conceptualizing mobility not only as an outcome that was affected by knee OA but also as an enabler of improved disease outcomes in OA.

This study was designed to assess the real-life impact of using Voltaren Gel (topical diclofenac) on functional mobility and QoL. This study utilised a research-grade validated wearable device: ActiGraph, to accurately measure objective changes in functional mobility. The purpose of the study was to investigate how topical diclofenac use can improve functional mobility and physical activity primarily, as well as other QoL parameters such as engagement in daily activities, sleep and mood.

This study was performed in full compliance with The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and all applicable local Good Clinical Practice (GCP) and regulations, and with applicable portions of EU MDR 2017/745 and European Nation International Organization for Standardization (ISO) 14155:2011 and ISO 14155:2020.

OBJECTIVES

Primary Objective

The primary objective of this study was to evaluate the effects of Voltaren Gel on physical activity, measured through connected activity tracker. Secondary Objectives

The secondary objectives of this study were: (1) To evaluate the effects of Voltaren Gel on functional mobility, measured through connected activity tracker; (2) To assess the functional mobility, measured through connected activity tracker; (3) To evaluate the effects of Voltaren Gel on functional mobility, measured through subject related outcomes; (4) To evaluate the effects of Voltaren Gel on pain intensity; (5) To evaluate the effects of Voltaren Gel on activity-related pain and stiffness; (6) To evaluate the effects of Voltaren Gel on correlates of quality of life (QoL).

Exploratory Objectives

The exploratory objectives of this study were: (a) To explore the link between Voltaren usage, level of pain relief and functional mobility/QoL and (b) To evaluate time to meaningful pain relief after Voltaren Gel use.

METHODOLOGY

This prospective open-label, single-arm, multi-countries (US and Poland) Real-world evidence (RWE) study, conducted in a hybrid format focusing on assessing the impact of Voltaren Gel on functional mobility and QoL in individuals with mild/non-serious OA of the knee.

The target population comprises adults aged between 40 and 85 years, diagnosed with mild/non- serious knee osteoarthritis and self-reporting pain at the time of recruitment. In this hybrid study design, subjects physically attended on site visits for screening (Day -7), baseline assessments (Day 0), and end of study evaluations (Day 21). The remaining treatment phase (Day 1 to 21) were conducted in a remote manner (e.g.at home) to observe the real-world usage of the product. Study period for each subject was maximum of 28 days.

In the EU, two strengths of Voltaren Gel are available, 11.6 mg/g and 23.2 mg/g diclofenac diethylammonium. During the screening and enrolment process, the Investigator assessed the subject's product preference as well as the need and the severity of OA to determine and dispense the appropriate percentage of gel. In the US, Voltaren Arthritis Pain Gel, containing 10 mg/g of diclofenac sodium was used.

ActiGraph device was provided post subject consent at Day -7 to collect baseline information. The baseline period lasted between 3 (minimum) and 7 days (maximum), to collect enough information on both subjective and objective aspects of mobility and sleep quality. End of baseline period was considered Day 0. Post-baseline period, (at Day 7 of the study) subjects were provided with the product (Voltaren) and ActiGraph device where there was a total of 21 days of product usage and assessment of parameters as highlighted in the objectives. Each subject was in the study for 28 days maximum.

NUMBER OF SUBJECTS (PLANNED AND ANALYZED^

Planned: 195 subjects

Analyzed for safety: 196 subjects

Analyzed for efficacy: 188 subjects

Enrolled: 196 subjects

Completed: 194 subjects

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION

Subjects between the age of 40 and 85 years; diagnosed with mild/non-serious knee osteoarthritis, proven via radiological evidence collected within the last 3 years; subjects with self-reported knee pain, with a score of > 40 mm and < 70 mm on the pain intensity visual analogue scale (VAS) at the time of Informed Consent Form (ICF) signature; subjects willing to use Voltaren Gel for up to 3 Weeks.

TEST PRODUCT, DOSE,

This study adopted a hybrid approach, wherein subjects are only obligated to be physically present for on site screening (Day -7), end of baseline (Day 0), and end of study visits (Day 21). The remaining treatment phase (Day 1 to 21) were conducted in a remote manner (e.g.at home) to observe the real-world usage of the product. Study period for each subject lasted a maximum of 28 days.

CRITERIA FOR EVALUATION Primary objective was to evaluate the change from baseline in the average minutes of Moderate and Vigorous Physical Activity (MVPA).

Secondary objectives were to evaluate:

• Change from baseline in: o daily average number of steps taken; o ratio of sedentary/non-sedentary time; o gait, assessed through speed and step irregularity (measured via cadence and gait speed); o indices of morning stiffness (assessed through levels of activity 30- and 60-mins post-wake); o indices of level of stiffness throughout the day as assessed via the Western Ontario and

McMaster Universities Arthritis Index (WOMAC) stiffness subscale change from baseline).

• Study subjects' perceived ability to exercise more regularly. Assessed using the WOMAC physical function subscale.

• Change from baseline in self-reported pain intensity, assessed through Numeric Rating Scale (NRS) (daily assessment).

• Change from baseline in the WOMAC total score and subscales in: Pain (composite), Stiffness (composite).

• Change from baseline in sleep/alertness: Karolinska sleepiness scale (KSS) assessed lx/day and health-related quality of life: EuroQol-5 Dimensions-5 Levels (EQ- 5D-5L).

Exploratory evaluation:

Exploratory evaluation included correlations between Voltaren usage, pain relief and mobility and QoL indices throughout the trial; and elapsed time from Voltaren Gel use to achieving time to meaningful pain relief to end of study.

STATISTICAL METHODS

For the primary and secondary endpoints where the data is collected through the activity tracker, only subjects who met the minimum wear threshold were included in the analysis. This is defined as a minimum of 3 valid days during the baseline period and a minimum of 3 valid days within each post-baseline 7-day period, where a valid day is defined as a minimum wear of 20 hours per day. The primary analysis followed a hierarchical approach as follows:

1. A Mixed Model with Repeated Measures (MMRM) was used to analyse the change from baseline in MVPA average minutes as the response variable with baseline as a fixed effect. Subjects were included as a random effect, and timepoint was treated as a repeated measure within each subject (with compound symmetry structure between visits). If the parameter for the intercept was found to be statistically significant (p-value < 0.05), then the second model below was used.

2. A MMRM was used to analyse the change from baseline in MVPA average minutes as the response variable with baseline and timepoint (with unstructured covariance structure between visits) as fixed effects. Adjusted means for each timepoint were presented along with p-values and 95% confidence intervals (Cis) for the mean change from baseline in MVPA.

Other than the global test for an overall change from baseline (i.e., intercept), there was no other adjustment for multiplicity. If data were found to be non-normal, the Friedman Test was used. If the Friedman test was found to be significant then Wilcoxon Signed Rank Pairwise Tests were used for each week comparison.

For the secondary objectives, functional mobility as measured through wearables and patient- reported outcomes, pain intensity assessed through NRS (daily assessment), activity-related pain and stiffness as measured in the (Likert Scale) WOMAC subscales for composite pain and composite stiffness were analysed in the same manner as the primary objective.

For the exploratory endpoints, correlations between pain relief, mobility, and QoL indices were measured throughout the trial. Additionally, the use of concomitant medications and any changes in use of pain relief medications were recorded throughout the trial.

Time to pain relief was evaluated using the Kaplan-Meier method.

SUMMARY CONCLUSIONS

Primary efficacy endpoint results:

• The mean average minutes of MVPA increased at Week 1, Week 2, and slightly decreased at Week 3, compared to baseline. The mean change from baseline in average minutes of MVPA was statistically significant at Week 1, Week 2 and statistically non-significant at Week 3. The comparison of change from baseline in average minutes of MVPA between weeks were statistically significant at Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (p=0.006) and statistically nonsignificant at Week 1 vs Week 2 (p=0.323). Similarly, the comparison of average minutes of MVPA between baseline and each week were statistically significant in Week 1 vs baseline (p<0.001), Week 2 vs baseline (p=0.005) and statistically non-significant in Week 3 vs baseline (p=0.733) analysed by Wilcoxon Signed Rank Pairwise Tests.

Secondary efficacy endpoint results:

• The mean in daily average number of steps taken via ActiGraph was increased at Week 1, Week 2, and decreased at Week 3, compared to baseline. The mean change from baseline in daily average number of steps taken was statistically significant at Week 1, Week 2 and statistically nonsignificant at Week 3. The comparison of change from baseline in daily average number of steps taken between weeks were statistically significant in Week 1 vs Week 3 (p=0.007) and statistically non-significant in Week 2 vs Week 3 (p=0.123) and in Week 1 vs Week 2 (p=0.076). Similarly, the comparison of daily average number of steps taken between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), Week 2 vs baseline (p=0.042) and statistically nonsignificant in Week 3 vs baseline (p=0.670) analysed by Wilcoxon Signed Rank Pairwise Tests.

• The indices of morning stiffness were assessed through levels of activity 30- and 60-mins post-wake via ActiGraph: o 30 Minutes post-wake: Mean in morning stiffness at 30 Minutes post-wake was increased at Week 1, Week 2, and decreased at Week 3, compared to baseline. Mean change from baseline in indices of morning stiffness at 30 Minutes post-wake were statistically non-significant at Week 1, Week 2 and Week 3. The comparison of change from baseline in indices of morning stiffness at 30 Minutes post-wake between weeks were statistically significant at Week 1 vs Week 3 (p=0.013), Week 2 vs Week 3 (p=0.011) and statistically non-significant at in Week 1 vs Week 2 (p=0.570). Similarly, comparison of indices of morning stiffness at 30 Minutes post-wake between baseline vs each week were statistically non-significant in Week 1 vs baseline (p=0.354), in Week 2 vs baseline (p=0.349), and in Week 3 vs baseline (p=0.151) analysed by Wilcoxon Signed Rank Pairwise Tests. o 60 Minutes post-wake: Mean in morning stiffness 60 Minutes post-wake was gradually increased at Week 1, Week 2 and significantly decreased at Week 3, compared to baseline. Mean change from baseline in indices of morning stiffness at 60 Minutes post-wake were statistically nonsignificant at Week 1, Week 2 and statistically significant at Week 3. The comparison of change from baseline in indices of morning stiffness at 60 Minutes post-wake between weeks were statistically significant in Week 1 vs Week 3 (p=0.002), in Week 2 vs Week 3 (p=0.003) and statistically nonsignificant in Week 1 vs Week 2 (p=0.930). Similarly, comparison of indices of morning stiffness at 60 Minutes post-wake between baseline vs each week were statistically non-significant in Week 1 vs baseline (p=0.136), in Week 2 vs baseline (p=0.276), and statistically non-significant in Week 3 vs baseline (p=0.050) analysed by Wilcoxon Signed Rank Pairwise Tests.

• Indices of level of stiffness throughout the day as assessed via the WOMAC stiffness subscale change from baseline in WOMAC physical function subscale o WOMAC Global Score: The mean WOMAC global score showed significant reduction at Week 1, Week 2, and at Week 3, compared to baseline. Mean change from baseline in WOMAC global score were statistically significant at Week 1, Week 2 and Week 3. The comparison of change from baseline in WOMAC global score between weeks was statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p<0.001). Similarly, comparison of WOMAC global score between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests. o WOMAC Pain Subscale (walking, stair climbing, nocturnal, rest, weightbearing): The mean WOMAC pain subscale showed significant reduction at Week 1, Week 2, and Week 3, compared to baseline. Mean change from baseline in WOMAC pain subscale were statistically significant at Week 1, Week 2 and Week 3. The comparison of change from baseline in WOMAC pain subscale between weeks were statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p<0.001). Similarly, comparison of WOMAC pain subscale between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), and in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests. o WOMAC Stiffness Subscale (morning stiffness and stiffness occurring during day): The mean WOMAC stiffness subscale showed significant reduction at Week 1, Week 2 and Week 3, compared to baseline. Mean change from baseline in WOMAC stiffness subscale were statistically significant at Week 1, Week 2 and Week 3. The comparison of change from baseline in WOMAC stiffness subscale between weeks were statistically significant at in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p=0.003). Similarly, comparison of WOMAC stiffness subscale between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests. o WOMAC Physical Function Subscale: Mean WOMAC physical function subscale showed significant reduction at Week 1, Week 2, and Week 3, compared to baseline. Mean change from baseline in WOMAC physical function subscale were statistically significant at Week 1, Week 2 and Week 3. The comparison of change from baseline in WOMAC physical function subscale each between weeks were statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p<0.001). Similarly, comparison of WOMAC physical function subscale between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests.

• The mean in NRS score showed significant reduction at Week 1, Week 2 and Week 3, compared to baseline. Mean change from baseline in NRS score were statistically significant at Week 1, Week 2 and Week 3. The comparison of change from baseline in NRS score between weeks were statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and Week 1 vs Week 2 (p<0.001). Similarly, comparison of NRS score between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests.

• Mean in KSS score showed slight reduction at Week 1, Week 2, and at Week 3 significant reduction observed, compared to baseline. Mean change from baseline in KSS score were statistically non-significant at Week 1 and Week 2, and statistically significant Week 3. The comparison of change from baseline in KSS score between weeks were statistically significant in Week 1 vs Week 3 (p=0.018), Week 2 vs Week 3 (p=0.018) and statistically non-significant in Week 1 vs Week 2 (p=0.247). Similarly, comparison of KSS score between baseline vs each week were statistically non-significant in Week 1 vs baseline (p=0.179) and in Week 2 vs baseline (p=0.159) and statistically significant in Week 3 vs baseline (p=0.002) analysed by Wilcoxon Signed Rank Pairwise Tests.

• The mean EQ-5D-5L score showed statistically significant reduction at Week 1, Week 2, and Week 3, compared to baseline. Mean change from baseline in EQ-5D-5L score were statistically significant at Week 1, Week 2 and Week 3. The comparison of change from baseline in EQ-5D-5L score between weeks were statistically significant at Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (p=0.005), and at Week 1 vs Week 2 (p=0.009). Similarly, comparison of EQ-5D-5L score between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests. • Two (1.1%) subjects completed study with events and 185 (98.4%) subjects completed or discontinued the study without event occurrence, the subjects were considered censored. Due to this, there is insufficient data to make any inferences on this endpoint.

STUDY OBJECTIVES

Primary Objective

The primary objective of this study was:

• To evaluate the effects of Voltaren Gel on physical activity, measured through connected activity tracker.

Secondary Objectives

The secondary objectives of this study were:

• To evaluate the effects of Voltaren Gel on functional mobility, measured through connected activity tracker.

• To assess the functional mobility, measured through connected activity tracker.

• To evaluate the effects of Voltaren Gel on functional mobility, measured through subject related outcomes.

• To evaluate the effects of Voltaren Gel on pain intensity.

• To evaluate the effects of Voltaren Gel on activity-related pain and stiffness.

• To evaluate the effects of Voltaren Gel on correlates of QoL.

Exploratory Objectives

The exploratory objectives of this study were:

• To explore the link between Voltaren usage, level of pain relief and functional mobility/quality of life.

• To evaluate time to meaningful pain relief after Voltaren Gel use.

INVESTIGATIONAL PLAN

Overall Study Design and Plan This prospective open-label, single-arm, multi-country (US and EU) RWE study, conducted in a hybrid format focusing on assessing the impact of Voltaren Gel on functional mobility and QoL in individuals with mild/non-serious OA of the knee.

The target population comprises adults aged between 40 and 85 years, diagnosed with mild/non- serious OA of the knee, and self-reporting pain at the time of recruitment. In this hybrid study design, subjects physically attended on site visits for screening (Day -7), baseline assessments (Day 0), and end of study evaluations (Day 21) as presented in Figure 1. The remaining treatment phase (Day 1 to 21) were conducted in a remote manner (e.g.at home) to observe the real-world usage of the product. Study period for each subject was a maximum of 28 days. In this study 196 subjects were enrolled, out of which 194 subjects completed the study and two subjects discontinued from the study.

In the EU, two strengths of Voltaren Gel are available, 11.6 mg/g (1.16%) and 23.2 mg/g (2.32%) diclofenac diethylammonium. During the screening and enrolment process, the Investigator assessed the subject's product preference as well as the need and the severity of OA to determine and dispense the appropriate percentage of gel. The aim was to include a minimum of 25 subjects utilising the 1.16% Voltaren Gel to enable understanding of its real-world usage.

ActiGraph device was provided post the subject's consent at Day -7 to collect baseline information. The baseline period ranged from a minimum of 3 days to a maximum of 7 days , allowing for the collection of sufficient information on both subjective and objective aspects of mobility and sleep quality. The end of baseline period was considered Day 0. At post-baseline period, (at Day 7 of the study) the subjects were provided with the product (Voltaren) and ActiGraph device. The total duration of Voltaren usage was up to 21 days and the assessment of parameters was as highlighted in the objectives. Each subject was in the study for a maximum of 28 days as presented in Figure 1.

Selection of Study Population

Inclusion Criteria

A subject who met all the following inclusion criteria was eligible to be included into the study:

1. Subject who signed and dated the informed consent document indicating that the subject had been informed of all pertinent aspects of the study before any assessment was performed.

2. Male or female who, at the time of screening, was between the ages of 40 and 85 years. 3. A subject who was willing and able to comply with scheduled visits, on-label Voltaren Gel use plan, and other study procedures.

4. A subject who was willing to wear ActiGraph continuously 24/7 for the study period.

5. A subject who was in good general and mental health.

6. A subject diagnosed with knee mild/non-serious OA, proven via radiological evidence collected within the last 3 years (any documentation that indicated mild/moderate OA was acceptable - such as Kellgren/Lawrence [K/L] method of assessment).

7. A subject with self-reported knee pain, with a score of > 40 mm and < 70 mm on the pain intensity visual analogue scale at the time of ICF signature.

8. A subject who was willing to use Voltaren Gel for up to 3 Weeks.

9. A subject of potential childbearing who was willing to follow an effective method of contraception from the time of screening (post consent prior to the use of product) to up to end of study visit.

Efficacy and Safety Measurements Assessed

Screening Assessments: Subject enrolment was determined based on the inclusion/exclusion criteria during screening.

The QoL Assessments: The following QoL tools were completed by subjects daily in the subject eDiary from receipt of product to study conclusion.

• WOMAC, NRS, and EQ-5D-5L Questionnaire

• QoL and Sleep/alertness Questionnaires

Wearable Assessments: The following wearable assessments were performed by ActiGraph daily and correlated with QoL assessments from receipt of product until the study conclusion.

• Moderate and Vigorous Physical Activity (MVPA)

• Physical and sleep based activities

• Mobiliy

• Gait Safety and Other Assessments: Subjects reported all AEs throughout the study from the giving of consent until the study conclusion. Subjects completed an eDiary to record product use each day. Subjects completed the end of the study questions as outlined to them during consent.

Study procedures and their timing are summarised in the Schedule of Activities (SoA) (Table 1): Table 1: Schedule of Activities a ActiGraph tracker was dispensed at screening visit post consent of subject during enrolment for the study (Day -7 to Visit 1) and Voltaren was dispensed immediately post eligibility of the subject at the end of baseline period (Day 0 to Visit 2). b The questionnaires such as: Pain visual analogue scale (VAS) / Numeric Rating Scale (NRS), was initially performed on site during enrolment period (Visit 1) and prior to dispensing of Voltaren (Visit 2), to complete the baseline assessment. Subjects performed the assessment of NRS, Western Ontario and McMaster University Osteoarthritis index (WOMAC), Karolinska sleepiness scale and the EQ-5D-5L health questionnaire at site prior to dispensing of Voltaren (Day 0 to Visit 2) and then at home during the study period and report the score within the eDiary. c Adverse events (AEs) and therefore all Serious Adverse Events (SAEs) were collected immediately after a subject provides consent to participate in the study by the completion of the Informed Consent Form (ICF). • Baseline period was flexible and last a minimum of 3 days and maximum 7 days to collect sufficient baseline information from study subjects. When pain levels reach >40 mm < 70 mm in the VAS/NRS scale, the day before starting the use of Voltaren, study subjects were prompted to answer relevant questionnaires to assess baseline levels. Site staff monitor subjects eDiary and dispense Voltaren when subjects have ended baseline period. Subjects instructed to notify site staff when their baseline period has ended to commence the study.

** Study period lasted a maximum of 28 days. Study subjects were allowed to stop using Voltaren if they feel that their pain has successfully resolved and do not need to use the product anymore.

***Urine test only needed for women of childbearing potential and postmenopausal women who were not surgically sterile. Urine samples were collected to detect the presence of human chorionic gonadotropin (hCG), a hormone produced during pregnancy.

Efficacy Measurements

Primary Efficacy Measurements

The primary efficacy endpoint of the study was change from baseline in the average minutes of MVPA, at Week 1 (Days 1 to 7), Week 2 (Days 8 to 14), and Week 3 (Days 15 to 20).

Secondary Efficacy Measurements

• Change from baseline in following parameters: o Daily Average number of steps taken on Week 1 (Days 1 to 7), Week 2 (8 to 14), and Week 3 (Days 15 to 20) o Ratio of sedentary/non-sedentary time on Week 1 (Days 1 to 7), Week 2 (8 to 14), and Week 3 (Days 15 to 20) o Gait, assessed through speed and step irregularity (measured via cadence and gait speed) on Week 1 (Days 1 to 7), Week 2 (8 to 14), and Week 3 (Days 15 to 20) o Indices of morning stiffness (assessed through levels of activity 30- and 60-mins post-wake) on Week 1 (Days 1 to 7), Week 2 (8 to 14), and Week 3 (Days 15 to 20)

• Indices of level of stiffness throughout the day as assessed via the WOMAC stiffness subscale change from baseline in: o WOMAC on Week 1 (Days 1 to 7), Week 2 (8 to 14), and Week 3 (Days 15 to 21) • MVPA on each day of the study (baseline to final treatment Day 20).

• Study subjects' perceived ability to exercise more regularly. Assessed using the WOMAC Physical Function subscale on Week 1 (Days 1 to 7), Week 2 (8 to 14), and Week 3 (Days 15 to 21)

• Change from baseline in self-reported pain intensity, assessed through NRS (daily assessment) on Week 1 (Days 1 to 7), Week 2 (8 to 14), and Week 3 (Days 15 to 21).

• Change from baseline in the WOMAC total score and subscales on Week 1 (Days 1 to 7), Week 2 (8 to 14), and Week 3 (Days 15 to 21) o Pain (composite) o Stiffness (composite)

• Change from baseline on Week 1 (Days 1 to 7), Week 2 (8 to 14), and Week 3 (Days 15 to 21) in following parameters o Sleep/alertness: Karolinska sleepiness scale (KSS) assessed l^day. o Health-related quality of life: EuroQol-5 Dimensions-5 Levels (EQ-5D-5L).

Exploratory Variables

• Correlations between Voltaren usage, pain relief and mobility, and QoL indices throughout the trial.

• Elapsed time from Voltaren Gel use to achieving time to meaningful pain relief until end of study.

Efficacy Variablefs)

Primary Efficacy Variables

For primary analysis, average minutes of MVPA on Week 1 was calculated over all non-missing days between Study Day 1 (product usage) through 7, inclusive and it was collected via the ActiGraph device. Average minutes of MVPA on Week 2 was calculated over all non-missing days between Study Day 8 through 14, inclusive. Average minutes of MVPA on Week 3 was calculated over all nonmissing days between Study Day 15 through 20, inclusive. Any days beyond Day 20 were excluded from all summaries and analyses and presented in listed data. Average baseline MVPA was computed as: • Average baseline MVPA = total minutes of MVPA over the baseline period/number of days with non-missing data over the baseline period.

Average MVPA for each 7-day period was calculated as:

• Average MVPA for 7-day period = total minutes of MVPA over the period/number of days with non-missing data over the period. o If every day within the 7-day period has non missing data, then the Average MVPA for 7- day period was computed as: total minutes of MVPA over the period/7.

Change from baseline was calculated as:

• Average MVPA for 7-Day period - Average baseline MVPA.

Secondary Efficacy Variables

Change from baseline on Week 1, Week 2 and Week 3 in Daily Average number of steps taken

Average baseline number of steps taken was calculated as:

• Average baseline number of steps taken = total number of steps taken over the baseline period/number of days with non missing data over the baseline period.

Daily average number of steps taken for each 7-Day period was calculated as:

• Daily average number of steps taken for 7-Day period = total number of steps over the period/number of days with non missing data over the period.

Change from baseline was calculated as:

• Daily average number of steps taken for 7-Day period - Average baseline number of steps taken.

Change from baseline on Week 1, Week 2 and Week 3 in Ratio of sedentanz/non-sedentarv time

Number of sedentary behaviour minutes in the day was defined as sedentary activity from the day level activity outcomes.

Number of non-sedentary behaviour minutes in the day was derived as:

• Sum of Light Activity and MVPA from the day level activity outcomes.

Ratio of sedentary/non-sedentary time per day was calculated as: • Ratio of sedentary/non-sedentary time per day = Number of minutes in the day defined as Sedentary behaviour Number of minutes in the day defined as non-sedentary behaviour.

Baseline ratio of sedentary/non-sedentary time was calculated, where the variable of interest was the ratio of sedentary/non-sedentary time.

Ratio of sedentary/non-sedentary time for each 7-day period was calculated as:

• Ratio of sedentary/non-sedentary time for 7-day period = Total number of minutes defined as Sedentary behaviour in the 7-day period/Total number of non-sedentary behaviour minutes in the 7-day period

Change from baseline was calculated as:

• Ratio of sedentary/non-sedentary time for 7-day period - Baseline ratio of sedentary/non- sedentary time.

Change from baseline on Week 1, Week 2 and Week 3 in Gait, assessed through speed and step irregularity (measured via cadence and gait speed)

Average baseline cadence was calculated as:

• Average baseline cadence = total mean cadence over the baseline period/number of days with non-missing data over the baseline period.

Average cadence for each 7-Day period was calculated as:

• Average cadence for 7-Day period = total mean cadence/number of days with non missing data over the period.

Change from baseline was calculated as:

• Average cadence for 7-Day period - Average baseline cadence.

Average baseline gait speed was calculated as:

• Average baseline gait speed = total mean gait speed over the baseline period/number of days with non-missing data over the baseline period.

Average gait speed for each 7-Day period was calculated as:

• Average gait speed for 7-Day period = total mean gait speed/number of days with non missing data over the period. Change from baseline was calculated as:

• Average gait speed for 7-Day period - Average baseline gait speed.

Change from baseline on Week 1, Week 2 and Week 3 in Indices of morning stiffness (assessed through levels of mobility 30- and 60-mins post-wake)

30 minutes post-wake was defined as the interval from bed interval end date/time from the sleep metrics by night outcome + 30 minutes.

Daily morning stiffness 30 minutes post-wake was defined as the total vector magnitude counts 30 minutes post-wake.

Average baseline morning stiffness 30 minutes post-wake was calculated as:

• Average baseline morning stiffness 30 minutes post-wake = total daily morning stiffness 30 minutes post-wake over the baseline period / number of days with non-missing data over the baseline period.

Average morning stiffness 30 minutes post-wake for each 7-Day period was calculated as:

• Average morning stiffness 30 minutes post-wake for 7-Day period = total daily morning stiffness 30 minutes post-wake / number of days with non missing data.

Change from baseline was calculated as:

• Average morning stiffness 30 minutes post-wake for 7-Day period - Average baseline morning stiffness 30 minutes post-wake.

60 minutes post-wake was defined as the interval from bed interval end date/time from the sleep metrics by night outcome + 60 minutes. Daily morning stiffness 60 minutes post-wake, average baseline morning stiffness 60 minutes post-wake, average morning stiffness 60 minutes post-wake for each 7-Day period, and change from baseline were calculated in the same way as described for 30 minutes post-wake.

MVPA on each day of the study (Baseline to final treatment Week 3)

The variable used was the total number of minutes of MVPA calculated for each study day.

Change from baseline in self-reported pain intensity, assessed through Numeric Rating Scale (NRS) (daily assessment). Self-reported pain intensity was recorded on the 'Numeric Rating Scale' eDiary page at each scheduled timepoint.

Baseline was the value collected on Day 0.

Change from baseline was calculated as:

• NRS score at Scheduled Timepoint - NRS baseline score (Day 0)

WOMAC Subscale Score (Pain WOMAC A, Stiffness WOMAC B, and Function WOMAC C)

The WOMAC® LK3.0 is composed of three subscales (A: Pain, B: Stiffness, C: Physical Function). There are five components for subscale A (Pain), 2 components for subscale B (Stiffness), and 17 components for subscale C (Physical Function) each component is measured on a 0-4 scale.

A WOMAC subscale score was calculated, at Day 0, Day 1, Week 1, Week 2 and Week 3, as the sum of the available component scores within the subscale. For convenience this was normalized on a 0- 100 scale by dividing the sum appropriately:

• Pain WOMAC A = (sum of raw score items in dimension) x 5

• Stiffness WOMAC B= (sum of raw score items in dimension) x 12.5

• Function WOMAC C = (sum of raw score items in dimension) x 1.47

The subscale score was set to missing according to the following:

• if > 2 Pain components were missing

• if both Stiffness components were missing

• if > 4 Physical Function components were missing

As outlined in the WOMAC scoring guide, if there were missing components within a subscale but the number of missing components did not meet the criteria for setting the subscale score to missing, then the value of the missing components were set equal to the mean of the available components of the respective subscale.

The WOMAC subscale scores and normalized subscale scores were calculated, for baseline (Day 0) and for all post-baseline time-points: Day 1, Week 1, Week 2 and Week 3

Normalized WOMAC subscale scores were used for the following endpoints: Change from baseline in WOMAC physical function subscale on Week 1, Week 2 and Week

3.

• Change from baseline in the WOMAC subscales, Pain (composite) and Stiffness (composite) on Week 1, Week 2 and Week 3.

For each scheduled time point:

• Baseline value collected on Day 0

• Change from baseline was calculated as: Normalized WOMAC subscale score at Scheduled Timepoint - Normalized WOMAC subscale baseline score (Day 0).

WOMAC Global Score

The total WOMAC® LK3.0 global score, calculated at, Day 0, Day 1, Week 1, Week 2 and Week 3, was computed as the sum of the three normalized WOMAC subscale scores.

The total WOMAC score was set to missing if any of the WOMAC subscale scores were set to missing. The WOMAC global score was calculated as:

• WOMAC global score = WOMAC A + WOMAC B + WOMAC C

WOMAC global score and change from baseline were calculated at all visits.

Change from baseline in Karolinska Sleepiness Scale on Week 1, Week 2 and Week 3

The KSS was recorded on the 'Karolinska sleepiness scale' eDiary page at each scheduled timepoint. Change from baseline was calculated as:

• KSS at Scheduled Timepoint - KSS at Day 0

EO-5D-5L

Health-related QoL was recorded on the 'EQ-5D-5L QoL Questionnaire' eDiary page.

The EQ-5D is a standardized instrument for assessing health-related QoL, which provides a simple descriptive profile and a single index value for health status in a variety of health conditions. The EQ-5D includes single item measures of five health dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D-5L includes five levels of severity (i.e., no problems, slight problems, moderate problems, severe problems, and extreme problems) for each of the five EQ-5D dimensions. These levels are scored from l=no problems to 5= extreme problems.

EQ-5D-5L Health State

The scores (1-5) for the five dimensions were concatenated into a 5-digit code (in the order mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that describes the subjects health state.

EQ-5D-5L Index

From the EQ-5D-5L health state the EQ-5D-5L index values were calculated based on the Crosswalk Value Set for the US. If one of the dimensions has a missing score, the EQ-5D-5L index value was derived as missing.

EQ-5D-5L index values were used for the following endpoint:

• Change from baseline in Health-related QoL, EQ-5D-5L, on Week 1, Week 2 and Week 3.

Exploratory Variables

Elapsed time from Voltaren Gel use to achieving time to meaningful pain relief to end of study

Date of meaningful pain relief was defined as the earliest date where:

• The answer to "Did you use yesterday the Voltaren Gel as per label and leaflet instructions?" was "No"

AND

• The answer to "If No, please specify the reason:" was "No pain anymore"

On the 'Study Product Use' eDiary page.

The time to event was derived in days as:

• Date of event/censoring - date of First Treatment Administration +1

Date of First Treatment Administration was derived.

For the primary and secondary endpoints where the data is collected through the activity tracker, only subjects who met the minimum wear threshold were included in the analysis. This is defined as a minimum of 3 valid days during the baseline period and a minimum of 3 valid days within each post-baseline 7-day period, where a valid day is defined as a minimum wear of 20 hours per day.

For the secondary objectives, functional mobility as measured through wearables and PRO, pain intensity assessed through NRS (daily assessment), activity- related pain and stiffness as measured in the (Likert Scale) WOMAC subscales for composite pain and composite stiffness were analysed in the same manner as the primary objective.

Time to pain relief was evaluated using the Kaplan-Meier method.

General Methods

For continuous variables, the mean, standard deviation, minimum, median, and maximum were presented, together with the total number of observations and the number of missing and nonmissing values. Unless otherwise specified, minimum and maximum values were reported to the same number of decimal places as the recorded measurements; mean and median were reported to one more decimal place and standard deviation one additional decimal place more than the mean.

For categorical variables, absolute and relative frequencies were reported. Relative frequencies were based on all observations and reported as percentages to one decimal place. Unless otherwise specified, percentages were based on the number of subjects with data and were not calculated for missing categories.

Adverse events were reported on a per subject basis, i.e. if a subject reported several events coded to the same coding term, the subject was counted only once at the respective level of display. The percentages were calculated using the number of subjects in the population Analysis Set as the denominator.

All hypotheses were tested at a 5% level of significance using a two-sided test unless otherwise specified.

P-values were rounded to three decimal places. If a p-value was less than 0.001 it was reported as "<0.001." If a p-value was greater than 0.999 it was reported as ">0.999.

Definition of Time-Points Date of First Study Treatment Administration

Date of first study treatment administration was derived as: (The earliest recorded date where the answer to the question "Did you use yesterday the Voltaren Gel as per label and leaflet instructions?" was "Yes" on the 'Study Product Use' eDiary page) - 1.

Date of Last Study Treatment Administration

Date of last study treatment administration was defined as:

• "Date of last application of study drug" as recorded in the 'Study Termination eCRF page).

Study Day

The study day of events/assessments was calculated as:

• Study day = (Date of assessment/event - Date of Baseline Visit).

Baseline

The baseline value for QoL data was defined as measurements collected on Day 0. Baseline for data collected through connected activity tracker was derived as an average per day:

• Sum of the variable of interest/baseline period.

Where the baseline period was the number of non-missing days between day -6 to day 0 - Prior to product usage.

Statistical Methods and Analysis Variables

Visual Analogue Scale (VAS): VAS score was recorded on the 'visual analogue scale' at screening and baseline and the value was entered in eCRF page.

Corrections to the scores were applied for scores recorded on or before 08 Jul 2024 due to the incorrect length of scale used in performing the test. This was documented in non-conformity number 61/2024. The following corrections were applied:

• For site 0201: VAS score = raw VAS score x 0.82. o Correction factor calculated as: 100 - 122 (actual length of scale)

• For site 0202: VAS score = raw VAS score x 0.88. o Correction factor calculated as: 100 - 113 (actual length of scale) Total Number of Days on Study

Total number of days on study was calculated as:

• Total Number of Days on Study = (Date of Study Completion/Discontinuation - Date of Screening Visit) +1.

Total Number of Days in Treatment Phase

Total Number of Days in Treatment Phase was calculated as:

• Total Number of Days Treatment Phase = (Date of Study Completion/Discontinuation - Date of Baseline Visit) + 1.

Duration of Exposure

Duration of exposure was calculated as:

• Duration of exposure (days) = (Date of Last Study Treatment Administration - Date of First Study Treatment Administration) + 1

Study Treatment Compliance

Study treatment compliance was determined from the 'Study Product Use' eDiary pages and calculated as:

• Treatment compliance (%) = (Number of days the answer to "Did you use yesterday the Voltaren Gel as per label and leaflet instructions?" was "Yes" - Duration of exposure) xlOO.

ActiGraph Device Compliance

The required ActiGraph daily minimum wear time was 20 hours. Daily wear minutes was collected via the ActiGraph device and converted to hours as:

• Daily wear time (hours) = Daily wear minutes - 60.

ActiGraph device compliance was calculated as:

• ActiGraph device compliance (%) = (Number of days the daily wear time (hours) was greater than or equal to 20 hours - Total number of days on study) x 100

Awake Trigger Compliance Awake trigger compliance was determined from the 'Study Product Use' eDiary pages and calculated as:

• Awake trigger compliance (%) = (Number of days the answer to "Did you click the event trigger at awake yesterday?" was "Yes" - Total Number of Days in Treatment Phase) x 100. Bedtime Trigger Compliance

Bedtime trigger compliance was determined from the 'Study Product Use' eDiary pages and calculated as:

• Bedtime trigger compliance (%) = (Number of days the answer to "Did you click the event trigger at bedtime yesterday?" was "Yes" - Total Number of Days in Treatment Phase) x 100. STUDY SUBJECTS

Disposition of Subjects

Summary of subject disposition is presented in Table 2.

Overall, 214 subjects were screened during study, in which 17 subjects were screen failure and 196 subjects were enrolled during study, out of which 194 (99.0%) subjects completed the study, and two (1.0%) subjects discontinued from the study (consent withdrawal and other).

Table 2: Summary of Subject Disposition (Total Set)

Data Sets Analyzed

The summary of analysis sets for all enrolled subjects is presented in Table 3. All subjects (N= 196) enrolled in the study were included in the safety population, used for safety analysis and 188 (95.9%) subjects were included in the mITT population, used for efficacy analysis. Two (1.0%) subjects were excluded from mITT due to not meeting the eligibility criteria and six (3.1%) subjects were excluded due to unavailability of post-baseline data.

Among all enrolled subjects, 39 subjects were included in Voltaren Gel 1%, 39 subjects were included in Voltaren Gel 1.16% and 118 subjects were included in Voltaren Gel 2.32% treatment groups.

Table 3: Summary of Analysis Sets (Enrolled Population)

Demographic and Other Baseline Characteristics

The summary of demographic information is presented in Table 4.

In this study, out of 196 enrolled subjects, 118 (60.2%) were female and 78 (39.8%) were male. The proportion of females were high across all the three treatment groups of Voltaren Gel dispensed i.e., 1%, 1.16% and 2.32%.

All enrolled subjects were between the age 41 to 83 years with a mean (SD) age 61.8 (9.33) years. The mean age was similar across all the three treatment groups of Voltaren Gel (1%, 1.16% and 2.32%). Majority of the subjects were of White race [188 (95.9%) The information on ethnicity was missing for two treatment groups of Voltaren Gel (1.16% and 2.32%) as ethnicity was collected only for patients recruited in US country. Maximum number of subjects using Voltaren Gel 1% were not Hispanic or Latino [20 (51.3%)].

Table 4: Summary of Demographic Data (Enrolled Population)

Change from baseline in the average minutes of MVPA

The analysis of change from baseline in average minutes of MVPA is presented in Table 5 and Figure 2. The mean (SD) average minutes of MVPA was 249.2 (92.99) at baseline, 263.4 (101.87) at Week 1, 259.9 (104.61) at Week 2, and 248.4 (104.60) at Week 3.

Overall, for treatment days (Week 1 to Week 3), the mean (SD) of average minutes of MVPA was greater [257.8 (99.30)] when compared with the baseline [249.2 (92.99]). The mean (SD) change from baseline in average minutes of MVPA was 14.2 (53.54) in Week 1 [Least Squares (LS) mean 15.6 (95% CI: 8.3, 22.8, p<0.001)], 10.7 (60.93) in Week 2 [LS mean 13.0 (95% CI: 5.2, 20.9, p=0.001)], and -0.8 (71.08) in Week 3 [LS mean 2.1 (95% CI: -7.1, 11.3, p=0.653)]. This indicates that the average minutes of MVPA significantly increased from baseline to Week 1 and Week 2 and a slight decrease was observed between baseline and Week 3.

Average minutes of MVPA was analysed by Shapiro- Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically significant result (p=0.003).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in average minutes of MVPA between weeks. The average minutes of MVPA was statistically significant in Week 1 vs Week 3 (p<0.001) and in Week 2 vs Week 3 (p=0.006) and statistically non-significant in Week 1 vs Week 2 (p=0.323).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of average minutes of MVPA between baseline and each week. The average minutes of MVPA was statistically significant in Week 1 vs baseline (p<0.001) and in Week 2 vs baseline (p=0.005) and statistically non-significant in

Week 3 vs baseline (p=0.733).

Overall, it was observed that the average minutes of MVPA increased during the treatment period (Week 1 to Week 3), compared with baseline, with the average minutes of MVPA being statistically significantly higher at Week 1 and Week 2 when compared with baseline. Table 5: Analysis of Change from Baseline Average Minutes of MVPA (Modified Intent-To-Treat Population)

Secondary Endpoint Results - Change from baseline in daily average number of steps taken via ActiGraph

The analysis of change from baseline in daily average number of steps is presented in Table 6. The mean (SD) in daily average number of steps taken was 13826.5 (5076.05) at baseline, 14428.8 (5380.53) at Week 1, 14149.6 (5474.71) at Week 2 and 13769.4 (5545.45) at Week 3.

Overall, for treatment days (Week 1 to Week 3), the mean (SD) of daily average number of steps taken was greater [14135.3 (5223.86)] when compared with the baseline [13826.5 (5076.05)]. The mean (SD) change from baseline in daily average number of steps taken was 602.3 (2930.69) in Week 1 [LS mean 707.0 (95% CI: 278.9, 1135.0, p=0.001)], 323.1 (3515.66) in Week 2 [LS mean 487.3 (95% CI: 22.0, 952.6, p=0.040, and -57.1 (3826.57) in Week 3 [LS mean 130.8 (95% CI: - 365.6, 627.2, p=0.603). This indicates that the daily average number of steps taken was significantly increased from baseline to Week 1, and Week 2 and a slight decrease was observed between baseline and Week 3. Daily average number of steps taken was analysed by Shapiro-Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically non-significant result (p=0.065).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in daily average number of steps taken between weeks. The daily average number of steps taken were statistically significant in Week 1 vs Week 3 (p=0.007) and statistically non-significant in Week 2 vs Week 3 (p=0.123) and in Week 1 vs Week 2 (p=0.076).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of daily average number of steps taken between baseline and each week. The daily average number of steps taken were statistically significant in Week 1 vs baseline (p<0.001) and in Week 2 vs baseline (p=0.042) and statistically non-significant in Week 3 vs baseline (p=0.670).

Overall, it was observed that the average number of steps taken increased during the treatment period (Week 1 to Week 3), compared with baseline, with the average number of steps taken being statistically significantly higher at Week 1 and Week 2 when compared with baseline. Table 6: Analysis of Change from Baseline Daily Average Number of Steps (Modified Intent-To-Treat Population)

Change from baseline in indices of morning stiffness (assessed through levels of mobility 30- and 60-mins post-wake) via ActiGraoh

The analysis of change from baseline in indices of morning stiffness is presented in Table 7 and Figures 6 and 7.

30 Minutes post- wake

Mean (SD) in morning stiffness at 30 Minutes post-wake was 75593.364 (44958.5420) at baseline, 77494.570 (44298.6087) at Week 1, 77650.379 (45155.0171) at Week 2 and 73220.860 (46054.5964) at Week 3 (Figure 6). Mean (SD) change from baseline in indices of morning stiffness at 30 Minutes post-wake were 1969.758 (28283.0182) in Week 1 [LS mean 2415.232 (95% CI: -1466.301, 6296.764, p=0.221)], 2332.422 (28420.8109) in Week 2 [LS mean 3041.705 (95% CI: -868.486, 6951.895, p=0.127)], and -1893.342 (34458.1863) in Week 3 [LS mean -2428.684 (95% CI: -7177.462, 2320.093, p=0.314)]. This indicates that the morning stiffness at 30 Minutes post-wake slightly increased from baseline to Week 1, and Week 2 and decreased at Week 3.

The indices of morning stiffness at 30 Minutes post-wake were analysed by Shapiro-Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically significant result (p=0.009). Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in indices of morning stiffness 30 Minutes post-wake between weeks. The indices of morning stiffness at 30 Minutes post-wake were statistically significant in Week 1 vs Week 3 (p=0.013), Week 2 vs Week 3 (p=0.011) and statistically non-significant in Week 1 vs Week 2 (p=0.570).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of indices of morning stiffness at 30 Minutes post-wake between baseline and each week. The indices of morning stiffness at 30 Minutes post-wake were statistically non-significant in Week 1 vs baseline (p=0.354), in Week 2 vs baseline (p=0.349), and in Week 3 vs baseline (p=0.151).

Overall, it was observed that indices of morning stiffness at 30 Minutes post-wake during the treatment period (Week 1 to Week 3), was similar when compared with baseline with no statistically significant differences between baseline and each week.

60 Minutes post- wake

Mean (SD) in morning stiffness at 60 Minutes post-wake was 149034.401 (86661.4977) at baseline, 151728.510 (86390.9308) at Week 1, 150912.387 (87318.8766) at Week 2 and 141510.829 (87510.5820) at Week 3 (Figure 7).

Mean (SD) change from baseline in indices of morning stiffness at 60 Minutes post-wake were 2891.276 (45249.4973) in Week 1 [LS mean 3409.868 (95% CI: -2911.441, 9731.177, p=0.289)], 2438.403 (48859.7477) in Week 2 [LS mean 3552.324 (95% CI: -3240.403, 10345.051, p=0.303)] , and -6734.944 (54957.9211) in Week 3 [LS mean -7820.660 (95% CI: -15512.824, - 128.496, p=0.046]. This indicates that the morning stiffness at 60 Minutes of post-wake slightly increased from baseline to Week 1, and Week 2 and significantly decreased in Week 3.

The indices of morning stiffness at 60 Minutes post-wake were analysed by Shapiro-Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically significant result (p<0.001).

Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in indices of morning stiffness at 60 Minutes post-wake for each week. The indices of morning stiffness at 60 Minutes post-wake were statistically significant in Week 1 vs Week 3 (p=0.002), in Week 2 vs Week 3 (p=0.003) and statistically non-significant in Week 1 vs Week 2 (p=0.930).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of indices of morning stiffness at 60 Minutes post-wake between baseline and each week. The indices of morning stiffness at 60 Minutes post-wake were statistically significant in Week 3 vs baseline (p=0.050), and statistically non-significant in Week 1 vs baseline (p=0.136), in Week 2 vs baseline (p=0.276).

Overall, it was observed that indices of morning stiffness at 60 Minutes post-wake during the treatment period (Week 1 to Week 3), was similar when compared with baseline with indices of morning stiffness at 60 Minutes post-wake being statistically significantly lower in Week 3 compared with baseline.

Table 7: Analysis of Change from Baseline Indices of Morning Stiffness (Modified Intent-To-Treat Population)

Indices of level of stiffness throughout the day as assessed via the WOMAC stiffness subscale change from baseline in WOMAC physical function subscale

The analysis of change from baseline in WOMAC scores are presented in Table 8 and Figure 5. WOMAC Global Score

The mean (SD) WOMAC global score was 147.040 (38.1349) at baseline, 120.662 (42.1799) at Week 1 at Week 2, 111.702 (42.8259) at Week 2, and 98.512 (48.6747) at Week 3.

Mean (SD) change from baseline in WOMAC global score was -27.359 (38.7623) in Week 1 [LS mean -26.529 (95% CI: -31.929, -21.129, p<0.001)], -36.062 (42.4964) in Week 2 [LS mean - 36.179 (95% CI: -42.090, - 30.269, p<0.001)], and - 47.852 (49.4526) in Week 3 [LS mean -48.834

(95% CI: -55.692, -41.976, p<0.001)]. This indicates that the WOMAC global score showed statistically significant reduction from baseline to Week 1, Week 2, and Week 3. The WOMAC global score was analysed by Shapiro-Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically significant result (P<0.001).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in WOMAC global score between weeks. The reduction of WOMAC global score was statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p<0.001). The Wilcoxon Signed Rank Pairwise Tests were used for comparison of WOMAC global score between baseline and each week. The WOMAC global score was statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001), and in Week 3 vs baseline (p<0.001).

Overall, it was observed that WOMAC global score during the treatment period (Week 1 to Week 3), was lower when compared with baseline with WOMAC global score being statistically significantly lower at Week 1, Week 2 and Week 3 compared with baseline.

WOMAC Pain Subscale (walking, stair climbing, nocturnal, rest, weightbearing)

The mean (SD) WOMAC pain subscale was 48.196 (13.2952) at baseline, 38.614 (13.5973) at Week 1, 35.882 (13.7319) at Week 2 and 31.594 (16.0770) at Week 3.

Mean (SD) change from baseline in WOMAC pain subscale was -9.458 (13.7044) in Week 1 [LS mean -9.213 (95% CI: -11.011, -7.415, p<0.001)], -12.422 (14.5893) in Week 2 [LS mean -12.570 (95% CI: -14.519, -10.621, p<0.001)], and -16.383 (16.6274) in Week 3 [LS mean -16.408 (95% CI: -18.669, -14.146, p<0.001)]. This indicates that the WOMAC pain subscale showed statistically significant reduction from baseline to Week 1, Week 2, and Week 3.

The WOMAC pain subscale was analysed by Shapiro-Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically significant result (P<0.001).

Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in WOMAC pain subscale between weeks. The reduction of WOMAC pain subscale was statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p<0.001).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of WOMAC pain subscale between baseline and each week. The WOMAC pain subscale was statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001), and in Week 3 vs baseline (p<0.001).

Overall, it was observed that WOMAC pain subscale during the treatment period (Week 1 to Week 3), was lower when compared with baseline with WOMAC pain subscale being statistically significantly lower at Week 1, Week 2 and Week 3 compared with baseline.

WOMAC Stiffness Subscale (morning stiffness and stiffness occurring during day)

The mean (SD) WOMAC stiffness subscale was 50.142 (16.7965) at baseline, 41.667 (17.7457) at Week 1, 38.750 (17.0195) at Week 2, and 34.270 (18.5098) at Week 3. Mean (SD) change from baseline in WOMAC stiffness subscale was -9.242 (18.6173) in Week 1 [LS mean -8.912 (95% CI: -11.401, -6.423, p<0.001)], -11.719 (19.2063) in Week 2 [LS mean -11.699 (95% CI: -14.177, - 9.221, p<0.001)], and -15.680 (20.6853) in Week 3 [LS mean -16.166 (95% CI: -18.858, -13.473, p<0.001)]. This indicates that the WOMAC stiffness subscale showed statistically significant reduction from baseline to Week 1, Week 2, and Week 3.

The WOMAC stiffness subscale was analysed by Shapiro-Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically significant result (P<0.001).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in WOMAC stiffness subscale between weeks. The reduction of WOMAC stiffness subscale was statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p=0.003).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of WOMAC stiffness subscale between baseline and each week. The WOMAC stiffness subscale was statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001), and in Week 3 vs baseline (p<0.001).

Overall, it was observed that WOMAC stiffness subscale during the treatment period (Week 1 to Week 3), was lower when compared with baseline with WOMAC stiffness subscale being statistically significantly lower at Week 1, Week 2 and Week 3 compared with baseline.

WOMAC Physical Function Subscale

Mean (SD) WOMAC physical function subscale was 48.702 (12.9284) at baseline, 40.375 (14.7527) at Week 1, 37.072 (15.9130) at Week 2 and 32.781 (17.2916) at Week 3.

Mean (SD) change from baseline in WOMAC physical function subscale was -8.677 (12.6188) in Week 1 [LS mean -8.392 (95% CI: -10.196, -6.588, p<0.001)], -11.926 (14.0764) in Week 2 [LS mean -11.882 (95% CI: -13.946, - 9.818, p<0.001)], and - 15.644 (16.9641) in Week 3 [LS mean - 15.929 (95% CI: -18.320, -13.537, p<0.001)]. This indicates that the WOMAC physical function subscale showed a statistically significant reduction from baseline to Week 1, Week 2, and Week 3.

The WOMAC physical function subscale was analysed by Shapiro-Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically significant result (P<0.001). The Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in WOMAC physical function subscale between weeks. The reduction of WOMAC physical function subscale was statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p<0.001). The Wilcoxon Signed Rank Pairwise Tests were used for comparison of WOMAC physical function subscale between baseline and each week. The WOMAC physical function subscale was statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001), and in Week 3 vs baseline (p<0.001).

Overall, it was observed that WOMAC physical function subscale during the treatment period (Week 1 to Week 3), was lower when compared with baseline with WOMAC physical function subscale being statistically significantly lower at Week 1, Week 2 and Week 3 compared with baseline.

Table 8: Analysis of Change from Baseline WOMAC - Total Score and Subscale Total Scores

(Modified Intent-To-Treat Population)

Change from baseline in Sleep /alertness - Karolinska Sleepiness Scale assessed Ix/dav

The analysis of change from baseline in sleep/alertness - KSS assessed lx/day is presented in Table 9 and Figure 3. Karolinska sleepiness scale measures the subjective level of sleepiness/alertness during the day. The slight reduction in KSS score was observed from baseline (3.9 = alert to fairly alert) to Week 3 (3.5 = alert to fairly alert).

Mean (SD) in KSS score was 3.9 (1.60) at baseline, 3.7 (1.60) at Week 1, 3.7 (1.60) at Week 2 and 3.5 (1.52) at Week 3. Mean (SD) change from baseline in KSS score was -0.2 (1.56) in Week 1 [LS mean -0.1 (95% CI: - 0.3, 0.1, p=0.237)], -0.2 (1.70) in Week 2 [LS mean -0.2 (95% CI: -0.4, 0.0, p=0.071)], and -0.4 (1.66) in Week 3 [LS mean -0.4 (95% CI: -0.6, -0.2, p<0.001)]. This indicates that the KSS score showed a slight reduction from baseline to Week 1, Week 2, however significant reduction observed in Week 3. The KSS score was analysed by Shapiro-Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically significant result (p=0.008). The Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in KSS score between weeks. The reduction of KSS score was statistically significant in Week 1 vs Week 3 (p=0.018), Week 2 vs Week 3 (p=0.018) and statistically non-significant in Week 1 vs Week 2 (p=0.247). The Wilcoxon Signed Rank Pairwise Tests were used for comparison of KSS score between baseline and each week. The KSS score was statistically significant in Week 3 vs baseline (p=0.002) and statistically non-significant in Week 1 vs baseline (p=0.179) and in Week 2 vs baseline (p=0.159).

Overall, it was observed that KSS score during the treatment period (Week 1 to Week 3), was slightly lower when compared with baseline with KSS score being statistically significantly lower in Week 3 compared with baseline.

Table 9: Analysis of Change from Baseline of Karolinska Sleepiness Scale (Modified Intent-To-Treat Population)

Change from baseline in Health-related quality of life EuroQol-5 Dimensions-5 Levels (EQ-5D-5L)

The analysis of change from baseline in EQ-5D-5L score is presented in Table 10 and Figure 4. The mean (SD) EQ-5D-5L score was 0.67 (0.124) at baseline, 0.71 (0.117) at Week 1, 0.72 (0.124) at Week 2 and 0.74 (0.129) at Week 3.

Mean (SD) change from baseline in EQ-5D-5L score was 0.04 (0.098) in Week 1 [LS mean 0.04 (95% CI: 0.02, 0.05, p<0.001)], 0.05 (0.097) in Week 2 [LS mean 0.05 (95% CI: 0.04, 0.07, p<0.001)], and 0.07 (0.111) in Week 3 [LS mean 0.07 (95% CI: 0.05, 0.09, p<0.001)]. This indicates that the EQ-5D-5L score showed a statistically significant increase from baseline to Week 1, Week 2, and Week 3.

The EQ-5D-5L score was analysed by Shapiro-Wilk test to check the normality of data, and the data was found to be non-normal (p<0.001). Hence, the Friedman test was performed and showed a statistically significant result (P<0.001).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of change from baseline in EQ- 5D-5L score between weeks. The EQ-5D-5L score was statistically significant at Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (p=0.005), and at Week 1 vs Week 2 (p=0.009).

The Wilcoxon Signed Rank Pairwise Tests were used for comparison of EQ-5D-5L score between baseline and each week. The EQ-5D-5L score was statistically significant in Week 1 vs baseline (p<0.001), and in Week 2 vs baseline (p<0.001), and in Week 3 vs baseline (p<0.001).

Overall, it was observed that EQ-5D-5L score during the treatment period (Week 1 to Week 3), was higher when compared with baseline with EQ-5D-5L score being statistically significantly higher at Week 1, Week 2 and Week 3 compared with baseline.

Table 10: Analysis of Change from Baseline of EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) (Modified Intent-To-Treat Population)

Efficacy Conclusions

The following conclusions are based on the results of efficacy analyses:

Primary efficacy endpoint results: • The mean average minutes of MVPA increased at Week 1, Week 2, and slightly decreased at

Week 3, compared to baseline. The mean change from baseline in average minutes of MVPA was statistically significant at Week 1, Week 2 and statistically non-significant at Week 3. The comparison of change from baseline in average minutes of MVPA between weeks were statistically significant at Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (p=0.006) and statistically non- significant at Week 1 vs Week 2 (p=0.323). Similarly, the comparison of average minutes of MVPA between baseline and each week were statistically significant in Week 1 vs baseline (p<0.001), Week 2 vs baseline (p=0.005) and statistically non-significant in Week 3 vs baseline (p=0.733) analysed by Wilcoxon Signed Rank Pairwise Tests.

Secondary efficacy endpoint results:

• The mean in ratio of sedentary/non-sedentary time via ActiGraph was increased at Week 2 and Week 3, compared to baseline. Mean change from baseline in ratio of sedentary/non-sedentary time was statistically non-significant at Week 1, Week 2 and statistically significant at Week 3. The comparison of change from baseline in ratio of sedentary/non-sedentary time between weeks were statistically significant in Week 1 vs Week 3 (p<0.001), in Week 2 vs Week 3 (p=0.006) and statistically non-significant in Week 1 vs Week 2 (p=0.221), Similarly, comparison in ratio of sedentary/non-sedentary time between baseline vs each week were statistically non-significant in Week 1 vs baseline (p=0.385) and in Week 2 vs baseline (p=0.899) and statistically significant in Week 3 vs baseline (p=0.036) analysed by Wilcoxon Signed Rank Pairwise Tests.

• The gait was analysed through speed and step irregularity (measured via cadence and gait speed) via ActiGraph: o Cadence: The mean in gait though cadence was decreased at Week 1, Week 2, and Week 3, compared to baseline. Mean change from baseline in gait though cadence was statistically nonsignificant at Week 1, Week 2, and Week 3. The comparison of change from baseline in gait though cadence between weeks were statistically non-significant in Week 1 vs Week 3 (p=0.406), Week 2 vs Week 3 (p=0.250), and Week 1 vs Week 2 (p=0.923). Similarly, comparison of gait though cadence between baseline vs each week were statistically non-significant in Week 1 vs baseline (p=0.289), Week 2 vs baseline (p=0.225), and Week 3 vs baseline (p=0.728) analysed by Wilcoxon Signed Rank Pairwise Tests. o Gait Speed: The mean in gait speed was decreased at Week 1, Week 2, and at Week 3, compared to baseline. The comparison of change from baseline in gait speed between weeks was statistically non-significant in Week 1 vs Week 3 (p=0.353), in Week 2 vs Week 3 (p=0.867), and in Week 1 vs Week 2 (p=0.140). Similarly, comparison of gait speed between baseline vs each week was statistically non-significant in Week 1 vs baseline (p=0.730), Week 2 vs baseline (p=0.234), and Week 3 vs baseline (p=0.550) analysed by Wilcoxon Signed Rank Pairwise Tests.

• Indices of level of stiffness throughout the day as assessed via the WOMAC stiffness subscale change from baseline in WOMAC physical function subscale o WOMAC Global Score: The mean WOMAC global score showed significant reduction at Week 1, Week 2, and at Week 3, compared to baseline. Mean change from baseline in WOMAC global score were statistically significant at Week 1, Week 2, and Week 3. The comparison of change from baseline in WOMAC global score between weeks was statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p<0.001). Similarly, comparison of WOMAC global score between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests. o WOMAC Pain Subscale (walking, stair climbing, nocturnal, rest, weightbearing): The mean WOMAC pain subscale showed significant reduction at Week 1, Week 2, and Week 3, compared to baseline. Mean change from baseline in WOMAC pain subscale were statistically significant at Week 1, Week 2, and Week 3. The comparison of change from baseline in WOMAC pain subscale between weeks were statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p<0.001). Similarly, comparison of WOMAC pain subscale between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), and in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests. o WOMAC Stiffness Subscale (morning stiffness and stiffness occurring during day): The mean WOMAC stiffness subscale showed significant reduction at Week 1, Week 2 and Week 3, compared to baseline. Mean change from baseline in WOMAC stiffness subscale were statistically significant at Week 1, Week 2, and Week 3. The comparison of change from baseline in WOMAC stiffness subscale between weeks were statistically significant at in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p=0.003). Similarly, comparison of WOMAC stiffness subscale between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests. o WOMAC Physical Function Subscale: Mean WOMAC physical function subscale showed significant reduction at Week 1, Week 2, and Week 3, compared to baseline. Mean change from baseline in WOMAC physical function subscale were statistically significant at Week 1, Week 2, and Week 3. The comparison of change from baseline in WOMAC physical function subscale each between weeks were statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and in Week 1 vs Week 2 (p<0.001). Similarly, comparison of WOMAC physical function subscale between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests. • The mean in NRS score showed significant reduction at Week 1, Week 2 and Week 3, compared to baseline. Mean change from baseline in NRS score were statistically significant at Week 1, Week 2 and Week 3. The comparison of change from baseline in NRS score between weeks were statistically significant in Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (P<0.001), and Week 1 vs Week 2 (p<0.001). Similarly, comparison of NRS score between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests.

• The mean EQ-5D-5L score showed statistically significant reduction at Week 1, Week 2, and Week 3, compared to baseline. Mean change from baseline in EQ-5D-5L score were statistically significant at Week 1, Week 2, and Week 3. The comparison of change from baseline in EQ-5D-5L score between weeks were statistically significant at Week 1 vs Week 3 (p<0.001), Week 2 vs Week 3 (p=0.005), and at Week 1 vs Week 2 (p=0.009). Similarly, comparison of EQ-5D-5L score between baseline vs each week were statistically significant in Week 1 vs baseline (p<0.001), in Week 2 vs baseline (p<0.001) and in Week 3 vs baseline (p<0.001) analysed by Wilcoxon Signed Rank Pairwise Tests.

• Two (1.1%) subjects completed study with events and 185 (98.4%) subjects completed or discontinued the study without event occurrence, the subjects were considered censored. Due to this, there is insufficient data to make any inferences on this endpoint.

The purpose of the above description is to illustrate some embodiments of the present invention without implying a limitation. It will be apparent to those skilled in the art that various modifications and variations may be made in the apparatus or procedure of the invention without departing from the scope or spirit of the invention.

Claims

1. A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in improving sleep quality in a subject.

2. The topical composition for use of claim 1 wherein the improvement in sleep quality is determined using the Karolinska Sleepiness Scale (KSS).

3. The topical composition for use of claim 2, wherein a second (later) KSS score is improved in comparison to a first (earlier) KSS score, particularly a baseline KSS score taken before treatment.

4. The topical composition for use of claim 3, wherein after up to 3 weeks of application of the topical composition, the second (later) KSS score is decreased by at least 0.25 in comparison to a first (earlier) KSS score, particularly a baseline KSS score taken before treatment.

5. A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in (a) ameliorating fatigue and/or (b) improving or increasing attention/alertness in a subject.

6. The topical composition for use of claim 5 wherein the amelioration of fatigue and/or (b) improvement or increase in attention/alertness is determined using the Karolinska Sleepiness Scale (KSS).

7. The topical composition for use of claim 2, wherein a second (later) KSS score is improved in comparison to a first (earlier) KSS score, particularly a baseline KSS score taken before treatment.

8. The topical composition for use of claim 3, wherein after up to 3 weeks of application of the topical composition, the second (later) KSS score is decreased by at least 0.25 in comparison to a first (earlier) KSS score, particularly a baseline KSS score taken before treatment.

9. A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in reducing morning stiffness in a subject.

10. The topical composition for use of claim 9, wherein the reduction in morning stiffness is demonstrated by an increase over a baseline measurement in levels of activity from 30 to 60 mins post-waking using an accelerometer.

11. The topical composition for use of claim 9, wherein the reduction in morning stiffness is demonstrated by an increase over a baseline measurement in levels of activity from 30 to 60 mins post-waking using the WOMAC stiffness subscale.

12. A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in a method of ameliorating quality of life (QoL) in a subject.

13. The topical composition for use of claim 12 wherein, the QoL is improved in one or more dimensions of the EuroQol-5 Dimensions-5 Levels (EQ- 5D-5L) quality of life questionnaire.

14. The topical composition for use of claim 13 wherein, the one or more EQ- 5D-5L QoL dimensions is selected from the group consisting of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.

15. A topical composition comprising diclofenac or a pharmaceutically acceptable salt thereof for use in increasing Moderate to Vigorous Physical Activity (MVPA) in a subject.

16. The topical composition for use of claim 15, wherein an increase in MVPA is determined by an increase in total time spent at or above the MVPA cut point level over a baseline measurement taken before treatment, for example using an accelerometer.

17. The topical composition for use of any preceding claim, wherein the topical composition comprises from about 1% to about 4% diclofenac or equivalent amount of pharmaceutically acceptable salt thereof.

18. The topical composition for use of claim 17 wherein the diclofenac is diclofenac sodium, particularly 1% diclofenac sodium.

19. The topical composition for use of claim 17, wherein the diclofenac is diclofenac diethylammonium, particularly 1.16% diclofenac diethylammonium or 2.32% diclofenac diethylammonium.

20. The topical composition for use of any one of claims 17, 18 or 19, wherein the topical composition is a gel or emulgel.

21. The topical composition for use of any one of claims 17 to 20, wherein the subject is a human subject experiencing pain associated with osteoarthritis.

22. The topical composition for use of claim 21, wherein the human subject is a human adult of at least 40 years of age or older, particularly a human adult of from 40 to 85 years of age.

23. The topical composition for use of any preceding claim, wherein the topical composition comprising diclofenac is applied 1 to 4 times per day with at least four hours between applications.