Osteoarthritis, Knee
Conditions
Brief summary
This randomized, double-blind, three-arm, placebo controlled, bioequivalence study with clinical endpoint has been designed to establish clinical equivalence and safety of Mylan's diclofenac gel in the symptomatic treatment of osteoarthritis of knee compared to Voltaren® gel and to establish superiority in efficacy of both compared to a placebo (vehicle) gel. Male or non-pregnant female aged ≥ 35 years with a clinical diagnosis of osteoarthritis of the knee according to the American College of Rheumatology (ACR) criteria Total study duration for the clinical part will be around 56 days that includes screening period of 28 days and treatment period of 4 weeks.
Interventions
Diclofenac Sodium Topical Gel, 1%. 4 gm, 4 times a day for 4 weeks
DRUGVoltaren® Gel (Diclofenac Sodium Topical Gel) 1%
Diclofenac Sodium Topical Gel, 1%. 4 gm, 4 times a day for 4 weeks
DRUGPlacebo gel
Vehicle Gel 4 gm, 4 times a day for 4 weeks
Sponsors
Mylan Pharmaceuticals Private Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Osteoarthritis knee as per American College of Rheumatology (ACR) criteria * Evidence of OA with Kellgren-Lawrence grade 1-3 disease. * After discontinuing all pain medications, had at least moderate pain on movement (POM) for target knee * After discontinuing all pain medications for at least 7 days has a baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC Likert (version 3.1)) pain subscale of ≥ 9 immediately prior to randomization. * Able to tolerate rescue medication with acetaminophen * Subjects who can read and understand WOMAC pain sub scale
Exclusion criteria
* Pregnancy, lactation * OA of Kellgren-Lawrence grade 4 * OA pain in the contralateral knee requiring medication (OTC or prescription) * History of OA of either Hip or Hands * History of secondary OA (e.g. congenital, traumatic, gouty arthritis), rheumatoid arthritis * History of chronic inflammatory disease (e.g., colitis) or fibromyalgia * History of Drugs or Alcohol abuse within the previous year * Symptomatic peripheral vascular disease of the study leg * Any musculoskeletal condition * Skin disease at the application site * Active asthma requiring periodic treatment with systemic steroids * Known history of positive HIV, hepatitis C virus, or HBsAg * Uncontrolled hypertension * History of myocardial infarction, thrombotic events, stroke etc. * Allergy to aspirin, nonsteroidal anti-inflammatory drugs (NSAID) or acetaminophen (paracetamol).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in the Total WOMAC Pain Subscale Score | From baseline to week 4 | Mean change in the total WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain subscale score for the target knee was compared to determine the clinical equivalence of Test Drug (Diclofenac sodium gel of 1% of Mylan Inc.) with the Reference Listed Drug (RLD) (Voltaren® Gel 1% of Novartis Consumer Health, Inc.) Measure Description: Western Ontario and McMaster Universities Osteoarthritis Index WOMAC pain subscale score (pain score = min 0 to max 20), was determined by the sum of subject's responses to five questions (S1-S5) using a 5-point Likert scale (i.e., 'none'=0; 'mild'=1, 'moderate'=2; 'severe'=3; 'extreme'=4). Higher values represent worse outcome. 'How much pain do you have' when 'Walking on a flat surface' (S1), 'Going up or down stairs' (S2), 'at night while in bed' (S3), 'Sitting or lying' (S4), 'Standing upright' (S5)\]. The timepoints considered for the primary outcomes include baseline and week 4. |
| Change From Baseline in WOMAC Pain Subscale Score | 4 weeks | Mean change in the total WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain subscale score for the target knee was compared to determine the superiority of the Test Drug and Reference Listed Drug (RLD) over placebo. Measure Description: Western Ontario and McMaster Universities Osteoarthritis Index WOMAC pain subscale score (pain score = min 0 to max 20), was determined by the sum of subject's responses to five questions (S1-S5) using a 5-point Likert scale (i.e., 'none'=0; 'mild'=1, 'moderate'=2; 'severe'=3; 'extreme'=4). Higher values represent worse outcome. 'How much pain do you have' when 'Walking on a flat surface' (S1), 'Going up or down stairs' (S2), 'at night while in bed' (S3), 'Sitting or lying' (S4), 'Standing upright' (S5)\]. The timepoints considered for the primary outcomes include baseline and week 4. |
Countries
India
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Diclofenac Sodium Gel Diclofenac Sodium Gel, 1%
Diclofenac sodium gel 1%: Diclofenac Sodium Topical Gel, 1%. 4 gm, 4 times a day for 4 weeks | 406 |
| Voltaren® Gel Voltaren® Gel (Diclofenac Sodium Topical Gel) 1%
Voltaren® Gel (Diclofenac Sodium Topical Gel) 1%: Diclofenac Sodium Topical Gel, 1%. 4 gm, 4 times a day for 4 weeks | 409 |
| Placebo Gel Placebo gel
Placebo gel: Vehicle Gel 4 gm, 4 times a day for 4 weeks | 405 |
| Total | 1,220 |
Baseline characteristics
| Characteristic | Diclofenac Sodium Gel | Voltaren® Gel | Placebo Gel | Total |
|---|---|---|---|---|
| Age, Continuous | 53.3 years STANDARD_DEVIATION 9.51 | 53.4 years STANDARD_DEVIATION 9.4 | 53.6 years STANDARD_DEVIATION 10.15 | 53.4 years STANDARD_DEVIATION 9.68 |
| Race/Ethnicity, Customized Asian/Not Hispanic or Latino | 406 Participants | 409 Participants | 405 Participants | 1220 Participants |
| Region of Enrollment India | 406 participants | 409 participants | 405 participants | 1220 participants |
| Sex: Female, Male Female | 275 Participants | 288 Participants | 273 Participants | 836 Participants |
| Sex: Female, Male Male | 131 Participants | 121 Participants | 132 Participants | 384 Participants |
| WOMAC Pain subscale score for target knee | 12.4 units on a scale STANDARD_DEVIATION 2.15 | 12.5 units on a scale STANDARD_DEVIATION 2.16 | 12.4 units on a scale STANDARD_DEVIATION 2.05 | 12.4 units on a scale STANDARD_DEVIATION 2.12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 398 | 1 / 405 | 0 / 400 |
| other Total, other adverse events | 11 / 398 | 19 / 405 | 20 / 400 |
| serious Total, serious adverse events | 0 / 398 | 1 / 405 | 0 / 400 |
Outcome results
Primary
Change From Baseline in WOMAC Pain Subscale Score
Mean change in the total WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain subscale score for the target knee was compared to determine the superiority of the Test Drug and Reference Listed Drug (RLD) over placebo. Measure Description: Western Ontario and McMaster Universities Osteoarthritis Index WOMAC pain subscale score (pain score = min 0 to max 20), was determined by the sum of subject's responses to five questions (S1-S5) using a 5-point Likert scale (i.e., 'none'=0; 'mild'=1, 'moderate'=2; 'severe'=3; 'extreme'=4). Higher values represent worse outcome. 'How much pain do you have' when 'Walking on a flat surface' (S1), 'Going up or down stairs' (S2), 'at night while in bed' (S3), 'Sitting or lying' (S4), 'Standing upright' (S5)\]. The timepoints considered for the primary outcomes include baseline and week 4.
Time frame: 4 weeks
Population: The mITT Population was used for analysis of superiority of Mylan's Diclofenac gel and Voltaren gel over placebo. The primary outcome tested in this population was the superiority of Mylan's Diclofenac sodium gel (1%) and the Voltaren gel (1%) over placebo and thus all the three arms are presented here.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diclofenac Sodium Gel | Change From Baseline in WOMAC Pain Subscale Score | -4.2 score on a scale | Standard Deviation 2.84 |
| Voltaren® Gel | Change From Baseline in WOMAC Pain Subscale Score | -4.4 score on a scale | Standard Deviation 2.74 |
| Placebo Gel | Change From Baseline in WOMAC Pain Subscale Score | -3.2 score on a scale | Standard Deviation 3.46 |
Primary
Mean Change in the Total WOMAC Pain Subscale Score
Mean change in the total WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain subscale score for the target knee was compared to determine the clinical equivalence of Test Drug (Diclofenac sodium gel of 1% of Mylan Inc.) with the Reference Listed Drug (RLD) (Voltaren® Gel 1% of Novartis Consumer Health, Inc.) Measure Description: Western Ontario and McMaster Universities Osteoarthritis Index WOMAC pain subscale score (pain score = min 0 to max 20), was determined by the sum of subject's responses to five questions (S1-S5) using a 5-point Likert scale (i.e., 'none'=0; 'mild'=1, 'moderate'=2; 'severe'=3; 'extreme'=4). Higher values represent worse outcome. 'How much pain do you have' when 'Walking on a flat surface' (S1), 'Going up or down stairs' (S2), 'at night while in bed' (S3), 'Sitting or lying' (S4), 'Standing upright' (S5)\]. The timepoints considered for the primary outcomes include baseline and week 4.
Time frame: From baseline to week 4
Population: The PP Population was used for analysis of clinical equivalence between Mylan's Diclofenac gel and Voltaren gel. The primary outcome tested in this population was the equivalence of Mylan's Diclofenac sodium gel (1%) verses the Voltaren gel (1%) and thus only Diclofenac Sodium Gel and Voltaren Gel arms are present here. The placebo arm is presented for the superiority analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diclofenac Sodium Gel | Mean Change in the Total WOMAC Pain Subscale Score | -4.3 score on a scale | Standard Deviation 2.64 |
| Voltaren® Gel | Mean Change in the Total WOMAC Pain Subscale Score | -4.6 score on a scale | Standard Deviation 2.64 |