Conditions: Osteoarthritis, Knee
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1220
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: Diclofenac Sodium Gel, 1% arm 2: Voltaren® Gel (Diclofenac Sodium Topical Gel) 1% arm 3: Placebo gel

Interventions: intervention 1: Diclofenac sodium gel 1% intervention 2: Voltaren® Gel (Diclofenac Sodium Topical Gel) 1% intervention 3: Placebo gel
Intervention descriptions: intervention 1: Diclofenac Sodium Topical Gel, 1%. 4 gm, 4 times a day for 4 weeks intervention 2: Diclofenac Sodium Topical Gel, 1%. 4 gm, 4 times a day for 4 weeks intervention 3: Vehicle Gel 4 gm, 4 times a day for 4 weeks

Protocol document:
Prot_000.pdf: 
 
PROTOCOL # MYL-1601N-3002 
 
Protocol Version: 1.0 
Date: 06 Dec 16 
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Page 1 of 70 
 
TITLE PAGE 
PROTOCOL NUMBER 
: MYL-1601N-3002 
CLINICAL PHASE 
: Bioequivalence study with clinical endpoint 
PROTOCOL TITLE 
: A Randomized, Double blind, Three-arm, Parallel, Placebo-
controlled, Clinical Study to Evaluate the Bioequivalence using 
Clinical Endpoint of Diclofenac Sodium Gel, 1% (Mylan Inc.) to 
Voltaren® Gel (Diclofenac Sodium Topical Gel) 1% (Novartis 
Consumer Health, Inc.) in Patients with Osteoarthritis (OA) of the 
Knee 
PROTOCOL VERSION 
: 1.0 
DATE 
: 06 Dec 2016 
SUPERSEDED 
VERSION AND DATE  
: None 
 
SPONSOR: 
Mylan 
, 
  
  
  
 
 
  
  
 
CONTRACT RESEARCH ORGANIZATION: 
 
 
 
 
 
 
 
 
"All financial and nonfinancial support for this study will be provided by Mylan. The concepts and information contained in this document or 
generated during the study are considered proprietary and may not be disclosed in whole or in part without the expressed, written consent of 
Mylan. The study will be conducted according to the International Conference on Harmonisation harmonized tripartite guideline E6 (R1): 
Good Clinical Practice." 
 










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CONTACT LIST
Sponsor Representative / Authorized Signatory Contact Details: 
 
 
  
  
  
  
 
 
 
Project Manager Contact Details: 
 
 
 
 
 
 
 
 
Medical Monitor Contact Details: 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
ACE 
: 
Angiotensin-converting-enzyme 
ACR 
: 
American College of Rheumatology 
AE 
: 
Adverse Event 
ANCOVA 
: 
Analysis of Covariance 
BUN 
: 
Blood Urea Nitrogen 
CABG 
: 
Coronary Artery Bypass Graft 
CFR 
: 
Code of Federal Regulations 
CI 
: 
Confidence Interval 
CMC 
: 
Carpometacarpal 
COX 
: 
Cyclooxygenase 
CRA 
: 
Clinical Research Associate 
CRO 
: 
Contract Research Organization 
DCF 
: 
Data Clarification Form 
EC 
: 
Ethics Committee 
ECG 
: 
Electrocardiogram 
eCRF 
: 
Electronic – Case Report Form 
FDA 
: 
Food and Drug Administration 
GCP 
JSN 
: 
: 
Good Clinical Practice 
Joint Space Narrowing 
gm 
: 
Grams 
GMP 
: 
Good Manufacturing Practice 
HBSag 
: 
Hepatitis B Surface Antigen 


 
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HCV 
: 
Hepatitis C virus 
HIV 
: 
Human Immunodeficiency Virus 
ICF 
: 
Informed Consent Form 
ICH 
: 
International Conference on Harmonization 
ICMR 
: 
Indian Council of Medical Research 
IEC 
: 
Institutional Ethics Committee 
IMP 
: 
Investigational Medicinal Products 
IRB 
: 
Institutional Review Board 
ITT 
: 
Intent to Treat 
IUD 
: 
Intrauterine Device 
IW 
: 
Impartial Witness 
LAR 
: 
Legally Acceptable Representative 
LOCF 
: 
Last Observation Carried Forward 
MedDRA 
: 
Medical Dictionary for Regulatory Activities 
mg 
: 
Milligram 
mITT 
: 
Modified Intent to Treat 
mm 
: 
Millimeter 
NIMP 
: 
Non-investigational medicinal products 
NSAIDs 
: 
Non-Steroidal Anti-Inflammatory Drugs 
OA 
: 
Osteoarthritis 
OTC 
: 
Over the counter 
PG 
: 
Prostaglandins 


 
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POM 
:  
Pain on Movement 
PP 
: 
Per Protocol 
PSRM 
: 
Product Safety and Risk Management 
RLD 
: 
Reference Listed Drug 
SAE 
: 
Serious Adverse Event 
SAF 
: 
Safety Population 
SAS 
: 
Statistical Analysis System 
SUSAR 
: 
Suspected Unexpected Serious Adverse Reaction 
ULN 
: 
Upper Limit Normal 
USFDA 
:  
United States Food and Drug Administration 
USP 
: 
United States Pharmacopoeia 
VAS 
: 
Visual Analog Scale 
WOMAC 
: 
Western Ontario and McMaster Universities Osteoarthritis Index 
 
 
 


 
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FACILITIES 
Contract Research Organization 
 
 
 
 
 
 
 
Clinical Laboratory Services 
 
 
 
 
 
 
 
Data Management and Statistical Services 
Sponsor’s designated facility  


 
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1. 
SYNOPSIS 
Protocol No: 
MYL-1601N-3002 
Title of Study: 
A Randomized, Double blind, Three-arm, Parallel, Placebo-controlled, Clinical 
Study to Evaluate the Bioequivalence using Clinical Endpoint of Diclofenac 
Sodium Gel, 1% (Mylan Inc.) versus Voltaren® Gel (Diclofenac Sodium Topical 
Gel) 1% (Novartis Consumer Health, Inc.) in Patients with Osteoarthritis (OA) of 
the Knee. 
Short Title: 
Bioequivalence study with clinical endpoint of generic diclofenac gel with 
Voltaren® gel in patients with osteoarthritis of knee. 
Study Phase: 
Bioequivalence study with clinical endpoint 
Sponsor: 
Mylan 
 
Objectives: 
Primary Objectives: 
1. 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.) as measured by mean change from 
baseline in the Western Ontario and McMaster Universities Osteoarthritis 
Index (WOMAC) Likert (version 3.1) pain score. 
2. To establish superiority of the Test Drug and Reference Listed Drug (RLD) 
over placebo in mean change from baseline in the WOMAC Likert (version 
3.1) pain score. 
Secondary Objectives: 
1. To assess the safety and tolerability of study treatments. 
2. To determine the clinical equivalence of Test Drug(Diclofenac Sodium gel) 
with the Reference Listed Drug (RLD) (Voltaren® Gel) as measured by mean 
change from baseline in subjects whose baseline WOMAC Likert (version 3.1) 
pain scores are less than or equal to 10. 
Design 
Randomized, Double-blind, Multicentric, Parallel, Active and Placebo Controlled, 
Three Arm, Bioequivalence study with clinical endpoint in the ratio of 1:1:1 of 
Test drug, Reference drug and Placebo respectively 
Test Product 
Diclofenac Sodium Gel, 1% manufactured by Mylan Inc. 
Reference Product Voltaren® Gel (Diclofenac Sodium Topical Gel) 1% manufactured by Novartis 
Pharma Produktions GmbH, marketed by: Endo Pharmaceuticals Inc., Malvern, PA 


 
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19355 
Placebo 
Placebo (vehicle) gel manufactured by Mylan Inc. 
Non-
Investigational 
Medicinal 
Products (NIMP) 
Acetaminophen (paracetamol) tablet will be given as a rescue medication 
Study Rationale 
Mylan is developing a generic diclofenac sodium gel to the Reference Listed Drug 
(RLD) Voltaren® gel. 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.  
The planned study design is also in compliance with the United States Food and 
Drug Administration’s Draft Guidance for Diclofenac Sodium Topical Gel.1 
Dose and Mode of 
Administration 
All subjects will have to apply 4 gm of gel to the affected area of target knee 4 
times daily. At the start of run-in period, placebo gel will be provided to the 
qualified subjects for application and during the treatment period, Mylan’s 
Diclofenac Sodium Topical Gel 1%, Voltaren® Gel 1% (Reference Listed Drug), or 
Placebo gel will be provided to the subjects for application. The proper amount of 
gel will be measured using the dosing card. The gel will be applied within the 
rectangular area of the dosing card up to 4-gram line.  Subjects will be instructed to 
rinse and dry the dosing card after use. Subjects will be trained via a detailed and 
translated instruction subject diary on how to administer the study drug.  
Study Population 
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 
Number of 
Subjects 
Around 1212 patients will be randomized in this study (404 patients in each 
treatment arm). 
Study Period 
Total study duration for the clinical part will be around 56 days that includes 
screening period of 28 days (including run-in period of 7 (+ 4) days) and treatment 
period of 4 weeks. 
Inclusion Criteria: 
1. Healthy male or non-pregnant female aged ≥ 35 years with a clinical diagnosis 
of OA of the knee according to the American College of Rheumatology (ACR) 
criteria2 i.e. Knee pain along with at least 3 of the following 6 criteria 
a. Age > 50 years 


 
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b. Stiffness < 30 minutes 
c. Presence of crepitus 
d. Bony tenderness 
e. Bony enlargement  
f. No palpable warmth  
2. Symptoms in target knee for at least 6 months prior to screening 
3. Knee (not referred) pain in target knee for 15 days of the preceding month 
(periarticular knee pain due to OA and not due to other conditions such as 
bursitis, tendonitis, etc.) 
4. Pain in the target knee requiring the use of NSAIDs or acetaminophen 
(paracetamol) (topical or oral treatments). 
5. Subject having an X-ray of the target knee, taken no more than 1 year before 
baseline, showing evidence of OA with Kellgren-Lawrence grade 1-3 disease. 
6. After discontinuing all pain medications(placebo run – in period) for at least 7 
days, has at least moderate pain on movement (POM) for target knee, defined 
as a baseline score of ≥ 50 mm on a 0-100 mm Visual Analog Scale (VAS) 
immediately prior to randomization.  
7. After discontinuing all pain medications (placebo run – in period) for at least 7 
days has a baseline Western and Ontario McMaster Universities Osteoarthritis 
Index (WOMAC Likert (version 3.1)) pain subscale of ≥ 9 immediately prior to 
randomization. 
8. Able to tolerate rescue medication with only acetaminophen (paracetamol) 
taken as l-2 tablets up to a maximum of 2 gm per day for the duration of the 
study. 
9. Subjects who can read and understand WOMAC pain sub scale. 
10. If female, patient must be either postmenopausal for at least one year prior to 
randomization, 
surgically 
sterile 
(bilateral 
tubal 
ligation, 
bilateral 
oophorectomy or hysterectomy), or practicing the following methods of birth 
control: 
a) Oral Contraceptives or Intrauterine Device in place for at least 3 months 
prior to the start of the study and remaining in place during the study period, 
or  
b) Double Barrier methods containing or used in conjunction with a 
spermicidal agent, or 
c) Contraceptive Patches/ Implants, or  
d) Abstinence: Subjects who will be practicing abstinence will agree to have a 
documented second acceptable method of birth control if the subject 
become sexually active during the course of her study participation. 
 


 
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Exclusion 
Criteria: 
1. Pregnant or lactating or planning to become pregnant during the study period. 
2. X-ray showing evidence of OA with Kellgren-Lawrence grade 4 disease. 
3. History of OA pain in the contralateral knee requiring medication (OTC or 
prescription) within 1 year prior to screening.  
4. After discontinuing all pain medications (placebo run-in period)for at least 7 
days, had a baseline score of ≥ 20 mm on a 0-100 mm Visual Analog Scale 
(VAS) for the contralateral knee immediately prior to randomization. 
5. History of OA of either Hip or Hands. 
6. History of secondary OA (e.g. congenital, traumatic, gouty arthritis) or 
rheumatoid arthritis. 
7. History of chronic inflammatory disease (e.g., colitis) or fibromyalgia. 
8. History of drugs or alcohol abuse with in the previous year. 
9. Symptomatic peripheral vascular disease of the study leg (prior or current). 
10. Any musculoskeletal condition that would impede measurement of efficacy at 
the target knee. 
11. History of regular headaches or backache which warrants frequent use of 
acetaminophen (paracetamol) or NSAIDs within the previous year. 
12. Concomitant skin disease at the application site which may affect study drug 
application or tolerability evaluation. 
13. History of active asthma within the previous year that may require periodic 
treatment with systemic steroids during the study period (note: inhaled steroids 
for this condition are allowed). 
14. History of aspirin sensitive asthma. 
15. History of uncontrolled hypertension (blood pressure more than 150/100 mm of 
Hg) in spite of treatment with in the previous year. 
16. History of myocardial infarction, thrombotic events, stroke, congestive heart 
failure, impaired renal function (Serum creatinine > 1.5 x ULN), or liver 
disease with in the previous year. 
17. History of coronary artery bypass graft within 6 months of screening. 
18. History of gastrointestinal bleeding or peptic ulcer disease in last one year. 
19. Known allergy to aspirin, nonsteroidal anti-inflammatory drugs (NSAID) or 
acetaminophen (paracetamol). 
20. Elevated transaminases (≥ 3 times ULN) and hemoglobin ˂ 9.0 g/dL at 
screening. 
21. Viscosupplementation in any joint including the target knee within 6 months 
prior to screening. 
22. Receiving physical therapy (at an outpatient/clinic setting) for the lower 
extremities or having received physical therapy for the lower extremities within 
1 month before screening. 


 
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23. Use of anticoagulants, ACE-inhibitors, cyclosporine, diuretics, lithium, or 
methotrexate prior to 30 days of screening. 
24. Concomitant use of intra articular corticosteroids, systemic corticosteroids, 
topical corticosteroids, or immunosuppressive drugs or their use prior to 30 
days of screening. 
25. Concomitant acetylsalicylic acid therapy other than a stable low dose used for 
cardiac prophylaxis (maximum 162 mg daily)3 taken for at least 3 months prior 
to enrollment and maintained throughout the duration of the study. 
26. History of major surgery or previous damage to the study knee at any time, or 
minor knee surgery (e.g. any surgery other than major surgery including, but 
not limited to, cartilage repair, collateral ligament repair, or arthroscopic 
debridement) to the study knee within 1 year prior to screening. 
27. Known history of positive HIV, HCV or HBsAg. 
28. Tense effusion requiring aspiration.  
29. Subjects who have been treated with an investigational drug or investigational 
device within a period of 30 days prior to enrollment. 
30. Any other acute or chronic illness that could compromise the integrity of study 
data or place the subject at risk by participating in the study. 
Study Design& 
Methodology: 
This is a double-blind, multiple-site, randomized, parallel-design study to 
investigate the clinical endpoint bioequivalence of Mylan’s Diclofenac Sodium 
Topical Gel, 1% to Voltaren® Gel, 1% (Novartis Consumer Health, Inc.) and to 
investigate that both the active products are superior to placebo. 
Subjects will have to visit the clinic for the following visits during the study – 
Visit 1 – Screening visit (within 28 days prior to randomization) 
Visit 2 – Start of Placebo Run-in period (Day -11 to Day -7) 
Visit 3 – Randomization (baseline) visit (Day 0) 
Visit 4 – Interim visit (Week 2/Day 14 ± 4) 
Visit 5 – End of study (Week 4/Day 28 ±4)/ Early termination visit 
After informed consent process and completion of all screening assessments, the 
eligible subjects will be requested to stop the currently ongoing osteoarthritis drug 
therapy. The wash out period (run-in period) of 7 days or ≥ 5 half-life of previous 
osteoarthritis drug therapy, whichever is longer, will be maintained before the 
baseline visit. Subjects will undergo at least 7 days of placebo run-in period. 
In case subject extends run-in period beyond 11 days, continuation of the subject 
will be decided in consultation with medical monitor. 
 
The Pain on Movement (POM) score on a Visual Analog Scale (VAS)  and Western 
Ontario and McMaster Universities Osteoarthritis Index (WOMAC Likert scale 
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of run-in period (i.e. immediately prior to randomization on the day of baseline 
visit). Recording of the VAS will be done for both the knees and recording of the 
WOMAC pain score will be done for the target knee.  
 
During the washout period, subjects will undergo a single-blind placebo run-in 
period. Subjects will be provided with placebo gel for the administration. 
Approximately 4 gm dose of placebo gel will be applied to the target knee four 
times daily for at least 7 days. Target knee means the knee, which is more painful, 
will be identified during the screening visit. First administration of gel will be 
supervised at the study center, with subsequent applications self-administered on an 
outpatient basis. 
 
At baseline visit, subjects will be randomly assigned in 1:1:1 fashion to Mylan’s 
Diclofenac Sodium Topical Gel 1%, Voltaren® Gel 1% (Reference Listed Drug), 
and Placebo. All the subjects will be instructed to apply the gel next day (Day 1) 
onwards. All subjects will be applying approximately 4 gm dose of either Mylan’s 
Diclofenac Sodium Topical Gel 1% or Voltaren® Gel 1% (Reference Listed Drug) 
or Placebo gel to the arthritic target knee four times daily for 4 weeks.  
 
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC 
Likert version 3.1) pain score for the target knee and pain on movement (POM) on 
a Visual Analog Scale (VAS) for both the knee will be recorded on Week 2 and 
Week 4 from the start of the treatment.  
 
Acetaminophen (paracetamol) tablets will be given to the subjects for use as a 
rescue medication or for the treatment of aches and pains unrelated to knee pain 
such as headache during treatment period (except 3 days prior to Visit 4 and Visit 
5) Maximum allowed dose of acetaminophen (paracetamol) will be 2 gm/day. 
Consumption of rescue medications in terms of number of tablets consumed will be 
monitored. 
 
Subject diary will be provided to subjects to record study medication gel 
application, rescue medication, side effects, and concomitant medication details. 
Subjects will be trained regarding how to use the subject diary. Subject diary will 
be used to evaluate drug application compliance. Subjects will be trained via a 
detailed and translated instruction subject diary on how to administer the study 
drug. 
 
Physical examination will be done during each visit (except at the start of run-in 


 
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period visit). Application site reaction assessment will be done on each visit after 
start of run-in period. 
 
A standard 12-lead ECG will be recorded after 5 minutes of rest in the supine 
position on screening visit and on end of study visit. Vital signs will be measured 
after 5 minutes of rest (sitting) on each visit. 
 
Serum pregnancy test for females of childbearing potential will be performed at 
screening and end of treatment visit. The urine pregnancy test can be performed if 
clinically indicated during other visits. If urine pregnancy is found to be positive, 
serum pregnancy test will be done for confirmation. If serum pregnancy test will 
found positive then patient will be excluded from the study and followed up. 
 
Laboratory assessments like hematology and biochemistry will be performed 
during screening and end of study. The hematology and biochemistry at screening 
to be performed within 14 days prior to baseline visit. If the gap between lab 
assessments and baseline visit will be more than 14 days, the lab assessments will 
be repeated at baseline visit. Laboratory investigations (if clinically significant) can 
be repeated once as per investigator’s discretion.  
 
Telephone contact: Principal investigator or designee will contact the subjects 
approximately midway between the visit 3-4 and visit 4-5 for assessment of the 
well-being, adverse event, concomitant medication, and treatment compliance. 
Additional telephonic contact will be done to remind the subject regarding stoppage 
of rescue medication usage prior to scheduled visits (Visit 4, and Visit 5). The same 
will be documented in the source notes. 
 
Statistical comparisons will be made between test and reference, test and placebo, 
and reference and placebo. 
Study Endpoints: 
 
Efficacy Endpoints: 
Primary Efficacy Endpoint:  
 Mean change in the total WOMAC pain subscale score for the target knee, 
from baseline to week 4 
Secondary Efficacy Endpoints: 
 Mean change in the total WOMAC pain subscale score for the target knee, 
from baseline to week 2.  
 Mean change in the WOMAC pain subscale score at week 4 for subgroup 
subjects whose baseline WOMAC pain score less than or equal to 10. 
 Mean change in pain on movement (POM) on a Visual Analog Scale (VAS) 
for target knee from baseline to week 4 


 
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 Average number of days of acetaminophen (paracetamol)consumption 
during the trial 
 Average dose of acetaminophen (paracetamol)during the trial 
Safety Endpoints: 
 The incidence of treatment-emergent adverse events. 
 Local tolerability evaluation 
Statistical 
Methods: 
Statistical Methods for Bioequivalence: 
Bioequivalence will be established for the primary endpoint (WOMAC® Likert 
version 3.1) if the 90% confidence interval for the test/reference ratio of mean 
change from baseline to week 4 is contained within [0.80, 1.25], using the per-
protocol population.  
The compound hypothesis to test is: 
H0: μT / μR ≤ θ1 or μT / μR ≥ θ2 versus HA : θ1<μT / μR< θ2 
Where μT = mean of test treatment, and μR = mean of reference treatment. 
H0 will be rejected with a type I error α = 0.05 (two 1-sided tests), if the 90% 
confidence interval for the ratio of means between test and reference products (μT / 
μR) is contained within the interval [θ1, θ2], where θ1 = 0.80 and θ2 = 1.25. 
Rejection of the null hypothesis H0 supports the conclusion of equivalence of the 
two products. 
 
Statistical Methods for Superiority: 
As a parameter for determining adequate study sensitivity, the Test Drug and RLD 
should both be statistically superior to placebo (p<0.05, two-sided) for the primary 
endpoint (mean change from baseline), using the mITT study population and last 
observation carried forward (LOCF). 
H0: μT or μR ≥ μPlacebo versus HA : μT or μR < μPlacebo 
Where μT = mean of test treatment, and μR = mean of reference treatment. 
H0 will be rejected with a type I error α = 0.05 (2-sided test). Rejection of the null 
hypothesis H0 supports the conclusion of superiority to placebo. Analysis of 
covariance (ANCOVA) will be used to compare Test Drug to placebo and RLD to 
placebo separately. The model will consist of treatment, investigator and baseline 
value as covariate. 
 
Analysis Populations: 
The following 3 analysis populations will be used in the statistical analyses: 
 
Per-protocol (PP) population: Includes all randomized subjects who meet all 
inclusion/exclusion criteria, compliant with the assigned study treatment, return 
to the study site for the primary endpoint visit within the specified window (± 4 
days) OR discontinue from the study as a treatment failure, and do not have any 
protocol violations. 
 
Modified Intent-to-treat (mITT) population: includes all randomized subjects 


 
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who meet all inclusion/exclusion criteria, receive study treatment, and return 
for at least one post-baseline visit. 
 
Safety (SAF) population: All randomized subjects who receive at least one 
study treatment. 
Note: Patients discontinuing early from the study due to lack of treatment effect will be included in 
the PP population, using Last Observation Carried Forward (LOCF). Subjects discontinuing early 
for other reasons will be excluded from the PP population, but will be included in the mITT 
population, using Last Observation Carried Forward (LOCF). 
Ethical Issues 
The study will commence only after a written approval is obtained from the 
Institutional Review Board for the submitted protocol, ICD and other relevant 
documents. The study will be conducted as per the ICMR Ethical Guidelines for 
Biomedical Research on Human Subjects (2006), ICH-GCP Guidelines and in 
accordance with the Declaration of Helsinki (Fortaleza, Brazil, October 2013). 
 


 
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2. 
INTRODUCTION AND STUDY RATIONALE 
2.1. Overview of Study Indication 
Osteoarthritis is a common degenerative disorder of the articular cartilage associated with 
hypertrophic changes in the bone. Risk factors include genetics, female sex, past trauma, advancing 
age, and obesity. The most common symptom of osteoarthritis is joint pain. The pain tends to worsen 
with activity, especially following a period of rest; this has been called the gelling phenomenon. 
Osteoarthritis can cause morning stiffness, but it usually lasts for less than 30 minutes, unlike 
rheumatoid arthritis, which causes stiffness for 45 minutes or more. Patients may report joint locking 
or joint instability. These symptoms result in loss of function, with patients limiting their activities of 
daily living because of pain and stiffness. The joints most commonly affected are the hands, knees, 
hips, and spine, but almost any joint can be involved. Osteoarthritis is often asymmetric. A patient 
may have severe, debilitating osteoarthritis of one knee with almost normal function of the opposite 
leg.4 Osteoarthritis (OA) of the knee is a major cause of pain and locomotor disability worldwide.5 In 
the United States, approximately 240 per 100,000 persons per year have knee osteoarthritis. In 2010, 
approximately 9.9 million adults had symptomatic knee osteoarthritis.6 
 
2.2. Current Treatments for Study Indication 
Pharmacologic modalities conditionally recommended for the initial management of patients with 
knee OA include acetaminophen (paracetamol), oral and topical NSAIDs, tramadol, and intra-articular 
corticosteroid injections. Intra-articular hyaluronate injections, duloxetine, and opioids are 
conditionally recommended in patients who had an inadequate response to initial therapy.7 
 
Topical diclofenac significantly reduced pain and morning stiffness and improved physical function 
and patient global assessment without major adverse effects reported in patients with OA of the knee. 
It was reported that topical diclofenac sodium gel 1% is superior to placebo vehicle gel.8,9,10 
 
2.3. Reference Product Information (Voltaren® Gel) 
VOLTAREN® GEL (diclofenac sodium topical gel) is a nonsteroidal anti-inflammatory drug 
(NSAID) for topical use only. The chemical name is 2-[(2, 6-dichlorophenyl) amino] benzene acetic 
acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2, 
and it has the following chemical structure.11 


 
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The structural formula of diclofenac is: 
 
 
Clinical Pharmacology11 
Mechanism of Action: Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. 
The mechanism of action of VOLTAREN® gel, like that of other NSAIDs, is not completely 
understood but involves inhibition of cyclooxygenases (COX-1 and COX-2). 
 
Diclofenac is a potent inhibitor of prostaglandin synthesis in-vitro. Diclofenac concentrations reached 
during therapy have produced in-vivo effects. Prostaglandins sensitize afferent nerves and potentiate 
the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of 
inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be 
due to a decrease of prostaglandins in peripheral tissues. 
 
Pharmacokinetics: The pharmacokinetics of VOLTAREN® GEL were assessed in healthy volunteers 
following repeated applications during 7 days of VOLTAREN® GEL to 1 knee (4 x 4 g per day) or to 
2 knees and 2 hands (4 x 12 g per day) versus the recommended oral dose of diclofenac sodium for the 
treatment of osteoarthritis (3 x 50 mg per day). A summary of the pharmacokinetic parameters is 
presented in below table: 
Table 1:  Pharmacokinetic Parameters and Comparison of VOLTAREN® GEL to Oral 
Diclofenac Sodium Tablets after Repeated Administration  
Treatment  
Cmax (ng/mL) 
Mean ± SD 
% of Oral (CI)  
Tmax (hr) 
Median 
Range  
AUC0-24 (ng.h/mL) 
Mean ± SD 
% of Oral (CI)  
VOLTAREN® GEL 
4 x 4 g per day 
(=160 mg diclofenac sodium per day) 
15 ± 7.3 
0.6% (0.5-0.7) 
14 (0-24) 
233 ± 128 
5.8% 
(5-6.7) 
VOLTAREN® GEL 
4 x 12 g per day 
(=480 mg diclofenac sodium per day) 
53.8 ± 32 
2.2% 
(1.9-2.6) 
10 (0-24) 
807 ± 478 
19.7% 
(17-22.8) 


 
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Treatment  
Cmax (ng/mL) 
Mean ± SD 
% of Oral (CI)  
Tmax (hr) 
Median 
Range  
AUC0-24 (ng.h/mL) 
Mean ± SD 
% of Oral (CI)  
Diclofenac sodium tablets,  
orally 3 x 50 mg per day 
(=150 mg diclofenac sodium per day) 
2270 ± 778 
100% 
6.5 (1-14) 
3890 ± 1710 
100% 
Cmax = maximum plasma concentration, tmax=time of Cmax. AUC0-24=area under the concentration 
time curve. SD=standard deviation. CI=confidence interval. 
 
The pharmacokinetics of VOLTAREN® GEL has been tested under conditions of moderate heat 
(application of a heat patch for 15 minutes prior to gel application) and of moderate exercise (first gel 
application followed by a 20-minute treadmill exercise). No clinically relevant differences of systemic 
absorption and of tolerability were found between applications of VOLTAREN® GEL (4 x 4 g per day 
on 1 knee) with and under the conditions tested. However, the pharmacokinetics of VOLTAREN® 
GEL were not tested under the condition of heat application following gel application. Therefore, 
concurrent use of VOLTAREN® GEL and heat is not recommended. 
 
2.4. Clinical Experience 
Study 1 evaluated the efficacy of VOLTAREN® GEL for the treatment of osteoarthritis of the knee in 
a 12-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial. 
VOLTAREN® GEL was administered at a dose of 4 g, 4 times daily, on 1 knee (16 g per day). Pain as 
assessed by the patients at Week 12 using the WOMAC (Western Ontario and McMaster Universities 
Osteoarthritis Index) Pain Sub index was lower in the VOLTAREN® GEL group than the placebo 
group. 
Study 2 evaluated the efficacy of VOLTAREN® GEL for the treatment of osteoarthritis in subjects 
with osteoarthritis of the hand in an 8-week, randomized, double-blind, multicenter, placebo-
controlled, parallel-group study. VOLTAREN® GEL was administered at a dose of 2 g per hand, 4 
times daily, on both hands (16 g per day). Pain in the target hand as assessed by the patients at Weeks 
4 and 6 on a visual analogue scale from 0 to 100 was lower in the VOLTAREN® GEL group than the 
placebo group.11 
Table 2:  Efficacy outcomes of VOLTAREN® GEL in Studies 1 and 2 
Efficacy outcomes of VOLTAREN® GEL in Studies 1 and 2  
 
VOLTAREN® GEL 
Placebo 
(Vehicle)  
Adjusted Difference (Placebo - 
VOLTAREN® GEL )  
Study 1 
(Knee)  
WOMAC 
Pain * #  
Sample Size 
127 
119 
 
Mean Outcome 
28 
37 
∆ = 7†  
95% Confidence  
 
(1, 12) 


 
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Efficacy outcomes of VOLTAREN® GEL in Studies 1 and 2  
 
VOLTAREN® GEL 
Placebo 
(Vehicle)  
Adjusted Difference (Placebo - 
VOLTAREN® GEL )  
at Week 12  
Interval 
Study 2 
(Hand)  
Pain Intensity 
#  
at Week 4  
Sample Size 
198 
187 
 
Mean Outcome 
43 
50 
∆ = 7 ‡  
95% Confidence 
Interval 
 
 
(2, 12) 
Study 2 
(Hand)  
Pain Intensity 
#  
at Week 6  
Sample Size 
198 
187 
 
Mean Outcome 
40 
47 
∆ = 7 ‡  
95% Confidence 
Interval 
 
 
(1, 13) 
* WOMAC = Western Ontario McMaster Osteoarthritis Index. 
# Scale from 0 (best) to 100 (worst). 
† Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of 
treatment and center and baseline covariate. 
‡ Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of 
treatment, center, and indicator of pain in the CMC-1 joint, and baseline as a covariate, and the 
treatment-by-CMC-1 strata. 
 
2.5. Contraindications 
 Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac 
or any components of the drug product11  
 History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other 
NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in 
such patients11  
 In the setting of coronary artery bypass graft (CABG) surgery11 
 
2.6. Study Rationale 
This is a study designed to evaluate the therapeutic equivalence and safety of a Diclofenac Sodium 
Gel in order to facilitate registration of a generic version of Diclofenac Sodium Gel, 1% of Mylan Inc. 
The Reference Listed Drug (RLD)is Voltaren® Gel (Diclofenac Sodium Topical Gel) 1%. This study 
will be conducted in male and female subjects with confirmed diagnosis of osteoarthritis of the knee. 
 
 
 


 
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2.7. Dosage & Administration 
Knee 
The proper amount of Diclofenac Sodium Gel should be measured using the dosing card. The dosing 
card should be used for each application of drug product. The gel should be applied within the 
rectangular area of the dosing card up to 4 gm line. The dosing card provided with the product can be 
used to apply the gel. The hands should then be used to gently rub the gel into the skin. After using the 
dosing card, hold with fingertips, rinse, and dry. 
 
2.8. Risks and Benefits 
Mylan 
. has developed the generic formulation of Diclofenac Sodium Gel, 1% 
which may or may not be effective. 
Most common adverse reactions (incidence >2% of patients treated with VOLTAREN® GEL and 
greater than placebo) are application site reactions, including dermatitis. 
Application site reaction reported with diclofenac gel includes: application site dermatitis, application 
site pruritus, application site erythema, application site paresthesia, application site dryness, 
application site vesicles, application site irritation and application site papules. 11 
Other adverse reactions includes cardiovascular thrombotic events, GI bleeding, ulceration and 
perforation, hepatotoxicity, hypertension, heart failure,  and edema, renal toxicity and hyperkalemia, 
anaphylactic reactions, serious skin reactions and  hematologic toxicity. Potential benefits include 
improvement in pain, stiffness and improved physical function associated with OA. 
 
2.9. Non-Investigational Medicinal Products (NIMP)/Rescue Medication – Acetaminophen 
(paracetamol): 
Use12:  
 Temporarily relives minor aches and pain due to: 
o Minor pain of arthritis 
o Muscular aches 
o Backache 
o Pre- menstrual and menstrual pain 
o Common cold 
o Headache 
o Toothache 
 Temporarily reduces fever 
Warnings 
Hepatic Effects12: 
 Severe liver damage may occur if patient will take 
o more than 4,000 mg of acetaminophen (paracetamol) in 24 hours with other drugs containing 
acetaminophen (paracetamol) 
o 3 or more alcoholic drinks every day while using this product 


 
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 Subjects with allergy to acetaminophen (paracetamol) 
 
3. 
OBJECTIVES 
Primary Objectives: 
1. 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.) as measured by mean change from baseline in the Western Ontario and McMaster 
Universities Osteoarthritis Index (WOMAC) Likert (version 3.1) pain score. 
2. To establish superiority of the Test Drug and Reference Listed Drug (RLD) over placebo in 
mean change from baseline in the WOMAC Likert (version 3.1) pain score. 
Secondary Objectives: 
1. To assess the safety and tolerability of study treatments. 
2. To determine the clinical equivalence of Test Drug(Diclofenac Sodium gel) with the 
Reference Listed Drug (RLD)(Voltaren® Gel) as measured by mean change from baseline in 
subjects whose baseline WOMAC Likert (version 3.1) pain scores are less than or equal to 10. 
4. 
STUDY DESIGN 
Randomized, Double-blind, Multi-centric, Parallel, Active and Placebo Controlled, Three Arm, 
Clinical Study, with subjects randomized in the ratio of 1:1:1 of Mylan’s Diclofenac Sodium Topical 
Gel 1%, Voltaren® Gel 1% (Reference Listed Drug), and Placebo gel respectively. 
4.1. Study Overview 
This is a double-blind, multiple-site, randomized, parallel-design study to investigate the 
bioequivalence with clinical endpoint of Mylan’s Diclofenac Sodium Topical Gel, 1% to Voltaren® 
Gel, 1% (Novartis US) and to investigate that both the active products are superior to placebo. 
Subjects will have to visit the clinic for the following visits during the study – 
Visit 1 – Screening visit (within 28 days prior to randomization) 
Visit 2 – Start of Placebo Run-in period (Day -11 to Day -7) 
Visit 3 – Randomization (baseline) visit (Day 0) 
Visit 4 – Interim visit (Week 2/Day 14 ± 4) 
Visit 5– End of study (Week 4/Day 28 ± 4)/ Early termination visit 
 


 
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Figure 1: Study Design Flow Chart 
 
 
After informed consent process and completion of all screening assessments, the eligible subjects will 
be requested to stop the currently ongoing osteoarthritis drug therapy. The wash out period (run-in 
period) of 7 days or ≥ 5 half-life of previous osteoarthritis drug therapy, whichever is longer, will be 
maintained before the baseline visit. Subjects will undergo at least 7 days of placebo run-in period. 
In case subject extends run-in period beyond 11 days, continuation of the subject will be decided in 
consultation with Medical monitor. 
 
 
The Pain on Movement (POM) score on a Visual Analog Scale (VAS) and Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC Likert version 3.1) pain score will be recorded 
at the start of run-in Period and at the end of run-in Period (i.e. immediately prior to randomization on 
the day of baseline visit). Recording of the VAS will be done for both the knees and recording of the 
WOMAC pain score will be done for the target knee.  
 


 
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During the washout period, subjects will undergo a single-blind placebo run-in period where the 
subjects will not be aware of the placebo nature of the drug. Subjects will be provided with placebo 
gel for the administration. Approximately 4 gm dose of placebo gel will be applied to the target knee 
four times daily for at least 7 days. Target knee means the knee which is more painful will be 
identified during the screening visit. First administration of gel will be done at the study site. 
 
At baseline visit, subjects will be randomly assigned in 1:1:1 ratio to Mylan’s Diclofenac Sodium 
Topical Gel 1%, Voltaren® Gel 1% (Reference Listed Drug) and Placebo.  All the subjects will be 
instructed to apply the gel next day (Day 1) onwards. All subjects will be applying approximately 4 
gm dose of either Mylan’s Diclofenac Sodium Topical Gel 1% or Reference Listed Drug (RLD)or 
Placebo gel to the arthritic target knee four times daily for 4 weeks.  
 
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC Likert version 3.1) 
pain score for the target knee and pain on movement (POM) on a Visual Analog Scale (VAS) for 
both the knees will be recorded on Week 2 and Week 4 from the start of the treatment.  
 
Acetaminophen (paracetamol) tablets will be given to the subjects for use as a rescue medication or 
for the treatment of aches and pains unrelated to knee pain such as headache during treatment period 
(except 3 days prior to Visit 4 and Visit 5). Maximum allowed dose of acetaminophen (paracetamol) 
will be 2 gm/day. Consumption of rescue medications in terms of number of tablets consumed will be 
monitored. 
 
Subject diary will be provided to subjects to record study medication gel application, rescue 
medication, side effects, and concomitant medication details. Subjects will be trained regarding how 
to use the subject diary. Subject diary will be used to evaluate drug application compliance. Subjects 
will be trained via a detailed and translated instruction subject diary on how to administer the study 
drug. 
 
Physical examination will be conducted during each visit (except at the start of run-in period visit). 
Application site reaction assessment will be conducted on each visit after start of run-in period. 
 
A standard 12-lead ECG will be recorded after 5 minutes of rest in the supine position on screening 
visit and on end of study visit. Vital signs will be measured after 5 minutes of rest (sitting) on each 
visit. 
 
Serum pregnancy test for females of childbearing potential will be performed at screening and end 
of treatment visit. The urine pregnancy test can be performed if clinically indicated during other 
visits. If urine pregnancy is found to be positive, serum pregnancy will be drawn and analyzed for 


 
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confirmation. If serum pregnancy test will found positive then patient will be excluded from the 
study and followed up. 
 
Laboratory assessments like hematology and biochemistry will be performed during screening and 
end of study. The hematology and biochemistry at screening to be performed within 14 days of 
baseline visit. If the gap between lab assessments and baseline visit will be more than 14 days, the 
lab assessments will be repeated at baseline visit. Laboratory investigations (if clinically 
significant) can be repeated once as per investigator’s discretion. 
 
Principal investigator or designee will contact the subjects approximately midway between the visit 
3-4 and visit 4-5 for assessment of the well-being, adverse event, concomitant medication, and 
treatment compliance.  
Additional telephonic contact to reiterate the instructions regarding the use of rescue medications 
during 3 days prior to visits 4 and 5 will be done. Use of rescue medications by subjects during this 
period for intolerable pain will require rescheduling the visits in such a way that visits happen after 
at least 3 days of stopping rescue medication and subjects will be required to inform the site about 
the rescue medication use. The same will be documented in the source notes. 
 
Statistical analysis will be done as per the Section 12.0. 
 
5. STUDY POPULATION 
1212 subjects will be randomized in the study.  
Patients are eligible for enrollment into the study if they meet all of the inclusion criteria and do not 
meet any of the exclusion criteria.  
5.1. Inclusion Criteria 
1. Healthy male or non-pregnant female aged ≥ 35 years with a clinical diagnosis of OA of the knee 
according to the American College of Rheumatology (ACR) criteria2 i.e. Knee pain along with at 
least 3 of the following 6 criteria 
a. Age > 50 years 
b. Stiffness < 30 minutes 
c. Presence of crepitus 
d. Bony tenderness 
e. Bony enlargement  
f. No palpable warmth  
2. Symptoms in target knee for at least 6 months prior to screening 
3. Knee (not referred) pain in target knee for 15 days of the preceding month (periarticular knee pain 
due to OA and not due to other conditions such as bursitis, tendonitis, etc.) 
4. Pain in the target knee requiring the use of NSAIDs or acetaminophen/paracetamol (topical or oral 
treatments). 


 
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5. Subject having an X-ray of the target knee, taken no more than 1 year before baseline, showing 
evidence of OA with Kellgren-Lawrence grade 1-3 disease. 
6. After discontinuing all pain medications (placebo run – in period)  for at least 7 days, had at least 
moderate pain on movement (POM) for target knee, defined as a baseline score of ≥ 50 mm on a 
0-100 mm Visual Analog Scale (VAS) immediately prior to randomization  
7. After discontinuing all pain medications (placebo run – in period) 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. 
8. Able to tolerate rescue medication with acetaminophen (paracetamol) taken as l-2 tablets up to a 
maximum 2 gm per day for the duration of the study. 
9. Subjects who can read and understand WOMAC pain sub scale. 
10. If female, patient must be either postmenopausal for at least one year prior to randomization, 
surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or practicing 
the following methods of birth control: 
a) Oral Contraceptives or Intrauterine Device in place for at least 3 months prior to the start of the 
study and remaining in place during the study period, or  
b) Double Barrier methods containing or used in conjunction with a spermicidal agent, or 
c) Contraceptive Patches/ Implants, or  
d) Abstinence: Subjects who will be practicing abstinence will agree to have a documented second 
acceptable method of birth control if the subject become sexually active during the course of 
her study participation. 
 
5.2. Exclusion Criteria 
1. Pregnant or lactating or planning to become pregnant during the study period. 
2. X-ray showing evidence of OA with Kellgren-Lawrence grade 4 disease. 
3. History of OA pain in the contralateral knee requiring medication (OTC or prescription) within 1 
year prior to screening.  
4. After discontinuing all pain medications  (placebo run-in period) for at least 7 days, had a baseline 
score of  ≥ 20 mm on a 0-100 mm Visual Analog Scale (VAS) for the contralateral knee 
immediately prior to randomization. 
5. History of OA of either Hip or Hands 
6. History of secondary OA (e.g. congenital, traumatic, gouty arthritis), rheumatoid arthritis. 
7. History of chronic inflammatory disease (e.g., colitis) or fibromyalgia. 
8. History of Drugs or Alcohol abuse within the previous year. 
9. Symptomatic peripheral vascular disease of the study leg (prior or current). 
10. Any musculoskeletal condition that would impede measurement of efficacy at the target knee. 
11. History of regular headaches or backache which warrants often use of acetaminophen 
(paracetamol) within the previous year. 


 
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12. Concomitant skin disease at the application site which may affect study drug application or 
tolerability evaluation. 
13. History of active asthma within the previous year that may require periodic treatment with 
systemic steroids during the study period (note: inhaled steroids for this condition are allowed). 
14. History of aspirin sensitive asthma. 
15. History of uncontrolled hypertension (blood pressure more than 150/100 mm of Hg) in spite of 
treatment within the previous year. 
16. History of myocardial infarction, thrombotic events, stroke, congestive heart failure, impaired 
renal function (Serum creatinine > 1.5 x ULN) or liver disease within the previous year. 
17. History of coronary artery bypass graft within 6 months of screening. 
18. History of gastrointestinal bleeding or peptic ulcer disease in last one year. 
19. Known allergy to aspirin, nonsteroidal anti-inflammatory drugs (NSAID) or acetaminophen 
(paracetamol). 
20. Elevated transaminases (≥ 3 times ULN) and Hemoglobin  ˂ 9.0 g/dL at screening. 
21. Viscosupplementation in any joint including the target knee within 6 months prior to screening 
22. Receiving physical therapy (at an outpatient/clinic setting) for the lower extremities or having 
received physical therapy for the lower extremities within 1 month before screening. 
23. Use of anticoagulants, ACE-inhibitors, cyclosporine, diuretics, lithium, or methotrexate prior to 
30 days of screening. 
24. Concomitant use of intra articular corticosteroids, systemic corticosteroids, topical corticosteroids, 
or immunosuppressive drugs or their use prior to 30 days of screening. 
25. Concomitant acetylsalicylic acid therapy other than a stable low dose used for cardiac prophylaxis 
(maximum 162 mg daily)3 taken for at least 3 months prior to enrollment and maintained 
throughout the duration of the study. 
26. History of major surgery or previous damage to the study knee at any time, or minor knee surgery 
(e.g. any surgery other than major surgery including, but not limited to, cartilage repair, collateral 
ligament repair, or arthroscopic debridement) to the study knee within 1 year prior to screening. 
27. Known history of positive HIV, HCV, or HBsAg. 
28. Tense effusion requiring aspiration. 
29. Subjects who have been treated with an investigational drug or investigational device within a 
period of 30 days prior to enrollment. 
30. Any other acute or chronic illness that could compromise the integrity of study data or place the 
subject at risk by participating in the study. 
 
6. RANDOMIZATION AND BLINDING PROCEDURES 
6.1. Randomization Procedure 
A computerized randomization will be generated by an independent third party (not involved in the 
packaging and labelling of the study medication).  
 


 
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Subjects will be randomly assigned in 1:1:1 ratio in three groups. Treatment allocation can be either 
Mylan’s Diclofenac Sodium Topical Gel 1%, Voltaren® Gel 1% (Reference Listed Drug), or Placebo. 
A balanced randomization schedule will be generated using SAS® software (Version: 9.1or higher; 
SAS Institute Inc., USA). The randomization code will be held by an independent third party 
throughout the conduct of the study in order to minimize bias.  
 
A sealed copy of the randomization code for each kit provided under separate cover inside the block 
will be retained at investigational site. It should be available to FDA investigators at the time of site 
inspection to allow for verification of the treatment identity of each subject. 
 
6.2. Blinding Procedure 
Placebo run-in period will be single blinded in which subjects will not be aware of the treatment 
given.  
Treatment period will be double blinded in which all the investigators, subjects, site staff, CRO team, 
study monitors, laboratory personnel and/or other designated individuals will be blinded to the 
medication codes. The formulation of test, reference and placebo investigational products would be 
identical in appearance to make any difference in treatment less obvious to the subjects and to 
maintain adequate blinding of evaluators.  
 
Unblinding will be performed by a designated person in case of SAE or other significant events (Refer 
section 11.2.5.3). The event of unblinding shall be documented in the source notes. 
 
Mylan Product Safety and Risk Management (PSRM) can unblind the treatment assignment for any 
subject with a SAE which qualifies for the unblinding based on country specific regulatory 
requirements.  
 
The event of unblinding shall be documented in the source notes. Reasons for treatment unblinding 
must be clearly explained and justified in the eCRF. The date on which the code was broken together 
with the identity of the person responsible must also be documented. 
 
If a subject’s treatment assignment is unblinded for any reason then the subject should be withdrawn 
from the study. 
 
7. STUDY TREATMENT, DESCRIPTION AND ALLOCATION 
7.1 Investigational Medicinal Products and Non - Investigational Medicinal Products (IMP and 
NIMP) 
Investigational Medicinal Products (IMP) 
The study medication supplied by the sponsor will consist of: 
 


 
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Treatment Arms 
Intervention 
Test product: 
Diclofenac Sodium Gel, 1% manufactured by Mylan Inc. 
Reference 
product: 
Voltaren® Gel (Diclofenac Sodium Topical Gel) 1% manufactured by Novartis 
Pharma Produktions GmbH, marketed by: Endo Pharmaceuticals Inc., Malvern, 
PA 19355 
Placebo 
formulation: 
Placebo gel 
. 
Identical dosing cards will be provided along with the investigational medicinal products. 
Non-Investigational Medicinal Products (NIMP) 
Acetaminophen (paracetamol) tablets will be given to all the subjects baseline for use as a rescue 
medication or for the treatment of aches and pains unrelated to knee pain such as headache during 
treatment period. 
 
7.2 Investigational Product Labeling, Packaging & Formulation 
Study drugs will be packaged and labeled based on the randomization schedule generated prior to the 
start of the study. The investigator will be overall responsible for ensuring that IPs are stored in a safe, 
limited access location, as per the condition noted in the label. Each site will receive the pre-labeled 
study drugs for the run-in period and treatment period. 
 
Labelling text will be compliant with local regulatory requirements. The label should include but not 
be limited to: Sponsor name/address, Dosage, route of administration, name/strength, batch 
number/code, study reference or protocol number, kit’s number, directions for use, statement ‘for 
clinical trial use only’, storage conditions, expiry/use by date. 
 
At the start of placebo run-in period and at baseline visit, each subject will receive the study drugs and 
at the baseline visit, subjects will receive the rescue medications.   
 
Formulation Details 
Test Formulation 
Active ingredient: Diclofenac sodium 
Inactive 
ingredients: 
 
 
 
 
 
 
 
 
 
Reference 
Formulation 
Active ingredient: Diclofenac sodium 
Inactive 
ingredients: 
 
Carbomer 
homopolymer 
Type 
C, 
cocoyl 
caprylocaprate, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, 
propylene glycol, purified water, and strong ammonia solution 
Placebo Formulation 
It will contain all the excipients (inactive ingredients) present in the test 
formulation. 


 
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7.3 Storage Conditions 
Study medication should be stored, prior to dispensing, at controlled temperature 20°C to 25°C (68°F 
to 77°F) in a locked, limited access area at the study center. Do not freeze the product. Dosing card 
should be stored along with study medication. After dispensing, the subject will be instructed to store 
the medication at 20°C to 25°C (68°F to 77°F) [USP Controlled Room Temperature]. Used/unused 
medications except the retention samples, will be handled as per instructed by the sponsor. 
7.4 Investigational Product Handling and Management 
The medication will be supplied in tubes as a kit. The tubes will be packed and labeled according to 
the randomization scheme generated prior to the start of the study. The containers/kit should not be 
opened by the subject at the study center. 
Details of the IP handling will be described in ‘IP Handling Work Instruction’. 
7.5 IP Retention Requirements 
The sponsor will supply sufficient quantities of the study formulation for the following: 1) completion 
of the study and 2) retention, as per applicable regulations. All drug supplies provided for this study 
will be stored in a secure area with restricted access, under storage conditions described in the 
reference drug package labeling. 
Details of the IP retention will be described in ‘Investigational Product Retention Plan’. 
Records will be made of receipt and dispensing of study drugs supplied. It is the responsibility of the 
Sponsor to ensure that all drug supplies provided for the study are manufactured under current Good 
Manufacturing Practices (cGMP) and are suitable for human use. 
Upon completion or termination of the study, a sample of all study supplies will be retained for a 
period of at least 5 years following the date on which the study is approved by USFDA or, if the study 
is not approved, at least 5 years following the date of completion of the study in which the 
investigational products were used. Retention samples should be randomly selected from the drug 
supplies received prior to dispensing to subjects. Retention samples should not be returned to the 
sponsor or CRO at any time.  
7.6 Study Medication Administration 
At the start of the placebo run-in period, placebo gel will be dispensed and during the treatment 
period, Mylan’s Diclofenac Sodium Topical Gel 1%, Voltaren® Gel 1% (Reference Listed Drug), and 
Placebo gel will be dispensed to the qualified subjects for the application of gel to the target knee. 
Target knee means the knee, which is more painful, will be identified during the screening visit. First 
administration of the study drug at the start of placebo run-in period will be supervised at the study 
center, with subsequent applications self-administered on an outpatient basis.  
Subject diary will be given at the start of the placebo run-in period and treatment period to the subjects 
containing instructions related to the proper administration method (see Appendix I). 


 
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Method of application during run-in period and treatment period: 
Study participants will have to apply 4 gm of study medication to the affected area of target knee 4 
times daily. The proper amount of gel will be measured using the dosing card. The gel will be applied 
within the rectangular area of the dosing card up to 4 gm line. 
 
 
.  
 
 
 
 
 
 
 
Rescue Medication Administration: 
Subjects will be allowed acetaminophen (paracetamol) tablet as rescue medication on an as-needed 
basis (up to 2 gm/ day) during the treatment period, except for the at least 3 days prior to each clinic 
visit. 
 
7.7 Subject withdrawal Criteria 
Subjects will be discontinued from the study for any of the following reasons: 
 If the subject withdraws his or her consent for any reason. 
 If the subject’s condition has worsened to the degree that the investigator feels, it is unsafe for 
the subject to continue in the study. 
 If the subject’s drug code is unblinded. 
 If an adverse event occurs for which the subject desires to discontinue treatment or the 
investigator determines that it is in the subject’s best interest to be discontinued. 
 If the subject with a score of ≥ 20 mm on a 0-100 mm Visual Analog Scale (VAS) for the 
contralateral knee 
 If there is a significant protocol violation. 
 If the subject is lost to follow-up. (The investigator will document all attempts to reach the 
subject by telephone and/or in person in source documents before considering that subject lost 
to follow-up.) 
 If the female subject becomes pregnant. 
 Treatment failure based on investigator’s discretion. 


 
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 Administrative reasons. 
The reasons for a subject being discontinued will be documented in the source notes and captured in 
case report form. 
If a subject is discontinued from the study for any reason, the Day 28/ Early Termination Visit 
procedures should be completed and any outstanding data and study drug should be collected. Data, in 
addition to the reason for discontinuation and the date of removal, will be captured on the End of 
Study section of eCRF. 
In the event that a subject discontinues from the study at any time due to an adverse event, the reason 
for discontinuation, the nature of the event and its clinical course must be fully documented.  For such 
a subject, the investigator must strive to follow the subject until the adverse event has resolved, 
become clinically insignificant, is stabilized, or the subject is lost to follow-up. 
Should a serious adverse event be noted, procedures stated in Section 11.2.2 must be followed. 
7.8 Premature Termination of Study in a Study Center 
The Sponsor reserves the right to discontinue the study at any time. The reasons will be discussed 
with the Investigator. A study site may also be discontinued by the Sponsor for significant deviations 
from the protocol or due to difficulties experienced in running the study at that center. 
The Sponsor may terminate this study in one particular or several study center(s) for one of the 
following reasons: 
 Non-compliance with GCP and/or regulatory requirements 
 Center cannot recruit an adequate number of patients 
 False documentation in the eCRF due to carelessness or deliberately 
 Inadequate co-operation with the Sponsor or its representatives 
 The Investigator requests closure of his/her study center 
If the study is prematurely terminated in one or more study centers, all Investigators have to inform 
their patients and take care of appropriate follow-up and further treatment of the patients. Ethics 
Committees and regulatory authorities will be informed about the reason and time of termination 
according to the applicable laws and regulations. 
7.9 Termination of the Study 
Premature termination of this study may occur because of a regulatory authority decision, change in 
opinion of the IRB/IEC, drug safety problems, or at the discretion of Mylan 
, 
. In addition, Mylan 
 retains the right to discontinue development of generic 
formulation of diclofenac gel at any time. 
If a study is prematurely terminated or discontinued, Mylan 
 will promptly notify 
the investigator. After notification, the investigator shall contact all participating subjects. As directed 


 
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by Mylan Laboratories Limited, all study materials must be collected and all CRFs completed to the 
greatest extent possible. 
7.10 
Treatment Compliance 
A Subject Diary will be provided to all subjects where it is required to document the date and time of 
application of the medication. In the subject diary, subjects will also note of any adverse event 
observed, date and time of rescue medication administration and any concomitant medication taken or 
changed.  
Compliance will be determined from the subject diary, which the subject will be trained and instructed 
to use to record all doses, as well as all missed doses. The number of missed and additional doses will 
be captured on the compliance page of the eCRF.   
The used study medication tubes will be returned to the study site at appropriate visits or early 
termination or as applicable. 
Subjects who are not compliant with application will be re-counseled during the study visits. 
Subjects who will take less than 75% (<84 applications) of total study drug during the study will be 
considered non-compliant and discontinued from the study. Subjects who will take more than 125% 
(>140 applications) of study drug are also considered non-compliant and the same subjects will not 
considered for the Per-protocol (PP) population. 
7.11 
Study Medication Accountability 
When a drug shipment is received at a study center, the investigator/designee shall sign the receipt 
form provided with the shipment.  
Subjects shall be instructed to return used, partially used, or unused study medication kits to the study 
center staff so that any remaining drug supplies can be accounted for and noted in the log for 
accountability.  
7.12 
Return of Clinical Supplies 
All used and unused kits of study medication will be handled as per Sponsor’s instructions in IP 
handling plan after completion of the study. 
7.13 
Concomitant/Prohibited Treatment: 
Any medication other than study drug, either prescription drug or OTC drug will be treated as 
concomitant medication. 
All medications taken on a regular basis should be recorded in source data. 
If drug therapy other than that specified in the protocol is required, it should be documented and have 
to be pre-approved by the investigator (if required in consultation with medical monitor/sponsor) prior 
to the subjects usage. Further, the Investigator (if required in consultation with medical 


 
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monitor/sponsor) decide the course of action for that participant based on the time the medication was 
administered and its pharmacology.  
The following are prohibited during this study: 
1. Any other topical or intraarticular products applied to the target site. 
2. ACE-inhibitors, anticoagulants, cyclosporine, diuretics, lithium, methotrexate or oral NSAIDs. 
3. Muscle relaxants 
4. Sedative/hypnotics (stable dose for at least 14 days prior to baseline visit will be allowed) 
5. Chondroitin/glucosamine 
6. Opioids 
7. Glucosamine 
8. Chondroitin 
9. Use occlusive bandages, ultrasound, transcutaneous electrical stimulation or any alternative 
therapies such as acupuncture, homeopathy or mesotherapy 
10. Systemic corticosteroids or immunosuppressive drugs. 
11. Pain medication other than acetaminophen (paracetamol) including topical NSAIDs 
12. Non-pharmacological devices for knee pain like knee brace, herbal remedies. 
 
Physical therapy will be permitted if this started at least 1 month before screening but cannot be 
initiated or changed during the study. Exercise regimens and the application of heat or cold will not be 
started, discontinued, or changed during the study. 
 
Permitted Medications 
Subjects will be allowed to continue taking stable (non-analgesic) medications that would not interfere 
with the metabolism of diclofenac. 
Concomitant use of acetylsalicylic acid for cardiac prophylaxis with maximum 162 mg daily will be 
allowed during the study if the therapy is stable for at least 3 months. 
7.14 
Rescue medication 
Subjects will be permitted to take acetaminophen (paracetamol) tablet as needed during the treatment 
period. Any use of rescue medication will be recorded by the subject in the subject diary (e.g., Date 
and time). 
 
 
 
 
 
 
 
 
 
 
 
 
). 
 
 
 
 
. Rescue medications will not be permitted within 3 days of the 
assessments during treatment period. Use of rescue medications by subjects during this period for 
intolerable pain will require rescheduling the visits in such a way that visits happen after at least 3 
days of stopping rescue medication and subjects will be required to inform the site about the rescue 


 
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medication use. Site staff will telephonically remind to subjects regarding stop usage of rescue 
medication before the visit and next visit date. The use of rescue medication will be compared 
between treatment groups. 
8 EFFICACY ASSESSMENTS 
8.1 Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Likert Scale 
3.1 
Western Ontario and McMaster Universities Osteoarthritis Index is used to assess pain, stiffness, and 
physical function in subjects with hip and / or knee osteoarthritis (OA). 
The WOMAC consists of 24 items divided into 3 subscales13:  
 
Pain (5 items): during walking, using stairs, in bed, sitting or lying, and standing 
 
Stiffness (2 items): after first waking and later in the day 
 
Physical Function (17 items): stair use, rising from sitting, standing, bending, walking, getting 
in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting 
in / out of bath, sitting, getting on / off toilet, heavy household duties, light household duties 
Among all the 3 subscales, pain score will be used during the study. 
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score will be 
recorded at the start and at the end of run-in Period (i.e. immediately prior to randomization on the day 
of baseline visit); and on Week 2 and Week 4 for target knee after start of treatment.  
 
WOMAC pain score (pain score = 0 to 20), will be determined by the 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). The questions pertain to the amount of pain the subject is currently experiencing in the 
target knee [i.e., ‘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)]. 
WOMAC pain score will be given to the subject along with the necessary instruction on the each visit. 
 
8.2 Pain on movement (POM) after 100 Meter Walk on a Visual Analog Scale (VAS) 
Pain on movement (POM) on a Visual Analog Scale (VAS) will be determined by the subject’s 
responses at the start and at the end of run-in Period (i.e. immediately prior to randomization on the 
day of baseline visit); and on Week 2 and Week 4 after start of treatment for the both the knees. The 
subject will be asked to place a mark to the VAS line at the point that represents pain intensity. The  
VAS  score  will be  determined  by  measuring  in  millimetres  from  the  left  hand end of the line to 
the point that the patient marks by site staff. The calibrated ruler will be used to estimate VAS score.14 
VAS scale: 
 
 
 
 
No Pain 
Worst pain 
imaginable 
0 
100 


 
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9 SAFETY ASSESSMENTS 
9.1 Adverse Events 
Safety will be determined by monitoring adverse events (AEs), which will be classified using 
MedDRA (Medical Dictionary for Regulatory Activities) terminology. 
9.2 Medical History 
A complete medical history, including a complete review of all current and past diseases and their 
respective treatments, must be done on screening visit. 
9.3 Physical Examination 
The investigator or sub-investigator must perform a physical examination on screening, baseline visit, 
interim visit (on day 14) and end of study visit. 
Joint examination of the affected knee will be performed during the screening includes following: 
 Recording of affected knee (left/right) 
 Receiving any physical therapy at screening 
 Subjects with periarticular pain 
 Range of motion 
 Extension (degree) 
 Neutral (degree) 
 Flexion (degree) 
 Tenderness on pressure (scale: 0 = none, 1=mild, 2=moderate and 3=severe) 
 Joint space medially 
 Joint space laterally 
 Patella medially 
 Patella laterally 
 Swelling of joint capsule(scale: 0 = none, 1=slight, 2=moderate and 3=severe) 
 Joint effusion (Yes/No) 
Vital signs (heart rate, respiratory rate, body temperature and blood pressure) will be measured after 
5 minutes of rest (sitting) on each visit. 
A standard 12-lead ECG will be recorded after 5 minutes of rest in the supine position on screening 
visit and on end of study visit.  
X-ray of target knee will be performed on screening if not performed for more than 1 year prior to 
baseline. 
9.4 Application Site Reaction 
Application site reaction will be assessed on each visit after start of run-in period to evaluate the 
adverse events if any.  
 
9.5 Laboratory Tests 
Following laboratory tests will be performed at screening and at the end of the study:  


 
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If the gap between screening laboratory assessments (hematology and biochemistry) and baseline visit 
is more than 14 days, the lab assessments should be repeated at baseline visit 
If warranted, other tests or examinations may be performed at the discretion of the Principal 
Investigator. Approximately 20 ± 5 ml of blood will be withdrawn during screening visit and at the 
end of study visit to perform above mentioned Clinical Laboratory Tests. 
9.6 Pregnancy Test 
Serum Pregnancy Test for females of childbearing potential will be performed during screening visit 
and at the end of study or early termination visit. The urine pregnancy test can be performed if 
clinically indicated during other visits. If urine pregnancy is found to be positive, serum pregnancy 
will be done for confirmation. If serum pregnancy test will found positive then patient will be 
excluded from the study and followed up. 
Acceptable forms of contraception include the following:   
 Oral Contraceptives or Intrauterine Device in place for at least 3 months prior to the start of 
the study and remaining in place during the study period, or  
 Double Barrier methods containing or used in conjunction with a spermicidal agent, or 
 Contraceptive Patches/ Implants, or  
 Abstinence: Subjects who will be practicing abstinence will agree to have a documented 
second acceptable method of birth control if the subject become sexually active during the 
course of her study participation. 
Hematology 
Hemoglobin 
Total RBC count 
Total WBC count 
Platelet count 
Differential Leukocyte count: 
Neutrophils 
Lymphocytes 
Eosinophils 
Monocytes 
Basophils 
Blood Chemistry 
Alkaline Phosphatase 
Serum 
Creatinine 
Random Glucose 
SGPT & SGOT 
Serum Bilirubin 


 
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10 SCHEDULE OF ACTIVITIES: (VISIT SCHEDULE) 
10.1 
Visit 1: Screening Visit (within 28 days prior to randomization) 
 Informed Consent: Subjects must provide a signed, IEC/IRB approved written informed 
consent. No study related procedures or activities will be performed until each subject is fully 
informed and the consent form is signed and dated. All subjects will be given a copy of the 
signed and dated consent form. 
 Inclusion/Exclusion Criteria Review 
 Demographic Data (Height, weight, age, sex, ethnicity etc.) 
 Medical History. A complete medical history will be recorded. Information regarding the 
subject’s current and past medical conditions will be captured including surgical procedures.  
 Physical Examination (along with baseline joint examination)and Vital Signs 
 Evaluation of ACR criteria for OA 
 Laboratory Tests 
 X-ray of target knee, evaluation as per the Kellgren-Lawrence grading (See Appendix III) 
 ECG 
 Serum Pregnancy Test (for all females of childbearing potential) 
 Assess Adverse Events (after signing of the ICF)   
10.2 
Visit 2: Start of Placebo Run-in Period (Day -11 to Day -7) 
 Discontinuation of current osteoarthritis therapy 
 Vital Signs 
 Inclusion/Exclusion Criteria Review 
 Urine Pregnancy Test (for all females of childbearing potential) if clinically indicated 
 Pain on Movement (POM) assessment in both the knees- 100mm VAS 
 WOMAC pain score assessment of the target knee 
 Study Medication and Subject Diary Dispensing for Run-in Period: Placebo gel for run-in 
period will be dispensed by the site staff to qualified subjects. A subject diary, containing 
instructions for subjects, will be dispensed to each qualified subject. First administration of gel 
will be supervised at the study center. 
 Instructions on placebo application and storage 
 First placebo gel application at the site 


 
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 Assess Adverse Events  
 Assessment of Concomitant Medications.  
 
10.3 
Treatment Period Visits 
10.3.1 Visit 3 (Baseline): Day 0 
The following procedures will be performed at the Randomization Visit: 
 Physical Examination and Vital Signs 
 Inclusion/Exclusion Criteria Review 
 Urine Pregnancy Test (for all females of childbearing potential) if clinically indicated.   
 Laboratory investigations (if not performed within 14 days of baseline visit) 
 Pain on Movement (POM) assessment in both the knees- 100mm VAS 
 WOMAC pain score assessment of the target knee 
 Subject diary (placebo run-in period) review and its collection 
 Assessment of treatment compliance 
 Application site reaction assessment 
 Study medication and Subject diary for treatment period dispensing: Study medication 
for treatment period will be dispensed by the site staff to qualified subjects. A subject diary, 
containing instructions for subjects, will be dispensed to each qualified subject.  
 Instructions on study medication application and Storage 
 Collection of the unused IP dispensing during placebo run-in period 
 Rescue medication dispensing 
 Assess Adverse Events 
 Assessment of Concomitant Medications 
10.3.2 Visit 4: Interim Visit (Week 2/Day 14 ± 4)  
The following procedures will be performed. 
 Physical Examination and Vital signs 
 Urine Pregnancy Test (for all females of childbearing potential) if clinically indicated.   
 Subject diary review 
 Assessment of treatment compliance 


 
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 Pain on Movement (POM) assessment in both the knees- 100mm VAS 
 WOMAC pain score assessment of the target knee 
 IMP dispensing  
 Collection of the unused IPs 
 Rescue medication dispensing (if required) 
 Application site reaction assessment  
 Assess Adverse Events 
 Assessment of Concomitant Medications.  
10.3.3 Visit 5: End of Study (Week 4/Day 28 ± 4)/Early Termination Visit 
The following procedures will be performed. 
 Physical Examination and Vital Signs 
 Serum Pregnancy Test (for all females of childbearing potential) 
 Laboratory investigations 
 ECG 
 Pain on Movement (POM) assessment in both the knees- 100mm VAS 
 WOMAC pain score assessment of the target knee 
 Subject diary (treatment period) review and its collection 
 Assessment of treatment compliance 
 Collection of the unused IPs and rescue medication 
 Application site reaction assessment Collection of unused medications (IP/NIMPs) 
 Assess Adverse Events 
 Assessment of Concomitant Medications 
Note:  
 Additional assessments could be performed as per Investigators’ discretion during the study. 
 All the subjects will be instructed to apply the gel next day (Day 1) onwards. 
 Telephone contact: Principal investigator or designee will contact the subjects approximately 
midway between the visit 3-4 and visit 4-5 for assessment of the well-being, adverse event, 
concomitant medication, and treatment compliance. Additional telephonic contact will be done 


 
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to remind the subject regarding stoppage of rescue medication usage prior to scheduled visits 
(Visit 4, and Visit 5). The same will be documented in the source notes. 
 In case subject extends run-in period beyond 11 days, continuation of the subject will be 
decided in consultation with Medical monitor. 
10.4 Unscheduled Visit 
An unscheduled visit is allowed at any time if in the investigator’s opinion it is warranted. If the 
investigator assesses the subject’s condition at any time and determines that the subject’s condition 
has worsened to the degree that it is unsafe for the subject to continue in the study (including 
suspected use of placebo), the subject may be discontinued from the study as treatment failure, and a 
standard of care treatment may be advised at the investigator’s discretion. 
If subject is discontinued early from the study, Day 28/ Early Termination Visit activities will be 
performed (see Appendix II). 
11 ADVERSE EVENT REPORTING 
11.1 Assessment of Safety 
11.1.1 Safety Parameters 
Safety may be assessed by the monitoring of adverse clinical events, electrocardiograms, clinical 
laboratory evaluations and physical examinations.  All adverse events occurring during the study must 
be recorded according to Section ‘Adverse Events’. 
11.2 Adverse Events 
The adverse event collection period begins at signing of informed consent and continues until 28 days 
after the last dose.  Adverse events occurring during this period need to be reported to the sponsor 
according to Section ‘Documentation of Adverse Events’.  
 
The investigator is also responsible for notifying the sponsor if he/she becomes aware of any adverse 
event after the study period has ended and it is considered related to the study medication (i.e. an 
adverse drug reaction).  
 
Once an AE is detected, it should be followed until its resolution or until it is judged by the principal 
investigator to be stable or permanent. 
11.2.1 Definitions 
Adapted from ICH Harmonised Tripartite Guideline: Clinical Safety Data Management Definition and 
Standards for Expedited Reporting: E2A  
 
 


 
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Adverse Event:  
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including a new, clinically important abnormal 
laboratory finding), symptom, or disease, temporally associated with, whether or not related to the 
product. 
 
Examples of adverse events include but are not limited to: 
 A new disease or exacerbation of an existing disease. Note: worsening of osteoarthritis pain of 
the knee (disease progression), the condition under study, will not be recorded as an adverse 
event. 
 A recurrence of an intermittent condition (e.g., migraine) not present at baseline; 
 A deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is considered 
clinically significant by the investigator or associated with symptoms or leads to a change in 
study treatment, concomitant therapy, or discontinuation from study drug; 
 A symptom or medical complication related to a protocol-mandated intervention, including 
screening and run-in period procedures. 
 
Serious Adverse Event: 
Any adverse event that: 
 Results in death 
 Is life-threatening – means an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were 
more severe 
 Requires inpatient hospitalization – any patient admission to a healthcare facility, even if for 
less than 24 hours. A planned hospitalization required by the protocol or scheduled prior to 
study initiation does not constitute an SAE 
 Prolongs hospitalization – any extension of hospitalization  
 Results in persistent or significant disability/incapacity - the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This definition is 
not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. 
sprained ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption 
 Is a congenital anomaly/birth defect. A pregnancy during the study meets the seriousness 
criteria in the following cases: miscarriage, congenital anomaly, neonatal death, infant death 


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
Is an important medical event that may not be immediately life-threatening or result in death or
hospitalization, but may jeopardize the patient or may require intervention to prevent one of
the other listed outcomes listed in the definition above? Examples of such events are any
cancer, intensive treatment in an emergency room or at home for allergic bronchospasm, blood
dyscrasias or convulsions that do not result in hospitalization, or development of drug
dependency or drug abuse.
Treatment emergent adverse event: 
Any adverse event that occurs after the first dose of study medication through 28 days after the last 
dose. 
Unexpected adverse event/Adverse Drug Reaction: 
An expected AE or adverse drug reaction (ADR) is defined as one whose nature or severity is 
consistent with the reference safety information in the approved label.  
An AE is considered unexpected if the nature or severity is not consistent with the applicable product 
reference safety information. Reports that add significant information on specificity or severity of a 
known, already documented ADR constitute unexpected events.  
11.2.2 Documentation of Adverse Events 
The investigator or designee must record all adverse events reported by subjects that have occurred 
during the adverse event collection period of the study.  
Adverse events should be solicited from subjects through open-ended questions, and as appropriate, 
by examination. Subjects should normally be evaluated for adverse events following drug 
administration and prior to discharge from the clinic. The subject should also be queried for any 
previously unreported adverse event as part of study exit procedures.  
All adverse events, whether or not caused by the study drug, will be recorded on source documents 
and reported to the Sponsor as per Section 11.2.5. The information in the source document will 
include: 

The date/time of onset of any new adverse event or the worsening of a previously observed
adverse event or worsening of any previously existing disease

The event in standard medical terminology

The date of resolution of the adverse event, when applicable

The relationship of the adverse event to the study drug(s)

The severity of the adverse event


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
Seriousness of the adverse event

Description of action taken in treating the adverse event and/or change in study drug
administration or dose
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECGs, vital signs measurements), including those that worsen from baseline, 
and felt to be clinically significant in the medical and scientific judgment of the investigator are to 
be recorded as AEs or SAEs. The following are examples of laboratory abnormalities that would 
normally qualify as adverse events: 

The abnormality suggests a change in disease severity and/or organ toxicity

The abnormality is of a degree that requires active management; e.g. change of dose,
discontinuation of the drug, more frequent follow-up assessments, further diagnostic
investigation, etc.
11.2.3 Relationship of Adverse Experiences to the Study Drug 
The Investigator is responsible for assessing relationship of adverse events to study medication (e.g., 
causality assessment).  Factors that need to be considered when making a causality assessment 
include: the temporal relationship (e.g., time to onset); the clinical and pathological characteristics of 
the events; pharmacological plausibility; exclusion of confounding factors (medical and medication 
history); drug interactions; dechallenge/rechallenge, and dose relationship, etc.. 
A suspected relationship (definite, probable, possible) between the events and the study medication 
means in general that there are facts (evidence) or arguments to suggest a causal relationship. Receipt 
of additional or clarifying information may warrant reassessment of causality.  
The Investigator is responsible for assessing relationship of adverse events to study medication in 
accordance with the following definitions:  
Definite – causal relationship is certain (e.g., the temporal relationship between drug exposure and the 
AE onset/course is reasonable, there is a clinically compatible response to dechallenge, other causes 
have been eliminated and the event must be definitive pharmacologically or phenomenologically, 
using a satisfactory rechallenge procedure if necessary). 
Probable – high degree of certainty for causal relationship (e.g., the temporal relationship between 
drug exposure and AE onset/course is reasonable, there is a clinically compatible response to 
dechallenge (rechallenge is not required), and other causes have been eliminated or are unlikely). 
Possible – causal relationship is uncertain (e.g., the temporal relationship between drug exposure and 
the AE onset/course is reasonable or unknown, dechallenge information is either unknown or 


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equivocal, and while other potential causes may or may not exist, a causal relationship to study drug 
does not appear probable). 
Assessments of Unlikely and Unrelated do not meet the threshold for reasonable suspected causal 
relationship and are therefore classified as Unrelated for regulatory reporting and within a binary scale 
of Related/Not Related. 
Unlikely – Temporal relationship between drug administration and event onset is improbable, and/or 
another explanation is more likely such as disease, environment, other drugs etc. Does not represent a 
known reaction to study drug.       
Unrelated/Not related – no possible relationship (e.g., the temporal relationship between drug 
exposure and the AE onset/course is unreasonable or incompatible, or a causal relationship to study 
drug is implausible). 
11.2.4 Severity of the Event 
The intensity or severity of AEs will be graded as follows: 

Mild- awareness of sign or symptom, but easily tolerated. Not expected to have a clinically
significant effect on the subject’s overall health and well-being. Does not affect daily
activities. Not likely to require medical attention.

Moderate - discomfort enough to cause interference with usual daily activities or affects
clinical status. May require medical intervention and/or prescription drug therapy.

Severe - incapacitating or significantly affecting clinical status. Severely limits daily activities.
Medical intervention, prescription drug therapy and/or hospitalization required.
Note that the term “severe” is a measure of intensity; thus, a severe AE is not necessarily serious. For 
example, nausea of several hours duration may be rated as severe, but may not be clinically serious. 
Likewise, mild or moderate events could, under some circumstances, result in a serious outcome as 
defined above. 
11.2.5 Expedited Reporting of Serious Adverse Events 
In addition to standard documentation of adverse events in the source and CRF, serious adverse events 
require immediate notification to Mylan Product Safety and Risk Management (PSRM).  “Immediate” 
is defined as within 24 hours of the investigator’s or site staff’s knowledge of the event. Serious 
adverse events are defined in section 11.2.1 ‘Serious Adverse Events’. 
The SAE Reporting Form is to be completed for all serious AEs, signed by the investigator, and 
emailed or faxed with supporting documentation (e.g. case report forms, hospital records, laboratory 
reports, etc.).  Subject identity details (such as but not limited to name or clinic/hospital number) must 
not be visible on SAE forms or any supporting documentation provided by the Investigator.  Any 
personal information on supporting documents should be redacted before submission to Mylan. The 


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study specific subject ID must be recorded on every page of the SAE report form and 
supporting documents sent to Mylan. 
The investigator will include a narrative description of the serious adverse event(s) that discusses: 

Study medication(s) administered, including dates

Date and time of the onset of the serious adverse event

Signs and symptoms

Description of the event in standard medical terminology

Date the event resolved or outcome of the event at last observation

Laboratory and/or confirmatory tests

Investigator’s assessment - the attribution of the adverse event to the study drug(s) or
possible alternative etiologies for the event. If considered related (i.e. definite, probable,
possible) to the study medication, the rationale for suspecting an adverse drug reaction
should be provided

Description of action taken in treating the adverse event and/or change in study drug
administration or dose
The report form must also contain the subject’s demographic information, medical history, and 
concomitant medication at the time of the event. 
All communication of AE/SAE information will be in English. 
All SAEs must be sent within 24 hours of awareness to: 
Mylan 
 
  
Note: Email is the preferred method of communication 
 
  
11.2.5.1 
Follow-up of Serious Adverse Events 
The Investigator is responsible for collecting and forwarding to Mylan PSRM any required 
information not available at the time of the initial report as well as the final outcome of the SAE. 
Follow-up information to a SAE report shall be submitted to Mylan’s PSRM department by the 
investigator as soon as the relevant information is available and reviewed by the investigator. Relevant 
information such as discharge summaries, autopsy reports, and medical consultations shall be 
reviewed in detail by the Investigator for important new information. The Investigator shall comment 
on any event, abnormal laboratory result, or any other finding, noting whether it shall be considered a 


 
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serious or non-serious AE or considered part of the subject’s history. In addition, the Investigator shall 
report on an SAE form all subsequent events or other findings determined to be relevant and shall 
state for each event or finding whether it is related to study drug. All events determined to be non-
serious shall be recorded on the relevant CRF page and entered into clinical database by the CRO or 
others as agreed in their contractual obligations. 
11.2.5.2 
Reporting Timelines for Serious Adverse Events and Follow-up Information 
Prompt notification of SAEs by the investigator to Mylan is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects are met. 
 
Mylan has a legal responsibility to notify both the local regulatory authority and other regulatory 
authorities about the safety of a product under clinical investigation. Mylan will comply with country 
specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) and investigators. 
 
In order for Mylan to meet these obligations, the Principal Investigator (or designee) will report to the 
Mylan any AE classified as serious via telephone, fax, or email within 24 hours of awareness. All 
available information must be included on the SAE Report form as soon as possible, but in any case 
no later than 2 calendar days after first knowledge of the SAE. The notification to the Sponsor should 
be directed to the safety contact
 the Sponsor CRA in parallel. The same timelines 
apply to reporting of follow-up information. 
 
The Investigator should also be aware of any reporting requirements under his/her responsibility, such 
as local institutional review boards or ethics committees.  
11.2.5.3 
Emergency Unblinding 
Treatment assignment for an individual subject should be unblinded only in case of a medical/surgical 
emergency by the investigator, when knowledge of the treatment assignment is urgently needed for 
the clinical management or welfare of the subject. Treatment should be provided in accordance with 
the medical condition.  
 
In case of unblinding, the CRO project manager should be contacted by telephone prior to unblinding 
but no later than 24 hours after unblinding. 
If a serious adverse event (SAE) occurred, an SAE Report Form must be completed and forwarded to 
Mylan’s PSRM department.  The investigator must document the breaking of the code, and the 
reasons for doing so on the eCRF, in the site file, and in the medical notes. 
 
The investigator must notify the sponsor in writing as soon as possible following the code break 
detailing the necessity of the code break. Unblinded information should not be shared with those 
persons responsible for ongoing conduct of the study such as monitors, statisticians, and other 


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investigators. The unblinded treatment assignment should only be provided to Mylan PSRM in the 
event of an SAE, via the SAE report form, for safety reporting to national competent authorities. 
11.2.6 Individual Case Management and Periodic Reporting 
Individual case management (including expedited reporting) and Development Safety Update Reports 
(if required) will be managed according to Mylan’s internal Standard Operating Procedures and 
applicable regulatory requirements.  
11.2.7 Special Situations 
The following situations may be associated with a serious outcome and should be evaluated for 
expedited reporting to the sponsor. 

Any diagnosis of Cancer or Neoplasm is to be reported as a serious adverse event.

Emergency Room Visits:  Events that result in emergency room visits that do not result in
admission to the hospital are not routinely considered to be serious events; however, these
events should be evaluated for one of the other serious outcomes (e.g., life-threatening, other
serious [medically significant] events).

Overdose:  Accidental or intentional overdose, should be reported to the sponsor on an
expedited basis (Sponsor CRA and safety contact 
’).
Subjects should be monitored appropriately by the investigator for latent effects if overdose is
confirmed or suspected. Signs and symptoms associated with overdose are to be recorded as
adverse events or as serious AEs. If adverse events associated with overdose fulfil any of the
serious criteria (as defined in section ‘Serious Adverse Event’), a completed SAE report form
is required to be submitted.

Reports of Drug-drug Interaction and Drug Abuse and Medication Errors: drug
interactions or abuse of the study medication must be recorded as AEs. Medication errors will
be captured as protocol deviations while any associated signs or symptoms must be recorded
as AEs on the CRF. In addition, any serious consequence of drug interactions, drug abuse, or
medication error must be reported immediately if these fulfil any of the SAE criteria.
11.3 Exposure to Study Drug During Pregnancy 
Any pregnancy occurring while the subject is on study drug or within 28 days of the subject’s last 
dose must be reported to Mylan PSRM within 24 hours of awareness.   
While pregnancy itself (or positive pregnancy test) is not considered an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons (e.g. medical or surgical 
management of ectopic pregnancy) will be recorded as an AE or a SAE. Any SAE involving the 


 
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mother or fetus must also be reported via the SAE Report Form. Miscarriage, congenital anomaly, 
neonatal death, and infant death are serious adverse events. 
 
Elective termination (i.e., without medical reasons) of an uncomplicated pregnancy is considered to be 
an elective procedure and not an adverse event; nevertheless, Mylan requests that the outcome (e.g. 
elective termination) be reported within 24 hours and sent as a follow-up on the Mylan Delivery and 
Infant Follow-up Form. 
 
Attempts should be made to collect and report details of the course and outcome of any pregnancy in 
the partner of a male patient exposed to study drug. Male subjects will be instructed through the ICF 
to immediately inform the investigator if their partner becomes pregnant during the study or 28 days 
after the subject’s discontinuation visit. Partner pregnancies are to be reported on the Pregnancy 
Report form after consent of the pregnant female is obtained.   
Pregnancy updates are to be submitted to Mylan 
at least every 3-months until birth or 
termination using the Pregnancy Report/Delivery and Infant Follow-up Form. 
 
12 STATISTICAL STATEMENT AND CONSIDERATIONS 
 
Statistical Analysis Plan (SAP) will be prepared and finalized prior to database lock. The SAP will 
include detailed statistical aspects of the efficacy and safety analysis. 
12.1 Significance Level 
Statistical tests will be conducted at the 5% significance level unless otherwise indicated. 
12.2 Analysis Populations 
Three analysis populations are defined as follows: 
12.2.1 Safety Population  
The safety population includes all randomized subjects who received study treatment.  
12.2.2 Modified Intent to Treat (mITT) 
1. The mITT population includes all randomized subjects who met the inclusion/exclusion criteria, 
received study treatment, and returned for at least one post-base line visit. 
2. The mITT population will be used to compare both test and reference products to placebo for the 
superiority analysis. 
3. Subjects discontinued early for other reasons included in the mITT population, using Last 
Observation Carried Forward (LOCF). 
12.2.3 Per-Protocol Population (PP) 
The per-protocol population (PP) includes 
1. The per-protocol population will be the definitive population for equivalence analysis. 


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2. All randomized subjects who meet all the inclusion/exclusion criteria.
3. Completed study in compliance with the protocol.
4. Administered a pre-specified proportion of the scheduled doses (e.g., 75% to 125%) of the
assigned product for the specified duration of the study.
5. Returned to the study site for the primary endpoint visit within the specified window (+/- 4 days)
OR discontinued from the study as a treatment failure.
6. Subjects discontinued early from the study due to lack of treatment effect should be included in
the PP population, using Last Observation Carried Forward (LOCF).
12.3 Efficacy Analysis 
1. The primary endpoint of the study is Mean change in the total WOMAC pain subscale score for 
the target knee, from baseline to week 4 in Section 8.1 of this protocol.
2. All Efficacy analyses will be performed on the per-protocol and mITT populations. PP population 
will be definitive for equivalence analysis and mITT population will be definitive for superiority 
analysis. 
12.3.1 Equivalence test between Test Drug and reference product 
Bioequivalence will be established for the primary endpoint (WOMAC® pain Score) if the 90% 
confidence interval for the test/reference ratio of mean change from baseline to week 4 is contained 
within [0.80, 1.25], using the per-protocol population.  
The compound hypothesis to test is: 
H0: μT / μR ≤ θ1 or μT / μR ≥ θ2 versus HA : θ1<μT / μR< θ2 
Where μT = mean of test treatment, and μR = mean of reference treatment. 
H0 will be rejected with a type I error α = 0.05 (two 1-sided tests), if the 90% confidence interval for 
the ratio of means between test and reference products (μT / μR) is contained within the interval [θ1, 
θ2], where θ1 = 0.80 and θ2 = 1.25. 
Rejection of the null hypothesis H0 supports the conclusion of equivalence of the two products. 
12.3.2 Superiority test between Test Drug and placebo & superiority test between reference 
product and placebo 
As a parameter for determining adequate study sensitivity, the Test Drugand RLD should both be 
statistically superior to placebo (p<0.05, two-sided) for the primary endpoint (mean change from 
baseline), using the mITT study population and last observation carried forward (LOCF). 
H0: μT or μR≥μPlacebo versus HA :μT or μR< μPlacebo 
Where μT = mean of test treatment, and μR = mean of reference treatment. 
H0 will be rejected with a type I error α = 0.05 (2-sided test). Rejection of the null hypothesis H0 
supports the conclusion of superiority to placebo. Analysis of covariance (ANCOVA) will be used to 


 
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compare Test Drugto placebo and RLD to placebo separately. The model will consist of treatment, 
investigator and baseline value as covariate. Post hoc test comparison will be made to detect the group 
difference. 
12.3.3 Analysis of Secondary Efficacy Endpoint 
1. Mean change in the total WOMAC pain subscale score for the target knee, from baseline to 
week 2.  
2. Mean change in the WOMAC pain subscale score at week 4 for subgroup subjects whose 
baseline WOMAC pain score less than or equal to 10. 
3. Mean change in pain on movement (POM) after 100 meter walk on a Visual Analog Scale 
(VAS) for target knee from baseline to week 4 
4. Average number of days of acetaminophen (paracetamol)consumption during the trial 
5. Average dose of acetaminophen (paracetamol)during the trial 
 
For subgroup analysis, similar method as primary analysis will be performed for equivalence and 
superiority tests. For other secondary endpoints, analysis of covariance (ANCOVA) will be used to 
compare Test Drugto placebo and RLD to placebo separately. The model will consist of treatment, 
center and baseline value as covariate. Average duration and dosage of acetaminophen (paracetamol) 
consumption during the trial will be summarized by descriptive statistics. 
12.4 Safety Analysis 
All safety analyses will be performed on safety population. 
 
Safety data will be summarized for the safety population by treatment group. Summary statistics (for 
example: n, mean, minimum, and maximum) will be included for continuous variables. 
Summarizations of categorical variables will be presented in tabular form (n and percentages). Safety 
of drug regimen will be assessed for treatment-emergent AEs and SAEs. Vital signs, clinical 
laboratory evaluations, pregnancy test, physical examinations, and ECG recordings may be performed 
for screening and safety monitoring, but will not be used to assess comparative safety.  Clinically 
significant changes from baseline for clinical laboratory tests, vital signs, ECGs, and changes in 
physical examination results will be recorded as adverse events.  
 
Adverse events will be classified by the primary MedDRA System Organ Class, MedDRA Preferred 
Term, and the investigator’s assessment of the relationship of the adverse event to the study 
medication. The analysis will be conducted on the safety population. 
Safety Endpoints: 
1. The incidence of treatment-emergent adverse events. 
2. Application site reaction evaluation 


 
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Vital Signs and Physical Examination 
Descriptive statistics of vital parameters and physical examinations at each visit (except at the start of 
run-in period visit) for each treatment group will be provided.  
Laboratory Investigations 
Descriptive statistics of each laboratory parameter investigated during the course of the study will be 
provided for each treatment group.  
12.5 Demographic and Baseline Characteristics 
Demographic characteristics and baseline Characteristics will be summarized by treatment, subject 
disposition, reasons for withdrawal or by any other variables as appropriate .All continuous variables 
will be represented by n, mean, standard deviation, minimum, median and maximum and All the 
categorical variables will be presented as counts and percentages.  
12.6 Sample Size Considerations 
Equivalence between test and reference product7 
At least 261 subjects in Test Drugand 261 subjects in Reference product will be required to show 
bioequivalence between Test and Reference product with 90% power and 5% level of significance 
assuming below estimates: 
1) 5% difference between Test and Reference of mean change in WOMAC score 
2) 75 % Inter subject coefficient of variation for Reference in WOMAC Score 
3) Equivalence margin of 80.00-125.00% 
Superiority of test and reference product over placebo 
At least 363 number of subjects will be required in each arm to prove the superiority of test/ reference 
product and placebo product with 90% power and 5% level of significance. 
Considering 10% dropout rate, around 1212 subjects would be required to enroll for the study. All 
Subjects would be randomize in 1:1:1 treatment allocation. 
Conclusion: Since the study has two hypotheses viz Equivalence and Superiority, we have chosen the 
highest sample size. 
Test Product: 404 subjects. 
Reference Product: 404 subjects 
Placebo: 404 subjects 


 
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13 ETHICAL REQUIREMENTS 
Sponsor and the Investigator must comply with all instructions, regulations, and agreements in this 
protocol and applicable International Conference on Harmonization (ICH) and Good Clinical Practice 
(GCP) guidelines and conduct the study according to local regulations. 
13.1 Informed Consent 
The principles of Informed Consent, according to International Conference on Harmonization 
Guidelines on Good Clinical Practice (ICH-GCP) will be followed. A copy of the proposed consent 
form must be submitted to the IEC/IRB, together with the protocol, for approval. 
Subjects must provide written informed consent prior to any study procedures being completed. The 
investigator is responsible for obtaining informed consent, signed by each subject prior to entry into 
the study. Each subject’s signed informed consent must be kept on file by the investigator for 
Regulatory Authorities’ inspection at any time. A copy of the signed consent form will be given to the 
subject or subject’s legally acceptable representative (LAR) & Impartial Witness (IW), if applicable. 
A notation will be made in the subject’s medical record indicating the date informed consent was 
obtained. 
13.2 Independent Ethics Committee/Institutional review Board 
The study and the patient informed consent form must be approved in writing by an appropriate IEC/ 
IRB prior to enrollment of any study subjects.  
Any changes to the protocol as well as a change of investigator, which is approved by the sponsor, 
must also be approved by the site’s IEC/IRB and documentation of this approval provided to the 
sponsor/designee. Records of the IEC/IRB review and approval of all documents pertaining to this 
study must be kept on file by the investigator and are subject to inspection by Regulatory Authorities 
during or after completion of the study. SAEs must also be reported to the IEC/IRB (or as applicable).  
Periodic status reports must be submitted to the IEC/IRB at least annually, as well as notification of 
completion or termination of the study. A copy of all reports submitted to the IEC/IRB must be sent to 
the sponsor/ designee. 
The investigator shall ensure that an IEC/IRB shall be responsible for the initial and continuing review 
and approval of the proposed clinical study. 
13.3 Subject Confidentiality 
The Subjects Medical records and study data will be kept confidential in compliance with the 
applicable regulatory guidelines.  However, as per the requirements  regarding the monitoring of 
clinical studies and in fulfillment of his/her obligations to the sponsor, it is required that the 
investigator permit the study monitor, sponsor auditor, and/or regulatory authority representative to 
review that portion of the subject’s medical record that is directly related to the study. This shall 


 
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include all study relevant documentation including subject medical histories to verify eligibility and 
other source documents.  
As part of the required content of informed consent, the subjects must be informed that his/her 
medical chart may be reviewed by the sponsor, the sponsor’s and/or regulatory authority’s 
representatives. Should access to the medical record require a separate waiver or authorization, it is 
the investigator’s responsibility to obtain such permission from the subject in writing before the 
subject is entered into the study. 
14 DOCUMENTATION 
14.1 Maintenance and Retention of Records 
All records pertaining to the receipt and return of study supplies (particularly study medication) and 
copies of final case report form, worksheets and other pertinent source documents must be retained in 
accordance with the applicable requirements of the country where the study is being conducted as well 
as the country where the study will be submitted. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in 
an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained. 
14.2 Case Report Forms (CRF) 
Data will be documented in the eCRF to capture the trial related data from source document/any other 
pertinent documents. 
SAE reporting by Investigator shall be done as per the regulatory requirements, and any related 
supporting information and/or documents shall be sent by appropriate mode of communication. 
Subjects are not to be identified on eCRFs by name; appropriately coded identification and the 
subject’s initials must be used. The investigator must keep a separate log of the subject’s names and 
addresses. 
14.3 Primary Source Documents 
The investigator must maintain primary source documents supporting significant data for each 
subject’s medical notes. These documents, which are considered “source data”, should include (but 
not limited to) documentation of: 
 Demographic information 


 
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 Evidence supporting the diagnosis/condition for which the subject is being studied 
 General information supporting the subject’s participation in the study 
 General history and physical findings 
 Hospitalization or Emergency Room records (if applicable) 
 Each study visit by date, including any relevant findings/notes by the investigator(s), occurrence 
(or lack) of adverse events, and changes in medication usage, including the date the study drug 
commenced and completed. 
 Any additional visits during the study 
 Any relevant telephone conversations with the subject regarding the study or possible adverse 
events 
 An original, signed informed consent for study participation 
 The investigator must also retain all subject specific printouts/reports of tests/procedures 
performed as a requirement of the study.  
14.4 Study Monitoring 
The study will be monitored by the assigned monitor in compliance with Good Clinical Practices 
Guideline and applicable regulations. The investigator will be visited by a monitor prior to the study 
and at regular intervals during the course of the study. These visits are for the purposes of verifying 
adherence to the protocol, standard operating procedures (SOPs), GCP and applicable regulatory 
requirements. 
The study monitor will review the informed consent forms and verify eCRF entries with the source 
documents (hospital/clinic records). The monitor will review the maintenance of regulatory 
documentation, drug accountability, and on a regular basis the progress of the study with the 
investigator and site personnel. At the end of the study, a closeout monitoring visit will be performed.   
The coordinator and/or investigator should be available to answer questions or resolve data 
discrepancies/clarifications. Adequate time and space for these visits should be made available by the 
investigator and by the site personnel for the monitoring activities at site.  
14.5 Audits and Inspections 
During the course of the study and/or after it is going to be completed, one or more site visits may be 
undertaken by auditors as authorized representatives of the sponsor. The purpose of the audit is to 
determine whether or not the study is being conducted and monitored in compliance with recognized 
GCP guidelines and laws.  


 
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Additionally, the study may be inspected by regulatory agencies. These inspections may take place at 
any time during/after the study and are based on the local and international regulations. 
14.6 Modifications to the Protocol 
The procedures defined in the protocol will be carefully reviewed to ensure that all parties involved 
with the study fully understand the protocol. In order to ensure the validity of the data, no deviations 
from the protocol, with minimal exceptions, may be made unless the issue is broad enough to warrant 
revision of the protocol. Such revisions must be submitted to and have documented approval from the 
sponsor and the IEC/IRB prior to implementation.  
All amendments to the protocol, which involve substantial changes in study design, procedure, 
analyses, will be submitted to regulatory authorities for prior approval. 
 
15 CONFIDENTIALITY, USE OF INFORMATION, AND PUBLICATION 
All information supplied by the sponsor in connection with this study and not previously published, is 
considered confidential information. This information includes, but is not limited to, data, materials 
(i.e. the clinical protocol, case report forms), equipment, experience (whether of a scientific, technical, 
engineering, operational, or commercial nature), designs, specifications, know-how, product uses, 
processes, formulae, costs, financial data, marketing plans and direct selling systems, customer lists 
and technical and commercial information relating to customers or business projections used by the 
sponsor in its business. Any data, inventions, or discoveries collected or developed, as a result of this 
study is considered confidential. This confidential information shall remain the sole property of the 
sponsor, shall not be disclosed to any unauthorized person or use in any unauthorized manner without 
written consent of the sponsor, and shall not be used except in the performance of the study. 
The information developed during the course of this clinical study is also considered confidential, and 
will be used by the sponsor in connection with the development of the drug. The information may be 
disclosed as deemed necessary by the sponsor. To allow the use of the information derived from this 
clinical study, the investigator is obliged to provide the sponsor with complete test results and all data 
developed in the study.  
The investigator shall not make any publication related to this study without the express written 
permission of the sponsor. 
16 FURTHER REQUIREMENTS AND GENERAL INFORMATION 
16.1 Contract Research Organization for Clinical Operations 
CRO will be responsible for administrative aspects of the study including, but not limited to, study 
initiation, monitoring, management of SAE reports, and data management. Before subjects are 




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4. Sinusas K. Osteoarthritis: diagnosis and treatment. Am Fam Physician. 2012 Jan 
1;85(1):49-56.
5. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, 
Hawker GA, Henrotin Y, Hunter DJ, Kawaguchi H, Kwoh K, Lohmander S, Rannou F, Roos 
EM, Underwood M. OARSI guidelines for the non-surgical management of knee 
osteoarthritis. Osteoarthritis Cartilage. 2014 Mar;22(3):363-88 .
6. Hauk L. Treatment of knee osteoarthritis: a clinical practice guideline from the AAOS. Am 
Fam Physician. 2014 Jun 1;89(11):918-20
7. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, 
Welch V, Wells G, Tugwell P; American College of Rheumatology. American College of 
Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic 
therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012 
Apr;64(4):465-74
8. Baraf HS, Gold MS, Clark MB, Altman RD. Safety and efficacy of topical diclofenac sodium 
1% gel in knee osteoarthritis: a randomized controlled trial. Phys Sports med. 2010 
Jun;38(2):19-28
9. Baraf HS, Gloth FM, Barthel HR, Gold MS, Altman RD. Safety and efficacy of topical 
diclofenac sodium gel for knee osteoarthritis in elderly and younger patients: pooled data from 
three randomized, double-blind, parallel-group, placebo-controlled, multicentre trials. Drugs 
Aging. 2011 Jan 1;28(1):27-40
10. Barthel HR, Haselwood D, Longley S, Gold MS, Altman RD. Randomized controlled trial of 
diclofenac sodium gel in knee osteoarthritis. Semin Arthritis Rheum. 2009 Dec;39(3):203-12
11. Prescribing information of VOLTAREN® GEL (Novartis Pharma Stein AG), Revised on 
May-2016
12. Prescribing information of TYLENOL (acetaminophen) 500 caplet (Johnson & Johnson 
Consumer Inc.), Revised on 10/2015.
13. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) –(Link: 
http  :  / /  www  .  rheumatology.org/I-Am-A/Rheumatologist/Research/Clinician-
Researchers/Western-Ontario-McMaster-Universities-Osteoarthritis-Index-WOMAC)
14. Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of 
clinical phenomena. Res Nurs Health. 1990 Aug;13(4):227-36.
15. Kellgren JH, Lawrence JS. Radiological Assessment of Osteo-Arthrosis. Annals of the 
Rheumatic Diseases. 1957;16(4):494-502
16. Medical review of Diclofenac 1% gel (NDA 22-122), Novartis, Inc. dated October 1, 2007 
Statistical review of Diclofenac 1% gel (NDA 22-122), Novartis, Inc. dated October 1, 2007 

SAP_001.pdf: 






Statistical Analysis Plan  
Study Code MYL-1601N-3002 
Version Version 2 Final  
Date 11/Jan/2018 
4
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate transaminase 
BMI 
Body Mass Index 
CI 
Confidence Interval 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
LOCF 
Last Observation Carried Forward 
LS 
Least Squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
OA 
Osteoarthritis 
OTC 
Over the Counter 
POM 
Pain On Movement 
PP 
Per Protocol 
PSRM 
Product Safety and Risk Management 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SE 
Standard Error 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamate-Pyruvate Transaminase 
TEAE 
Treatment-emergent Adverse Event 
US 
United States 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
 


5
Statistical Analysis Plan  
Study Code MYL-1601N-3002 
Version Version 2 Final  
Date 11/Jan/2018 
CHANGES FROM VERSION 1 TO VERSION 2 
1. Additional subgroup descriptive summaries of WOMAC Pain Subscale score (for
subjects with baseline WOMAC Pain Subscale score <= 10 and by Kellgren-
Lawrence grade)
2. Additional summary of percentage of patients that used acetaminophen (paracetamol)
at least once during the trial.
3. Average daily dose of acetaminophen is calculated only over days when
acetaminophen was used.
4. Added forest plot for test/reference ration in various subgroups.
 


Statistical Analysis Plan  
 
Study Code MYL-1601N-3002 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical analyses 
that have been outlined within the protocol "A Randomized, Double blind, Three-arm, Parallel, 
Placebo-controlled, Clinical Study to Evaluate the Bioequivalence using Clinical Endpoint of 
Diclofenac Sodium Gel, 1% (Mylan Inc.) to Voltaren® Gel (Diclofenac Sodium Topical Gel) 1% 
(Novartis Consumer Health, Inc.) in Patients with Osteoarthritis (OA) of the Knee" version 1.1 
dated May 3, 2017. 
Mylan is developing a generic diclofenac sodium gel to the Reference Listed Drug (RLD) 
Voltaren® gel. 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. 
This SAP describes the study endpoints, derived variables, anticipated data transformations and 
manipulations, and other details of the analyses not provided in the study protocol. The SAP also 
outlines the statistical programming specifications for the tables, listings and figures.  
2. 
OBJECTIVES 
The primary objectives of this study are:  
1. To determine the clinical equivalence of the Test Drug (Diclofenac sodium gel of 1% of 
Mylan Inc.) with the Reference Listed Drug (RLD) (Voltaren® Gel 1% of Novartis 
Consumer Health, Inc.) as measured by mean change from baseline in the Western 
Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Likert (version 3.1) 
pain score. 
2. To establish superiority of the Test Drug and Reference Listed Drug (RLD) over placebo 
in mean change from baseline in the WOMAC Likert (version 3.1) pain score. 
The secondary objectives of this study are: 
1. To assess the safety and tolerability of study treatments. 
2. To determine the clinical equivalence of the Test Drug (Diclofenac Sodium gel) with the 
Reference Listed Drug (RLD) (Voltaren® Gel) as measured by mean change from 
 


Statistical Analysis Plan  
 
Study Code MYL-1601N-3002 
Version Version 2 Final  
Date 11/Jan/2018 
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baseline in subjects whose baseline WOMAC Likert (version 3.1) pain scores are less 
than or equal to 10. 
3. 
STUDY OVERVIEW 
3.1 
Study Design 
This is a double-blind, multiple-site, randomized, parallel-design study to investigate the 
bioequivalence with clinical endpoint of Mylan’s Diclofenac Sodium Topical Gel, 1% to 
Voltaren® Gel, 1% (Novartis US) and to investigate that both the active products are superior to 
placebo.  
Subjects will have to visit the clinic for the following visits during the study: 
• Visit 1 – Screening visit (within 28 days prior to randomization)  
• Visit 2 – Start of Placebo Run-in period (Day -11 to Day -7)  
• Visit 3 – Randomization (baseline) visit (Day 0)  
• Visit 4 – Interim visit (Week 2/Day 14 ± 4)  
• Visit 5– End of study (Week 4/Day 28 ± 4)/Early termination visit  
After informed consent process and completion of all screening assessments, the eligible subjects 
will be requested to stop the currently ongoing osteoarthritis drug therapy. The wash out period 
(run-in period) of 7 days or ≥ 5 half-life of previous osteoarthritis drug therapy, whichever is 
longer, will be maintained before the baseline visit. Subjects will undergo at least 7 days of 
placebo run-in period. In case subject extends run-in period beyond 11 days, continuation of the 
subject will be decided in consultation with Medical monitor. 
The Pain on Movement (POM) score on a Visual Analog Scale (VAS) and Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC Likert version 3.1) pain score will be 
recorded at the start of run-in Period and at the end of run-in Period (i.e. immediately prior to 
randomization on the day of baseline visit). Recording of the VAS will be done for both knees 
and recording of the WOMAC pain score will be done for the target knee. Target knee is defined 
as the knee that is more painful and will be identified during the screening visit. 
During the washout period, subjects will undergo a single-blind placebo run-in period where the 
subjects will not be aware of the placebo nature of the drug. Subjects will be provided with 
 


Statistical Analysis Plan  
 
Study Code MYL-1601N-3002 
Version Version 2 Final  
Date 11/Jan/2018 
8 
placebo gel for the administration. Approximately 4 g dose of placebo gel will be applied to the 
target knee four times daily for at least 7 days. First administration of gel will be done at the 
study center. 
At the baseline visit, subjects will be randomly assigned in 1:1:1 ratio to Mylan’s Diclofenac 
Sodium Topical Gel 1%, Voltaren® Gel 1% (Reference Listed Drug) and Placebo. All the 
subjects will be instructed to apply the gel next day (Day 1) onwards. All subjects will be 
applying approximately 4 g dose of either Mylan’s Diclofenac Sodium Topical Gel 1% or 
Reference Listed Drug (RLD) or Placebo gel to the arthritic target knee four times daily for 4 
weeks. 
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC Likert version 
3.1) pain score for the target knee and pain on movement (POM) on a Visual Analog Scale 
(VAS) for both the knees will be recorded on Week 2 and Week 4 from the start of the treatment. 
Acetaminophen (paracetamol) tablets will be given to the subjects for use as a rescue medication 
or for the treatment of aches and pains unrelated to knee pain such as headache during treatment 
period (except 3 days prior to Visit 4 and Visit 5). Maximum allowed dose of acetaminophen 
(paracetamol) will be 2 g/day. Consumption of rescue medications in terms of number of tablets 
consumed will be monitored. 
Subject diary will be provided to subjects to record study medication gel application, rescue 
medication, side effects, and concomitant medication details. Subject diary will be used to 
evaluate drug application compliance.  
Physical examination will be conducted during each visit (except at the start of run-in period 
visit). Application site reaction assessment will be conducted on each visit after start of run-in 
period. 
A standard 12-lead ECG will be recorded after 5 minutes of rest in the supine position on 
screening visit and on end of study visit. Vital signs will be measured after 5 minutes of rest 
(sitting) on each visit. 
 


Statistical Analysis Plan  
Study Code MYL-1601N-3002 
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Date 11/Jan/2018 
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Serum pregnancy test for females of childbearing potential will be performed at screening and 
end of treatment visit. The urine pregnancy test can be performed if clinically indicated during 
other visits. If urine pregnancy is found to be positive, serum pregnancy will be drawn and 
analyzed for confirmation. If serum pregnancy test will found positive then patient will be 
excluded from the study and followed up. 
Laboratory assessments like hematology and biochemistry will be performed during screening 
and end of study. The hematology and biochemistry at screening is to be performed within 14 
days of baseline visit. If the gap between lab assessments and baseline visit will be more than 14 
days, the lab assessments will be repeated at baseline visit. Laboratory investigations (if 
clinically significant) can be repeated once as per investigator’s discretion. 
Principal investigator or designee will contact the subjects approximately midway between the 
visit 3-4 and visit 4-5 for assessment of the well-being, adverse event, concomitant medication, 
and treatment compliance. Additional telephonic contact to reiterate the instructions regarding 
the use of rescue medications during 3 days prior to visits 4 and 5 will be done. Use of rescue 
medications by subjects during this period for intolerable pain will require rescheduling the visits 
in such a way that visits happen after at least 3 days of stopping rescue medication and subjects 
will be required to inform the center about the rescue medication use.  
Study design is represented graphically in Figure 1 Study Design. 
 


Statistical Analysis Plan  
 
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Figure 1 Study Design 
3.2 
Sample Size  
The study protocol, MYL-1601N-3002, is designed to demonstrate the Bioequivalence of 
Diclofenac Sodium Gel to Voltaren® Gel and the superiority of Diclofenac Sodium Gel and/or 
Voltaren® Gel over Placebo by using a clinical endpoint in patients with Osteoarthritis (OA) of 
the Knee. The clinical endpoint under consideration is the change from baseline Western Ontario 
and McMaster Universities Osteoarthritis Index (WOMAC) Likert (version 3.1) pain score. The 
framework under consideration and the sample size requirements were fine-tuned to satisfy the 
objectives of bioequivalence of test drug with the reference drug as well as superiority of the test 
drug to placebo. The sample size estimation is done to ensure 90% statistical power to test two 
hypotheses of bioequivalence and superiority, the hypotheses are briefly described below: 
1. Null Hypothesis (Equivalence) is that the ratio of mean change from baseline in 
WOMAC Likert pain score between test and reference drug is less than or equal to 0.80 
or greater than or equal to 1.25 Vs. the alternative hypothesis of ratio of mean change 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
   
 
 
 
 


Statistical Analysis Plan  
 
Study Code MYL-1601N-3002 
Version Version 2 Final  
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from baseline in WOMAC Likert pain score between test and reference drug lies within 
the limits of 0.80 to 1.25, where the equivalence limit of 0.80 to 1.25 is adapted.  
2. Null Hypothesis (Superiority): The mean change from baseline WOMAC Likert pain 
score of test or reference drug is greater than or equal to Placebo vs the alternative 
hypothesis of mean change from baseline WOMAC Likert pain score of test or reference 
drug is less than the placebo group. 
To meet the requirement for the two hypotheses, three tests need to be performed to meet overall 
objectives: 
1) Bioequivalence between Diclofenac Sodium Gel and Voltaren® 
2) Superiority of Diclofenac Sodium Gel over Placebo 
3) Superiority of Voltaren® over Placebo 
Sample size calculations are performed under the following assumptions: 
1. Mean (± Standard Deviation) reduction from baseline in WOMAC pain score is 5.85 
(±4.23) for both active treatments. 
2. Mean (± Standard Deviation) reduction from baseline in WOMAC pain score is 4.68 
(±4.89) for placebo. 
3.2.1 
Equivalence between test and reference product 
At least 261 subjects in Test Drug and 261 subjects in Reference Drug group will be required to 
show bioequivalence between Test and Reference product with 90% power and 5% level of 
significance assuming the following estimates: 
1) 5% difference between Test and Reference of mean change in WOMAC score 
2) 75 % inter subject coefficient of variation for Reference in WOMAC Score 
3) Equivalence margin of 80.00-125.00% 
3.2.2 
Superiority of test and reference product over placebo 
At least 363 subjects will be required in each arm to prove the superiority of test/reference drug 
to placebo with 90% power and 5% level of significance. 
Considering 10% dropout rate, around 1212 subjects will be required to enroll in the study. All 
subjects will be randomized in 1:1:1 ratio. 
Overall, to satisfy both hypotheses of equivalence and superiority, the highest sample size will be 
used in the study: 1212 subjects equally randomized to Test, Reference and Placebo treatments: 
1. Diclofenac Sodium Gel: 404 subjects. 
 


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2. Voltaren® Gel : 404 subjects 
3. Placebo: 404 subjects 
3.3 
Randomization and Unblinding Procedures  
A computerized randomization will be generated by an independent statistician (not involved in 
the packaging and labelling of the study medication). 
Subjects will be randomly assigned in 1:1:1 ratio to three groups. Treatment allocation can be 
Mylan’s Diclofenac Sodium Topical Gel 1%, Voltaren® Gel 1% (Reference Listed Drug), or 
Placebo. A balanced randomization schedule will be generated using SAS® software (Version: 
9.3 or higher; SAS Institute Inc., USA). The randomization code will be held by an independent 
statistician throughout the conduct of the study in order to minimize bias. 
A sealed copy of the randomization code for each kit provided under separate cover inside the 
block will be retained at investigational center. It should be available to FDA investigators at the 
time of center inspection to allow for verification of the treatment identity of each subject. 
Placebo run-in period will be single blinded, in which subjects will not be aware of the treatment 
given. 
Treatment period will be double blinded, in which all the investigators, subjects, center staff, 
CRO team, study monitors, laboratory personnel and/or other designated individuals will be 
blinded to the medication codes. The formulation of test, reference and placebo investigational 
products will be identical in appearance to make any difference in treatment less obvious to the 
subjects and to maintain adequate blinding of evaluators. 
Planned unblinding will occur after the database lock. 
Unplanned unblinding (prior to database lock) will be performed by a designated person in case 
of SAE or other significant events. Mylan Product Safety and Risk Management (PSRM) can 
unblind the treatment assignment for any subject with a SAE which qualifies for the unblinding 
based on country specific regulatory requirements. 
The event of unplanned unblinding prior to database lock shall be documented in the source 
notes. Reasons for treatment unplanned unblinding must be clearly explained and justified in the 
 


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eCRF. The date on which the code was broken together with the identity of the person 
responsible must also be documented. 
If a subject’s treatment assignment is unblinded  prior to database lock for any reason then the 
subject should be withdrawn from the study. 
4. 
STUDY ENDPOINTS/OUTCOMES 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Week 4 in total WOMAC Pain 
Subscale score for the Target Knee.  
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• The change from baseline to Week 2 in total WOMAC Pain Subscale score for the Target 
Knee. 
• The change from baseline to Week 4 in total WOMAC Pain Subscale score for the Target 
Knee for the subgroup of subjects whose baseline WOMAC pain score is less than or 
equal to 10. 
• The change from baseline to Week 4 in POM VAS score for the Target Knee. 
• Number of days of acetaminophen (paracetamol) consumption during the trial. 
• Average daily dose of acetaminophen (paracetamol) during the trial 
Safety Endpoints 
1. The incidence of treatment-emergent adverse events 
2. Application site reaction evaluation 
5. 
HYPOTHESES TESTING 
Hypothesis of Equivalence (Primary Endpoint) 
The null hypothesis to be tested is that the ratio of mean change from baseline in WOMAC 
Likert pain score between test and reference drug is less than or equal to 0.80 or greater than or 
equal to 1.25 vs the alternative hypothesis that this ratio is within the interval from 0.80 to 1.25: 
 


Statistical Analysis Plan  
 
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H0: μT / μR ≤ θ1 or μT / μR ≥ θ2 versus HA : θ1 < μT / μR < θ2  
Where μT = mean of test treatment, and μR = mean of reference treatment  
Typically, H0 will be rejected with a type I error α = 0.05 (two 1-sided tests), if the 90% 
confidence interval for the ratio of means between test and reference products (μT / μR) is 
contained within the interval [θ1, θ2], where θ1 = 0.80 and θ2 = 1.25. 
A two-sided, 90% confidence interval on the test/reference ratio for mean change from baseline 
to Week 4 in total WOMAC Pain Subscale score for the Target Knee will be constructed using 
Fieller’s method.  The estimates of treatment means and standard errors will be obtained from 
Analysis of Covariance (ANCOVA) of the Test and Reference results, using a statistical model 
containing fixed effects for treatment and center and baseline WOMAC Pain Subscale score as 
covariate.   
Bioequivalence will be established if the 90% confidence interval for the ratio of test/reference 
means is contained within the interval [0.80, 1.25] for Per Protocol population. 
Hypothesis of Superiority (Primary Endpoint) 
The null hypothesis to be tested is that there is no difference in the mean change from baseline to 
Week 4 in total WOMAC Pain Subscale score for the Target Knee between the active treatment 
and the Placebo treatment vs the alternative hypothesis that the reduction in the WOMAC Pain 
Subscale score is greater for both active treatments than for placebo:  
H0: μT = μP and μR = μP versus HA: μT < μP and μR < μP 
Where μT = mean of test treatment, μR = mean of reference treatment, μP = mean of Placebo 
treatment. 
The hypothesis testing will be performed separately for the Test treatment versus the Placebo 
treatment and for the Reference treatment versus the Placebo treatment using Analysis of 
Covariance (ANCOVA) with a statistical model containing fixed effects for treatment and center 
and baseline WOMAC Pain Subscale score as covariate.  
Superiority will be established if the mean change from baseline for each active treatment is less 
than, and statistically significantly different from (p<0.05), that for the Placebo using the 
 


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modified intent-to-treat (mITT) population and with Last Observation Carried Forward (LOCF) 
approach.   
Hypotheses of Equivalence and Superiority (Secondary Endpoints) 
The secondary endpoints will be evaluated in the same way as the primary endpoint, but will be 
considered as supportive information. 
6. 
ANALYSIS SUBSETS 
6.1 
Run-in Population 
The run-in population includes all subjects who make at least one application of placebo gel in 
the run-in period of the study. 
6.2 
Randomized Population 
The randomized population consists of all subjects who were randomized. 
6.3 
Safety Population 
A safety population subject is any individual who was randomized into the study and has 
evidence of usage of at least one dose of the randomized investigational product according to 
subject's diary. For subjects who were randomized but fail to return their diary and for whom no 
evidence of study drug use is thus available, the following conservative approach will be applied: 
• if some safety or efficacy data for these patients is available after Visit 3, they will be 
included in the safety population; 
• if no safety or efficacy data for these patients is available after Visit 3, they will be 
considered lost to follow-up and excluded from the safety population. 
The safety population will be the primary population for the safety analysis. Analyses on the 
safety population will be based on actual treatment received, as determined by kit schedule. 
6.4 
Intent to Treat Population (ITT Population) 
Following the intent-to-treat principle, the ITT population includes all randomized subjects. 
Analyses on the ITT population will be based on randomized treatment, as determined by 
randomization schedule. This population will be used for sensitivity analysis of both equivalence 
and superiority, LOCF method will be used for imputing missing data. 
 


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6.5 
 Modified Intent to Treat Population (mITT Population) 
The mITT population includes all Safety population subjects who met all inclusion/exclusion 
criteria and return for at least one post-baseline evaluation of WOMAC Pain Subscale.  
Subjects who discontinued early and have at least one post-baseline efficacy evaluation will be 
included in the mITT population using LOCF. This population will be used for testing 
superiority. Analyses on the mITT population will be based on randomized received, as 
determined by randomization schedule. 
6.6 
Per Protocol Population (PP Population) 
The Per Protocol (PP) population includes all mITT subjects who: 
•
met all inclusion/exclusion criteria
•
apply 75% to 125% (both inclusive) of the scheduled applications of the assigned product
•
return for the 4 week evaluation of WOMAC Pain Subscale score within the visit window 
(+/- 4 days; i.e., study Day 24-32) or discontinue from the study due to treatment failure 
(included as treatment failures)
•
have no major protocol deviations  impacting the primary efficacy outcome measure. 
These major protocol deviations are described in section 7.9. The list of protocol 
deviations which lead to exclusion of subjects from the PP population will be finalized at 
the Blind Data Review (BDR) meeting to be held prior to database lock. 
This population will be used for testing the clinical equivalence. 
7.
STATISTICAL METHODS OF ANALYSIS
7.1 
General Principles
If not otherwise specified, statistical significance is defined as p<0.05 and is two-tailed. No
adjustment will be made for multiplicity. Data will be summarized with respect to demographic
and baseline characteristics, efficacy variables and safety variables.
For categorical variables, the number and percent of each category within a parameter will be 
calculated for non-missing data.  For continuous variables, statistics will include number of 
observations, mean, standard deviation, median, minimum and maximum values.  
 


Statistical Analysis Plan  
 
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All statistical analyses will be conducted using SAS®, Version 9.3 or higher. Data will be 
summarized using descriptive statistics for continuous variables. Unless otherwise specified, 
descriptive statistics will include the number of subjects, mean, standard deviation, minimum, 
median and maximum. A subset of these statistics may be presented in some tables. The 
minimum and maximum statistics will be presented to the same number of decimal places as the 
original data. The mean and median will be presented to one more decimal place than the 
original data. The standard deviation will be presented to two more decimal places than the 
original data. 
In by-visit summary tables only scheduled visits will be presented. All visits, both scheduled and 
unscheduled, will be presented in listings. 
Baseline will be defined as the last assessment, scheduled or unscheduled, made prior to the first 
application of the randomized study drug. For subjects who are randomized, but do not receive 
the randomized study drug, baseline will be defined as the last assessment, scheduled or 
unscheduled, made prior to the randomization. 
7.1.1 
Derivation of dates 
The start of the run-in period will be taken from the “Run-In Period Day 1 Date” field collected 
at the “Run-In Period Dosing Log” CRF page. 
The end of the run-in period will be derived as the date corresponding to the maximum day 
recorded at the “Run-In Period Dosing Log” CRF page when gel was applied. 
The start of the treatment period, i.e. the date of the first application of the randomized study 
drug, will be taken from the “Treatment Period Day 1 Date” field collected at the “Treatment 
Period Dosing Log” CRF page. 
For subjects who started the treatment period, the end of the treatment period, i.e. the date of the 
last application of the randomized study drug, will be taken from the “Date of Last Gel 
Application” field collected at the “End of Study” CRF page. It must correspond to the 
maximum day recorded at the “Treatment Period Dosing Log” CRF page when gel was applied 
or the maximum date recorded at the “Treatment Period Dosing Log (Extended)” CRF page, if 
any. 
 


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Study days will be defined relative to the start of the treatment period. For dates after the start of 
the treatment period: 
Study Day = Date of Assessment – Start of the treatment period + 1 
For dates prior to the start of the treatment period: 
Study Day = Date of Assessment – Start of the treatment period 
All dates will be displayed in DDMMMYYYY format. 
7.1.2 
Adjustment for multiplicity 
The study will test three hypotheses: 
1. Equivalence of the Test and Reference treatments 
2. Superiority of Test to Placebo treatment 
3. Superiority of Reference to Placebo treatment 
Possible inflation of Type I error rate will be controlled by declaring the study a success only if 
all 3 hypotheses are simultaneously true. Therefore there will be no need to apply any 
multiplicity adjustment methods. 
7.2 
Subject Disposition 
The number of subjects screened for the study, failing screening (with breakdown by reason), 
number of subjects entering the run-in period, number of subjects discontinued during the run-in 
period (with break-down by reason for discontinuation) will be presented.   
The number of subjects randomized in the double-blind period of the study, included in the 
safety, intent to treat, modified intent to treat, per protocol populations, prematurely discontinued 
from the study (along with the reasons for discontinuation) will be presented by treatment. 
Number of subjects enrolled by center will be tabulated for all randomized subjects, safety, 
mITT and PP populations. 
7.3 
Inclusion/Exclusion criteria 
Number and percentage of subjects violating each inclusion/exclusion criterion will be presented 
by criterion. This analysis will be based on all screened subjects. 
Violation of inclusion/exclusion criteria will be listed. 
 


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7.4 
Diagnosis of Osteoarthritis according to ACR Criteria 
Number and percentage of subjects answering Yes to the following CRF questions will be 
presented by treatment for the safety population: 
• Is the subject having knee pain? 
• Did the Subject meet at least 3 of the following 6 criteria for the target knee? 
o Age > 50 years 
o Stiffness < 30 minutes 
o Presence of crepitus 
o Bony tenderness 
o Bony enlargement 
o No Palpable warmth 
Kellgren-Lawrence grade will also be summarized descriptively, presenting the number and 
percentage of subjects with each grade (0 to 4). 
All details of the osteoarthritis diagnosis collected on the CRF will be listed. 
7.5 
Joint examination 
Results of joint examination will be summarized descriptively for each question asked at the 
Joint Examination CRF page. Results also will be listed. 
7.6 
Demographic and Baseline Characteristics 
Demographic characteristics will include: 
• age 
• gender 
• race 
• ethnicity. 
Baseline characteristics include: 
• height 
• weight 
• body mass index (BMI) 
• Baseline POM VAS target knee pain score 
 


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• Baseline WOMAC Pain Subscale score. 
Descriptive statistics will be presented for age (years), BMI, VAS and WOMAC scores. 
Frequency counts and percentage will be presented for sex, race, ethnicity. BMI will be reported 
in kg/m2. 
Age will be derived from Informed Consent Signed Date (INFCSD) and Date of Birth (DOB) as 
the number of whole years between those two dates. 
Demographic and baseline characteristics will be evaluated for comparability across treatment 
groups in the following manner. Continuous variables (age, BMI, VAS and WOMAC scores) 
will be analyzed with an analysis of variance with factors of treatment and investigational center. 
Overall p-value for the global null hypothesis of all groups being equal will be displayed. 
Categorical variables (gender, ethnicity, race) will be analyzed with a Cochran-Mantel-Haenszel 
general association test, stratified by investigational center. 
These analyses will be performed for the ITT, Safety, mITT and PP populations. 
Demographic and baseline characteristics will be presented in the by-subject listings. 
7.7 
Medical History 
Medical history will be recorded at Visit 1 Screening. Reported terms will be coded using 
MedDRA dictionary version 20.0. 
Medical history will be summarized by MedDRA system organ class and preferred term for the 
safety population. 
7.8 
Prior and Concomitant Medication 
Prior and concomitant medications will be assessed at screening and at each subsequent study 
visit. Medications will be coded using WHO Drug Dictionary version Sep-2016 B2. 
Medication will be classified as prior, if the end date is known and is prior to the first use of the 
study medication (any study medication, including run-in). Medications that are ongoing or 
ended after the first use of the study medication will be classified as concomitant. If the end date 
of the medication is unknown, it will also be considered concomitant. If the end date is partially 
known, the medication will be considered concomitant, unless the known part of the end date 
 


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rules out the possibility that the medication could have ended after the start of the study 
drug. Please see appendix 11.3 for more details on handling of partial dates. 
Prior and concomitant medications will be separately summarized by ATC class (the highest 
available level) and preferred name for the safety population. 
The prior and concomitant medications will be listed in a by-subject listing. 
7.9 
Protocol Deviations 
Protocol deviations will be derived algorithmically and additionally reported by study centers 
according to the MYL-1601N-3002 Protocol Deviations Guidance Document. Eventually all 
approved protocol deviations will be entered in the Protocol Deviations eCRF page. 
Subjects with protocol deviations deemed to have an impact on treatment evaluation will be 
excluded from the Per Protocol population. The list of protocol deviations which lead to 
exclusion of subjects from the PP population will be finalized at the Blind Data Review (BDR) 
meeting to be held prior to database lock.  
Major deviations that have an impact on treatment evaluation may include: 
•
Violation of inclusion/exclusion criteria
•
Use of prohibited medications
•
Missing WOMAC Pain Subscale assessments
•
Final visit out of window
•
Missing visits
•
Violation of rescue medication use rules
•
IP compliance <75% or >125%
•
Administration of incorrect or expired IP
Protocol deviations will be summarized by deviation category and treatment group. This analysis 
will be performed for all randomized subjects.  
7.10 
Handling of Missing Data 
For demographic and baseline characteristics, each variable will be analyzed using all available 
data. Subjects with missing data will be excluded only from analyses for which data are not 
 


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available. For efficacy analysis, patients who discontinued the study early will be included in the 
ITT and mITT analysis with LOCF approach; subjects who discontinue the study due to lack of 
treatment effect will also be included in the PP analysis with LOCF approach. 
For WOMAC pain total score, the following imputation method will be used for handling missing 
values. If one item is missing, the missing value will be imputed by averaging remaining 4 items and 
total score will be calculated using sum of 5 items. If more than one items are missing, then the total 
pain score will be assigned to missing value at that visit. The LOCF method will be used for endpoint 
analysis if Visit 5 value is missing. 
7.11 
Efficacy Analyses  
All efficacy analyses will be based on the randomized treatment group as determined by the 
randomization schedule. 
7.11.1 
Center pooling 
To eliminate potential effect of random fluctuations at small center on the efficacy endpoints 
small centers will be pooled. A study center will be pooled if it doesn't meet both of the 
following conditions: 
• It has at least 10 patients in the Per Protocol population; 
• It has at least one patient in each treatment group in the Per Protocol population. 
The smallest center that does not meet the above requirements will be pooled with the next 
smallest center. The procedure will be repeated until all pooled centers meet the above two 
requirements. 
Pooled center will be used in all efficacy analyses. 
7.11.2 
Analyses of Primary Endpoint  
At all post-screening visits the subjects will complete the WOMAC Osteoarthritis Pain Subscale 
Ratings for the target (most severe) knee. The Pain Subscale score will be reported on the eCRF.  
Missing Week 4 assessments will be imputed as follows. In the ITT and mITT analysis, if a 
subject discontinued from the study prior to Week 4 or misses the Week 4 assessment for any 
 


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other reason, the LOCF rule will be used to impute the score (the change in the score from the 
baseline visit to the last completed visit prior to discontinuation will be carried forward). In the 
Per Protocol analysis, if a subject discontinued from the study prior to Week 4 due to treatment 
failure, the LOCF rule will be used to impute the score (the change in the score from the baseline 
visit to the last completed visit prior to discontinuation due to treatment failure will be carried 
forward). If a subject is missing the Week 4 assessment for any other reason, the subject will be 
excluded from Per Protocol population. 
The baseline score will be defined as the results from the latest exam prior to the start of study 
drug applications. For each post-baseline visit the change from baseline in the WOMAC Pain 
Subscale score will be calculated. The baseline value, time point value and change from baseline 
to the timepoint will be analyzed using descriptive statistics and will be tabulated by center, visit 
and treatment group. This summary will also be prepared for the subset of subjects with baseline 
WOMAC Pain Subscale score ≤ 10. 
Mean WOMAC Pain Subscale score will also be plotted graphically by visit with +/- SD bars. A 
separate line will be plotted for each treatment group.  
7.11.2.1 Analysis of clinical equivalence of test and reference treatments 
To show the clinical equivalence, estimates of LS mean change from baseline to Week 4 in the 
WOMAC Pain Subscale score will be calculated for the test and reference treatment, and then 
the 90% CI for the LS mean ratio will be constructed using Fieller’s method. Bioequivalence will 
be established if the 90% confidence interval for the ratio of test/reference LS means is contained 
within the interval [0.80, 1.25]. 
To this end, first an ANCOVA model will be fit with change from baseline to Week 4 in the 
WOMAC Pain Subscale score as outcome, baseline WOMAC Pain Subscale score as covariate 
and treatment, center and treatment-by-center interaction as factors on the data from test and 
reference treatments only (excluding Placebo subjects): 
Yijk = b + a·Bijk + Ti + Cj + TCIij+ εijk 
Where 
 


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•
Yijk is the change from baseline to Week 4 in WOMAC Pain Subscale score for the kth
subject in the jth center with ith treatment
•
b is model intercept
•
Bijk is the baseline WOMAC Pain Subscale score for the kth subject in the jth center with
ith treatment
•
a is the model parameter associated with baseline WOMAC Pain Subscale score
•
Ti is the effect of the ith treatment
•
Cj is the effect of the jth center
•
TCIij is the interaction effect of the ith treatment and the jth center
•
εijk is the random error (normally distributed with zero expected value)
If the treatment-by-center interaction factor is not significant at the 0.05 level, the model will be 
rerun without the interaction term. Treatment LS means and standard errors will be estimated 
from this model. Then Fieller’s formula will be applied; covariance between treatment 
means will be assumed to be 0. See appendix 11.2 for complete description of Fieller’s formula. 
Equivalence will be illustrated graphically by a plot including a vertical line corresponding to the 
90% CI around the Test/Reference ratio with the ratio itself indicated by a dot with reference 
lines for 80% and 125%. 
Analysis of bioequivalence will be performed primarily on the Per Protocol population, and 
additionally on the ITT and mITT populations as a sensitivity analysis. 
7.11.2.2 Analysis of superiority to placebo control 
The analysis of superiority will be performed for the primary endpoint separately for the Test 
treatment versus the Placebo treatment and for the Reference treatment versus the Placebo 
treatment. Each of these analyses will be performed using an ANCOVA model with change from 
baseline to Week 4 in the WOMAC Pain Subscale score as outcome, baseline WOMAC Pain 
Subscale score as covariate and treatment, center and treatment-by-center interaction as factors 
(mathematical statement of this model is the same as for the equivalence model). If the 
treatment-by-center interaction factor is not significant at the 0.05 level, the model will be rerun 
without the interaction term. The model will be fit on data from the Test and Placebo treatment 
 


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for analysis of superiority of the Test treatment and separately on data from the Reference and 
Placebo treatment for analysis of superiority of the Reference treatment. From this model, the 
least square (LS) mean estimate for each treatment group with the 95% CI will be calculated; 
further, an estimate of the LS mean difference between the active treatment (Test or Reference) 
and Placebo with 95% CI and the p-value for test of no difference will be calculated. 
Superiority will be established if the mean change from baseline to Week 4 for each active 
treatment is estimated to be less than, and statistically significantly different from (p<0.05 for 
test of no difference) that for the Placebo. 
Superiority will be illustrated graphically by a plot including two vertical lines (for Test drug vs. 
Placebo and Reference Drug vs. Placebo) corresponding to the 95% CI around the Active – 
Placebo difference with the difference itself indicated by a dot with reference line for 0 
difference. 
Analysis of superiority will be performed primarily using the mITT population, and additionally 
on the ITT and PP populations as a sensitivity analysis. 
7.11.3 
Analyses of Secondary Endpoint Outcomes 
The following secondary endpoints will be evaluated in the same way as the primary endpoint, 
but will be considered as supportive information. 
• The change from baseline to Week 2 in total WOMAC Pain Subscale score for the Target 
Knee. 
• The change from baseline to Week 4 in total WOMAC Pain Subscale score for the Target 
Knee for the subgroup of subjects whose baseline WOMAC pain score is less than or 
equal to 10. 
• The change from baseline to Week 4 in POM VAS score for the Target Knee. 
Missing Week 2 assessments will be imputed as follows. In the ITT and mITT analysis, the 
LOCF rule will be used to impute the score, i.e. the change in the score from the baseline visit to 
the Early Termination visit, provided it occurs after baseline and within 18 days, (2 weeks + 4 
days allowed window) will be carried forward. In the Per Protocol analysis, if a subject 
 


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discontinued from the study prior to Week 2 due to treatment failure, the LOCF rule will be used 
to impute the score as for ITT and mITT analyses. If a subject is missing the Week 2 assessment 
for any other reason, the subject will be excluded from Per Protocol analysis. 
In the analysis of secondary endpoints a 95% CI for the Test/Reference ratio will also be 
presented in addition to 90% CI. 
A descriptive summary by visit will also be created for POM VAS score. 
Mean POM VAS score will also be plotted graphically by visit with Mean +/- SD error bars. A 
separate line will be plotted for each treatment group. 
The following secondary endpoints will be summarized descriptively by treatment group: 
• Number of days of acetaminophen (paracetamol) consumption during the trial. 
• Average daily dose of acetaminophen (paracetamol) during the trial 
• Total dose (mg) of acetaminophen (paracetamol) during the trial 
• Percentage of patients that used acetaminophen (paracetamol) at least once during the 
trial 
When calculating these endpoints, only days from the day of the first application of the 
randomized study drug to the day of the last application of the randomized study drug will be 
counted.  
Number of days with any acetaminophen consumption will be counted from the subject’s diary. 
Average daily dose of acetaminophen will be calculated as follows: 
(Sum over all days from the first application of the randomized study drug to the last application 
of the randomized study drug of [Strength (mg) * Number of Tablets]) / ([Date of the last 
application of the randomized study drug] -  [Date of the first application of the randomized 
study drug] + 1) 
Total dose (mg) of acetaminophen will be calculated as follows: 
Sum over all days from the first application of the randomized study drug to the last application 
of the randomized study drug of [Strength (mg) * Number of Tablets]) 
 


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For these calculations the days without any consumption of acetaminophen will count as zero 
tablets. 
These analyses will be performed on mITT, ITT and PP populations. 
7.11.4 
Subgroup analyses 
The following subgroups will be considered: 
1. Subjects with baseline Kellgren-Lawrence grade 1 or 2; 
2. Subjects with baseline Kellgren-Lawrence grade 3. 
The analyses of the primary endpoint described above will be repeated by subgroup. This will be 
an exploratory analysis and inference about equivalence and superiority of the study drug on the 
subgroups will not be drawn. 
7.11.5 
Forest Plot 
A forest plot representing Test/Reference ration with 90% CI will be presented for all endpoints 
and subgroups for the PP, mITT and ITT popuplations: 
1. Change from Baseline to Week 4 in WOMAC Pain Subscale Score: 
a. All subjects 
b. Subjects with Baseline WOMAC Pain Subscale Score <= 10 
c. Subjects with Baseline Kellgren-Lawrence Grade 1-2 
d.  Subjects with Baseline Kellgren-Lawrence Grade 3 
2. Change from Baseline to Week 2 in WOMAC Pain Subscale Score: for all subjects 
3. Change from Baseline to Week 4 in POM VAS Score: for all subjects 
Each CI will be represented by a horizontal line with a dot marking the ratio itself. Reference 
lines will be drawn to represent ratios of 100%, 80% and 125% 
7.12 
Safety Analyses 
7.12.1 
Adverse Events  
Adverse Events will be coded using the Medical Dictionary of Regulatory Activities (MedDRA 
version 20.0) AE coding system for purposes of summarization. 
 


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An AE will be considered as treatment-emergent if the time of onset is after the time of the first 
randomized study drug administration or if it increased in severity during the study period. AEs 
with unknown start dates will be counted as treatment-emergent unless the AE resolution date is 
prior to the study drug start date. If the start date is partially missing, AE will be considered 
treatment-emergent unless the known part of the start date or the end date rules out that 
it occurred after the start of the study drug. See appendix 11.3 for more details on handing 
of partial dates. 
A TEAE is defined as treatment-related if it is recorded as definitely, probably or possibly 
related to the study medication at the eCRF. In case the relatedness was not assessed, the most 
conservative result – related will be chosen for the analysis.  
An overall summary will include, by treatment group and overall, the number and percentage of 
subjects reporting at least one TEAE and subjects discontinuing the study drug due to TEAE, as 
well as counts of AEs by severity, relationship, count of serious AEs and deaths. 
A summary of the frequencies (number and percentage) of subjects with TEAEs and counts of 
TEAEs will be presented by system organ class and preferred term. Similar summaries will be 
created for serious TEAEs, TEAEs leading to treatment discontinuation and for TEAEs leading 
to death (if any). 
Similar summaries of non treatment-emergent AEs and serious non treatment-emergent AEs by 
system organ class and preferred term will be created for the run-in population. 
Additionally number and percentage of subjects with TEAE will be presented by preferred term 
only in the descending order of frequency for TEAEs experienced by >1% of subjects.  
TEAEs will also be summarized by system organ class, preferred term and maximum severity as 
well as by system organ class, preferred term and closest relationship to the study drug (not 
related or related). 
A subject experiencing the same AE multiple times will only be counted once for that preferred 
term. Similarly, if a subject experiences multiple AEs within the same system organ class that 
subject will be counted only once in that system organ class. In summaries by severity or by 
relationship, if a subject has the same AE on multiple occasions, the highest severity, and the 
closest relationship to study drug, respectively, will be used. 
 


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All information pertaining to adverse events noted during the study will be listed by subject, 
detailing verbatim, preferred term, system organ class, start date, stop date, severity, outcome, 
action taken and causal relationship to the study drug. 
7.12.1.1 Application Site Reactions 
Application site reactions are a subset of treatment-emergent adverse events. They will be 
identified by specific preferred terms. The list of preferred terms for application site reactions 
will be finalized prior to the database lock.  
Number and percent of subjects and number of events will be summarized for application site 
reactions by preferred term and treatment. Application site reactions also will be listed. 
7.12.2 
Exposure to Product 
The subjects will be instructed to use the diary to document all doses taken by checking the yes 
or no box for the appropriate date.  
Study drug compliance will be defined as 
[Actual number of applications] / [Planned number of applications] * 100%  
where: 
• 
Actual number of applications will be calculated from the subject diary as the number of 
gel application in the treatment period dosing log. 
• 
Planned number of applications is 112 (28 days, 4 times daily). 
Subjects will be considered treatment compliant if they apply at least 75% and not more than 
125% of doses. 
Duration of exposure will be defined as [Date of last study drug application] – [Date of first 
study drug application] + 1; 
Compliance, actual number of applications and duration of exposure will be summarized 
descriptively by treatment group for the safety population. 
Duration of exposure to the placebo treatment in the run-in period will also be summarized 
descriptively for the run-in population. 
7.12.3 
Vital Signs  
Vital signs will be assessed at each visit. Systolic and diastolic blood pressure, respiratory rate, 
heart rate and body temperature will be measured.  
 


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Vital signs and their changes from baseline will be summarized descriptively at baseline and at 
each post-baseline visit (Visit 4 and Visit 5). Results also will be listed. 
7.12.4 
Physical Examination 
Physical examination will be performed at Visits 1, 3, 4 and 5. The following body systems will 
be assessed: general appearance; skin; head, eyes, ears, nose, throat; lymph nodes; 
cardiovascular; abdominal; musculoskeletal; nervous; respiratory and other if applicable. Each 
body system will be classified as either normal or abnormal. 
A summary of these findings will be presented by visit, body system and treatment group. 
Results also will be listed. 
7.12.5 
Laboratory Tests 
Blood samples for safety laboratory tests (clinical chemistry and haematology) will be collected 
at Visit1 (Screening) and Visit 5. If the gap between the screening lab assessments and baseline 
visit (Visit 3) is more than 14 days, the lab assessments should be repeated at baseline visit. 
The following tests will be performed: 
• Hematology: Hemoglobin, Total RBC count, Total WBC count, Platelet count, 
Differential Leukocyte counts: Neutrophils, Lymphocytes, Eosinophils, Monocytes, 
Basophils. 
• Blood Chemistry: Alkaline Phosphatase,  Serum Creatinine, Random Glucose, SGPT 
(ALT) & SGOT (AST), Serum Bilirubin. 
Values of laboratory tests and their changes from baseline will be summarized descriptively by 
visit, test and treatment group.  
Shifts from baseline to Visit 5 among the categories Low (below the low limit of normal), 
Normal (within the normal limits) and High (above the upper limit of normal) will be presented. 
Only subjects with both baseline and Visit 5 assessments will be included 
Results also will be listed. 
 


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7.12.6 ECG 
ECG will be performed Visit1 (Screening) and Visit 5. Overall interpretation will be recorded as 
Normal, Abnormal not clinically significant or Abnormal clinically significant. 
Number and percentage of subjects with each level of interpretation will be presented by 
treatment and visit. In addition, a summary of shifts from Visit 1 (Screening) to Visit 5 will be 
presented. 
All ECG results will be listed.  
8. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES  
There are no changes from the protocol-specified analyses. 
9. 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS 
See separate document with the table, figure and listing shells. 
10. 
LITERATURE CITATIONS / REFERENCES 
1. Study Protocol: "A Randomized, Double blind, Three-arm, Parallel, Placebo-controlled, 
Clinical Study to Evaluate the Bioequivalence using Clinical Endpoint of Diclofenac 
Sodium Gel, 1% (Mylan Inc.) to Voltaren® Gel (Diclofenac Sodium Topical Gel) 1% 
(Novartis Consumer Health, Inc.) in Patients with Osteoarthritis (OA) of the Knee " 
version 1.1 dated May 3, 2017. 
2. Draft Guidance on Diclofenac Sodium Gel 1%. Office of Generic Drugs, FDA. 
Recommended March 2011. 
 






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‘none’=0; ‘mild’=1, ‘moderate’=2; ‘severe’=3; ‘extreme’=4). The questions pertain to the amount of pain the subject is currently experiencing in the target 
knee [i.e., ‘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)] 
jAEs: The active reporting period to Mylan or its designated Representative begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, i.e., prior to undergoing any study-related procedure and/or receiving investigational product, through 
and including 28 days after the last application of the investigational product. All AEs should be followed until resolution or deemed stable or until the event 
is found to be due to another known cause (concurrent condition or medication) and clinical judgment indicates that further evaluation is not warranted, with 
Mylan concurring with that assessment. This may imply that observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the Monitoring Team up to and as required by the sponsor. However, SAEs should be reported any time after the active 
reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. All SAEs should be immediately 
(24 hours) reported 
kTelephone contact: Principal investigator or designee will contact the subjects one time between the schedule visit for assessment of the well-being, adverse 
event, concomitant medication, and treatment compliance. Additional telephonic contact will be done to remind the subject regarding stoppage of rescue 
medication usage prior to scheduled visit and next visit date. The same will be documented in the source notes. 
* Based on the requirement for wash out period, screening and start of run-in can occur on the same day. The wash out period of 7 days or ≥ 5 half-life of 
previous osteoarthritis drug therapy, whichever is longer, will be maintained before the baseline visit.