Clinical trial NCT03570554
Conditions: Osteoarthritis, Knee
Sponsor: Bayer
Start date: 2018-06-29; Completion date: 2019-06-14
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Osteoarthritis is a common, chronic, progressive, skeletal, degenerative disorder that frequently affects several joints such as knee, hip, spine and hands.This placebo-controlled clinical trial assessed the effects of naproxen sodium, acetaminophen and celecoxib on stiffness in subjects with osteoarthritis.

Detailed description:
The primary objective of the study was to assess the responsiveness of the Brief Arthritis Stiffness Scale (BASS) for detecting treatment effects of common over-the-counter (OTC) analgesics and a common prescription analgesic in subjects with knee osteoarthritis.

Arms: arm 1: Participants received naproxen 660 mg daily for 3 days and 440 mg on the fourth day; followed by placebo for 4 days; followed by celecoxib 200 mg daily for 3 days and 100 mg on the fourth day; followed by acetaminophen 3900 mg daily for 3 days and 1300 mg on the fourth day. Treatment periods were separated by a washout period of 3 to 7 days. arm 2: Participants received acetaminophen 3900 mg daily for 3 days and 1300 mg on the fourth day; followed by celecoxib 200 mg daily for 3 days and 100 mg on the fourth day; followed by placebo for 4 days; followed by naproxen 660 mg daily for 3 days and 440 mg on the fourth day. Treatment periods were separated by a washout period of 3 to 7 days. arm 3: Participants received celecoxib 200 mg daily for 3 days and 100 mg on the fourth day; followed by naproxen 660 mg daily for 3 days and 440 mg on the fourth day; followed by acetaminophen 3900 mg daily for 3 days and 1300 mg on the fourth day; followed by placebo for 4 days. Treatment periods were separated by a washout period of 3 to 7 days. arm 4: Participants received placebo for 4 days; followed by acetaminophen 3900 mg daily for 3 days and 1300 mg on the fourth day; followed by naproxen 660 mg daily for 3 days and 440 mg on the fourth day; followed by celecoxib 200 mg daily for 3 days and 100 mg on the fourth day. Treatment periods were separated by a washout period of 3 to 7 days
Interventions: intervention 1: Naproxen Sodium (Aleve, BAY117031) intervention 2: Acetaminophen ER intervention 3: Celecoxib intervention 4: Placebo
Intervention descriptions: intervention 1: 660 mg daily for 3 days, 440 mg on the fourth day, over-encapsulated tablet, oral (Treatment A) intervention 2: 3900 mg daily for 3 days, 1300 mg on the fourth day, over-encapsulated extended release (ER) tablet, oral (Treatment B) intervention 3: 200 mg daily for 3 days, 100 mg on the fourth day, over-encapsulated capsule, oral (Treatment C) intervention 4: Over-encapsulation capsule, 4 days, oral (Treatment D)

Protocol documents:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
A Pilot Study Assessing the Treatment Responsiveness of a 
Novel Osteoarthritis Stiffness Scale 
NCT Number: 
NCT03570554 
Document Date: 
11-SEP-2018 
 


Clinical Study Protocol 19783 
Page 1 of 89 
Final Version 3.0 / 11-Sep-2018 
 
 
Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
1. Title page 
 
A Pilot Study Assessing the Treatment Responsiveness of a Novel Osteoarthritis Stiffness Scale 
Test drugs: 
BAY 117031 / Naproxen Sodium 
Study purpose: 
Clinical efficacy 
Clinical study phase: 
Phase 2 
Date: 
11-Sep-2018 
Registration: 
Not Applicable 
Version no.: 
3.0 
IMPACT Number: 
19783 
 
 
Sponsor: 
Bayer HealthCare LLC, Consumer Health 
100 Bayer Boulevard 
Whippany, NJ 07981-0915, USA 
Sponsor’s medical expert: 
  
Sr. Associate Director, Global Medical Affairs 
Bayer HealthCare LLC, Consumer Health 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical investigation 
or its use for any other purpose without the prior written consent of the sponsor is not 
permitted. 
 
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.   
Hence, the appearance of product names without these symbols does not imply that these names are not protected. 
 
 
 
PPD


PPD
PPD


Clinical Study Protocol 19783 
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Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
2. 
Synopsis - amendment 1 and 2 
 
Title 
A Pilot Study Assessing the Treatment Responsiveness of a Novel Osteoarthritis 
Stiffness Scale 
IMPACT 
19783 
Clinical study phase 
2 
Study objective(s) 
To assess the responsiveness of the Brief Arthritis Stiffness Scale (BASS) for 
detecting treatment effects of common OTC analgesics and a common 
prescription analgesic in subjects with knee OA 
Test drug(s) 
Name of active ingredient 
Naproxen sodium 
 
Dose(s) 
220 mg (660 mg daily) 
Route of administration 
Oral 
Duration of treatment 
4 days 
1. Reference drug(s) 
 
Name of active ingredient 
Acetaminophen  
Dose(s) 
650 mg (3900 mg daily) 
Route of administration 
Oral 
Duration of treatment 
4 days 
2. Reference drug(s) 
 
Name of active ingredient 
Celecoxib              
Dose(s) 
100 mg (200 mg daily) 
Route of administration 
Oral 
Duration of treatment 
4 days 
3. Reference drug(s) 
 
Name of active ingredient 
Placebo 
Dose(s) 
Not applicable 
Route of administration 
Oral 
Duration of treatment 
4 days 
Background treatment 
Not applicable 
Indication 
Osteoarthritis of the knee 
 
 


Clinical Study Protocol 19783 
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Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
Diagnosis and main criteria for 
inclusion /exclusion 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria - amendment 1 and 2 
• 
Signed Informed Consent; 
• 
Ambulatory (as deemed appropriate by the Investigator) male and 
female subjects between 40 and 80 years of age; 
• 
Body Mass Index (BMI) between 18 to <40 kg/m2; 
• 
Unilateral or bilateral OA of the knee based on the American College of 
Rheumatology (ACR) clinical criteria: Knee pain plus at least 3 of the 
following:  
o 
age >50 years;  
o 
less than 30 minutes of morning stiffness; 
o 
crepitus on active motion and osteophytes; 
o 
bony tenderness; 
o 
bony enlargement; 
o 
no palpable warmth. 
• 
Have had diagnostic quality radiography of the target knee performed 
no more than 1 year prior to baseline showing evidence of OA with 
Kellgren and Lawrence grade of II or III; 
 
Note: X-ray of both knees should not be repeated if performed in the 
 
previous 12 months, the radiographs are of diagnostic quality and 
 
information is available to the investigator. 
• 
History of analgesic use for >4 days/week for past month and willing to 
discontinue use at least 4 days prior to randomization (low-dose [100 
mg or less] aspirin regimen permitted); 
• 
Joint Stiffness Severity score ≥3 on a 0-10 NRS at Screening; 
• 
Female subjects of childbearing potential must be using a medically 
acceptable form of birth control for at least 1 month prior to screening 
(or 3 months if using oral contraceptives) [e.g., hormonal contraceptives 
(oral, patch, injectable or vaginal ring), implantable device (implantable 
rod or intrauterine device), or a double barrier], or in same sex 
relationship and have a negative pregnancy test at Screening and prior to 
study drug administration.  Female subjects of non-childbearing 
potential must be amenorrheic for at least two years or have undergone 
surgical sterilization (e.g., hysterectomy and/or bilateral oophorectomy); 
• 
Willing to wear an accelerometer during each treatment period of the 
Treatment Phase.  Subjects who decline to wear the accelerometer are 
still eligible for study participation provided they meet all other required 
criteria. 
 
For Randomization 
• 
48-hour WOMAC pain subscale average score ≥3.0 and/or 24-hour 
Average Pain Intensity score ≥3 on the 0-10 NRS at Screening; 
• 
48-hour WOMAC pain subscale average score ≥4.0 at Visit 2, 
Treatment Period 1 of 4; 
• 
24-hour Average Pain Intensity score ≥3 on the 0-10 at Visit 2, 
Treatment Period 1 of 4; 
• 
Current pain intensity score ≥4 and ≤9 on the 0-10 NRS at Visit 2, 
Treatment Period 1 of 4; 
• 
A Day 1 baseline post-STEPP current pain intensity score ≥5, and ≥1 
unit higher than the pre-STEPP current pain score on the 0-10 NRS; 
• 
Experience knee stiffness at least 5-7 days per week over the past month 
as reported on the Baseline Stiffness Questionnaire. 
 
Exclusion Criteria - amendment 1 
• 
History of underlying inflammatory arthropathy, rheumatoid arthritis or 
fibromyalgia; 
• 
History of or scheduled for knee replacement surgery (in the target 
knee) within the next 6 months at screening; 
 


Clinical Study Protocol 19783 
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Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
  
• 
Recent injury in the OA affected knee (past 4 months); oral, intra-
muscular, intravenous or intra-articular corticosteroid, platelet rich plasma 
intraarticular knee injections,  stem cell therapy or hyaluronic acid 
injections in either knee within the last 3 months; 
• 
Subject reports moderate or severe (score of 2 or 3) pain or tenderness on 
the 0-3 Regional Pain Scale for any joint or body area other than the target 
knee and, in the Investigator’s opinion, the subject is not able to distinguish 
pain in the target knee from other painful areas; 
• 
Use of any pain medications from the start of the Screening/Washout Phase 
through trial completion, other than IMP provided by the Sponsor or 
Rescue Pain medication provided by the study site; 
• 
Subject who takes an opioid ≥4 days per week over the past 4 weeks; 
• 
Subject is taking more than one antidepressant. Subjects who are on a 
stable dose of one antidepressant, for at least 1 month, are eligible for 
enrollment; 
• 
Subject is taking more than one anxiolytic medication.  Subjects who are 
on a stable regimen of one anxiolytic for at least 1 month, are eligible for 
enrollment; 
• 
Initiating any new physical therapy for the lower extremities from 4 weeks 
prior to study start through the duration of the study; 
• 
Positive urine drug test for illegal drug substances, non-prescribed 
controlled substances, or breath/saliva alcohol at screening or Visit 2; 
 Note: prescribed marijuana is allowed provided the subject is willing to 
 wash out and not use during the study. 
• 
Subject has an alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥2 times the upper limit of normal; 
• 
Subject has a hemoglobin <10.0 g/dL; 
• 
Subject has an estimated glomerular filtration rate (eGFR) <60 
mL/min/1.73 m²; 
• 
Subject is breast feeding or has a positive pregnancy test at screening or 
Visit 2; 
• 
Kellgren and Lawrence grade of 0, I or IV in the target knee; 
• 
Subjects with a medical disorder, condition or history of such that could 
impair the subject’s ability to participate or complete this trial in the 
opinion of the investigator; 
• 
History of hypersensitivity (including but not limited to anaphylactic 
reactions and serious skin reactions)  to naproxen sodium, celecoxib, 
acetaminophen, NSAIDS, aspirin, similar pharmacological agents or 
components of the investigational products 
• 
History of asthma, urticaria, or other allergic-type reactions after taking 
aspirin or other NSAIDs. 
• 
History of allergic-type reactions to sulfonamides; 
• 
Current or past history of gastrointestinal bleeding or other bleeding 
disorder(s); 
• 
Prior history of peptic ulcer disease and/or gastro-intestinal bleeding; 
• 
Evidence or history of clinically significant (in the judgment of the 
investigator) hematological, renal, endocrine, pulmonary, gastrointestinal, 
cardiovascular, hepatic, psychiatric, neurologic diseases, or malignancies 
within the last 5 years that makes the subject unfit to participate in the trial; 
• 
Recent (within the past 1 year) MI or in the peri-operative period  
surrounding coronary artery bypass graft (CABG) surgery; 
• 
Heart failure, advanced renal disease or advanced hepatic disease; 
• 
Current participation in any other trials involving investigational or 
marketed products within 30 days prior to the Screening Visit; 
• 
Inability to report pain accurately as assessed at Screening. 
Study design 
The trial consists of an up to 14 day Screening Phase, a 4 (+3) day Screening 
Washout Phase and a Treatment Phase consisting of four 4-day treatment periods 
separated by washout periods lasting several days. 


Clinical Study Protocol 19783 
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Final Version 3.0 / 11-Sep-2018 
 
 
Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
Methodology 
A multi-center, randomized, double-blind, 4-period crossover, placebo-controlled 
pilot trial in male and female adult subjects with pain due to OA of the knee 
conducted at approximately 3-5 sites in the United States. 
Type of control 
Active and placebo 
Data Monitoring Committee 
No 
Number of subjects 
50 randomized subjects (40 subjects anticipated to complete all visits) 
Primary variable(s) 
Sum of change from baseline in the Daily BASS score over the 4 day treatment 
period. 
Time point/frame of 
measurement for primary 
variable(s) 
Morning of Days 1 (baseline), 2, 3 and 4 of each Treatment Period 
Plan for statistical analysis 
All statistical tests will be 2-sided at the significance level of 5% and no 
multiplicity adjustment will be made. The primary and secondary efficacy 
endpoints will be analyzed
 
 
CCI


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Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
Table of contents 
1. 
Title page ............................................................................................................................. 1 
2. 
Synopsis - amendment 1 and 2 ............................................................................................ 3 
3. 
Introduction ....................................................................................................................... 12 
4. 
Study objectives - amendment 1 ....................................................................................... 14 
5. 
Study design ...................................................................................................................... 15 
5.1 
Design Overview - amendment 1 and 2 ................................................................ 15 
5.2 
Study Methodology ............................................................................................... 17 
5.3 
Selection of Study Population - amendment 2 ...................................................... 17 
6. 
Study population ............................................................................................................... 20 
6.1 
Inclusion criteria - amendment 1 and 2 ................................................................. 20 
6.2 
Exclusion criteria - amendment 1 .......................................................................... 21 
6.3 
Justification of selection criteria ............................................................................ 23 
6.4 
Withdrawal of subjects from study ....................................................................... 23 
6.4.1 
Withdrawal .............................................................................................. 23 
6.4.2 
Replacement ............................................................................................ 24 
6.5 
Subject identification ............................................................................................. 24 
7. 
Treatment(s) ...................................................................................................................... 24 
7.1 
Treatments to be administered - amendment 1 ..................................................... 24 
7.2 
Identity of study treatment .................................................................................... 26 
7.3 
Treatment assignment - amendment 1 ................................................................... 27 
7.4 
Dosage and administration .................................................................................... 28 
7.5 
Blinding ................................................................................................................. 28 
7.5.1 
Blinding measures ................................................................................... 28 
7.5.2 
Unblinding ............................................................................................... 28 
7.5.3 
Emergency unblinding by the investigator ............................................. 28 
7.6 
Drug logistics and accountability - amendment 1 ................................................. 29 
7.7 
Treatment compliance ........................................................................................... 29 
8. 
Non-study therapy ............................................................................................................. 30 
8.1 
Prior and concomitant therapy - amendment 1 ..................................................... 30 
8.2 
Post-study therapy ................................................................................................. 30 
9. 
Procedures and variables ................................................................................................... 31 
9.1 
Tabular schedule of evaluations ............................................................................ 31 
9.2 
Visit description .................................................................................................... 31 
9.2.1 
Screening Phase Visit 1 (Day -18 to -5) - amendment 1 and 2 ............... 31 
9.2.2 
Screening Washout Phase (Day -4 to Day -1 +3 days) ........................... 32 
9.2.3 
Visit 2 (Day 1, Start Treatment Period) - amendment 1 and 2................ 32 
9.2.4 
Day 2 and 3 (Continue Treatment Period) - amendment 1 ..................... 34 
9.2.5 
Visit 3 (Day 4, End of Treatment Period X of 4) - amendment 1 
and 2 ........................................................................................................ 34 
9.2.6 
Washout between Treatment Periods (3 to 7 days after Visit 3) ............. 34 


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9.2.7 
Visit 3 (Day 4, End of Treatment Period 4 of 4) ..................................... 35 
9.2.8 
End of Study (7 to 10 days after Visit 3, Treatment Period 4 of 4) ........ 35 
9.2.9 
Rescue therapy ........................................................................................ 35 
9.3 
Population characteristics ...................................................................................... 35 
9.3.1 
Demographic ........................................................................................... 35 
9.3.2 
Medical history ........................................................................................ 36 
9.3.3 
Other baseline characteristics .................................................................. 36 
9.4 
Efficacy analysis .................................................................................................... 36 
9.4.1 
Primary efficacy endpoint ....................................................................... 36 
9.4.2 
Secondary efficacy endpoints.................................................................. 36 
9.4.3 
Exploratory efficacy endpoints - amendment 1 and 2 ............................ 36 
9.4.4 
Safety analysis - amendment 1 ................................................................ 37 
9.5 
Pharmacokinetics / pharmacodynamics ................................................................ 38 
9.5.1 
Pharmacodynamics ................................................................................. 38 
9.6 
Safety ..................................................................................................................... 38 
9.6.1 
Adverse events ........................................................................................ 38 
9.6.1.1 
Definitions ............................................................................ 38 
9.6.1.2 
Classifications for adverse event assessment ....................... 39 
9.6.1.2.1 
Seriousness ........................................................................... 39 
9.6.1.2.2 
Intensity ................................................................................ 40 
9.6.1.2.3 
Causal relationship ............................................................... 40 
9.6.1.2.4 
Action taken with study treatment ........................................ 41 
9.6.1.2.5 
Other specific treatment(s) of adverse events ....................... 41 
9.6.1.2.6 
Outcome ............................................................................... 42 
9.6.1.3 
Assessments and documentation of adverse events ............. 42 
9.6.1.4 
Reporting of serious adverse events and pregnancy ............. 42 
9.6.1.5 
Expected adverse events ....................................................... 43 
9.6.2 
Pregnancies ............................................................................................. 43 
9.6.3 
Safety Examinations ................................................................................ 44 
9.7 
Other procedures and variables - amendment 1 and 2 .......................................... 45 
9.8 
Appropriateness of procedures / measurements .................................................... 46 
10. Statistical methods and determination of sample size ....................................................... 47 
10.1 
General considerations .......................................................................................... 47 
10.2 
Analysis sets .......................................................................................................... 47 
10.3 
Variables and planned statistical analyses ............................................................. 47 
10.3.1 
Primary endpoint ..................................................................................... 47 
10.3.2 
Secondary endpoints ............................................................................... 47 
10.3.3 
Exploratory endpoints - amendment 1 and 2 .......................................... 48 
10.3.4 
Efficacy analysis ..................................................................................... 48 
10.3.5 
Safety and Tolerability ............................................................................ 49 
10.4 
Determination of sample size ................................................................................ 49 
10.5 
Planned interim analyses ....................................................................................... 49 


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11. Data handling and quality assurance ................................................................................. 50 
11.1 
Data recording - amendment 1 .............................................................................. 50 
11.2 
Monitoring ............................................................................................................. 50 
11.3 
Data processing ..................................................................................................... 51 
11.4 
Missing data .......................................................................................................... 51 
11.5 
Audit and inspection .............................................................................................. 51 
11.6 
Archiving ............................................................................................................... 51 
12. Premature termination of the study ................................................................................... 53 
13. Ethical and legal aspects ................................................................................................... 54 
13.1 
Investigator(s) and other study personnel ............................................................. 54 
13.2 
Funding and financial disclosure ........................................................................... 54 
13.3 
Ethical and legal conduct of the study ................................................................... 54 
13.4 
Subject information and consent ........................................................................... 55 
13.5 
Publication policy and use of data ......................................................................... 56 
13.6 
Compensation for health damage of subjects / insurance ..................................... 56 
13.7 
Confidentiality ....................................................................................................... 57 
14. Reference list ..................................................................................................................... 58 
15. Protocol amendments ........................................................................................................ 60 
15.1 
Amendment 2 (11-Sep-2018) ................................................................................ 60 
15.1.1 
Overview of changes to the study ........................................................... 60 
15.1.2 
Changes to the protocol text .................................................................... 60 
15.2 
Amendment 1 (13-Apr-2018) ................................................................................ 63 
15.2.1 
Overview of changes to the study ........................................................... 63 
15.2.2 
Changes to the protocol text .................................................................... 64 
16. Appendices ........................................................................................................................ 74 
16.1 
Study Flow Chart - amendment 1 and 2 ................................................................ 74 
16.2 
Subjective Assessments - amendment 1 and 2 ...................................................... 76 
 
Table 1: Treatments administered ............................................................................................ 25 
Table 2: Study treatments ......................................................................................................... 26 
Table 3: Urine drug screen panel ............................................................................................. 44 
Table 4: Safety laboratory evaluations - amendment 1 ............................................................ 44 
Table 5: Study schema ............................................................................................................. 74 
 
Figure 1 – Design Overview - amendment 1 and 2 .................................................................. 18 


Clinical Study Protocol 19783 
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Supplement: Version 9 
List of abbreviations - amendment 1 
AE 
Adverse Event 
ACR 
American College of Rheumatology 
ANOVA 
Analysis of Variance 
ALT 
Alanine Aminotransferase 
AP 
Anteroposterior 
AST 
Aspartate Aminotransferase 
BASS 
Brief Arthritis Stiffness Scale 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CABG 
Coronary Artery Bypass Graft Surgery 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
Cl 
Chloride 
CO2 
Carbon Dioxide 
COX 
Cyclooxygenase 
CSR 
Clinical Study Report 
(e)CRF 
(electronic) Case Report Form  
eGFR 
Estimated Glomerular Filtration Rate 
ER 
Extended Release 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
Intent-to-Treat 
IUD 
intra-uterine device 
K 
Potassium 
MedDRA 
Medical Dictionary for Regulatory Activities 
Na 
Sodium 
NRS 
Numerical Rating Scale 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
OA 
Osteoarthritis 
OTC 
Over-the-Counter 
PA 
Posteroanterior 
PGIC (P) / (S) 
Patient Global Impression of Change (Pain) / (Symptoms) 
PID 
Pain Intensity Differences 
PP 
Per Protocol 
QA 
Quality Assurance 
RBC 
Red Blood Cell 
RNR 
Randomization Number 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SNR 
Screening Number 
SOC 
System Organ Class 
SPI 
Sum of Pain Intensity 


Clinical Study Protocol 19783 
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SPID 
Summed Pain Intensity Difference 
STEPP 
Staircase-Evoked Pain Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
US(A) 
United States (of America) 
WBC 
White Blood Cell 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 


Clinical Study Protocol 19783 
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3. Introduction 
Background 
Osteoarthritis (OA) is a common, chronic, progressive, skeletal, degenerative disorder that 
frequently affects several joints such as knee, hip, spine and hands. OA is associated with 
damage to the cartilage and surrounding tissues and characterized by pain, stiffness, and loss 
of function. (1) Being a highly prevalent disease and a main form of arthritis, OA is the most 
common cause of disability in the U.S. In fact, 52.5 million U.S. adults (approximately 1 in 4) 
aged ≥18 years have self-reported having doctor-diagnosed arthritis according to 2010-2012 
data collected by the National Health Interview Survey. (2)  The incidence of large joint OA 
in the U.S., particularly of the knee, is predicted to increase with the aging of the population 
and obesity epidemic. (3)  
Currently, a variety of prescription and over-the-counter (OTC) medications are available. 
Acetaminophen has been a mainstay of OA pharmacological management for many years and 
has been tested in many clinical trials although its effectiveness in clinical trials appears 
limited. (4) An extended release (ER) formulation containing acetaminophen 650 mg in a 
bilayer form has been shown to be more efficacious than placebo in hip and knee OA. (5)  
Each caplet contains 650 mg of acetaminophen.  The maximum daily dose is 3900 mg. 
Aleve®, naproxen sodium, the sodium salt of naproxen, was developed as an analgesic 
because it is more rapidly absorbed than naproxen.  It is available as an OTC 
analgesic/antipyretic that temporarily reduces fever and relieves minor aches and pains due to: 
minor pain of arthritis, muscular aches, backache, menstrual cramps, headache, toothache, and 
the common cold. OTC doses of naproxen sodium have been shown to be efficacious for 
relieving OA pain. (6, 7, 8)  Each tablet contains 220 mg of naproxen sodium with a 
maximum daily dose of 660 mg. 
Celecoxib, a COX-2 selective NSAID, is a commonly used prescription analgesic for OA and 
its efficacy is supported by a large body of data. (9)  For relief of the signs and symptoms of 
OA the recommended oral dose is 200 mg per day.   
Along with pain, stiffness is a frequent symptom of OA. (6) The Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC), a commonly used patient reported 
outcome (PRO) instrument for the measurement of OA-related joint pain and physical 
function includes a 2-item subscale for measuring joint stiffness. (10)   However, the 
WOMAC’s 2-item subscale for measuring joint stiffness shows low test-retest reliability. (11)  
FDA has informed Bayer that the WOMAC stiffness subscale has not been accepted as a 
stand-alone measure suitable for use as an endpoint.   
In order to examine the efficacy of treatments on improving joint stiffness, the Brief Arthritis 
Stiffness Scale (BASS), a PRO instrument designed specifically to measure stiffness was 
developed and validated for use in clinical trials.  A non-interventional study has previously 
been conducted to examine the psychometric properties of the BASS.  The study provided 
evidence for the reliability, construct validity, and discriminant validity of both the daily and 
weekly average BASS score, as well as preliminary responder thresholds.   Further evaluation 
of the BASS to assess the instrument’s responsiveness to treatment is needed.  A study 
including an active intervention will provide information to formally evaluate the instrument’s 
ability to detect change and provide utility for the responder definition.  
This placebo-controlled clinical trial will assess the effects of naproxen sodium, 
acetaminophen and celecoxib on stiffness in subjects with OA.  Furthermore, data will be 


Clinical Study Protocol 19783 
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collected to confirm the psychometric evidence supporting the use of the BASS as a patient 
reported outcome in assessing the effect of treatment in OA. 
Benefit-risk assessment 
Subjects with OA of the knee who would typically take over-the-counter (OTC) nonsteroidal 
anti-inflammatory drugs (NSAIDs) for pain relief will be enrolled in this study.  The 4 day 
treatment duration falls within established treatment guidelines. (12)  
During the study, subjects will be closely monitored for evidence of adverse events.  Potential 
risks to subjects participating in this study include the risks associated with OTC analgesic 
use and the risk of inadequate relief in placebo-treated subjects.  Subjects will be given the 
option of taking rescue therapy between each Treatment Period.  Given the ability to mitigate 
risk through close monitoring, this study is considered clinically and ethically acceptable. 


Clinical Study Protocol 19783 
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4. 
Study objectives - amendment 1 
Primary 
• To assess the responsiveness of the Brief Arthritis Stiffness Scale (BASS) for 
detecting treatment effects of common OTC analgesics and a common prescription 
analgesic in subjects with knee OA. 
Exploratory 
• To assess the assay sensitivity of the STaircase-Evoked Pain Procedure (STEPP™) to 
detect treatment effects of commonly used analgesics compared to placebo and to 
detect differences between active treatments; 
 
• To determine/identify effect size measurements, determine single dose vs. multi-dose 
efficacy, identify optimal sample size, and logistical issues for planning comparative 
analgesic efficacy studies using the STEPP. 
 
• To assess levels of activity captured by the accelerometer between active treatments 
and placebo during Days 1 (partial), 2 and 3 of the Treatment Phase. 
 
• To evaluate the safety and tolerability of naproxen sodium, celecoxib and 
acetaminophen ER. 
 
 


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5. 
Study design 
5.1 
Design Overview - amendment 1 and 2 
This is a multi-center, randomized, double-blind, 4-period crossover, placebo-controlled pilot 
trial in male and female adult subjects with pain due to OA of the knee.  At the completion of 
Screening and Baseline Phases, eligible subjects will be randomized to a blinded treatment 
sequence of naproxen sodium, acetaminophen ER, celecoxib and placebo.   
 
The trial consists of an up to 14 day Screening Phase, a 4 (+3) day Screening Washout Phase 
and a Treatment Phase consisting of four 4-day treatment periods separated by washout 
periods lasting several days.  The study center may schedule screening testing on multiple 
days as needed provided all screening tests are done within 14 days.  Approximately 192 
subjects will be screened with 62 eligible to start the Screening Washout Phase.  
Approximately 12 subjects are anticipated to fail baseline randomization criteria to obtain 
approximately 50 randomized subjects of whom approximately 10 are anticipated to drop out 
leaving approximately 40 completed subjects. 
 
Screening Phase Visit 1 - (Day -18 to -5) 
 
Eligible subjects will be selected within a period of up to 14 days prior to the start of the 
Screening Washout Phase of the trial.  Subjects are required to have a diagnosis of OA of the 
knee based on American College of Rheumatology (ACR) clinical criteria prior to inclusion 
into the trial.  The target knee will need to be identified per inclusion criteria (exam, 
radiographs and pain scores). In addition, the subject must have an average score of ≥3.0 on 
the WOMAC pain subscale (0-10 numeric rating scale [NRS] 48-hour recall version) at 
Screening AND/OR a 24-hour Average Pain Intensity score of ≥3 on the 0-10 NRS and a 
Joint Stiffness Severity score ≥3 on a 0-10 NRS.  If OA is present in both knees, the more 
painful knee will be considered the target knee. Subjects will receive accurate pain reporting 
training, and training on appropriate expectations for a clinical trial.    Additionally, subjects 
must self-report that they have experienced knee stiffness at least 5-7 days per week over the 
past month as reported on the Baseline Stiffness Questionnaire. 
 
Subjects will be instructed to discontinue use of all pain medications including supplements 
and topicals at the start of the Screening Washout phase (Day -4 to -1 +3 days) through trial 
completion, other than investigational medicinal product (IMP) or rescue medication provided 
by the study site.  Subjects will choose a daily wake-up time to establish a dosing routine that 
will be entered in a diary.   The range for wake-up hours must be between 5:00 am and 9:00 
am.  Subjects will need to commit to following a consistent wake-up routine for the duration 
of the trial. 
 
Screening Washout Phase (Day -4 to Day -1+3 days) 
Eligible subjects will start a minimum 4-day Screening Washout Phase.  Subjects will be 
required to abstain from taking all pain medications, including topicals, and supplements 
during the entire 4-day Screening Washout Phase, with the exception noted below. 
If needed, subjects can return to the study center up to 3 days after the completion of the 
Screening Washout Phase provided all current medication restrictions are maintained.      


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Subjects can take acetaminophen (up to 2000 mg/day) provided by the study site during this 
Screening Washout Phase, but not within 24 hours of the Randomization visit (Day 1 of 
Treatment Period 1).  No other analgesic medications are permitted. 
 
Start of Treatment Period X of 4 - Visit 2 (Day 1) 
Subjects will return to the study center upon completion of the Screening Washout Phase or 
between-treatment Washout Period.  To be eligible for randomization prior to Treatment 
Period 1, subjects must meet the following randomization criteria: self-reported average score 
of ≥4 on the WOMAC pain subscale (0-10 NRS, 48-hour recall version) related to OA pain in 
the target knee; current pain intensity score of ≥4 and ≤9 on the 0-10 NRS; and, a score of ≥4 
on the 0-10 NRS for average pain over the past 24-hours.  In addition, the Day 1 baseline 
post-STEPP current pain intensity 0-10 NRS score must be ≥5, and ≥1 unit higher than the 
pre-STEPP current pain intensity 0-10 NRS score.   
Subjects who do not meet all the randomization criteria will be considered a Screening failure 
and will not be randomized into the study.  Subjects who qualify will be asked additional 
questions related to knee pain, stiffness and function. 
Randomized subjects will receive their treatment period specific investigational medicinal 
product (IMP) or treatment kit that includes study medication at the start of each treatment 
period.  Randomization occurs only once during the start of the first treatment period. 
Subjects will take their first dose of IMP from the treatment kit while at the study center and 
will undergo the STEPP periodically over the next 8 hours to induce knee pain.  Subjects will 
complete pain assessments over 8 hours post-dose, take their afternoon (approximately 4 pm) 
dose after all assessments are complete, and then will be discharged from the study center.  
Following discharge from the study center, subjects will take the next two doses of IMP at 
home approximately as directed for a total of 4 doses on Day 1. 
During the completion of Visit 2, subjects will be fitted with an accelerometer to measure the 
number of steps taken and level of activity (e.g., low, medium, high).  Accelerometer data 
collection will start after completion of the Day 1 activities prior to leaving the study site.  
Day 2 and Day 3 
The morning following Day 1, subjects will continue with the same blinded treatment.  On 
Day 2 and 3, subjects will be asked to complete the 24-hour BASS assessments and will then 
take their first (morning) dose of IMP.  Subjects will continue to take their IMP as directed for 
a total of 4 doses per day.  Subjects will continue to wear their accelerometer except when 
showering or bathing. 
No rescue therapy will be allowed. 
End of Treatment Period X of 4 - Visit 3 (Day 4) 
Subjects will return to the study center wearing their accelerometer.  They must bring their 
diary and treatment kit with remaining study medication.  The accelerometer will be removed 
at the study site prior to the pre-dose STEPP.  Subjects will complete pain, stiffness and 
function assessments.  Subjects will then take their final remaining IMP morning dose in the 
(X of 4) treatment sequence.  Subjects will undergo the STEPP to induce knee pain 
periodically over the next 8 hours.  Subjects will complete pain assessments hourly over the 8 
hours post-dose and then will be discharged from the study center to start the washout period. 
 


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Reference Number: BHC-RD-OI-107 
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Washout between Treatment Periods 
Subjects will start a new Washout Period following the completion of Visit 3 (Day 4) of each 
Treatment Period (except Treatment Period 4). The Washout Period will last from 3 to 7 days 
after Visit 3.  Subjects will not be allowed to take any pain medication not dispensed by the 
study center.  Subjects can take acetaminophen (up to 2000 mg/day) provided by the study 
site during this Washout Period but not within 24 hours of Day 1 of the next Treatment 
Period.  Subjects will be scheduled to return to the study center to start the next Treatment 
Period (X of 4) for Day 1, Visit 2. 
End of Study (follow up) – after Visit 3, Treatment Period 4 of 4 
Subjects will receive a follow up phone call to assess adverse events and document any new 
concomitant medications.  Additionally, subjects will participate in a semi-structured 
qualitative interview about their experiences in the clinical trial.  Upon completion of all trial 
procedures, subjects will be discharged from the study. 
The duration of each subject’s participation will be approximately 68 days. For an overview 
on the trial design and trial procedures see Figure 1. 
5.2 
Study Methodology 
The study is a multi-center double-blind, randomized, crossover, placebo-controlled design 
with four treatment periods conducted in the United States.  Approximately 3-5 sites will be 
utilized for recruitment. 
 
5.3 
Selection of Study Population - amendment 2 
All male and female potential subjects 40 to 80 years of age with OA of the knee who would 
typically take OTC NSAIDs for pain relief may be eligible to participate in the study provided 
they meet inclusion/exclusion criteria. 
 
 
 


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Reference Number: BHC-RD-OI-107 
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Figure 1 – Design Overview - amendment 1 and 2 
 
 
 
 
 
Screening 
Phase 
Screening 
Washout 
Treatment Phase (4 arms) 
Washout 
Phase 
Follow up 
Phase 
Trial 
days 
Screening   
Visit 1         
Day -18 to -5 
Day -4       
to -1       
(+3 d) 
Start Treatment Period 
Visit 2                        
Day 1 
Continue 
Treatment 
Day 2 & 3 
End 
Treatment 
Period    
Visit 3       
Day 4 
Between 
Treatment 
Periods 
End of 
Study 
 
Accurate Pain 
Reporting 
Training 
Clinical Trial 
Expectations 
Training 
Baseline 
Stiffness 
Questionnaire 
WOMAC Pain 
WOMAC 
Stiffness  
WOMAC 
Function 
Stiffness 
Severity 
Question 
24-hour 
average pain 
(0-10 NRS) 
STEPP test 
Regional Pain 
Scale 
Washout 
before 1st 
IMP dose 
 
 
 
 
 
 
Daily BASS 
 
WOMAC    
Pain ≥4 
 
24-hour 
average      
pain ≥4        
(0-10 NRS) 
 
Current pain 
≥4 and ≤9      
(0-10 NRS) 
 
Post STEPP 
pain ≥5 and 
≥1 unit higher 
than pre-
STEPP pain    
(0-10 NRS) 
 
WOMAC 
Stiffness 
WOMAC 
Function 
Daily BASS 
 
Daily BASS 
prior to 1st IMP 
dose 
 
IMP doses 2, 3 
& 4 each day 
 
Accelerometer 
use 
Daily BASS 
WOMAC 
Pain 
WOMAC 
Stiffness 
WOMAC 
Function 
Morning 
IMP dose 
 
 
 
 
 
 
 
 
3 to 7 days 
of washout 
needed 
before 
starting the 
next 
treatment in 
the 
sequence 
 
After 
washout, 
repeat 
Treatment 
Phase for 
the 
remaining 
treatment(s) 
in the 
sequence    
(X of 4) 
 
 
 
 
 
 
7-10 days 
after 
completion 
of 
treatment 
period       
4 of 4 
 
Phone call 
 
Qualitative 
Interviewa 
1st IMP 
dose
 
 
 
 
 
2nd , 3rd & 
4th IMP 
dose 
 
Accelero-
meter use 
after 
completion 
of study 
procedures 
 
PGIC 
Treatment 
Preferencea 
 
 
  = Randomized to a 4 arm blinded treatment sequence (only for treatment 1 of 4) 
 
= Staircase-Evoked Pain Procedure (STEPP) completed pre-dose, and then 2, 4, 6 and 8 hours post-dose 
   = 0-10 point current pain NRS at pre-dose immediately before and 2-5 minutes after the STEPP, which is also completed at 2, 4, 6 and 8 
  
hours post-dose.  Additionally, hourly current pain intensity NRS at 1, 3, 5, and 7 hours post-dose when not completing the STEPP 
   a After Treatment period 4 of 4 or if the subject is withdrawn from the study prior to completion 


Clinical Study Protocol 19783 
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Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
Justification of the design 
The pilot study was designed to capture pain and stiffness data in subjects who could benefit 
from the administration of an OTC pain reliever.  OTC pain relievers are commonly used to 
treat the pain of OA.  The STEPP pain model has been included in multiple studies of new 
and approved medications to treat pain due to OA of the knee, and is expected to increase 
treatment effects observed in this study.   By including the STEPP in this study, standardized 
effect sizes can be assessed under short-term use conditions.  
 
Accurate Pain Reporting Training 
The Accurate Pain Reporting Program (“Reporting Your Pain,” Analgesic Solutions, 
Wayland, MA) consists of a set of subject and staff educational materials and instructions on 
how to accurately and reliably report pain scores, and on the proper use of pain intensity 
scales, with the aim of increasing subjects’ pain reporting accuracy.  Staff training is 
conducted prior to the first subject visit. Subjects receive training at the Screening Visit, and 
at on Day 1 of each of the four Treatment Periods.  The training video takes approximately 30 
minutes and should be completed prior to pain assessments. 
 
Appropriate Expectations Training 
This training (“Participating in a Research Study, What you need to know,” Analgesic 
Solutions, Wayland, MA) also consists of a set of subject and staff educational materials for 
training on appropriate expectations of personal benefit while participating in a clinical trial.  
The purpose is to provide subjects truthful information that will neutralize the typically 
excessive expectations that drive high placebo responses in clinical trials.  Subjects receive 
training at the Screening Visit, and at on Day 1 of each of the four Treatment Periods.  The 
training video takes approximately 30 minutes and should be completed prior to pain 
assessments. 
 
 


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6. 
Study population 
6.1 
Inclusion criteria - amendment 1 and 2 
Those who inquire about the trial will be allowed to participate in the study if they meet the 
following eligibility criteria: 
1. Signed Informed Consent; 
2. Ambulatory (as deemed appropriate by the Investigator) male and female subjects 
between 40 and 80 years of age; 
3. Body Mass Index (BMI) between 18 to <40 kg/m2; 
4. Unilateral or bilateral OA of the knee based on the American College of Rheumatology 
(ACR) clinical criteria: Knee pain plus at least 3 of the following:  
• age >50 years;  
• less than 30 minutes of morning stiffness; 
• crepitus on active motion and osteophytes; 
• bony tenderness; 
• bony enlargement; 
• no palpable warmth. 
5. Have had diagnostic quality radiography of the target knee performed no more than 1 year 
prior to baseline showing evidence of OA with Kellgren and Lawrence grade of II or III 
(see Section 16.2); 
Note: X-ray of both knees should not be repeated if performed in the previous 12 months, 
the radiographs are of diagnostic quality and information is available to the investigator. 
6. History of analgesic use for >4 days/week for past month and willing to discontinue use at 
least 4 days prior to randomization (low-dose [l00 mg or less] aspirin regimen permitted); 
7. Joint Stiffness Severity score ≥3 on a 0-10 NRS at Screening; 
8. Female subjects of childbearing potential must be using a medically acceptable form of 
birth control for at least 1 month prior to screening (or 3 months if using oral 
contraceptives) [e.g., hormonal contraceptives (oral, patch, injectable or vaginal ring), 
implantable device (implantable rod or intrauterine device), or a double barrier], or in 
same sex relationship and have a negative pregnancy test at Screening and prior to study 
drug administration.  Female subjects of non-childbearing potential must be amenorrheic 
for at least two years or have undergone surgical sterilization (e.g., hysterectomy and/or 
bilateral oophorectomy); 
9. Willing to wear an accelerometer during each Treatment Period of the Treatment Phase.  
Subjects who decline to wear the accelerometer are still eligible for study participation 
provided they meet all other required criteria. 
For Randomization: 
10. 48-hour WOMAC pain subscale average score ≥3.0 and/or 24-hour Average Pain 
Intensity score ≥3 on the 0-10 NRS at Screening; 


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11. 48-hour WOMAC pain subscale average score ≥4.0 at Visit 2, Treatment Period 1 of 4; 
12. 24-hour Average Pain Intensity score ≥4 at Visit 2, Treatment Period 1 of 4; 
13. Current pain intensity score ≥4 and ≤9 on the 0-10 NRS at Visit 2, Treatment Period 1 of 
4; 
14. A Day 1 baseline post-STEPP current pain intensity score ≥5, and ≥1 unit higher than the 
pre-STEPP current pain score on the 0-10 NRS; 
15. Experience knee stiffness at least 5-7 days per week over the past month as reported on 
the Baseline Stiffness Questionnaire at the Screening Visit. 
6.2 
Exclusion criteria - amendment 1 
Subjects presenting with any of the following will not be included in the trial: 
1. History of underlying inflammatory arthropathy, rheumatoid arthritis or fibromyalgia; 
2. History of or scheduled for knee replacement surgery (in the target knee) within the next 6 
months at screening; 
3. Recent injury in the OA affected knee (past 4 months); oral, intra-muscular, intravenous 
or intra-articular corticosteroid,  platelet rich plasma intraarticular knee injections, stem 
cell therapy or hyaluronic acid injections in either knee within the last 3 months; 
4. Subject reports moderate or severe (score of 2 or 3) pain or tenderness on the 0-3 Regional 
Pain Scale for any joint or body area other than the target knee and, in the Investigator’s 
opinion, the subject is not able to distinguish pain in the target knee from other painful 
areas; 
5. Use of any pain medications from the start of the Screening/Washout Phase through trial 
completion, other than IMP provided by the Sponsor or Rescue Pain medication provided 
by the study site; 
6. Subject who takes an opioid ≥4 days per week over the past 4 weeks; 
7. Subject is taking more than one antidepressant. Subjects who are on a stable dose of one 
antidepressant, for at least 1 month, are eligible for enrollment; 
8. Subject is taking more than one anxiolytic medication.  Subjects who are on a stable 
regimen of one anxiolytic for at least 1 month, are eligible for enrollment; 
9. Initiating any new physical therapy for the lower extremities from 4 weeks prior to study 
start through the duration of the study; 
10. Positive urine drug test for illegal drug substances, non-prescribed controlled substances, 
or breath/saliva alcohol at screening or Visit 2; 
Note: prescribed marijuana is allowed provided the subject is willing to wash out and not 
use during the study. 
11. Subject has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 
times the upper limit of normal; 
12. Subject has a hemoglobin <10.0 g/dL; 
13. Subject has an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²; 
14. Subject is breast feeding or has a positive pregnancy test at screening or Visit 2; 


Clinical Study Protocol 19783 
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15. Kellgren and Lawrence grade of 0, I or IV in the target knee (see Section 16.2); 
16. Subjects with a medical disorder, condition or history of such that could impair the 
subject’s ability to participate or complete this trial in the opinion of the investigator; 
17. History of hypersensitivity (including but not limited to anaphylactic reactions and serious 
skin reactions)  to naproxen sodium, celecoxib, acetaminophen, NSAIDS, aspirin, similar 
pharmacological agents or components of the investigational products 
18. History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other 
NSAIDs. 
19. History of allergic-type reactions to sulfonamides; 
20. Current or past history of gastrointestinal bleeding or other bleeding disorder(s); 
21. Prior history of peptic ulcer disease and/or gastro-intestinal bleeding; 
22. Evidence or history of clinically significant (in the judgment of the investigator) 
hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 
psychiatric, neurologic diseases, or malignancies within the last 5 years that makes the 
subject unfit to participate in the trial; 
23. Recent (within the past 1 year) MI or in the peri-operative period  surrounding coronary 
artery bypass graft (CABG) surgery; 
24. Heart failure, advanced renal disease or advanced hepatic disease; 
25. Current participation in any other trials involving investigational or marketed products 
within 30 days prior to the Screening Visit; 
26. Inability to report pain accurately as assessed at Screening; 
27. Unwilling or unable to comply with all requirements outlined in the protocol;  
28. Member or relative of study staff or the Sponsor directly involved in the study. 
In addition to the above stated inclusion/exclusion criteria and restrictions, subject selection in 
this study is to be made consistent with all the warnings, precautions, and contraindications 
associated with the use of Aleve®, 
 8 HR Arthritis Pain and celecoxib. The 
Investigator should review and be familiar with the information available on these marketed 
products and the information in the package label. 
CCI


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6.3 
 Justification of selection criteria 
The selection criteria are chosen to ensure that subjects with specific risks for administration 
of the study medication and/or subjects with conditions which may have an impact on the 
safety of the subject or data integrity during their participation in the study are excluded. 
6.4 
Withdrawal of subjects from study 
6.4.1 
Withdrawal 
Withdrawal criteria 
Subjects must be withdrawn from the study if any of the following occurs: 
• At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further.  The subject will not suffer any disadvantage as a result. 
Subjects may be withdrawn from the study if any of the following occurs: 
• Serious adverse events; 
• If, in the Investigator's opinion, continuation of the study would be harmful to the 
subject's well-being; 
• At the specific request of the Sponsor and in liaison with the Investigator (e.g., 
obvious non-compliance, safety concerns); 
• Protocol violation: if the subject develops conditions which would have prevented 
entry into the study according to the inclusion/exclusion criteria, the subject must be 
withdrawn immediately if safety is concerned; in other cases, the investigator will 
decide whether there is a conflict with the study objectives 
Depending on the time point of withdrawal, a withdrawn subject is referred to as either a 
“screening failure” or “dropout” as specified below: 
Screening failure 
A subject who, for any reason (e.g., failure to satisfy the selection criteria), terminates the 
study prior to randomization is regarded as a “screening failure”. 
Re-starting the defined set of screening procedures (re-screening) to enable the “screening 
failure” subject’s participation at a later time point is not allowed – with the following 
exceptions: 
• The subject had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule. 
• Initial screening occurred too early to complete the required washout period after prior 
therapy. 
• The in- / exclusion criteria preventing the subject’s initial attempt to participate have 
been changed (via protocol amendment). 


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• Other situations where the subject had to withdraw consent due to “life circumstances” 
though they otherwise qualified.  These situations will be considered on a case by case 
basis by the sponsor or sponsor representative in consultation with the investigator. 
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk.  Also, for re-screening, the subject has to re-
sign the informed consent form, even if it was not changed after the subject’s previous 
screening. 
Dropout 
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has been randomized and administered at least one dose of study 
drug. 
General procedures 
In all cases, the reason for withdrawal must be recorded in the case report form/electronic 
case report form (CRF/eCRF) data collection system and progress noted in the subject's 
medical records.  
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4. 
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (Premature termination of the Study). 
6.4.2 
Replacement 
Subjects who prematurely discontinue participation after randomization will not be replaced. 
6.5 
Subject identification 
Each subject is identified by the study site’s unique subject identification code. After 
informed consent procedure every subject is given a screening number (SNR). At the time 
point of randomization, subjects who meet the entry criteria will be sequentially assigned to a 
four-digit number in ascending order (randomization number, RNR).  See Section 7.3. 
7. 
Treatment(s) 
The study center will dispense a blinded treatment sequence after successfully completing 
screening and baseline assessments.  The overencapsulated tablets or capsules (IMP) for each 
treatment sequence will be dispensed using a computer generated randomization schedule. 
 
7.1 
Treatments to be administered - amendment 1 
The treatments to be administered during the study are displayed in Sections 7.1 and 7.2. 


Clinical Study Protocol 19783 
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Table 1: Treatments administered 
 
Dose Time 
Treatment A  
Naproxen 
Treatment B 
Acetaminophen 
Treatment C 
Celecoxib          
Treatment D 
Placebo 
Day 1 
Visit 2 
8 AM 
440 mg 
1300 mg 
100 mg 
Placebo 
4 PM 
Placebo 
1300 mg 
Placebo 
Placebo 
8 PM 
220 mg 
Placebo 
100 mg 
Placebo 
12 AM 
Placebo 
1300 mg 
Placebo 
Placebo 
 
 
 
 
 
 
Day 2 
At home 
8 AM 
440 mg 
1300 mg 
100 mg 
Placebo 
4 PM 
Placebo 
1300 mg 
Placebo 
Placebo 
8 PM 
220 mg 
Placebo 
100 mg 
Placebo 
12 AM 
Placebo 
1300 mg 
Placebo 
Placebo 
 
 
 
 
 
 
Day 3 
At home 
8 AM 
440 mg 
1300 mg 
100 mg 
Placebo 
4 PM 
Placebo 
1300 mg 
Placebo 
Placebo 
8 PM 
220 mg 
Placebo 
100 mg 
Placebo 
12 AM 
Placebo 
1300 mg 
Placebo 
Placebo 
 
 
 
 
 
 
Day 4 
Visit 3 
8 AM 
440 mg 
1300 mg 
100 mg 
Placebo 
 
Subjects will receive study medication 4 times per day on Days 1-3 and one dose of study 
medication on Day 4.  Doses will be administered at approximately 8 AM, 4 PM, 8 PM and 
12 AM (midnight) on Days 1-3 with a dosing window of ± 1 hour.  At time points when an 
active treatment is not called for, subjects will receive placebo to ensure that the study can 
remain blinded. 
 
Note: Number of doses per day are approximate based on subject’s dosing times provided the 
subject doses within the window for each listed time, they will be considered to have met 
protocol requriements. 
 
 


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7.2 
Identity of study treatment 
Table 2: Study treatments 
Treatment 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
Dose 
Naproxen sodium 
660 mg/day  
Acetaminophen ER    
3900 mg/day 
Celecoxib            
200 mg/day 
Placebo 
 
Pharmaceutical 
Form 
over-encapsulated 
tablet 
over-encapsulated 
tablet 
over-encapsulated 
capsule 
NA 
Strength 
220 mg 
650 mg 
100 mg 
NA 
Formulation 
naproxen sodium 
FD&C blue #2 lake 
hypromellose 
magnesium stearate 
microcrystalline 
cellulose 
polyethylene glycol 
povidone 
talc 
titanium dioxide 
 
Swedish orange 
opaque DBcaps® size 
AA-el capsules* 
micro crystalline 
cellulose* 
acetaminophen 
carnauba wax 
corn starch 
hydroxyethyl 
cellulose 
hypromellose 
magnesium stearate 
microcrystalline 
cellulose 
povidone 
powdered cellulose 
pre-gelatinized starch 
 sodium starch 
glycolate 
titanium dioxide 
triacetin 
 
Swedish orange 
opaque DBcaps® size 
AA-el capsules*       
micro crystalline 
cellulose* 
celecoxib            
lactose monohydrate 
sodium lauryl sulfate 
povidone 
croscarmellose 
sodium 
magnesium stearate 
gelatin 
edible inks 
 
Swedish orange 
opaque DBcaps® size 
AA-el capsules*       
micro crystalline 
cellulose* 
dibasic calcium 
phosphate dihydrate 
magnesium stearate 
 
Swedish orange 
opaque DBcaps® size 
AA-el capsules* 
micro crystalline 
cellulose* 
Route of 
administration 
/ Dosing 
instructions 
orally with a full 
glass of water 
orally with a full 
glass of water 
orally with a full 
glass of water 
orally with a full 
glass of water 
Batch Number 
available in the study 
file 
available in the study 
file 
available in the study 
file 
available in the study 
file 
Manufacturer 
Bayer               
Bitterfeld, Germany 
Johnson & Johnson 
Consumer Inc.       
Fort Washington, PA 
USA 
Greenstone 
Pepack, NJ USA 
Bayer 
Morristown, NJ USA 
*components of the over-encapsulation and filler material. 
All study drugs will be manufactured and labeled according to Good Manufacturing Practice 
(GMP) and applicable local laws.  Label text will be approved according to the sponsor’s 
agreed procedures, and a copy of the labels will be made available to the study site upon 
request. 
For all study drugs, a system of numbering in accordance with all requirements of GMP will 
be used, ensuring that each dose of study drug can be traced back to the respective bulk batch 
of the ingredients.  Lists linking all numbering levels will be maintained by the sponsor’s 
clinical supplies Quality Assurance (QA) group.  


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A complete record of batch numbers and expiry dates of all investigational products as well as 
the labels will be maintained in the clinical supply file. 
The source of test and reference products will be documented in the clinical supply file. 
7.3 
Treatment assignment - amendment 1 
At the beginning of the first treatment period, after completion of the pre-treatment baseline 
procedures/assessments, subjects who meet the entry criteria will be sequentially assigned to a 
unique number in ascending order (randomization number, RNR) according to the 
randomization schedule prepared prior to the study.  
Subjects will be numbered according to the following scheme: 
14001XXXX 
Whereas the “Xs” will be replaced with a four digit sequentially assigned number as each 
subject enters the study (e.g., first subject number of the study will be 
). 
Once a number has been assigned to a subject, it cannot be reassigned to another subject.   
Subjects who do not meet all of the randomization criteria will not be randomized.  Upon 
successful completion of all remaining inclusion and exclusion criteria, subjects enter the 
Treatment Phase and are randomized into one of four blinded treatment sequences using a 
Williams design to ensure a balanced stratification.  See example below: 
A B D C 
B C A D 
C D B A 
D A C B 
• Treatment A: Naproxen sodium 660 mg (three tablets of naproxen sodium 220 mg and 
five tablets of placebo daily); On Days 1, 2 and 3, first dose of two tablets of naproxen 
in the morning at 8:00 AM ± 1 hour followed by two tablets of placebo 8 hours later at 
4:00 PM ± 1 hour, followed by one tablet of naproxen and one tablet of placebo 4 
hours later at 8 PM ± 1 hour, followed by two tablets of placebo 4 hours later at 12 
AM ± 1 hour; 
 
• Treatment B: Acetaminophen 3900 mg (six tablets of acetaminophen 650 mg and two 
tablets of placebo daily); On Days 1, 2 and 3, first dose of two tablets of 
acetaminophen in the morning at 8:00 am ± 1 hour followed by two tablets of 
acetaminophen 8 hours later at 4:00 PM ± 1 hour followed by two tablets of placebo 4 
hours later at 8 PM ± 1 hour followed by two tablets of acetaminophen 8 hours later at 
12 AM ± 1 hour; 
 
• Treatment C: Celecoxib 200 mg (two capsules of celecoxib 100 mg and six tablets of 
placebo daily); On Days 1, 2 and 3, first dose of one capsule of celecoxib and one 
tablet of placebo in the morning at 8:00 am ± 1 hour followed by two tablets of 
placebo 8 hours later at 4:00 PM ± 1 hour followed by one capsule of celecoxib and 
one tablet of placebo 8 hours later at 8:00 PM ± 1 hour 1 followed by two tablets of 
placebo 8 hours later at 12 AM ± 1 hour; 
 
• Treatment D: Placebo (eight tablets of placebo daily); On Days 1, 2 and 3, first dose of 
two tablets of placebo in the morning at 8:00 AM ± 1 hour followed by two tablets of 
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placebo 8 hours later at 4:00 PM ± 1 hour followed by two tablets of placebo 4 hours 
later at 8 PM ± 1 hour followed by two tablets of placebo 8 hours later at 12AM ± 1 
hour. 
 
Note:  The Day 4 treatment is a single morning (8 AM) two tablet/capsule dose similar 
to the morning dosing for Days 1-3. 
7.4 
Dosage and administration 
Subjects will follow the dosing schedule as outlined in Section 7.1.  The blister package will 
be blinded to the specific treatments in the sequence.  All subjects will randomly receive one 
drug treatment (A, B, C or D) during each dosing period.  Depending upon which treatment in 
the sequence, they could be taking naproxen sodium, acetaminophen, celecoxib or placebo.  
Subjects will administer the drug with a full glass of non-refrigerated, non-carbonated water 
(about 8 ounces or 240 mL).   
The subject will bring their dosing blister package 
 with them to each visit.  The 
 blister electronically records the date and time when the subjects depresses the blister 
to take a dose of IMP.  The study center will download and review the dosing data from the 
 blister package for compliance.  Any deviations related to dosing outside of the 
allowable window (± 1 hour) will be documented in the subject’s medical record.  The study 
center will counsel all subjects with dosing window deviations. 
7.5 
Blinding 
7.5.1 
Blinding measures 
Subjects enrolled in the trial, investigators and their staff involved in protocol procedures or 
data collection analysis will be blinded to the identity of the treatment sequence. The study 
monitor will conduct product accountability during and after database lock. To preserve the 
blinding, all investigational products will be over encapsulated and prepackaged according to 
the randomization schedule. 
7.5.2 
Unblinding  
In the case of a medical emergency, such as serious adverse events (SAE), breaking the blind 
may become necessary during the trial.  Randomization code-break envelopes are securely 
maintained at the trial site and with the Sponsor. 
In compliance with applicable regulations, in the event of a SUSAR related to the blinded 
treatment, the subject’s treatment code will usually be unblinded before reporting to the health 
authorities, ethic committees and investigators (see Section 9.6.1.4). 
7.5.3 
Emergency unblinding by the investigator 
The investigator will be provided code-break envelopes that can be used to break the blinding 
of the study drug.  Any subject who was unblinded using the code-break envelopes must have 
the occurrence documented in the subject’s medical record.  The investigator should notify 
the sponsor or sponsor medical monitor prior to unblinding if at all possible unless a delay in 
doing so will deleteriously affect the subject’s well being. The investigator must report the 
CCI
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blind break in conjunction with a SAE as defined in Section 9.6.1.  Subjects that have been 
unblinded will not be included in the ITT or PP efficacy analysis. 
The Sponsor will collect all code-break envelopes at the end of the study. 
7.6 
Drug logistics and accountability - amendment 1 
The Sponsor will provide sufficient quantity of the investigational medicinal product (IMP) to 
the study site.  All study centers will dispense IMP according to the computer generated 
randomization schedule. 
All study drugs will be stored at the investigational site in accordance with GCP requirements 
and the instructions given by the clinical supplies department of the sponsor (or its 
affiliate/CRO), and will be inaccessible to unauthorized personnel. Special storage conditions 
and a complete record of batch numbers and expiry dates can be found in the Sponsor’s study 
file; the site-relevant elements of this information will be available in the investigator site file. 
On the day of receipt, the responsible site personnel will confirm receipt of study 
investigational products in writing. The personnel will use the study investigational products 
only within the framework of this clinical study and in accordance with this protocol. Receipt, 
distribution, return and destruction (if any) of the study drug must be properly documented 
according to the sponsor’s agreed and specified procedures. 
7.7 
Treatment compliance 
The distribution of the study medication will be supervised by a member of the Investigator’s 
team. Subjects not at the study center will administer IMP at their pre-determined dose time.  
Dosing performed at the study center will be monitored by the study staff.  The study center 
will monitor used and unused IMP for compliance.  Any discrepancies between actual and 
expected amount of returned study medication must be discussed with the subject at the time 
of the visit, and any explanation must be documented in the source records. 
 
 


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8. 
Non-study therapy 
8.1 
Prior and concomitant therapy - amendment 1 
 
The following treatments are prohibited:  
• Use of any pain medications from the start of the Screening Washout Phase 
through trial completion, other than IMP provided by the Sponsor and rescue pain 
medication provided by the study site  This includes medications such as 
gabapentin, cannabidiol etc. if prescribed to the subject for the purpose of pain 
control; 
• Taking more than one antidepressant. Subjects who are on a stable dose of one 
antidepressant, for at least 1 month, are eligible for enrollment; 
• Taking more than one anxiolytic medication. Subjects who are on a stable regimen 
of one anxiolytic for at least 1 month, are eligible for enrollment; 
• Fish oil (supplements are permitted if the dose is stable for at least 4 weeks). 
From 4 days prior to randomization until the completion of the Treatment Phase (Treatment 
Period 4 of 4), subjects are not allowed to take pain treatments (including supplements and/or 
topicals) other than the provided trial treatment (IMP and rescue therapy).  Prohibited 
treatements include: 
• Topical capsaicin, NSAIDs, lidocaine, and cannabidiol oil; 
• Glucosamine-chondroitin and turmeric (curcumin); 
• Supplements intended for pain relief. 
If the subject uses an excluded/prohibited medication (analgesic or other medication) after 
being enrolled into the study, the investigator will use his/her judgement to determine  
whether the subject is able to continue however, the subject must be discontinued if safety is 
concerned.  In other cases, the subject may be able to continue if the concomitant medication 
is for short term use and/or is not likely to conflict with the study objectives in subsequent 
Treatment Periods. 
All medications (prescription and nonprescription products, vitamin and herbal products) 
taken by the subject from 30 days prior to Screening to End of Study (Follow up phone call) 
will be documented.  The reported medications will be reviewed and evaluated by the 
Principal Investigator or designee to determine if they affect the subject’s eligibility to 
participate in the study. 
8.2 
Post-study therapy 
This a blinded four period, four treatment crossover study for subjects with knee pain due to 
OA and therefore no additional treatment after the 4th treatment period (treatment period 4 of 
4) will be allocated.  Subjects will be discharged upon their completion of Follow up phone 
call. 
 
 


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9. 
Procedures and variables 
9.1 Tabular schedule of evaluations 
See flow chart in Section 16.1 
Regarding protocol deviations, the processes and responsibilities defined by the Sponsor will 
be followed. Respective details (e.g., identification and classification of protocol deviations) 
are described separately. 
9.2 
Visit description 
If not stated otherwise, the measures / actions listed in the following Sections 9.2.1 to 9.2.8 
will be performed by or under the supervision of the investigator. 
9.2.1 
Screening Phase Visit 1 (Day -18 to -5) - amendment 1 and 2 
At the Screening visit, the Principal Investigator or appropriate designee will discuss with 
each subject the nature of the trial, its requirements and its restrictions.  Written informed 
consent will be obtained prior to performance of any protocol-specific procedures.   
The Screening Phase will be up to 14 days long.  The following will be conducted during the 
Screening Visit: 
• Signed Informed Consent; 
• Review Inclusion and Exclusion Criteria; 
• Subject demographics; 
• Medical history; 
• Medication history of all prescription and over-the-counter drugs and other products 
(including topicals, herbal products, vitamins and nutritional supplements) and 
investigational drugs, taken within 30 days prior to screening; 
• Alcohol breath/saliva test; 
• Urine drug screen; 
• Urine pregnancy test for female subjects of child bearing potential; 
• Blood and urine specimens for safety laboratory tests (hematology, chemistry and 
urinalysis); 
• History of drug, alcohol and tobacco use; 
• Height, weight, and Body Mass Index (BMI); 
• Physical examination; 
• OA assessment of each potentially qualifying knee using ACR criteria; 
• Radiograph of each potentially qualifying knee (anteroposterior [AP] or 
posteroanterior [PA] and lateral projections); 
Note: A historical knee radiograph could be used provided the images were taken 
within the previous 1 year and can be digitally exported to a central reading lab and are 
of diagnostic quality. 
• Baseline Stiffness Questionnaire of each knee; 
• Joint Stiffness Severity rating of each knee; 
• Regional Pain Scale (13); 
• Vital signs (blood pressure, heart rate, respiratory rate and body temperature after 5 
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• Accurate Pain Reporting Training; 
• Appropriate Expectations Training; 
• 48-hour recall WOMAC subscales for stiffness, physical function and pain 
questionnaire to establish the target knee; 
• 24-hour Average Pain Intensity on 0-10 NRS; 
• STEPP test with pre- and post- current pain intensity NRS (confirm understanding and 
ability to perform the exercise); 
• Discuss the procedure to report adverse events; 
• Schedule Visit 2 (eligible subjects only). 
 
To qualify for randomization (Day 1), subjects must have an average score ≥3.0 on the 48-
hour WOMAC pain subscale AND/OR score ≥3.0 on the 24-hour Average Pain Intensity 
Scale. 
 
The Principal Investigator or his/her designee must review all screening results before 
proceeding to the Baseline phase of the study.  This includes the radiographic interpretation of 
the knee radiographs using the Kellgren and Lawrence scale as well as safety laboratory 
values.  Subjects will be reminded once screening criteria have been met, to discontinue use 
of all pain medications, including topicals, and supplements until they return for Visit 2.  
Subjects can take acetaminophen (up to 2000 mg/day), for knee pain but not within 24 hours 
of the Randomization visit. The rescue therapy will be provided by the study site.  Subjects 
will record a diary entry with the day and time of each dose of rescue analgesic used. 
 
An external centralized vendor chosen by the sponsor will read/ interpret the knee radiographs 
and communicate the findings to the study center.  Subjects that do not meet qualification 
after leaving the test site at Visit 1, will not be required to return their paper diary. 
 
9.2.2 
Screening Washout Phase (Day -4 to Day -1 +3 days) 
Eligible subjects will abstain from taking any pain medications, including topicals, and 
supplements during the Screening Washout Phase, except acetaminophen as noted below.  
This is necessary so that subjects can accurately document their untreated baseline pain and 
stiffness prior to treatment randomization. If needed, subjects can take acetaminophen (up to 
2000 mg/day) during the Screening Washout Phase, but not within 24 hours of the 
Randomization visit. 
Subjects can return to the study center up to 3 days after the 4th day of the Screening Washout 
Phase provided medication restrictions are maintained.  The study center will contact the 
subject to remind them of their Visit 2 appointment.   
9.2.3 
Visit 2 (Day 1, Start Treatment Period) - amendment 1 and 2 
Visit 2 will occur 4 to 7 days after starting the Screening Washout Phase (within 21 days of 
the initial screening visit).  The following activities will be completed: 
• Review inclusion and exclusion criteria; 
• Concomitant medication review; 
• Review changes in the subject’s medical/medication history since previous visit; 
• Vital signs (blood pressure and heart rate after 5 minutes in a sitting position); 
• Accurate Pain Reporting Training; 


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• Appropriate Expectations Training; 
• Alcohol breath/saliva test; 
• Urine drug screen; 
• Urine pregnancy test for female subjects of child bearing potential; 
• 48-hour recall WOMAC (0-10 NRS version) subscales for stiffness, physical function 
and pain questionnaires; 
• 24-hour Average Pain Intensity assessment (0-10 NRS); 
• Daily BASS assessment; 
• Adverse Event assessment; 
• Subjects will report the current pain intensity for their target knee on the 0-10 NRS;  
• Immediately thereafter, subjects will perform the STEPP pre-dose (time 0). Subjects 
will report the current pain intensity for their target knee on the 0-10 NRS 2-5 minutes 
after performance of the STEPP. 
 
Randomization Criteria:  
Subjects must self-report the following pain ratings in order to be randomized and start 
Treatment Period 1 of 4: 
• An average score of ≥4.0 on WOMAC pain subscale summation score (0-10 NRS, 48-
hour recall version); 
• 24-hour Average Pain Intensity score of ≥4 on the 0-10 NRS; 
• Current pain intensity score of ≥4 and ≤9 on the 0-10 NRS; 
• Day 1 baseline post -STEPP current pain intensity score ≥5 and ≥1 unit higher than the 
pre-STEPP current pain intensity score on the 0-10 NRS. 
 
Subjects who do not meet all of the randomization criteria will not be randomized.  Upon 
successful completion of all remaining inclusion and exclusion criteria, subjects enter the 
Treatment Phase and are randomized into one of four blinded treatment sequences (see 
Section 7.3). 
 
Subjects will perform the STEPP pre-dose (time 0) and at 2, 4, 6 and 8 hours post-dose. 
Subjects will report the current pain intensity for their target knee on the 0-10 NRS 
immediately before and 2-5 minutes after each performance of the STEPP. 
 
In addition, subjects will self-report the current pain intensity of their target knee on the 0-10 
NRS at post-dose hours 1, 3, 5, and 7. 
 
Subjects will take their first (morning) dose at the direction of the study staff.  Their second 
dose in the afternoon of Day 1 will be taken after completing all of the hour 8 activities and 
prior to leaving the study site.  Their 3rd dose in the evening and their 4th dose in the late 
evening (around midnight) will be taken at home.  Subjects will be reminded of their selected 
wake up time and encouraged to keep this schedule for the duration of the trial.  Subjects will 
be fitted with an accelerometer on their lower leg (ankle) area on Day 1, directly after 
completion of the 8 hour activities.  Subjects will wear the accelerometer at the completion of 
the clinic visit.  Subjects will be trained to wear the accelerometer during the treatment 
periods.  Subjects will be scheduled for Visit 3 and reminded to bring their diary, treatment kit 
for review and wear their accelerometer which will be removed at the study site prior to 
performing any study related procedures. 
 


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Note: subjects will wear the accelerometer on the ankle for Days 1 (at the conclusion of the 
clinic visit), 2 and 3 of each Treatment Period without removal except when showering or 
bathing. The accelerometer cannot be used in conjunction with any swimming or watersport 
activity.  The accelerometer may be removed for sleep. The subject may request to use the 
opposite ankle for placement of the accelerometer during the trial. 
 
9.2.4 
Day 2 and 3 (Continue Treatment Period) - amendment 1 
Subjects will rate their knee joint stiffness using the Daily BASS assessments in their diary 
before taking their first (approximately 8 AM) dose of two capsules or tablets.  Subjects will 
follow the dosing instructions provided for the remaining doses to be taken each day.  
Subjects will continue to wear their accelerometer as instructed. 
Subjects cannot use any rescue therapy at this time. 
9.2.5 
Visit 3 (Day 4, End of Treatment Period X of 4) - amendment 1 and 2 
Subjects will return to the study center (wearing their accelerometer) for final assessments of 
the Treatment Period (X of 4).  Subjects must take the morning (approximately 8 AM) dose of 
study medication at the study center.  The following activities will be performed prior to 
dosing: 
• Review inclusion and exclusion criteria; 
• Concomitant medication review; 
• Remove accelerometer from subject (prior to pre-dose STEPP); 
• Accelerometer data download and battery charging (~1 hour); 
• Vital signs (blood pressure, heart rate, after 5 minutes in a sitting position); 
• Daily BASS assessment; 
• 24-hour Average Pain Intensity on 0-10 NRS assessment; 
• Current pain intensity on 0-10 NRS (immediately prior to the pre-dose STEPP); 
• 48-hour recall WOMAC  (0-10 NRS version) subscales for stiffness, physical 
function and pain questionnaires; Adverse Event assessment. 
 
Subjects will perform the STEPP pre-dose (time 0) and at 2, 4, 6 and 8 hours post-dose. 
Subjects will report the current pain intensity for their target knee on the 0-10 NRS 
immediately before and 2-5 minutes after each performance of the STEPP. 
 
In addition, subjects will self-report the current pain intensity of their target knee on the 0-10 
NRS at post-dose hours 1, 3, 5, and 7. 
 
• Approximately 8 hours after dosing, prior to leaving the study center on Day 4 of each 
Treatment Period, subjects will complete two Patient Global Impression of Change 
(PGIC) scales: the PGIC for OA Pain, and the PGIC for OA Symptoms 
 
Upon completion of data download and re-charge (~1 hour), the accelerometer will be stored 
at the clinic until the next Visit 2 of the next Treatment Period occurs. 
9.2.6 
Washout between Treatment Periods (3 to 7 days after Visit 3) 
After the completion of Visit 3, subjects will start a new Washout Period of at least 3 days 
before returning to the study center for their next Visit 2 (i.e., the start of the next Treatment 


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Period).  The use of rescue therapy (up to 2000 mg of acetaminophen per day) provided by 
the study site is allowed, but not within 24 hours of returning to the study center for the start 
of the next Treatment Period. 
Subjects are required to return to the study site to start the next treatment in the sequence 
provided at randomization.  Subjects will repeat the Treatment Period of study until all 4 
blinded treatments have been dosed.  Subjects will follow the treatment sequence in numeric 
order (1 of 4, 2 of 4, 3 of 4 and 4 of 4) and not deviate in order. 
9.2.7 
Visit 3 (Day 4, End of Treatment Period 4 of 4) 
Subjects will complete the Treatment Preference rating and the accelerometer will be 
removed from the subject and the data downloaded. 
9.2.8 
End of Study (7 to 10 days after Visit 3, Treatment Period 4 of 4) 
At the completion of the final treatment/visit in the sequence (4 of 4) or if the subject 
withdraws prior to the last treatment visit, subjects will receive a phone call from the study 
site to review concomitant medications and assess adverse events.  Additionally, subjects will 
participate in a semi-structured qualitative interview about their experiences in the clinical 
trial (see Section 16.2). 
9.2.9 
Rescue therapy 
Rescue analgesic therapy will be available for subjects during the Screening Washout Phase 
and washout between Treatment Periods.  The Study Site will provide subjects with 
acetaminophen 500 mg tablets.  The total daily dosage must not exceed 2000 mg. Rescue 
therapy is not allowed 24 hours prior to Day 1 pre-treatment assessments and it is not allowed 
from Day 1 through Day 4 assessments of each Treatment Period. 
 
The amount of rescue therapy dispensed will be recorded.  Subjects will record the amount 
and date and time of all rescue therapy doses used in their diary.  At the start of all Treatment 
Periods, subjects will return all unused rescue therapy and the study center will account for 
the amount used against the subject’s record. 
 
Subjects will be queried in a nonspecific fashion for any adverse events (e.g., “Have you had 
any changes in health?”).  Any reported AEs will be collected and recorded on the CRF/e-
CRF data collection system.  The information recorded will be based on signs and symptoms 
reported by the subject or observed by the research coordinator during the clinical evaluation.  
9.3 
Population characteristics 
9.3.1 Demographic 
For basic subject assessment prior to screening, some demographic information may be 
collected before obtaining written informed consent: 
• Year of birth (approximate age); 
• Native language. 
Collection of demographic information is subject to all applicable local regulations. 


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9.3.2 
Medical history 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator: 
• Start before signing of the informed consent; 
• Considered relevant for the subject’s study eligibility. 
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1. 
9.3.3 
Other baseline characteristics 
Information on smoking (including e-cigarettes), as well as drug and alcohol consumption 
will be collected. 
9.4 
Efficacy analysis 
9.4.1 
Primary efficacy endpoint 
All efficacy analyses will be based on the PP population.  
• Sum of change from baseline (Day 1 of the Treatment Period) in BASS score over the 
4 day treatment period. 
9.4.2 
Secondary efficacy endpoints 
The secondary efficacy endpoints related to the primary objective include: 
• Absolute BASS score at each time point. 
• Day 4 change from baseline (Day 1 of the treatment period) in BASS score. 
Note:  Key pairwise comparisons of absolute BASS score and change from baseline BASS 
score will be assessed, including, but not limited to: naproxen versus placebo, 
celecoxib versus placebo, acetaminophen versus placebo, naproxen versus 
acetaminophen and naproxen versus celecoxib. 
9.4.3 
Exploratory efficacy endpoints - amendment 1 and 2 
• Day 1 and Day 4 post-STEPP sum of pain intensity difference (SPID) at 4, 6, and 8 
hours post-dose, based on 0-10 NRS; 
• Day 1 and Day 4 post-STEPP sum of pain intensity (SPI) at 4, 6, and 8 hours post-
dose, based on 0-10 NRS; 
• Day 1 and Day 4 post-STEPP pain intensity difference (PID) from baseline at 2, 4, 6 
and 8 hours post-dose, based on 0-10 NRS;   
CCI


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• Day 1 and Day 4 post-STEPP pain intensity (PI) at 2, 4, 6, and 8 hours post-dose, 
based on 0-10 NRS; 
• Current hourly PI using the 0–10 NRS pre-dose, and from 1 to 8 hours post-dose;   
• Mean change from baseline (Day 1 of the Treatment Period) to end of Treatment 
Period on the Western Ontario and McMaster Universities Arthritis (WOMAC) pain 
subscale, 48-hour recall version, assessed on Day 1 and Day 4, including an 
assessment of all key pairwise comparisons; 
• Mean change from baseline to end of treatment period on WOMAC stiffness subscale, 
48-hour recall version, assessed on Day 1 and Day 4, including an assessment of all 
key pairwise comparisons; 
• Absolute WOMAC stiffness subscale scores, 48-hour recall version, for each study 
treatment at each time point; 
• Physical activity level outcomes during Days 1 (partial), 2 and 3 as measured by the 
accelerometer; 
• Change from baseline to end of treatment period on WOMAC function subscale, 48-
hour recall version, assessed on Day 1 and Day 4, including an assessment of all key 
pairwise comparisons; 
• Patient Global Impression of Change (PGIC) on Day 4 of each Treatment Period, 
including PGIC for OA Pain (PGIC-P) and PGIC for OA Symptoms (PGIC-S); 
• Subject preference for treatment assessed at the end of the study; 
• Qualitative (semi-structured) interview to assess subjects’ experience with treatments, 
and experience with the STEPP, relevance to their disease status, how to improve it, 
etc. (see Section 16.2). 
9.4.4 
Safety analysis - amendment 1 
The following laboratory tests will be performed at screening: 
• Hematology  (Hemoglobin, Hematocrit, RBC count, Platelet count, WBC count), 
• Serum Chemistry (BUN, Creatinine, Glucose, Ca++, Na+, K+, Cl-, Total CO2 
(Bicarbonate), AST, ALT, Total Bilirubin, Alkaline phosphatase, Albumin, Total 
protein )  
• Urinalysis (Specific gravity, pH, Glucose (qual), Protein (qual), Blood (qual), 
Ketones, Leukocyte Esterase, Nitrite, Bilirubin, Urobilinogen) 
Adverse events will be collected throughout the treatment and safety follow-up periods and 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  
Only treatment-emergent AEs will be included, i.e., AEs that begin or worsen after the first 
dose of the investigational products in the Treatment Phase.  The number and percent of 
subjects who experience any event, by System Organ Class (SOC), and by Preferred Term 
will be displayed by treatment group.  Tables will also be produced by severity and 
relationship to investigational product. Seriousness, severity, relationship to investigational 
product, duration, and outcome will also be listed. 


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9.5 
Pharmacokinetics / pharmacodynamics 
Not applicable 
 
9.5.1 
Pharmacodynamics 
Not applicable 
9.6 
Safety 
9.6.1 
Adverse events 
9.6.1.1 
Definitions 
Definition of adverse event (AE) 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of 
a medicinal (investigational) product.  
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE). 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g., physical examination findings, symptoms, diseases. 
• Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g., seasonal allergy without acute complaints); 
• Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g., allergic pollinosis); 
• Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  This includes intercurrent illnesses. 
Definition of serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition refers to 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. 


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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met: 
- The admission results in a hospital stay of less than 12 hours 
- The admission is pre-planned  
(e.g., elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2) 
- The admission is not associated with an AE  
(e.g., social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence. 
d. Results in persistent or significant disability / incapacity 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
e. Is a congenital anomaly / birth defect 
f. Is another serious or important medical event as judged by the investigator 
9.6.1.2 Classifications for adverse event assessment 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.   
9.6.1.2.1 Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1. 


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9.6.1.2.2 Intensity 
The intensity of an AE is classified according to the following categories: 
• Mild: Presents with signs and symptoms easily tolerated, does not need treatment, or 
prolonged hospitalization and does not necessarily require stopping the drug; 
• Moderate:  A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research participant; 
• Severe: A type of adverse event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects clinical status. The event 
possesses a significant risk of harm to the research participant and hospitalization may be 
required. 
9.6.1.2.3 Causal relationship  
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the CRF/eCRF data collection system. 
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question. 
Possible answers are “yes” or “no” 
An assessment of “no” would include: 
1. The existence of a highly likely alternative explanation, e.g., mechanical bleeding at 
surgical site. 
or 
2. Non-plausibility, e.g., the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration. 
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment. 
Important factors to be considered in assessing the relationship of the AE to study treatment 
include: 
- The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event. 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge):  Subject’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question. 
- Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have. 
- Concomitant medication or treatment:  
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might have caused the event in question. 


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- Known response pattern for this class of drug: Clinical/preclinical 
- Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event 
- The pharmacology and pharmacokinetics of the study treatment:  
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered. 
- The assessment is not possible 
Causal relationship to protocol-required procedure(s) 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s). 
Possible answers are “yes” or “no” 
9.6.1.2.4 Action taken with study treatment  
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
The study treatment action should be recorded separately for each study treatment as detailed 
in the CRF/eCRF data collection system. 
- Drug withdrawn 
- Drug interrupted 
- Dose reduced 
- Dose not changed 
- Dose increased 
- Not applicable 
- Unknown 
9.6.1.2.5 Other specific treatment(s) of adverse events 
- None 
- Remedial drug therapy 
- Other 


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9.6.1.2.6 Outcome 
The outcome of the AE is to be documented as follows:  
- Recovered/resolved 
- Recovering/resolving 
- Recovered/resolved with sequelae 
- Not recovered/not resolved 
- Fatal 
- Unknown 
9.6.1.3 
Assessments and documentation of adverse events 
AEs observed, mentioned upon open questioning by a member of the investigator’s team or 
spontaneously reported by the subject will be documented. The observation phase for AEs 
will start with signing the informed consent form and will end in general with the last visit of 
follow-up. After the end of follow-up there is no requirement to actively collect AEs. 
In case of ongoing AEs after the last follow-up visit – especially when related to treatment 
with the study medication – the respective AE will be followed until resolution, if possible. 
The type of information that should be assessed and recorded by the investigator for each AE 
is listed in Section 9.6.1.2. 
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness 
and causal relationship to treatment with the study medication. 
The investigator has to record on the respective CRF/eCRF data collection system all adverse 
events occurring in the period between the signing of the informed consent and the end of the 
Follow-up Visit, there is no requirement to actively collect AEs including deaths.  The type of 
information that should be assessed and recorded by the investigator for each AE is listed in 
Section 9.6.1.2.   
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s). 
For all serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug. 
9.6.1.4 Reporting of serious adverse events and pregnancy 
The definition of serious adverse events (SAEs) is given in Section 9.6.1.1.  Each SAE must 
be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient. 
Investigator’s notification of the sponsor 
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as 
needed. 
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
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detailed in the instructions for SAE reporting included in the Investigator File.  For this, an 
AE page in the CRF/eCRF data collection system as well as the complementary pages 
provided in the Investigator File must be completed for each SAE.   
Pregnancy occurring during a clinical investigation, although not considered a serious adverse 
event, must be reported to Bayer within the same timelines as a serious adverse event on a 
Pregnancy Monitoring Form.  The outcome of a pregnancy should be followed up carefully 
and any abnormal outcome of the mother or the child should be reported.  This also applies to 
pregnancies following the administration of the investigational product to the father prior to 
sexual intercourse.  Send the completed SAE or pregnancy forms to: 
 or Fax:
 (in the USA) 
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations. 
Notification of the IRB 
Notification of the Institutional Review Board (IRB) about all relevant events (e.g., SAEs, 
suspected, unexpected, serious adverse reactions [SUSARs]) will be performed by the 
sponsor and/or by the investigator according to all applicable regulations. 
Notification of the authorities 
The processing and reporting of all relevant events (e.g., SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations. 
Sponsor’s notification of the investigational site 
The sponsor will inform the investigational site about reported relevant events (e.g., SUSARs) 
according to all applicable regulations. 
9.6.1.5 Expected adverse events 
For this study, the applicable reference document is the most current version of the package 
insert or Investigator Brochure for naproxen, acetaminophen and celecoxib.  If relevant new 
safety information is identified, the information will be integrated into an update of the safety 
information and distributed to all participating sites. 
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations. 
9.6.2 
Pregnancies 
A subject’s participation is to be terminated immediately if a pregnancy is supposed (i.e. 
in case her pregnancy test becomes positive).   
The investigator must report to the sponsor any pregnancy occurring in a female subject 
during her participation in this study.  The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported. 
For all reports, the forms provided are to be used.  The investigator should submit them within 
the same timelines as an SAE (see Section 9.6.1.4.).  Send the completed pregnancy forms to: 
 or Fax: 
 (in the USA) 
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9.6.3 
Safety Examinations 
The following safety examinations will be performed at the time points specified in the study 
flowchart, see Section 16.1. 
• Physical examination 
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician (or appropriately licensened designee) at the study site covering at least the 
organs of the cardiovascular, respiratory, and abdominal systems. 
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1). 
• Body weight and height, BMI 
Body weight will be measured by a member of the investigator’s team under the following 
conditions: 
− Subject without shoes after having emptied his or her bladder 
− Physician scale, measurement units 0.1 kg 
The subject’s height will be measured (without shoes) to calculate the BMI. 
• Blood pressure / heart rate 
Systolic and diastolic blood pressure and heart rate will be measured by a member of the 
investigator’s team under the following conditions: 
− Systolic blood pressure (after resting for at least 5 min in sitting position) 
− Diastolic blood pressure (after resting for at least 5 min in sitting position) 
− Heart rate (after resting for at least 5 min in sitting position) 
− Measuring site: cuff to be placed on the right / left upper arm (if possible, the same 
arm will be used for all measurements in one subject); cuff location will be 
documented 
− Method: oscillometric by automatic or manual measurement device 
• Laboratory examinations 
Urine samples will be collected to assess for illicit drugs at Screening Visit 1 and Visit 2.  
Safety laboratory examination will collected at Screening. 
Table 3: Urine drug screen panel 
 
Table 4: Safety laboratory evaluations - amendment 1 
Test Panel 
Parameter 
Urine Drug Screen 
Methamphetamines, Amphetamines, cannabinoids, 
cocaine, opiates, benzodiazepines, barbiturates, 
Methylenedioxymethamphetamine, Methadone, 
Oxycodone, Adulterants 
Hematology 
Hemoglobin, Hematocrit, RBC count, Platelet count, 
WBC count 
Chemistry 
BUN, Creatinine, Glucose, Ca++, Na+, K+, Cl-, Total 


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9.7 
Other procedures and variables - amendment 1 and 2 
STEPP 
 
The STEPP consists of stepping fully up and down on a standardized stair that will be 
provided to the sites.  Pain measures are performed immediately before and 2-5 minutes after 
the exercise using a 0-10 pain intensity NRS.  Details about the STEPP will be provided in the 
STEPP Manual.  
 
0-10 point pain intensity NRS 
 
The 0-10 point current pain intensity NRS will be assessed at the Screening Visit before and 
after one performance of the STEPP, and at Visits 2 and 3 of each Treatment Period before 
and after the STEPP performed pre-dose and at 2, 4, 6, and 8 hours post-dose.  It will also be 
assessed at 1, 3, 5, and 7 hours post-dose when not completing the STEPP.  The 0-10 point 
average pain intensity over the last 24 hours NRS will be assessed at the Screening Visit and 
at Visits 2 and 3 of each Treatment Period. 
WOMAC (0-10 NRS version; version 3.1) 
WOMAC Pain, Stiffness and Physical Function subscales (0-10 NRS, 48-hour recall version) 
will be measured at the Screening Visit, and Visits 2 and 3 of each Treatment Phase. 
Baseline Stiffness Questionnaire 
The Baseline Stiffness questionnaire will be assessed at the Screening Visit.  It is used to 
characterize the subjects knee stiffness over the past month. 
Joint Stiffness Severity Rating 
The Joint Stiffness Severity rating will be assessed at the Screening Visit.  It is a subjective 
rating of joint stiffness severity on a typical day. 
Daily BASS  
The Daily BASS is a PRO instrument measuring of the severity of OA-related stiffness in the 
target knee joint.  
The Daily BASS will be assessed daily during each Treatment Period. Subjects will report 
their Daily BASS score in-clinic at Visits 2 and 3 (Days 1 and 4), and at home in diaries 
during Days 2 and 3. 
 
 
 
CO2 (Bicarbonate), AST, ALT, Total Bilirubin, 
Alkaline phosphatase, Albumin, Total protein 
Urinalysis 
Specific gravity, pH, Glucose (qual), Protein (qual), 
Blood (qual), Ketones, Leukocyte Esterase, Nitrite, 
Bilirubin, Urobilinogen 


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PGIC for OA Pain  
 
A question that rates the effects of the investigational product on OA pain is asked at Visit 3 
for each Treatment Period. 
 
PGIC for OA Symptoms 
 
A question that rates the effects of the investigational product on OA symptoms is asked at 
Visit 3 for each Treatment Period. 
Treatment Preference 
 
A question that asks which treatment gave the most pain relief is asked at Visit 3 for 
Treatment Period 4 of 4. 
 
Qualitative Interview – amended  
 
Mixed-methods research, which combines quantitative methods with qualitative methods, is 
becoming more common in all areas of human subjects research, including clinical 
trials.(14,15,16)  Quantitative research, in which subjects answer questions on fixed forms, is 
limited by the imagination and assumptions of the researchers.  Patients often have helpful 
observations about their experiences that may trigger hypotheses about the medications being 
studied, the assessments used in the study, and the patient experience with logistical and other 
aspects of study conduct that may improve subsequent clinical trials.  Therefore this study 
will include a semi-structured interview to provide subjects the opportunity to share their 
perspectives on these issues with investigators.  The qualitative interview will be conducted 
after Visit 3 of Treatment Period 4 of 4 (during the follow up phone call) or if the subject is 
withdrawn prior to study completion. 
 
Accelerometer Data Collection (new for amendment 1) 
 
Subjects will wear an accelerometer on their lower leg during each Treatment Period of the  
Treatment Phase.  The accelerometer 
) will measure physical activity 
level outcomes captured during Days 1 (partial), 2 and 3 of the Treatment Phase. 
 
Subjects will wear the accelerometer on the lower leg area (ankle) for each Treatment Period 
without removal except when showering or bathing. The accelerometer cannot be used in 
conjunction with any swimming or watersport activity.  The accelerometer may be removed 
for sleep. The subject may request to use the opposite ankle for placement of the 
accelerometer during the trial. 
 
9.8 
Appropriateness of procedures / measurements 
All efficacy and safety parameters, as well as the methods to measure them, are standard 
variables / methods in clinical studies and / or clinical practice. They are widely used and 
generally recognized as reliable, accurate and relevant. 
 
 
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10. 
Statistical methods and determination of sample size 
10.1 
General considerations 
Statistical analysis will be performed using Statistical Analysis Software (SAS) and the 
version used will be specified in the Statistical Analysis Plan (SAP) and placed on file.  The 
SAP will contain a more comprehensive explanation than described below of the 
methodology used in the statistical analyses.  The SAP will also contain the rules and data 
handling conventions used to perform the analyses, and the procedure used for accounting for 
missing data. 
10.2 
Analysis sets 
Three sets will be identified in this trial.  
Safety Population (Set):  
 
All subjects who take at least one dose of IMP (regardless of their randomization status). 
Safety measures will be analyzed for all subjects in the safety population. 
 
Intent to Treat (ITT) Population (Set):  
 
All randomized subjects who have taken at least one dose of IMP. 
 
Per Protocol (PP) Population (Set): 
 
The Per Protocol set will include all subjects in ITT who do not have any major protocol 
violations that could affect the evaluability of the primary efficacy parameter.  Any exclusion 
from PP Population will be determined and documented prior to the database lock. 
 
The primary efficacy analysis population will be PP population and ITT Population will be 
secondary. The same analysis on ITT Population will be repeated for the primary and 
secondary efficacy endpoints to assess the robustness of the results based on PP Population. 
10.3 
Variables and planned statistical analyses 
10.3.1 
Primary endpoint 
The primary efficacy endpoint is:  
• Sum of change from baseline (Day 1 of the Treatment Period) in BASS score over the 
4 day treatment period  
10.3.2 
Secondary endpoints 
The secondary efficacy endpoints include: 
• Absolute BASS score at each time point 
• Day 4 change from baseline in BASS score 


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10.3.3 
Exploratory endpoints - amendment 1 and 2 
• Day 1 and Day 4 post-STEPP sum of pain intensity difference (SPID) at 4, 6, and 8 
hours post-dose, based on 0-10 NRS; 
• Day 1 and Day 4 post-STEPP sum of pain intensity (SPI) at 4, 6, and 8 hours post-
dose, based on 0-10 NRS; 
• Day 1 and Day 4 post-STEPP pain intensity difference (PID) from baseline at 2, 4, 6 
and 8 hours post-dose, based on 0-10 NRS;   
• Day 1 and Day 4 post-STEPP pain intensity (PI) at 2, 4, 6, and 8 hours post-dose, 
based on 0-10 NRS; 
• Current hourly PI using the 0–10 NRS pre-dose, and from 1 to 8 hours post-dose;   
• Mean change from baseline (Day 1 of the Treatment Period) to end of Treatment 
Period on the Western Ontario and McMaster Universities Arthritis (WOMAC) pain 
subscale, 48-hour recall version, assessed on Day 1 and Day 4; 
• Mean change from baseline to end of treatment period on WOMAC stiffness subscale, 
48-hour recall version, assessed on Day 1 and Day 4; 
• Absolute WOMAC stiffness subscale scores, 48-hour recall version, at each time 
point; 
• Mean change from baseline to end of treatment period on WOMAC function subscale, 
48-hour recall version, assessed on Day 1 and Day 4; 
• Patient Global Impression of Change (PGIC) on Day 4 of each Treatment Period, 
including PGIC for OA Pain (PGIC-P) and PGIC for OA Symptoms (PGIC-S); 
• Subject preference for treatment assessed at the end of the study; 
• Qualitative (semi-structured) interview to assess subjects’ experience with treatments, 
and experience with the STEPP relevance to their disease status, how to improve it, 
etc. (see Section 16.2); 
• Level of activities during Days 1 (partial), 2 and 3 as measured by the accelerometer 
).  
o Number of steps per day 
o Total distance 
o Minutes active vs. inactive per day 
o Percent time in low, medium or high activity 
o Peak performance of the day (30 minutes) 
o Maximum performance (1, 5, 20, 60 minutes) 
o Stride velocity 
o Stride length 
o Cadence 
10.3.4 
Efficacy analysis 
 
 
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10.3.5 
Safety and Tolerability 
AEs will be collected from screening throughout the Treatment Phase and Follow-up Phase 
and will be coded using the Medical Dictionary for Regulatory Activities. Only treatment-
emergent AEs will be included, i.e., AEs that begin or worsen after the first dose of the 
investigational medicinal product (IMP) in the Treatment Phase.  The number and percent of 
subjects who experience any event and the number of events overall, by System Organ Class, 
and by Preferred Term will be displayed by treatment period and treatment group.  Tables will 
also be produced by severity and relationship to each IMP. Seriousness, severity, relationship 
to each IMP duration, and outcome will also be listed. 
Quantitative data for blood pressure, heart rate will be described by summary statistics for the 
original data as well as for the differences to baseline.  Frequency tables will be provided for 
qualitative data. Laboratory data outside the reference range will be listed and highlighted 
with ‘L’ for low and ‘H’ for high. An additional table with all abnormal values will be 
presented. 
Listings of individual subject data (e.g., vital signs) will be provided. 
10.4 
Determination of sample size 
Because there are no reference data on the impact of naproxen, acetaminophen and placebo on 
stiffness with the utilization of the BASS scale, an estimated 50 subjects randomized to 
achieve approximately 40 subjects completing the study are considered adequate for this pilot 
study.  Screening will continue until 50 subjects are randomized in the study. 
10.5 
Planned interim analyses 
No interim analysis is planned for this study. 
 
 
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11. 
Data handling and quality assurance 
11.1 
Data recording - amendment 1 
Data collection and storage 
The data collection tool for this study will be a validated electronic data capture system to be 
used at the study site. Subject data necessary for analysis and reporting will be provided to the 
Sponsor in CDISC (Clinical Data Interchange Standards Consortium) standards. 
Interface to local laboratory 
Laboratory and/or Radiology test results will be received as electronic data files or 
results/reports from the local laboratory. For easy access and tracking by the investigator, the 
results will be additionally provided in printed form. Test results originating directly from the 
site (e.g., urine drug screen) will be entered into the CRF/eCRF data collection system by 
designated site personnel. 
Source documentation 
Entries made in the CRF/eCRF data collection system must be either verifiable against source 
documents, or have been directly entered into the CRF/eCRF data collection system, in which 
case the entry in the CRF/eCRF data collection system will be considered as the source data 
(e.g., time points of blood sampling).  The site has to ensure the availability of all required 
documentation. 
Data recorded from screening failures 
Data of 'only screened subjects' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable.  At minimum, the following data should be 
recorded in the screening log: 
• Demographic information (subject number; year of birth  or age, sex); 
• Date of informed consent; 
• Reason for premature discontinuation; 
• Date of last visit. 
For screening failures with an SAE, the following data should be collected in the CRF/eCRF 
data collection system in addition to the data specified above: 
• All information related to the SAE such as:  
- Concomitant medication 
- Medical history 
- Other information needed for SAE complementary page 
11.2 
Monitoring 
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items. 


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The sponsor/designee will monitor the site activity to verify that the: 
• Data are authentic, accurate and complete.   
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes); 
• Safety and rights of subjects are being protected; 
• Study is conducted in accordance with the currently approved protocol  
(including study treatment being used in accordance with the protocol); 
• Any other study agreements, GCP, and all applicable regulatory requirements are met. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. 
11.3 
Data processing 
Data will be collected as described in Section 11.1.  Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures.  This is applicable for data recorded on the CRF/eCRF data collection system as 
well as for data from other sources (e.g., laboratory, ECG). 
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used. 
11.4 
Missing data  
Reasons for missing data, especially inability to perform a test, must be documented. 
11.5 
Audit and inspection 
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome. 
In addition, inspections by regulatory health authority representatives and IRB(s) are possible.  
The investigator should notify the sponsor immediately of any such inspection. 
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study. 
11.6 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
Study subject files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the study site.  Where the archiving procedures do not 


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meet the minimum timelines required by the sponsor, alternative arrangements must be made 
to ensure the availability of the source documents for the required period. 
The investigator/institution notifies the sponsor if the archival arrangements change (e.g., 
relocation or transfer of ownership). 
The investigator site file is not to be destroyed without the sponsor’s approval. 
The contract with the investigator/institution will contain all regulations relevant for the study 
center. 
 
 


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12. 
Premature termination of the study 
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g., treatment arms; dose steps; centers]) at any time, which may be due but not limited to 
the following reasons:  
• If risk-benefit ratio becomes unacceptable owing to, for example, 
- Safety findings from this study (e.g., SAEs) 
- Results of any interim analysis 
- Results of parallel clinical studies 
- Results of parallel animal studies  
(on e.g., toxicity, teratogenicity, carcinogenicity or reproduction toxicity); 
• If the study conduct (e.g., recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame. 
The investigator has the right to close his/her center at any time. 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing; 
• All affected institutions (e.g., IRB(s); competent authority(ies); study center; head of 
study center) must be informed as applicable according to local law; 
• All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification is given by the sponsor for destruction; 
• In the event of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner. 
Details for individual subject's withdrawal can be found in Section 6.4.1. 
 
 


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13. 
Ethical and legal aspects 
13.1 
Investigator(s) and other study personnel 
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file. 
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site. 
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g., health authority, ethics committee, sponsor) 
before subject recruitment may start at the respective center.  Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center. 
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file. 
The global sponsor of this study is identified on the title page of this protocol.  If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages. 
13.2 
Funding and financial disclosure 
Funding 
This study will be funded by its sponsor. 
Financial disclosure  
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file. 
13.3 
Ethical and legal conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). 
Documented approval from appropriate IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IRB approval 
must be obtained and also forwarded to the sponsor.  The responsible unit (e.g., IRB, head of 


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the study center/medical institution) must supply to the sponsor, upon request, a list of the 
EC/IRB members involved in the vote and a statement to confirm that the IRB is organized 
and operates according to GCP and applicable laws and regulations. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.   
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator. 
Details on discontinuation of the entire study or parts thereof can be found in Section 12. 
13.4 
Subject information and consent 
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center.  A sample 
subject information and informed consent form is provided as a document separate to this 
protocol. 
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject prior to her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms). 
The investigator will also mention that written approval of the IRB has been obtained. 
Each subject will be informed about the following aspects of premature withdrawal: 
• Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision;   
• The subject’s consent covers End of Study tasks as specified in the visit description 
described in Section 9.2.7 to be conducted after withdrawal of consent; 
• The subject’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan; 
• Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g., image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan.  The subject has the right to object to the 
generation and processing of this post-withdrawal data.  For this, he/she needs to sign a 
corresponding declaration of objection; alternatively, the subject’s oral objection may be 
documented in the subject’s source data. 
Each subject will have ample time and opportunity to ask questions. 


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Only if the subject agrees to sign the informed consent form and has done so, may he/she 
enter the study.  Additionally, the investigator will personally sign and date the form.  The 
subject will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the subject’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures. 
The informed consent form and any other written information provided to subjects will be 
revised whenever important new information becomes available that may be relevant to the 
subject’s consent, or there is an amendment to the protocol that necessitates a change to the 
content of the subject information and / or the written informed consent form.  The 
investigator will inform the subject of changes in a timely manner and will ask the subject to 
confirm her participation in the study by signing the revised informed consent form.  Any 
revised written informed consent form and written information must receive the IRB`s 
approval / favorable opinion in advance of use. 
13.5 
Publication policy and use of data 
The sponsor will make the information regarding the study publicly available on the internet 
at www.clinicaltrials.gov as applicable to local regulations. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators. 
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.   
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.   
13.6 
Compensation for health damage of subjects / insurance 
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed. 


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13.7 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the sponsor.  Only the subject numbers (SNR and RNR) 
will be recorded in the CRF/eCRF data collection system, and if the subject name appears on 
any other document (e.g., pathologist report), it must be obliterated before a copy of the 
document is supplied to the sponsor.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  As part of the informed consent process, the 
subjects will be informed in writing that representatives of the sponsor, IRB, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and 
in accordance with local data protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. 
The investigator will maintain a list to enable subjects to be identified. 
 
 


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14. 
Reference list  
 
1. Altman, R. Osteoarthritis (OA). In Merck manual online. Retrieved from 
http://www.merckmanuals.com/home/bone,-joint,-and-muscle-disorders/joint-
disorders/osteoarthritis-%28oa%29 Accessed on April 11, 2016. 
 
2. Centers for Disease Control and Prevention (CDC). Prevalence of doctor diagnosed 
arthritis and arthritis attributable activity limitation—United States, 20072009. Morb 
Mortal Wkly Rep. 2013; 59(39):1261-5. 
 
3. Zhang Y, Jordan, M. Epidemiology of Osteoarthritis. Clin Geriatr Med. 2010; 26(3): 
355-369. 
 
4. Bannuru, R. et al. Comparative Effectiveness of Pharmacologic Interventions for Knee 
Osteoarthritis. Ann Intern Med, 2015; 162:46-54. 
 
5. Altman, R. et al. Three-Month Efficacy and Safety of Acetaminophen Extended-
Release for Osteoarthritis Pain of the Hip or Knee: A Randomized, Double-Blind, 
Placebo-Controlled Study. Osteoarthritis Cartilage. 2007; 15, 454-461. 
 
6. Golden, HE, Moskowitz, RW, and Minic, M. Analgesic efficacy and safety of 
nonprescription doses of naproxen sodium compared with acetaminophen in the 
treatment of osteoarthritis of the knee. Am J Ther. 2004;11:85-94. 
 
7. Schiff, M and Minic, M. Comparison of the analgesic efficacy and safety of 
nonprescription doses of naproxen sodium and Ibuprofen in the treatment of 
osteoarthritis of the knee. Journal of Rheumatology. 2004;31:1373-1383. 
 
8. Cuoto A, Troullos E, Moon J, Paredes-Diaz A.  Analgesic efficacy & safety of 
nonprescription doses of naproxen sodium in the treatment of osteoarthritis of the knee 
or hip.  Osteoarthritis and Cartilage 2017;25 (supplement 1): S420 Abstract #692. 
 
9. Puljak L, Marin A, Vrdoljak D, Markotic F, Utrobicic A, Tugwell P. Celecoxib for 
osteoarthritis. Cochrane Database of Systematic Reviews 2017, Issue 5. Art. No.: 
CD009865. DOI: 10.1002/14651858.CD009865.pub2. 
 
10. Bellamy N, Buchanan W, Goldsmith C, Campbell J, Stitt L. Validation Study of 
WOMAC: A Health Status Instrument for Measuring Clinically Important Patient 
Relevant Outcomes to Antirheumatic Drug Therapy in Patients with Osteoarthritis of 
the Hip or Knee. J Rheumatol. 1988 Dec; 15(12):1833-40. 
 
11. Dixon SJ, Hinman RS, Creaby MW, Kemp G, Crossley KM.  Knee Joint Stiffness 
During Walking in Knee Osteoarthritis. Arthritis Care Res. 2010 Jan 15;62(1):38-44. 
 
12. McAlindon, T. et al. OARSI Guidelines for the Non-Surgical Management of Knee 
Osteoarthritis. Osteoarthritis Cartilage. 2014; 22(3): 363-88. 
 
13. Wolfe F. Pain extent and diagnosis: development and validation of the regional pain 
scale in 12,799 patients with rheumatic disease. J Rheumatol. 2003 Feb;30(2):369-78. 


Clinical Study Protocol 19783 
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Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
 
14. Tonkin-Crine S, Anthierens S, Hood K, Yardley L, Cals JW, Francis NA, Coenen S, 
van der Velden AW, Godycki-Cwirko M, Llor C, Butler CC, Verheij TJ, Goossens H, 
Little P; GRACE INTRO/CHAMP consortium. Discrepancies between qualitative and  
quantitative evaluation of randomised controlled trial results: achieving clarity through 
mixed methods triangulation. Implement Sci. 2016 May 12;11:66. 
 
15. Richards DA, Ross S, Robens S, Borglin G. The DiReCT study-improving 
recruitment into clinical trials: a mixed methods study investigating the ethical 
acceptability, feasibility and recruitment yield of the cohort multiple randomised 
controlled trials design. Trials. 2014 Oct 16;15:398. 
 
16. O'Cathain A, Thomas KJ, Drabble SJ, Rudolph A, Goode J, Hewison J. Maximising  
the value of combining qualitative research and randomised controlled trials in health 
research: the QUAlitative Research in Trials (QUART) study-a mixed methods study. 
Health Technol Assess. 2014 Jun;18(38):1-197, v-vi. 
 
 
 
 


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15. 
Protocol amendments 
15.1 
Amendment 2 (11-Sep-2018) 
15.1.1 
Overview of changes to the study 
The protocol was amended from version 2.0 to modify I/E critiera, screening and 
randomization requirements to enhance recruitment.  Other changes include removing the 
Investigator signature page and updating the WOMAC NRS to the licensed version. 
The following sections have been modified for Amendment 2: 
• Section 2.0 (Synopsis, Inclusion/Exclusion Criteria only) 
• Section 5.1 (Design Overview) 
• Section 5.3 (Selection of Study Population) 
• Figure 1 (Design Overview) 
• Section 6.1 (Inclusion Criteria) 
• Section 9.2.1 (Screening Phase Visit 1) 
• Section 9.2.3 (Visit 2) 
• Section 9.2.5 (Visit 3) 
• Section 9.4.3 (Exploratory efficacy endpoints) 
• Section 9.7 (Other procedures and variables) 
• Section 10.3.3 (Exploratory endpoints) 
• Section 16.1 (Study Flow Chart) 
• WOMAC Osteoarthritis Index NRS 3.1 
15.1.2 
Changes to the protocol text 
Section 2.0 (Synopsis, Inclusion/Exclusion Criteria only) 
Changes are identified in Sections 6.1 and 6.2 of the amendment. 
Section 5.1 (Design Overview) 
Screening Phase Visit 1 - (Day -18 to -5) 
The target knee will need to be identified per inclusion criteria (exam, radiographs and pain 
scores). In addition, the subject must have an average score of ≥43.0 on the WOMAC pain 
subscale (0-10 numeric rating scale [NRS] 2448-hour recall version) at Screening, AND/OR a 
24-hour Average Pain Intensity score of ≥43 on the 0-10 NRS and a Joint Stiffness Severity 
score ≥3 on a 0-10 NRS.   
Start of Treatment Period X of 4 - Visit 2 (Day 1) 
Subjects will return to the study center upon completion of the Screening Washout Phase or 
between-treatment Washout Period.  To be eligible for randomization prior to Treatment 
Period 1, subjects must meet the following randomization criteria: self-reported average score 
of ≥54 on the WOMAC pain subscale (0-10 NRS, 2448-hour recall version) related to OA 
pain in the target knee; current pain intensity score of ≥4 and ≤9 on the 0-10 NRS; and, a 
score of ≥54 on the 0-10 NRS for average pain over the past 24-hours.  In addition, the Day 1 
baseline post-STEPP current pain intensity 0-10 NRS score must be ≥65, and ≥1 unit higher 
than the pre-STEPP current pain intensity 0-10 NRS score. 


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Section 5.3 (Selection of Study Population) 
All male and female potential subjects 40 to 75 80 years of age with OA of the knee who 
would typically take OTC NSAIDs for pain relief may be eligible to participate in the study 
provided they meet inclusion/exclusion criteria. 
Figure 1 (Design Overview) 
Start of Treatment Period, Visit 2, Day 1 
WOMAC 
 
24-hour 
 
Post STEPP      
Pain ≥54 
 
average 
 
pain ≥65 and 
 
 
 
pain ≥54 
 
≥1 unit higher 
 
 
 
 
 
 
than pre-  
STEPP pain            
(0-10 NRS) 
 
Section 6.1 (Inclusion Criteria) 
2.  Ambulatory (as deemed appropriate by the Investigator) male and female subjects between    
40 and 7580 years of age; 
3.  Body Mass Index (BMI) between 18-35to <40 kg/m2; 
 
For Randomization: 
10.  48-hour WOMAC pain subscale average score ≥3.0 and/or 24-hour Average Pain 
Intensity score ≥3 on the 0-10 NRS at Screening; 
11.  2448-hour WOMAC pain subscale average score ≥43.0 at Screening and ≥54.0 at Visit 2, 
Treatment Period 1 of 4; 
12.  24-hour Average Pain Intensity score ≥43 on the 0-10 NRS at Screening and ≥54 at Visit 2, 
Treatment Period 1 of 4; 
14.  A Day 1 baseline post-STEPP current pain intensity score ≥65, and ≥1 unit higher than 
the pre-STEPP current pain score on the 0-10 NRS; 
 
Section 9.2.1 (Screening Phase Visit 1) 
• 2448-hour recall WOMAC subscales for stiffness, physical function and pain 
questionnaire to establish the target knee; 
To qualify for randomization (Day 1), subjects must have either an average score ≥3.0 
on the 48-hour WOMAC pain subscale OR score ≥3.0 on the 24-hour Average Pain 
Intensity Scale. 
 
Section 9.2.3 (Visit 2) 
• 2448-hour recall WOMAC (0-10 NRS version) subscales for stiffness, physical 
function and pain questionnaires; 
 
Randomization Criteria:  
Subjects must self-report the following pain ratings in order to be randomized and start 
Treatment Period 1 of 4: 


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• An average score of ≥54.0 on WOMAC pain subscale summation score (0-10 NRS, 
2448-hour recall version); 
• 24-hour Average Pain Intensity score of ≥54 on the 0-10 NRS; 
• Day 1 baseline post -STEPP current pain intensity score ≥65 and ≥1 unit higher than 
the pre-STEPP current pain intensity score on the 0-10 NRS. 
 
Section 9.2.5 (Visit 3) 
 
• 2448-hour recall WOMAC  (0-10 NRS version) subscales for stiffness, physical 
function and pain questionnaires; Adverse Event assessment. 
 
Section 9.4.3 (Exploratory efficacy endpoints) 
• Mean change from baseline (Day 1 of the Treatment Period) to end of Treatment 
Period on the Western Ontario and McMaster Universities Arthritis (WOMAC) pain 
subscale, 2448-hour recall version, assessed on Day 1 and Day 4, including an 
assessment of all key pairwise comparisons; 
• Mean change from baseline to end of treatment period on WOMAC stiffness subscale, 
2448-hour recall version, assessed on Day 1 and Day 4, including an assessment of all 
key pairwise comparisons; 
• Absolute WOMAC stiffness subscale scores, 2448-hour recall version, for each study 
treatment at each time point; 
• Physical activity level outcomes during Days 1 (partial), 2 and 3 as measured by the 
accelerometer; 
• Change from baseline to end of treatment period on WOMAC function subscale, 
2448-hour recall version, assessed on Day 1 and Day 4, including an assessment of all 
key pairwise comparisons; 
 
Section 9.7 (Other procedures and variables) 
 
WOMAC (0-10 NRS version; version 3.1) 
WOMAC Pain, Stiffness and Physical Function subscales (0-10 NRS, 2448-hour recall 
version) will be measured at the Screening Visit, and Visits 2 and 3 of each Treatment Phase. 
Section 10.3.3 (Exploratory endpoints) 
• Mean change from baseline (Day 1 of the Treatment Period) to end of Treatment 
Period on the Western Ontario and McMaster Universities Arthritis (WOMAC) pain 
subscale, 2448-hour recall version, assessed on Day 1 and Day 4; 
• Mean change from baseline to end of treatment period on WOMAC stiffness subscale, 
2448-hour recall version, assessed on Day 1 and Day 4; 
• Absolute WOMAC stiffness subscale scores, 2448-hour recall version, at each time 
point; 
• Mean change from baseline to end of treatment period on WOMAC function subscale, 
2448-hour recall version, assessed on Day 1 and Day 4; 


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Section 16.1 (Study Flow Chart) 
The table was amended to correctly reflect the WOMAC under Trial Procedures. 
2448 hour WOMAC Pain 
2448 hour WOMAC Stiffness 
2448 hour WOMAC Function 
 
footnote b - WOMAC pain subscale average score must be ≥54.0 on 0-10 scale to be eligible 
for Randomization on Day 1 of Treatment Period 1 of 4 
 
 
 
 WOMAC Osteoarthritis Index NRS 3.1 
 
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)                
(0-10 NRS, 2448-hour recall version) - amendment 2 
Examples only and not representative of the licensed version. 
 
The licensed version was copied into the protocol. 
 
15.2 
Amendment 1 (13-Apr-2018) 
15.2.1 
Overview of changes to the study 
The protocol was amended from version 1.0 to include the use of accelerometers.  These 
devices will be worn by each subject starting at the conclusion of Visit 2 (Day 1) after 8 hours 
of study procedures and for all awake times for Days 2 and 3 of the Treatment Phase.  The 
data from the accelerometer will be downloaded at the completion of each Visit 3.  The 
purpose is to collect data regarding activity levels in a treatment scenario that could be used to 
further investigate in future studies with naproxen.  Additional changes to the protocol are 
moving the Qualitative Interview from Visit 3 of Treatment Period 4 to the follow up phone 
call or if the subject withdraws from the study prior to completing Visit 3 of Treatment Period 
4.  Safety labs were added to the Screening Visit.  Other changes constituted text changes to 
clarify inclusion/exclusion criteria, prohibited medications as well as minor text changes in 
other sections of the protocol. 
The following sections have been modified for Amendment 1: 
• Section 2.0 (Synopsis, Inclusion/Exclusion Criteria only) 
• List of Abbreviations 
• Section 4.0 (Study Objectives) 
• Section 5.1 (Design Overview) 
• Section 5.3 (Selection of Study Population) 
• Figure 1 (Design Overview) 
• Section 6.1 (Inclusion Criteria) 
• Section 6.2 (Exclusion Criteria) 
• Section 7.1 (Treatments to be Administered) 
• Section 7.3 (Treatment Assignment) 


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• Section 7.6 (Drug Logistics and accountability) 
• Section 8.1 (Prior and Concomitant Therapy) 
• Section 9.2.1 (Screening Phase Visit 1) 
• Section 9.2.3 (Visit 2) 
• Section 9.2.4 (Day 2 and 3) 
• Section 9.2.5 (Visit 3, Day 4, End of Treatment Period X of 4) 
• Section 9.2.7 (Visit 3, Day 4, End of Treatment Period 4 or 4) 
• Section 9.2.8 (End of Study) 
• Section 9.2.9 (Rescue Therapy) 
• Section 9.4.3 (Exploratory Endpoints) 
• Section 9.4.4 (Safety Analysis) 
• Section 9.6.3 (Safety Examinations) 
• Section 9.7 (Other Procedures and Variables) 
• Section 10.3.3 (Exploratory Endpoints) 
• Section 11.1 (Data Recording) 
• Section 15 (Protocol Amendments) 
• Section 16.1 (Study Flow Chart) 
• Section 16.2 (Subjective Assessments) 
 
15.2.2 
Changes to the protocol text 
List of Abbreviations  
The following abbreviations were added to the table: 
ALT Alanine Aminotransferase 
AP 
Anteroposterior 
AST 
Aspartate Aminotransferase 
BUN Blood Urea Nitrogen 
Ca 
Calcium 
Cl 
Chloride 
CO2 
Carbon Dioxide 
eGFR Estimated Glomerular Filtration Rate 
K 
Potassium 
Na 
Sodium 
PA 
Posteroanterior 
RBC Red Blood Cell 
WBC White Blood Cell 
 


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Section 2.0 (Synopsis, Inclusion/Exclusion Criteria only) 
Changes are identified in Sections 6.1 and 6.2 of the amendment. 
 
Section 4.0 (Study Objectives) 
Exploratory 
• To determine/identify effect size measurements, determine single dose vs. multi-dose 
efficacy, identify optimal sample size, and logistical issues for planning comparative 
analgesic efficacy studies using the STEPP. 
• To assess levels of activity captured by the accelerometer between active 
treatments and placebo during Days 1 (partial), 2 and 3 of the Treatment Phase. 
• To evaluate the safety and tolerability of naproxen sodium, celecoxib and 
acetaminophen ER. 
Section 5.1 (Design Overview) 
Screening Phase Visit 1 - (Day -18 to -5) 
In addition, the subject must have an average score of ≥4.0 on the WOMAC pain subscale (0-
10 numeric rating scale [NRS] 24-hour recall version) at Screening, a 24-hour Average Pain 
Intensity score of ≥4 on the 0-10 NRS and a Joint Stiffness Severity score ≥43 on a 0-10 NRS. 
Start of Treatment Period X of 4 - Visit 2 (Day 1) 
During the completion of Visit 2, subjects will be fitted with an accelerometer to 
measure the number of steps taken and level of activity (e.g., low, medium, high).  
Accelerometer data collection will start after completion of the Day 1 activities prior to 
leaving the study site.  
 
Day 2 and Day 3 
Subjects will continue to take their IMP as directed for a total of 4 doses per day.  Subjects 
will continue to wear their accelerometer except when showering or bathing. 
End of Treatment Period X of 4 - Visit 3 (Day 4) 
Subjects will return to the study center wearing their accelerometer.  They must bring their 
diary and treatment kit with remaining study medication.  The accelerometer will be 
removed at the study site prior to the pre-dose STEPP. 
End of Treatment Period X of 4 - Visit 3 (Day 4) 
Subjects will return to the study center wearing their accelerometer.  They must bring their 
diary and treatment kit with remaining study medication.  The accelerometer will be 
removed at the study site prior to the pre-dose STEPP.   
End of Study (follow up) – after Visit 3, Treatment Period 4 of 4 
Subjects will receive a follow up phone call to assess adverse events and document any new 
concomitant medications.  Additionally, subjects will participate in a semi-structured 
qualitative interview about their experiences in the clinical trial.  Upon completion of all 
trial procedures, subjects will be discharged from the study. 
 


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Figure 1 (Design Overview) 
The addition of accelerometer use on Visit 1, Day 1 and Days 2 and 3 of the Treatment Phase.  
The Qualitative Interview was moved from Visit 3 to the Follow up Phase.   
Footnote a - After Treatment period 4 of 4 only or if the subject is withdrawn from the 
study prior to completion 
 
Section 5.3 (Selection of Study Population) 
Accurate Pain Reporting Training 
Staff training is conducted prior to the first subject visit. Subjects receive training at the 
Screening Visit, and at on Day 1 of each of the four Treatment Periods.  The training video 
takes approximately 30 minutes and should be completed prior to pain assessments. 
 
Appropriate Expectations Training 
Subjects receive training at the Screening Visit, and at on Day 1 of each of the four Treatment 
Periods.  The training video takes approximately 30 minutes and should be completed 
prior to pain assessments. 
 
Section 6.1 (Inclusion Criteria) 
8. Female subjects of childbearing potential must be using a medically acceptable form 
of birth control for at least 1 month prior to screening (or 3 months if using oral 
contraceptives) [e.g., hormonal contraceptives (oral, patch, injectable or vaginal ring), 
implantable device (implantable rod or intrauterine device), or a double barrier], or 
in same sex relationship and have a negative pregnancy test at Screening and prior to 
study drug administration.  Female subjects of non-childbearing potential must be 
amenorrheic for at least two years or have undergone surgical sterilization (e.g., 
hysterectomy and/or bilateral oophorectomy); 
9. Willing to wear an accelerometer during each Treatment Period of the Treatment 
Phase.  Subjects who decline to wear the accelerometer are still eligible for study 
participation provided they meet all other required criteria. 
 
Section 6.2 (Exclusion Criteria) 
3. Recent injury in the OA affected knee (past 4 months); oral, intra-muscular, intravenous 
or intra-articular corticosteroid,  platelet rich plasma intraarticular knee injections, 
stem cell therapy or hyaluronic acid injections in either knee within the last 3 months; 
5. Use of any pain medications from the start of the Baseline Screening/Washout Phase 
through trial completion, other than IMP provided by the Sponsor or Rescue Pain 
medication provided by the study site; 
9. Initiating any new physical therapy for the lower extremities from 4 weeks prior to 
study start through the duration of the study; 
10.Positive urine drug test for illegal drug substances, non-prescribed controlled substances, 
or breath/saliva alcohol at screening or Visit 2; 


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  Note: prescribed marijuana is allowed provided the subject is willing to wash out and 
not use during the study. 
11.Subject has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≥2 times the upper limit of normal; 
12.Subject has a hemoglobin <10.0 g/dL; 
13.Subject has an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²; 
15.Kellgren and Lawrence grade of 0, I or IV in the target knee (see Section 16.2); 
23.Recent (within the past 1 year) MI or in the peri-operative period  surrounding coronary 
artery bypass graft (CABG) surgery; 
 
Section 7.1 (Treatments to be Administered) 
Note: Number of doses per day are approximate based on subject’s dosing times 
provided the subject doses within the window for each listed time, they will be 
considered to have met protocol requriements. 
 
Section 7.3 (Treatment Assignment) 
Whereas the “Xs” will be replaced with a four digit sequentially assigned number as each 
subject enters the study (e.g., first subject number of the study will be
). 
• Treatment D: Placebo (eight tablets of placebo daily); On Days 1, 2 and 3, first dose of 
two tablets of placebo in the morning at 8:00 AM ± 1 hour followed by two tablets of 
placebo 8 hours later at 4:00 PM ± 1 hour followed by two tablets of placebo 4 hours 
later at 8 PM ± 1 hour followed by two tablets of placebo 8 hours later at 12AM ± 1 
hour. 
Note:  The Day 4 treatment is only a single morning (8 AM) two tablet/capsule dose similar 
to the morning dosing for Days 1-3. 
 
Section 7.6 (Drug Logistics and accountability) 
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate/CRO), and will be inaccessible to unauthorized personnel. 
 
Section 8.1 (Prior and Concomitant Therapy) 
The following treatments are prohibited:  
• Use of any pain medications from the start of the Screening Washout Phase 
through trial completion, other than IMP provided by the Sponsor and rescue pain 
medication provided by the study site  This includes medications such as 
gabapentin, cannabidiol etc. if prescribed to the subject for the purpose of 
pain control; 
• Taking more than one antidepressant. Subjects who are on a stable dose of one 
antidepressant, for at least 1 month, are eligible for enrollment; 
PPD


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• Taking more than one anxiolytic medication. Subjects who are on a stable regimen 
of one anxiolytic for at least 1 month, are eligible for enrollment; 
• Fish oil (supplements are permitted if the dose is stable for at least 4 weeks). 
From 4 days prior to randomization until the completion of the Treatment Phase (Treatment 
Period 4 of 4), subjects are not allowed to take pain treatments (including supplements and/or 
topicals) other than the provided trial treatment (IMP and rescue therapy).  Prohibited 
treatements include: 
• Topical capsaicin, NSAIDs, lidocaine, and cannabidiol oil; 
• Glucosamine-chondroitin and turmeric (curcumin); 
• Supplements intended for pain relief. 
If the subject uses an excluded/prohibited medication (analgesic or other medication) 
after being enrolled into the study, the investigator will use his/her judgement to 
determine  whether the subject is able to continue however, the subject must be 
discontinued if safety is concerned.  In other cases, the subject may be able to continue if 
the concomitant medication is for short term use and/or is not likely to conflict with the 
study objectives in subsequent Treatment Periods. 
 
Section 9.2.1 (Screening Phase Visit 1) 
The Screening Phase will be up to 14 days long.  The following will be conducted during the 
Screening Visit: 
• Signed Informed Consent; 
• Review Inclusion and Exclusion Criteria; 
• Subject demographics; 
• Medical history; 
• Medication history of all prescription and over-the-counter drugs and other products 
(including topicals, herbal products, vitamins and nutritional supplements) and 
investigational drugs, taken within 30 days prior to screening; 
• Alcohol breath/saliva test; 
• Urine drug screen; 
• Urine pregnancy test for female subjects of child bearing potential; 
• Blood and urine specimens for safety laboratory tests (hematology, chemistry 
and urinalysis); 
• History of drug, alcohol and tobacco use; 
• Height, weight, and Body Mass Index (BMI); 
• Physical examination; 
• OA assessment of the each potentially qualifying  knee using ACR criteria; 
• Radiograph of the target each potentially qualifying  knee (anterioposterior [AP] or 
posteroanterior [PA] and lateral projections); 
Note: A historical knee radiograph could be used provided the images were taken 
within the previous 1 year and can be digitally exported to a central reading lab and are 
of diagnostic quality. 
• Baseline Stiffness Questionnaire of each knee; 
• Joint Stiffness Severity rating of each knee; 
• Regional Pain Scale (13); 


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• Alcohol breath/saliva test; 
• Urine drug screen; 
• Urine pregnancy test for female subjects of child bearing potential; 
• Vital signs (blood pressure, heart rate, respiratory rate and body temperature after 5 
minutes in a sitting position); 
This includes the radiographic interpretation of the knee radiographs using the Kellgren and 
Lawrence scale as well as safety laboratory values.  Subjects will be reminded once 
screening criteria have been met, to discontinue use of all pain medications, including 
topicals, and supplements until they return for Visit 2.  Subjects can take acetaminophen (up 
to 2000 mg/day), for knee pain but not within 24 hours of the Randomization visit. 
An external centralized vendor chosen by the sponsor will read/ interpret the knee radiographs 
and communicate the findings to the study center.  Subjects that do not meet qualification 
after leaving the test site at Visit 1, will not be required to return their paper diary. 
 
Section 9.2.3 (Visit 2) 
Visit 2 will occur 4 to 7 days after starting the Screening Washout Phase (within 21 days of 
the initial screening visit).  The following activities will be completed: 
• Review inclusion and exclusion criteria; 
• Concomitant medication review; 
• Review changes in the subject’s medical/medication history since previous visit; 
• Vital signs (blood pressure and heart rate after 5 minutes in a sitting position); 
• Accurate Pain Reporting Training; 
• Appropriate Expectations Training; 
 
Subjects will be reminded of their selected wake up time and encouraged to keep this 
schedule for the duration of the trial.  Subjects will be fitted with an accelerometer on their 
lower leg (ankle) area on Day 1, directly after completion of the 8 hour activities.  
Subjects will wear the accelerometer at the completion of the clinic visit.  Subjects will 
be trained to wear the accelerometer during the treatment periods.  Subjects will be 
scheduled for Visit 3 and reminded to bring their diary, and treatment kit for review and wear 
their accelerometer which will be removed at the study site prior to performing any 
study related procedures. 
 
Note: subjects will wear the accelerometer on the ankle for Days 1 (at the conclusion of 
the clinic visit), 2 and 3 of each Treatment Period without removal except when 
showering or bathing. The accelerometer cannot be used in conjunction with any 
swimming or watersport activity.  The accelerometer may be removed for sleep. The 
subject may request to use the opposite ankle for placement of the accelerometer during 
the trial. 
 
Section 9.2.4 (Day 2 and 3) 
Subjects will follow the dosing instructions provided for the remaining doses to be taken each 
day.  Subjects will continue to wear their accelerometer as instructed. 
 
 


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Section 9.2.5 (Visit 3, Day 4, End of Treatment Period X of 4) 
Subjects will return to the study center (wearing their accelerometer) for final assessments 
of the Treatment Period (X of 4).  Subjects must take the morning (approximately 8 AM) dose 
of study medication at the study center.  The following activities will be performed prior to 
dosing: 
• Review inclusion and exclusion criteria; 
• Concomitant medication review; 
• Remove accelerometer from subject (prior to pre-dose STEPP); 
• Accelerometer data download and battery charging (~1 hour); 
• Vital signs (blood pressure, heart rate, after 5 minutes in a sitting position); 
 
In addition, subjects will self-report the current pain intensity of their target knee on the 0-10 
NRS at post-dose hours 1, 3, 5, and 7. 
 
• Approximately 8 hours after dosing, prior to leaving the study center on Day 4 of each 
Treatment Period, subjects will complete two Patient Global Impression of Change 
(PGIC) scales: the PGIC for OA Pain, and the PGIC for OA Symptoms 
 
Upon completion of data download and re-charge (~1 hour), the accelerometer will be 
stored at the clinic until the next Visit 2 of the next Treatment Period occurs. 
Section 9.2.7 (Visit 3, Day 4, End of Treatment Period 4 or 4) 
Subjects will complete the Treatment Preference rating and participate in a semi-structured 
qualitative interview about their experiences in the clinical trial (see Section 16.2).  The 
accelerometer will be removed from the subject and the data downloaded. 
 
Section 9.2.8 (End of Study) 
At the completion of the final treatment/visit in the sequence (4 of 4) or if the subject 
withdraws prior to the last treatment visit, subjects will receive a phone call from the study 
site to review concomitant medications and assess adverse events.  Additionally, subjects 
will participate in a semi-structured qualitative interview about their experiences in the 
clinical trial (see Section 16.2). 
 
Section 9.2.9 (Rescue Therapy) 
Rescue therapy is not allowed 24 hours prior to Day 1 pre-treatment assessments and it is 
not allowed from Day 1 through Day 4 assessments of each Treatment Period. 
Subjects will be queried in a nonspecific fashion for any adverse events (e.g., “Have you had 
any changes in health?”).  Any reported AEs will be collected and recorded on the CRF/e-
CRF data collection system. 
 
Section 9.4.3 (Exploratory Endpoints) 
• Physical activity level outcomes during Days 1 (partial), 2 and 3 as measured by 
the accelerometer; 


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• Mean change Change from baseline to end of treatment period on WOMAC function 
subscale, 24-hour recall version, assessed on Day 1 and Day 4, including an 
assessment of all key pairwise comparisons; 
 
Section 9.4.4 (Safety Analysis) 
The following laboratory tests will be performed at screening: 
• Hematology  (Hemoglobin, Hematocrit, RBC count, Platelet count, WBC count), 
• Serum Chemistry (BUN, Creatinine, Glucose, Ca++, Na+, K+, Cl-, Total CO2 
(Bicarbonate), AST, ALT, Total Bilirubin, Alkaline phosphatase, Albumin, Total 
protein )  
• Urinalysis (Specific gravity, pH, Glucose (qual), Protein (qual), Blood (qual), 
Ketones, Leukocyte Esterase, Nitrite, Bilirubin, Urobilinogen) 
Safety measures will be analyzed for all subjects in the safety population.  
  
Section 9.6.3 (Safety Examinations) 
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician (or appropriately licensened designee) at the study site covering at least the 
organs of the cardiovascular, respiratory, and abdominal systems. 
Urine samples will be collected to assess for illicit drugs at Screening Visit 1 and Visit 2.  
Safety laboratory examination will collected at Screening. 
 
Table 4: Safety laboratory evaluations 
 
Section 9.7 (Other Procedures and Variables) 
The qualitative interview will be conducted at after Visit 3 of Treatment Period 4 of 4 
(during the follow up phone call) or if the subject is withdrawn prior to study 
completion. 
Accelerometer Data Collection (new for amendment 1) 
Hematology 
Hemoglobin, Hematocrit, RBC count, 
Platelet count, WBC count 
Chemistry 
BUN, Creatinine, Glucose, Ca++, Na+, K+, 
Cl-, Total CO2 (Bicarbonate), AST, ALT, 
Total Bilirubin, Alkaline phosphatase, 
Albumin, Total protein 
Urinalysis 
Specific gravity, pH, Glucose (qual), Protein 
(qual), Blood (qual), Ketones, Leukocyte 
Esterase, Nitrite, Bilirubin, Urobilinogen 


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Subjects will wear an accelerometer on their lower leg during each Treatment Period of 
the  Treatment Phase.  The accelerometer 
) will measure physical 
activity level outcomes captured during Days 1 (partial), 2 and 3 of the Treatment 
Phase. 
Subjects will wear the accelerometer on the lower leg area (ankle) for each Treatment 
Period without removal except when showering or bathing. The accelerometer cannot be 
used in conjunction with any swimming or watersport activity.  The accelerometer may 
be removed for sleep. The subject may request to use the opposite ankle for placement of 
the accelerometer during the trial. 
 
Section 10.3.3 (Exploratory Endpoints) 
• Qualitative (semi-structured) interview to assess subjects’ experience with treatments, 
and experience with the STEPP relevance to their disease status, how to improve it, 
etc. (see Section 16.2); 
• Level of activities during Days 1 (partial), 2 and 3 as measured by the 
accelerometer
).  
o Number of steps per day 
o Total distance 
o Minutes active vs. inactive per day 
o Percent time in low, medium or high activity 
o Peak performance of the day (30 minutes) 
o Maximum performance (1, 5, 20, 60 minutes) 
o Stride velocity 
o Stride length 
o Cadence 
 
Section 11.1 (Data Recording) 
Laboratory and/or Radiology test results will be received as electronic data files or 
results/reports from the local laboratory. They will be transferred to the clinical study 
database at the study site. For easy access and tracking by the investigator, the results will be 
additionally provided in printed form. 
 
Section 16.1 (Study Flow Chart) 
The table was amended to include Clinical Laboratory Testing at the Screening Visit, 
Accelerometer setup, use, data download  and battery charging.  The Qualitative Interview 
was moved from Visit 3 to the Follow up phone call. 
Footnote i - Completed atafter Visit 3, Treatment Period 4 of 4 only or if the subject is 
withdrawn prior to completion 
 
 
 
 
CCI
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Section 16.2 (Subjective Assessments) 
0-10 Point Numerical Rating Scale (NRS) 
Location (check one) 
 
 Left Knee  Right Knee 
 
Qualitative Interview 
The qualitative interview will consist of a series of open-ended questions administered by a 
trained interviewer in one-on-one interviews with study subjects during the follow up phone 
call at the conclusion of Treatment 4 of 4or if withdrawn prior to completion. The primary 
purpose of the qualitative interview is to provide additional data to augment the quantitative 
data collected from instruments such as the BASS, WOMAC, and NRS.   
The qualitative interview will take approximately 30-60 minutes to complete, and will consist 
of 15-20 approximately 30 questions designed to collect information about: 1) subjects’ 
experiences on the study treatments, to determine if there are any advantages of naproxen 
sodium (Aleve) that were not discovered using the quantitative instruments; 2) subjects’ 
experiences with the STEPP, to determine if the procedure can be optimized to elicit OA pain 
and stiffness to a greater degree, which would increase assay sensitivity in trials of new 
treatments for pain due to OA of the knee; and, 3) subjects’ perspectives on factors to 
optimize recruitment and retention in future OA studies conducted by Bayer. 
 
 
 
 


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16. 
Appendices 
16.1 
Study Flow Chart - amendment 1 and 2 
Table 5: Study schema 
Trial Procedure 
Visit 1 
Screening 
Screening 
Washout 
Phase 
Treatment Phase 
These events are repeated during each of the 4 Treatment Periods. 
Treatment Periods will be separated by a washout of 3 to 7 days 
End of 
Study 
(Phone call) 
Visit 2 
Start of               
Treatment Period 
Continue 
Treatment 
Period 
Outpatient  
Visit 3 
End of                     
Treatment Period 
 
Day -18 
to -5 
Day -4   
to -1       
(+3 d) 
Day 1 
2, 4, 6, 8 hrs 
Day 2-3 
Day 4 
2, 4, 6 hrs 
8 hrs 
7-10 days 
after 
Treatment 
Period 4 of 4 
Signed Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria review 
X 
 
X 
 
 
X 
 
 
 
Subject demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Prior/Concomitant medications 
X 
 
X 
 
 
X 
 
 
X 
History of drug, alcohol and tobacco 
use 
X 
 
 
 
 
 
 
 
 
Body weight, height and BMI 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
OA assessment of the knee 
(includes radiograph) 
X 
 
 
 
 
 
 
 
 
Vital signsa 
X 
 
X 
 
 
X 
 
 
 
Clinical Laboratory Tests        
(hematology, chemistry, urinalysis) 
X 
 
 
 
 
 
 
 
 
Alcohol breath/saliva test 
X 
 
X 
 
 
 
 
 
 
Urine drug screen 
X 
 
X 
 
 
 
 
 
 
Urine pregnancy test (if applicable) 
X 
 
X 
 
 
 
 
 
 
Accurate pain reporting training 
X 
 
X 
 
 
 
 
 
 
Appropriate expectations training 
X 
 
X 
 
 
 
 
 
 
Regional Pain Scale 
X 
 
 
 
 
 
 
 
 
48 hour WOMAC Pain 
X 
 
Xb 
 
 
X 
 
 
 
48 hour WOMAC Stiffness 
X 
 
X 
 
 
X 
 
 
 
48 hour WOMAC Function 
X 
 
X 
 
 
X 
 
 
 
24 hour Average Pain Intensity NRS 
X 
 
X 
 
 
X 
 
 
 
Baseline Stiffness questionnaire 
X 
 
 
 
 
 
 
 
 
Joint Stiffness Severity NRS 
X 
 
 
 
 
 
 
 
 
Washout from analgesic medications 
 
X 
 
 
 
 
 
Xd 
 
Daily BASS  
 
 
X 
 
X 
X 
 
 
 
Accelerometer Setup 
 
 
 
X 
 
 
 
 
 
Accelerometer Use 
 
 
 
X 
X 
 
 
 
 
Accelerometer Data Download 
 
 
 
 
 
X 
 
 
 
Accelerometer Battery Charge 
 
 
 
 
 
X 
 
 
 
Current Pain Intensity NRS 
 
 
Xe 
 
 
Xe 
 
 
 
STEPP 10 point pain NRS 
Xc  
 
Xf 
Xf 
 
Xf 
Xf 
Xf 
 
Randomization 
 
 
Xg 
 
 
 
 
 
 
IMP self-administration   
 
 
X 
 
X 
Xh 
 
 
 
IMP compliance review 
 
 
X 
 
 
X 
 
 
 
Patient Global Impression of Change 
 
 
 
 
 
 
 
X 
 
Subject treatment preference 
 
 
 
 
 
 
 
Xi 
 
Qualitative interview 
 
 
 
 
 
 
 
 
Xi 
Adverse events 
 
 
X  
X 
X 
X 
X 
X 
X 
a Vital signs (blood pressure, respiratory rate, heart rate and body temperature after 5 minutes of rest in a sitting position). After the screening assessment, vital 
signs assessments will consist of heart rate and blood pressure 
b WOMAC pain subscale average score must be ≥4.0 on 0-10 scale to be eligible for Randomization on Day 1 of Treatment Period 1 of 4 
c Screening STEPP is to confirm subject is capable of performing the exercise and completing the pre-STEPP and post-STEPP NRS 


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d A washout period of 3 to 7 days will occur at the start of Treatment Periods: 2 of 4, 3 of 4, and 4 of 4. During each washout, only acetaminophen will be allowed 
as rescue therapy (as needed up to 2000 mg/day) 
e Current pain intensity performed immediately prior to the pre-dose STEPP and hourly at 1, 3, 5 and 7 hours after dosing 
f Subjects will complete the 0-10-point NRS pain scale pre-dose (time 0) and immediately before (at rest) and then 2-5 minutes after completing the STEPP at 2, 4, 
6 and 8 hours post-dose.  Additionally, subjects will complete hourly current pain intensity rating 1, 3, 5, and 7 hours post-dose when not completing the STEPP 
g Subjects will be randomized to a treatment sequence at Treatment Period 1 of 4 
h  Subjects will only take the 8 AM dose that day 
i Completed after Visit 3, Treatment Period 4 of 4 or if the subject is withdrawn prior to completion  
 
 


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16.2 Subjective Assessments - amendment 1 and 2 
Regional Pain Scale 
 
Please indicate below the amount of pain and/or tenderness you have had over THE PAST 7 
DAYS in each of the joint and body areas listed below. Please make an X in the box that best 
describes your pain or tenderness. Be sure to mark both right side and left side separately. If 
you have had no pain or tenderness in a particular joint or body part, mark "None." There 
should be an answer for every joint or body part listed. (13) 
  
 


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Baseline Stiffness Questionnaire 
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Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
0-10 Point Numerical Rating Scale (NRS) 
 
 
Location (check one) 
 
 
 Left Knee 
 Right Knee 
 
Current Pain Assessment 
 
How would you rate the pain in your KNEE right now? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No  
pain 
 
Worst 
possible 
pain 
 
 
 
 
Average Pain Intensity 
 
How would you rate the average pain in your KNEE over the last 24 hours? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No  
pain 
 
Worst 
possible 
pain 
 
 
 
 


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Patient Global Impression of Change – Pain and Symptoms Due to OA of the Knee 
PGIC in PAIN (PGIC-P): 
Completed at the end of Day 4 of each Treatment Period: 
√ (Check) the box you feel most closely describes how the pain in your knee has changed since you 
began this four-day treatment period. Please rate only your pain and not any other symptoms related to 
your index knee. 
Choose only ONE response. 
Very Much Better  
Much Better  
  
Minimally Better  
  
No Change  
Minimally Worse  
  
Much Worse  
Very Much Worse 
 
PGIC in SYMPTOMS (PGIC-S): 
Completed at the end of Day 4 of each Treatment Period: 
√ (Check) the box you feel most closely describes how all of the symptoms related to your index knee 
have changed since you began this four-day treatment period. Please include pain, stiffness, ability to 
function, and all other symptoms related to your index knee. 
Choose only ONE response. 
Very Much Better  
Much Better  
  
Minimally Better  
  
No Change  
Minimally Worse  
  
Much Worse  
Very Much Worse 


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Reference Number: BHC-RD-OI-107 
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Treatment Preference 
 
Which treatment was the most effective for relief of your knee pain? 
 Treatment Period 1 
 Treatment Period 2 
 Treatment Period 3 
 Treatment Period 4 
 
 
 
 
 
 
Qualitative Interview - amendment 1 
 
The qualitative interview will consist of a series of open-ended questions administered by a 
trained interviewer in one-on-one interviews with study subjects during the follow up phone 
call or if withdrawn prior to completion. The primary purpose of the qualitative interview is to 
provide additional data to augment the quantitative data collected from instruments such as 
the BASS, WOMAC, and NRS.  It is anticipated that subjects will provide additional details 
not revealed through the quantitative instruments used to assess pain and stiffness, such as 
their perception regarding the clinical trial experience (e.g., pros and cons), additional details 
about the impact of each treatment on their daily function and quality of life, and information 
that may be useful to optimize the STEPP for inducing experimental pain in clinical studies. 
 
The qualitative interview will take approximately 30-60 minutes to complete, and will consist 
of approximately 30 questions designed to collect information about: 1) subjects’ experiences 
on the study treatments, to determine if there are any advantages of naproxen sodium (Aleve) 
that were not discovered using the quantitative instruments; 2) subjects’ experiences with the 
STEPP, to determine if the procedure can be optimized to elicit OA pain and stiffness to a 
greater degree, which would increase assay sensitivity in trials of new treatments for pain due 
to OA of the knee; and, 3) subjects’ perspectives on factors to optimize recruitment and 
retention in future OA studies conducted by Bayer. 
 
Audio from each interview will be recorded, transcribed, and analyzed using qualitative data 
analysis software
  The specific procedures 
related to interviewer training, interview script, audio data collection, data analysis and 
reporting of results will be documented separately outside of the protocol. 
 
CCI


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Reference Number: BHC-RD-OI-107 
Supplement: Version 9 
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)                
(0-10 NRS, 48-hour recall version) - amendment 2 
Examples of the licensed version. 
 
 
 
 
 
 
CCI


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Joint Stiffness Severity 
 
 
CCI
CCI


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Daily Brief Arthritis Stiffness Scale 
 
 
 
 
 
 
CCI


Clinical Study Protocol 19783 
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Final Version 3.0 / 11-Sep-2018 
 
 
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. 
 
 
 
 
 
Kellgren and Lawrence Scale 
 
Criteria for Radiologic Diagnosis of Osteoarthritis according to the Kellgren and 
Lawrence Criteria* 
 
Grading 
Interpretation 
Grade 0 
Normal 
Grade I 
Doubtful narrowing of joint space and possible osteophytic lipping 
Grade II 
Definite osteophytes and possible narrowing of joint space 
Grade III 
Moderate multiple osteophytes, definite narrowing of joint space, some 
sclerosis, and possible deformity of bone contour 
Grade IV 
Large osteophytes, marked narrowing of joint space, severe sclerosis, and 
definite deformity of bone contour 
*The Epidemiology of Chronic Rheumatism: Atlas of Standard Radiographs, Vol. 2, Oxford Scientific 
Publishers, 1963. 
 
 
 

SAP_001.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
A Pilot Study Assessing the Treatment Responsiveness of a 
Novel Osteoarthritis Stiffness Scale 
NCT Number: 
NCT03570554 
Document Date: 
25-SEP-2019 
 


Refai•ence Number: ID-SOP-6021 
S11ppleme11t Version: 3.0 
Statistical Analysis Plan Appl'oval Form 
Cllnicnl Protocol Title: 
A Pilot Study Assessing the Treatment Responsiveness of a Novel Oste·oarthritis Stiffaess Scale 
h1vestigatio11alProcl11ct; BAY 117031 /Naproxen Sodium 
TrialIMPACTNo.: 19783 
IPhase: 2 
Version No,/Date(dd/111111111/vvvvl: V 1.0 Final/ 25Sen2019 
Signing this form constitutes agreement with the Statistical Analysis Plan or any Amendment. 
APPROVED BY: 
Role 
Name 
Signature 
Date 
ClinicRI Development 
Sel'vices Repl'esentative 
1S-5ff,'lo/i 
ITrinl Statlsticinn 
~J7/ 
::idical Affnll's 
-z.<~~ 
pl'escntatlve 
-Z::. \ '\ 
CJ 
CRO Statistician 
 
Paga 1 of1 
PPD
PPD
PPD
PPD
PPD
CCI


Bayer HealthCare 
19783 
A Pilot Study Assessing the Treatment Responsiveness of a Novel Osteoarthritis 
Stiffness Scale 
Confidential 
25SEP2019 
Statistical Analysis Plan 
Version 1.0 
Prepared by: 
CCI


Bayer HealthCare 
19783 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
TABLE OF CONTENTS 
1.
INTRODUCTION .......................... ...................................................................................................... 6 
2.
OBJECTIVES ................................................................. , ........................................................................... 7 
3.
INVESTIGATIONAL PLAN ......................................................................................................................... 7 
3. 1. 
OVERALL STUDY DESIGN AND PLAN .................................................................................. 7 
3.2. 
STUDY ENDPOINTS ............................................................................................................ 11
3.2.1. 
Prima,y Efficacy Endpoint ....................................................................................... 11 
3.2.2. 
Secondary Efficacy Endpoints .................................................................................. 11 
3.2.3. 
Exploratory Efficacy Endpoints ................................................................................ 11 
3.2.4. 
Safety EndJJoints ........................................................................................................ 12 
3 .3. 
TREATMENTS .................................................................................................................... 12 
4.
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 13 
4.1. 
SAMPLE SIZE .................................................................................................................... 14 
4.2. 
RANDOMIZATION AND BLINDING ..................................................................................... 14 
4.3. 
ANALYSIS SETS ..... ; .......................................................................................................... 15 
4. 3.1. 
Intent-to-Treat (ITT) ............................................................................................. .... 15 
4.3.2. 
Per Protocol (PP) ..................................................................................................... 15 
4.3.3. 
Safety ........................................................................................................ · ................. 15 
4.4. 
ASSESSMENT WINDOWS ................................................................................................... 16 
4.4.1. 
Treatment Periods ..................................................................................................... 16 
5.
SUBJECT DISPOSITION ........................... ............... , ...................... ................................... ..... .............................. .......... 17 
5 .1. 
STUDY SETS ...................................................................................................................... 17 
5.2. 
DISPOSITION ..................................................................................................................... 17 
5.3. 
PROTOCOL DEVIATIONS ................................................................................................... 17 
6.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 18 
6.1. 
DEMOGRAPHICS ................................................................................................................ 18 
6.2. 
ALCOHOL, TOBACCO AND DRUG USAGE .......................................................................... 18 
6.3. 
MEDICAL HISTORY ........................................................................................................... 18 
6.3.1. 
General Medical Hist01y .......................................................................................... 18 
6.4. 
INCLUSION AND EXCLUSION CRITERIA ............................................................................. 18 
7.
TREATMENTS AND MEDICATIONS ............................................................................... ũ ............................................... 19 
7.1. 
PRIORANDC0NCOMITANTMEDICATI0NS ........................................................................ 19 
7.2. 
STUDY TREATMENTS ........................................................................................................ 19 
7.2.1. 
Extent of Exposure and Compliance ......................................................................... 19 
8.
EFFICACY ANALYSIS ..................................................................................................... 20 
8. 1. 
PRIMARY EFFICACY ENDPOINT ... ,,, ................................................................................... 20 
8.1.1. 
Primary Analysis ....................................................................................................... 20 
8.2. 
SECONDARY EFFICACY ENDPOINT .................................................................................... 21 
8. 2.1. 
Absolute BASS Score at Each Time Point .................................................. ; .............. 21 
8.2.2. 
Day 4 Change from Baseline in BASS Score ............................................................ 21 
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Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
8.3. 
EXPLORATORY EFFICACY ENDPOINTS .............................................................................. 21 
8.3.1. 
Day 1 and Day 4 Post-STEPP Sum of Pain Intensity Difference (SPID) at 4, 6, and 8 
Hours Post-Dose .................................................................................................................... 21 
8.3.2. 
Day 1 and Day 4 Post-STEPP Sum o_f Pain Intensity (SP!) at 4, 6, and 8 Hours Post­
Dose 
22 
8.3.3. 
Day 1 and Day 4 Post-STEPP Pain Intensity Difference (PID) at 2, 4, 6, and 8 
Hours Post-Dose .................................................................................................................... 22 
8.3.4. 
Day 1 and Day 4 Post-STEPP Pain Intensity (PI) at 2, 4, 6, and 8 Hours Post-Dose 
22 
8.3.5. 
Current Hourly PI Using the 0-10 NRS Pre-Dose, andfi·om 1 to 8 Hours Post-Dose 
22 
8.3.6. 
Mean Change from Baseline to End of Treatment Period on the WOMAC Pain 
Subscale, 48-Hour Recall Version ......................................................................................... 23 
8.3. 7.
Mean Changefi·om Baseline to End o_fTreatment Period on the WOMAC Stfffness 
Subscale, 48-Hour Recall Version ......................................................................................... 23 
8. 3. 8. Absolute WOMAC Stijfiiess Subscale Scores, 48-Hour Recall Version, at Each Time
Point 
23 
8.3.9. 
Mean Changeji·om Baseline to End a/Treatment Period on the WOMAC Physical 
Function Subscale, 48 Hour Recall Version .......................................................................... 23 
8. 3.10. 
Patient Global Impression of Change (PGIC) on Day 4 of Each Treatment Period
24 
8.3.11. 
Subject Preference for Treatment Assessed at the End of the Study ..................... 24 
8.3.12. 
Level ofActivities During Days 1 (Partial), 2 and 3 as Nfeasured by the 
Accelerorneter ......................................................................................................................... 24 
9.
SAFETY ANALYSIS ................................................................................................................ 25 
9.1. 
ADVERSE EVENTS ............................................................................................................. 25 
9.1.1. 
Incidence ofTEAEs ................................................................................................... 25 
9.1.2. 
Relationship o_f Adverse Events to IA1P .................................................................... 26 
9.1.3. 
Intensity of Adverse Event ......................................................................................... 26 
9.1.4. 
Serious Adverse Events ............................................................................................. 26 
9.1. 5. 
Deaths, Adverse Events Leading to Treatment Discontinuation/Study 
Discontinuation ...................................................................................................................... 2 7 
9.2. 
CLINICAL LABORATORY EVALUATIONS ........................................................................... 27 
9.2.1. 
Hen1atology ............................................................................................................... 27 
9.2.2. 
Serun1 Chen1istry ....................................................................................................... 27 
9.2.3. 
Urinalysis ............................................................ _ ...................................................... 27 
9.2.4. 
Urine Drug Screen .................................................................................................... 27 
9. 2. 5. 
Breath/Saliva Alcohol Test ....................................................................................... 27 
9.2. 6. 
Urine Pregnancy Test ............................................................................................... 28 
9.3. 
VITAL SIGN MEASUREMENTS .......... .-................................................................................ 28 
9.4. 
PHYSICAL EXAMINATION ................................................................................................. 28 
10.
INTERIM ANALYSIS ................................................................................................... 28 
11.
REFERENCES ............................................................................................................................... 28 
12.
APPENDICES ................................................................................................................. 30 
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19783 
12.1. 
12.2. 
12.3. 
Draft Statistical Analysis Plan, Version LO 
Date Issued :25SEP2019 
Notable Abnormal Vital Signs .................................................................................. 30 
Schedule of Study Procedures ................................................................................... 30 
WOMAC Function Subscale Questions ......................................... .......................... 33 
IV 


Bayer HealthCare 
19783 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
List of Abbreviations 
AE 
ANCOVA 
ATC 
BASS 
BMI. 
CABG 
CI 
cox 
CRF 
CSR 
DSMB 
ER 
eCRF 
FDA 
ICF 
IMP 
ITT 
IUD 
MedDRA 
NRS 
.NSAID 
OA 
OTC 
PI 
PID 
pp 
PT 
PVG 
SAE 
SAP 
soc 
SPI 
SPID 
STEPP 
SUSAR 
TEAE 
WHO 
WOMAC 
Adverse Event 
Analysis of Covariance 
Anatomical Therapeutic Chemical 
Brief Arthritis Stiffness Scale 
Body Mass Index 
Coronary Artery Bypass Graft Surgery 
Confidence Interval 
Cyclooxygenase 
Case Rep01i Fonn 
Clinical Study Report 
data safety monitoring board 
Extended Release 
(electronic) Case Report Form 
Food and Drug Administration 
Informed Consent Fonn 
Investigational Medicinal Product 
Intent-to-Treat 
Intra-uterine Device 
Medical Dictionary for Regulatory Activities 
Numerical Rating Scale 
Nonsteroidal Anti-inflammatory Drug 
Osteoatihritis 
Over-the-Counter 
Pain Intensity 
Pain Intensity Differences 
Per Protocol 
Preferred Term 
Pharmacovigilance 
Serious Adverse Event 
Statistical Analysis Plan 
System Organ Class 
Sum of Pain Intensity 
Summed Pain Intensity Difference 
Staircase-Evoked Pain Procedure 
Suspected Unexpected Serious Adverse Reaction 
Treatment-Emergent Adverse Events 
World Health Organization 
Western Ontario and McMaster Universities Osteoatihritis Index 
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1. Introduction 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
Osteoaiihritis (OA) is a common, chronic, progressive, skeletal, degenerative disorder that 
frequently affects several joints such as knee, hip, spine and hands. Osteoaiihritis is associated 
with damage to the caiiilage and surrounding tissues and characterized by pain, stiffness, and 
loss of function.(!) Being a highly prevalent disease and a main form of aiihritis, OA is the most 
common cause of disability in the U.S. In fact, 52.5 million U.S. adults (approximately 1 in 4) 
aged 2:18 years have self-reported having doctor-diagnosed aiihritis according to 2010-2012 data 
collected by the National Health Interview Survey. (2) The incidence of large joint OA in the 
U.S., particularly of the knee, is predicted to increase with the aging of the population and 
obesity epidemic. (3) 
Cu1Tently, a variety of prescription and over-the-counter (OTC) medications are available. 
Acetaminophen has been a mainstay of OA phaimacological management for many years and 
has been tested in many clinical trials although its effectiveness in clinical trials appeai·s limited. 
( 4) An extended release (ER) formulation containing acetaminophen 650 mg in a bilayer form 
has been shown to be more efficacious than placebo in hip and knee OA. (5) Each ER caplet 
contains 650 mg of acetaminophen. The.maximum daily dose is 3900 mg. 
Aleve®, naproxen sodium, the sodium salt ofnaproxen, was developed as an analgesic because 
it is more rapidly absorbed than naproxen. It is available as an OTC analgesic/antipyretic that 
temporarily reduces fever and relieves minor aches and pains due to: minor pain of aiihritis, 
muscular aches, backache, menstrual craiups, headache, toothache, and the common cold. OTC 
doses ofnaproxen sodium have been shown to be efficacious for relieving OA pain. (6, 7, 8) 
Each tablet contains 220 mg of naproxen sodium with a maximum daily dose of 660 mg. 
Celecoxib, a COX-2 selective NSAID, is a commonly used prescription analgesic for OA and its 
efficacy is suppmied by a large body of data. (9) For relief of the signs and symptoms of OA the 
recommended oral dose is 200 mg per day. 
Along with pain, stiffness is a frequent symptom ofOA. (6) The Western Ontario and McMaster 
Universities Osteoatihritis Index (WOMAC), a commonly used subject repmied outcome (PRO) 
instrument for the measurement of QA-related joint pain and physical function includes a 2-item 
subscale for measuring joint stiffness. (10) However, the WOMAC's 2-item subscale for 
measuring joint stiffness shows low test-retest reliability. (11) FDA has informed Bayer that the 
WOMAC stiffness subscale has not been accepted as a stand-alone measure suitable for use as 
an endpoint. 
In order to examine the efficacy of treatments on improving joint stiffness, the Brief Atihritis 
Stiffness Scale (BASS), a PRO instrument designed specifically to measure stiffness was 
developed and validated for use in clinical trials. A non-interventional study has previously been 
conducted to exaiuine the psychometric propetiies of the BASS. The study provided evidence 
for the reliability, construct validity, and discriminant validity of both the daily and weekly 
average BASS score, as well as preliminai-y responder thresholds. Further evaluation of the 
BASS to assess the instrument's responsiveness to treatment is needed. A study including an 
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Bayer HealthCare 
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Draft Slatistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
active intervention will provide information to formally evaluate the instrument's ability to 
detect change and provide utility for the responder definition. 
This placebo-controlled clinical trial' will assess the effects of naproxen sodium, acetaminophen 
ER and celecoxib on stiffuess in subjects with OA. Fu1ihe1more, data will be collected to 
confirm the psychometric evidence suppotiing the use of the BASS as a subject reported 
outcome in assessing the effect of treatment in OA. 
2. Objectives 
Primary 
• 
To assess the responsiveness of the Brief Atihritis Stiffness Scale (BASS) for detecting 
treatment effects of common OTC analgesics and a common prescription analgesic in 
subjects with knee OA. 
Exploratory 
• 
To assess the assay sensitivity of the STaircase-Evoked fain frocedure (STEPP"') to 
detect treatment effects of commonly used analgesics compared to placebo and to detect 
differences between active treatments; 
• 
To determine/identify effect size measurements, determine single dose vs. multi-dose 
efficacy, identify optimal sample size, and logistical issues for planning comparative 
analgesic efficacy studies using the STEPP. 
• 
To assess levels of activity captured by the accelerometer between active treatments and 
placebo during Days 1 (partial), 2 and 3 of the treatment phase. 
• 
To evaluate the safety and tolerability of naproxen sodium, celecoxib and acetaminophen 
ER. 
3. lnvestigational Plan 
3.1. Overall Study Design and Plan 
This is a multi-center, randomized, double-blind, four period crossover, placebo-controlled pilot 
study in adult male and female subjects between 40 and 80 years of age with pain due to 
osteoatihritis of the knee. At the completion of the Screening phase and baseline, eligible subjects 
will be randomized in a I :I :1:1 crossover fashion (A:B:D:C, B:C:A:D, C:D:B:A, D:A:C:B) to a 
treatment sequence administered as shown in Table 1.: 
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Table 1: Treatments administered 
Dose Time 
Treatment A 
Naproxen 
Day 1 
8AM 
440mg 
Visit 2 
4PM 
Placebo 
8PM 
220mg 
12AM 
Placebo 
Day2 
8AM 
440mg 
At home 
4PM 
Placebo 
8PM 
220mg 
12AM 
Placebo 
Day3 
8AM 
440mg 
At home 
4PM 
Placebo 
8PM 
220mg 
12AM 
Placebo 
Day4 
8AM 
440mg 
Visit 3 
TreatmentB 
Acetaminophen 
ER 
1300mg 
1300mg 
Placebo 
1300mg 
1300 mg 
1300mg 
Placebo 
1300 mg 
1300 mg 
1300mg 
Placebo 
1300 ID!! 
1300mg 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
Treatment C 
TreatmentD 
Celecoxlb 
Placebo 
100mg 
Placebo 
Placebo 
Placebo 
100 mg 
Placebo 
Placebo 
Placebo 
100 mg 
Placebo 
Placebo 
Placebo 
100mg 
Placebo 
Placebo 
Placebo 
100mg 
Placebo 
Placebo 
Placebo 
100 ill!! 
Placebo 
Placebo 
Placebo 
100 mg 
Placebo 
The study consists ofup to 14-day Screening Phase, a 4(+3) day Screening Washout Phase, and a 
Treatment Phase consisting of four 4-day treatment periods separated by washout periods lasting 
several days. The study center may schedule screening testing on multiple days as needed, provided 
all screening tests are done within 14 days. The target knee will be established at the screening visit. 
Approximately 192 subjects will be screened with 62 eligible to start the Screening Washout Phase. 
Approximately 12 subjects are anticipated to fail baseline randomization criteria to obtain 
approximately 50 randomized subjects of whom approximately 10 are anticipated to drop out leaving 
approximately 40 completed subjects. Duration of trial participation will be approximately 68 days 
as detailed in Figure I. See Section Error! Reference source not found.for complete schedule of 
events. 
Note that concomitant pain therapies, including topicals, and supplements must be discontinued at 
the start of the Screening Washout Phase (Day-4 to -I +3 days) through trial completion. Subjects 
can take acetaminophen ER(up to 2000 mg/day) provided by the study site during this Screening 
Washout Phase, but not within 24 hours of the Randomization visit (Day 1 of Treatment Period 
1 ). No other analgesic medications are permitted. 
Subjects will return to the study center at the beginning of each treatment period, upon 
completion of the Screening Washout Phase or between-treatment washout period. In the 
original version of the protocol, in order to be eligible for randomization prior to Treatment 
Period 1, subjects needed to meet the following randomization criteria: self-reported average 
score of2:5 on the WOMAC pain subscale (0-10 NRS, 24-hour recall version) related to OA pain 
in the target knee; cmTent pain intensity score of 2:4 and -:':c9 on the 0-10 NRS; and, a score of 2:5 
on the 0-10 NRS for average pain over the past 24-hours. In addition, the Day 1 baseline post-
STEPP cmTent pain intensity 0-10 NRS score must be 2:6, and 2: 1 unit higher than the pre-
STEPP cmTent pain intensity 0-10 NRS score, and the subject must experience lmee stiffness at 
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Bayer HealthCare 
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Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
least 5-7 days per week over the past month as reported on the Baseline Stiffness Questionnaire 
at the Screening Visit. 
In Protocol Version 3 .0, the randomization criteria was amended: 48-hour WOMAC pain 
subscale average score of2:3 and/or a 24-hour Average Pain Intensity score 2:3 on the 0-10 NRS 
at Screening Visit, 48-hour WOMAC pain subscale average score·of:':4 on the 0-10 NRS at Visit 
2, Treatment Period 1 of 4, 24-hour Average Pain Intensity score 2:3 at Visit 2, Treatment Period 
1 of 4, cmTent pain intensity score of 2: 4 and s9 on the 0-10 NRS at Visit 2, Treatment Period 1 
of 4 and Day 1 baseline post-STEPP current pain intensity score 2:5, and 2:1 unit higher than the 
pre-STEPP cmTent pain intensity 0-10 NRS score, and the subject must experience knee stiffness 
at least 5-7 days per week over the past month as reported on the Baseline Stiffness 
Questionnaire at the Screening Visit. 
Subjects who do not meet all the randomization criteria will be considered a Screening failure 
and will not be randomized into the study. Subjects who qualify will be asked additional 
questions related to knee pain, stiffness and function. 
Randomized subjects will receive their treatment period specific investigational medicinal 
product (IMP) or treatment kit that includes study medication at the stmt of each treatment 
period. Randomization occurs only once during the stmt of the first treatment period. 
Withdrawn subjects may be classified as a screening failure, an inadequate pain repmter, or a 
dropout, depending on the time point of withdrawal. Withdrawn subjects will not be replaced in 
this study. 
During the completion of Visit 2 (Day 1 ), subjects will be given a diary to record daily BASS 
scores prior to next visit and fitted with an accelerometer to measure the number of steps taken 
and level of activity ( e.g., low, medium, high). Accelerometer data collection will start after 
completion of the Day 1 activities prior to leaving the study site, however only data from full 
days (Day 2 and Day 3) will be used in data analysis 
Subjects will stmt a new Washout Period following the completion of Visit 3 (Day 4) of each 
Treatment Period (except Treatment Period 4). The Washout Period will last from 3 to 7 days 
after Visit 3. Subjects will not be allowed to take any pain medication not dispensed by the 
study center. Subjects can take acetaminophen ER (up to 2000 mg/day) as a rescue medication 
provided by the study site during this Washout Period but not within 24 hours of Day 1 of the 
next Treatment Period. Subjects will be scheduled to return to the study center to stmt the next 
Treatment Period (X of 4) for Day 1, Visit 2. 
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Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
Figure 1: Design Overview 
Screening 
Screening 
Treatment Phase (4 arms) 
Washout 
Phase 
Washout 
Phase 
End 
Trial 
Screening 
Day-4 
Start Treatment Period 
Continue 
Treatment 
Between 
days 
Visit 1 
to -1 
Visit2 
Treatment 
Period 
Treatment 
Day -18 to -5 
(+3 d) 
Day 1 
Day 2 & 3 
Visit3 
Periods 
Day4 
Daily BASS 
WOMAC 
Accurate Pain 
WOMAC 
Pain 
Reporting 
Stiffness 
WOMAC 
Training 
WOMAC 
Stiffness 
Clinical Trial 
Daily BASS 
Function 
WOMAC 
Expectations 
WOMAC 
Daily BASS 
Function 
3 to 7 days 
Training 
Pain ~4 
Morning 
of washout 
Baseline 
IMP dose 
needed 
Stiffness 
24-hour 
before 
Questionnaire 
average 
1st IMP 
starting the 
pain ~4 
dose 
Daily BASS 
next 
WOMAC Pain 
(0-10 NRS) 
ir 
treatment in 
ir 
prior to 1 ' t IMP 
the 
WOMAC 
Washout 
Current pain 
dose 
Stiffness 
* 
sequence 
before 1st 
~4 and $9 
IMP doses 2, 3 
WOMAC 
IMP dose 
(0-10 NRS) 
& 4 each day 
After 
Function 
washout, 
Stiffness 
. 
Post STEPP 
Accelerometer 
repeat 
Severity 
pain ~5 and 
2nd, 3rd & 
PGIC 
Treatment 
~1 unit 
4th IMP 
use 
Phase for 
Question 
higher than 
dose 
Treatment 
the 
24-hour 
pre-STEPP 
Preference8 
remaining 
average pairl 
pain 
Accelero-
treatment(s) 
(0-10 NRS) 
(0-10 NRS) 
meter use 
in the 
after 
sequence 
STEPP test 
completion 
(X of 4) 
Regional Pain 
of study 
Scale 
procedures 
* = Randomized to a 4 arm blinded treatment sequence (only for treatment 1 of 4) 
jfr. = Staircase-Evoked Pain Procedure (STEPP) completed pre-dose, and then 2, 4, 6 and 8 hours post-dose 
Follow up 
Phase 
End of 
Study 
7-10 days 
after 
completion 
of 
treatment 
period 
4 of 4 
Phone call 
Qualitative 
lnterviewa 
= 0-10 point current pain NRS at pre-dose immediately before and 2~5 minutes after the STEPP, which is also completed at 2, 4, 6 and 8 
hours post-dose. Additionally, hourly current pain intensity NRS at 1, 3, 5, and 7 hours post-dose when not completing the STEPP 
aTreatment period 4 of 4 only or if the subject is withdrawn from the studv orior to completion 
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3.2. Study Endpoints 
3.2.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
Draft Statistical Analysis Plan, Version l.O 
Date Issued ;25SEP20l9 
• 
Sum of change from baseline (Day 1 of the Treatment Period) in BASS score over the 
4 day treatment period 
3.2.2. Secondary Efficacy Endpoints 
The secondary efficacy endpoints include 
• 
Absolute BASS score at each time point. 
• 
Day 4 change from baseline (Day 1 of the treatment period) in BASS score 
Note: Key pairwise comparisons of absolute BASS score and change from baseline BASS 
score will be assessed, including, but not limited to: naproxen versus placebo, 
celecoxib versus placebo, acetaminophen ER versus placebo, naproxen versus 
acetaminophen ER and naproxen versus celecoxib. 
3.2.3. Exploratory Efficacy Endpoints 
• 
Day 1 and Day 4 post-STEPP sum of pain intensity difference (SPID) at 4, 6, and 8 
hours post-dose, based on 0-10 NRS; 
• 
Day 1 and Day 4 post-STEPP sum of pain intensity (SPI) at 4, 6, and 8 hours post-
dose, based on 0-10 NRS; 
• 
Day 1 and Day 4 post-STEPP pain intensity difference (PID) from baseline at 2, 4, 6, 
and 8 hours post-dose, based on 0-10 NRS; 
• 
Day 1 and Day 4 post-STEPP pain intensity (PI) at 2, 4, 6, and 8 hours post-dose, 
based on 0-10 NRS; 
• 
Cunent hourly PI using the 0-10 NRS pre-dose, and from 1 to 8 hours post-dose; 
• 
Mean change from baseline (Day 1 of the Treatment Period) to end of Treatment 
Period on the Western Ontario and McMaster Universities Arthritis (WOMAC) pain 
subscale, 48-hour recall version, assessed on Day 1 and Day 4 including an 
assessment of all key pairwise comparisons; 
• 
Mean change from baseline to end of Treatment Period on WOMAC stiffness 
subscale, 48-hour recall version, assessed on Day 1 and Day 4 including an 
assessment of all key pairwise comparisons; 
• 
Absolute WOMAC stiffness subscale scores, 48-hour recall version, for each study 
treatment at each time point; 
• 
Physical activity level outcomes during Days 1 (partial), 2 and 3 as measured by the 
accelerometer; 
11 


Bayer HealthCare 
19783 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
• 
Mean change from baseline to end of treatment period on WOMAC function 
subscale, 48-hour recall version, assessed on Day 1 and Day 4, including an 
assessment of all key pairwise comparisons; 
• 
Patient Global Impression of Change (PGIC) on Day 4 of each Treatment Period, 
including PGIC for OA Pain (PGIC-P) and PGIC for OA Symptoms (PGIC-S); 
• 
Subject preference for treatment assessed at the end of the study; 
• 
Qualitative (semi-strnctured) interview to assess subjects' experience with treatments, 
and experience with the STEPP, relevance to their disease status, how to improve it, 
etc. 
• 
Level of activities during Days 1 (partial), 2 and 3 as measured by the accelerometer 
(Modus StepWatch4). 
o Number of steps per day 
o 
Minutes of active vs. inactive per day 
o Percent of time in low, medium or high activity 
o 
Peak performance of the day (30 minutes) 
o 
Maximum performance (1, 5, 20, 60 minutes) 
o 
Cadence 
3.2.4. Safety Endpoints 
The following laboratory tests will be performed at screening: 
• 
Hematology (Hemoglobin, Hematocrit, RBC count, Platelet count, WBC count) 
• 
Serum Chemistty (BUN, Creatinine, Glucose, CA++, NA+, K +, Cl-, Total CO2 
(Bicarbonate), AST, ALT, Total Bilirubin, Alkaline Phosphatase, Albumin, Total 
protein) 
• 
Urinalysis (Specific gravity, pH, Glucose (qua!), Protein (qua!), Blood (qua!), 
Ketones, Leukocyte Esterase, Nitrite, Bilirubin, Urobilinogen) 
Adverse events will be collected throughout the treatment and safety follow-up periods and 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary, 
version 21.1. Only treatment-emergent AEs will be included, i.e., AEs that begin or worsen 
after the first dose of the investigational products in the Treatment Phase. The number and 
percent of subjects who experience any event, by System Organ Class (SOC), and by 
Preferred Tem1 will be displayed by treatment group. Tables will also be produced by 
intensity and relationship to.investigational product. Seriousness, intensity, relationship to 
investigational product, duration, and outcome will also be listed. 
3.3. Treatments 
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Bayer HealthCare 
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Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
Subjects will follow the dosing schedule as outlined in Table I. The blister package will be 
blinded to the specific treatments in the sequence. All subjects will randomly receive one drng 
treatment (A, B, C, or D) during each dosing period. Depending upon which treatment in the 
sequence, they could be taken naproxen sodium, acetaminophen ER, celecoxib or placebo. 
4. General Statistical Considerations 
All statistical analyses will be conducted using SAS Version 9.3 or higher (SAS Institute, Cary, 
North Carolina). 
 
 
 
Continuous data will be summarized by treatment group using descriptive statistics (n, mean, 
median, standard deviation [SD], minimum, and maximum). Categorical data will be 
summarized by treatment group using frequency tables (frequencies and percentages). Mean and 
median will be presented to one decimal place beyond the precision with which the data was 
captured. SD will be presented to two decimal places beyond the precision with which the data 
was captured. Minimum and maximum will be presented to the precision with which the data 
was captured. When count data are.presented, the percentage will be suppressed when the count 
is zero in order to draw attention to the non-zero counts. A row denoted "Missing" will be 
included in couut tabulations where specified on the shells to account for dropouts and missing 
values. The denominator for all percentages will be the number of subjects in that treatment 
group within the analysis set of interest, unless otherwise specified. 
All study-related raw data that suppott the corresponding tables and figures will be presented in 
data listings. Additional data listings may be generate¢ as needed. All table, listing and figure 
(TLF) shells will appear in landscape fotmat employing Courier New 9 point font. Unless 
otherwise noted, all tables will summarize subject results by treatment group sorted in the 
following order: Naproxen Sodium, Acetaminophen ER, Celecoxib, Placebo. As this is a 
crossover study, we expect that individual subjects will be included in all treatment groups. 
Unless otherwise noted, all data listings will be sotted by treatment group and subject 
identification number defined as investigator identification number concatenated with the subject 
number. 
The baseline value for an assessment will be defined as the last non-missing measurement 
including unscheduled assessments before the first dose of IMP for each treatment period. 
Change from baseline is defined as the post-baseline value minus the baseline value for the given 
assessment. 
13 
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Bayer HealthCare 
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4.1. Sample Size 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
Because there are no reference data on the impact of naproxen, acetaminophen ER and placebo on 
stiffness with the utilization of the BASS scale, an estimated 50 subjects randomized to achieve 
approximately 40 subjects completing the study are considered adequate for this pilot study. 
Screening will continue until 50 subjects are randomized in the study. 
4.2. Randomization and Blinding 
At the beginning of the first treatment period, after completion of the pre-treatment baseline 
procedures/assessments, subjects who meet the entry criteria will be sequentially assigned to a 
unique number in ascending order (randomization number, R.NR) according to the randomization 
schedule prepared prior to the study. 
Subjects will be numbered according to the following scheme: 
14001.XXXX 
Whereas the "Xs" will be replaced with a four digit sequentially assigned number as each subject 
enters the study (e.g., first subject number will be 
). 
Once a number has been assigned to a subject, it cannot be reassigned to another subject. 
Subjects who do not meet all of the randomization criteria will not be randomized. Upon 
successful completion of all remaining inclusion and exclusion criteria, subjects enter the 
Treatment Phase and are randomized into one of four blinded treatment sequences using a 
Williams design to ensure a balanced stratification. See example below; treatments are defined 
in Table 1: 
ABDC 
BCAD 
CDBA 
DACB 
Subjects enrolled in the study, investigators and their staff involved in protocol procedures or data 
collection analysis will be blinded to the identity of the treatment sequence. The study monitor will 
conduct product accountability during and after database lock. To preserve the blinding, all 
investigational products will be over encapsulated and prepackaged according to the randomization 
schedule. 
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4.3. Analysis Sets 
Draft Statistical Analysis Plan, Version LO 
Date Issued :2SSEP2019 
Three populations will be identified in this study. Subjects' inclusion status in each of the 
analysis sets will be presented in a data listing. 
4.3.1. Intent-to-Treat (ITT) 
The ITT will consist of all subjects who were randomized and have taken at least one dose of 
IMP. ITT population will be used for all efficacy analyses to assess the robustness of the results 
for all primary, secondaiy, and exploratory efficacy endpoints. All analyses using the ITT will 
group paiticipants according to planned treatment. 
4.3.2. Per Protocol (PP) 
The PP will consist of all subjects in ITT who do not have major protocol violations that could 
affect the evaluability of the primary efficacy parameter. The PP population will be used as the 
primary analysis for all efficacy parameters. Protocol deviations, including assessment of 
significance, will be identified prior to database lock and study unblinding. All analyses using 
the PP will group paiticipants according to treatment sequence actually received. The following 
incidences will be considered as a protocol violation and excluded from the PP analysis if any 
one of the following occurred during the treatment period: 
• 
Patient took rescue medication day before Day I of Treatment Period or Day 1 was 
outside allowable visit window; 
• 
Patient took a prohibited concomitant medication preceding or during the study 
Treatment Period; 
Patient failed to continue to meet the inclusion/exclusion criteria prior to the Treatment 
Period; 
Patient compliance rate for that treatment period is below 7 5%; 
• 
Patient did not complete required assessments for the Treatment Period 
Subjects may be invalid for one period but valid for another period. Therefore, invalidity for one 
period does not make them invalid for all. Protocol violations which lead to exclusion from the 
per-protocol group will be surnmai-ized and listed. 
4.3.3. Safety 
The Safety set is comprised of all subjects who received at least one dose of IMP. The Safety set 
is usually used to tabulate all of the safety information for a study, such as adverse events, 
treatment compliance, laboratory results, and vital signs. 
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4.4. Assessment Windows 
4.4.1. Treatment Periods 
For classifying AEs, the treatment periods will be defined as: 
Draft Statistical Analysis Plan, Version 1,0 
Date Issued :25SEP2019 
• 
Treatment Period 1: The onset date of the AE is on or after the stati date of study 
medication in treatment period 1 but before the start date of the study medication in 
treatment period 2. 
• 
Treatment Period 2: The onset date of the AE is on or after the stati date of study 
medication in treatment period 2 but before the stati date of the study medication in 
treatment period 3. 
· 
• 
Treatment Period 3: The onset date of the AE is on or after the start date of study 
medication in treatment period 3 but before the stati date of the study medication in 
treatment period 4. 
• 
Treatment Period4: The onset date of the AE is on or after the stati date of study 
medication in treatment period 4. 
Patiial dates will be imputed for AE stati dates in order to determine the treatment period to 
which the event will be assigned. 
• If the onset date is completely missing, onset date is set to the date of first dose and will 
be considered TEAE for all treatment periods. 
• If the year is present and the month is missing, then the month is set to Januat·y. If the 
yeat· is same as the year of the date of first dose and the AE end date is not prior to the 
date of first dose, then onset date is set to the date of first dose. 
• If the month and yeat· are present and the day is missing, then the day is set to the 1st day 
of month. If the month and year are same as the month and year of the date of first dose 
and the AE end date is not prior to the date of first dose, then onset date is set to the date 
of first dose. 
• If the AE end date is present, then the imputed start date will be no later than the end 
date. 
Partial dates will be imputed for medication stati dates in order to determine if a medication is 
prior or concomitant. 
• 
Partial start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. 
· 
• If the year is present and the month is missing, then the month is set to January. 
• If the month and yeat· are present and the day is missing, then the day is set to the 1st day 
of month. 
• If the year is missing, then the year will be assumed to be the year pati of the subject's 
informed consent date. 
Patiial or missing medication stop dates for medications that are not ongoing will be handled as 
follows: 
• 
Partial stop dates of prior and concomitant medications will be assumed to be the latest 
possible date consistent with the partial date. 
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Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
• If the year is present and the month is missing, then the month is set to December. 
• If the month and year are present and the day is missing, then the day is set to the last day 
of month. 
• 
For subjects who are treated, if the year is missing and the month or day are not missing, 
then the year will be assumed to be the year part of the subject's last recorded study visit 
date. 
• 
For subjects who are not treated, if the year is missing and the month or day is not 
missing, then the year will be assumed to be the year part of the subject's discontinuation 
date. 
• If the complete stop date is missing, the stop date will be considered to be either the 
subject's last recorded visit date for treated subjects or the subject's discontinuation date 
for non-treated subjects. 
5. Subject Disposition 
5.1. Study Sets 
The number of subjects who were emolled and the number of subjects within each analysis set 
(ITT, PP, and Safety) will be summarized for each treatment sequence and treatment period for 
all randomized subjects. A by-subject listing indicating the subject's inclusion in each analysis 
set and reason(s) that the subject is excluded from an analysis set will be presented. 
5.2. Disposition 
The counts and percentages of subjects who complete or discontinue from the study treatment 
will be presented based on the number of subjects in each treatment sequence and overall for all 
randomized subjects. The count and percentage of subjects who complete or discontinue from 
the study will be summarized in a similar manner. Reasons for discontinuation of treatment for 
subjects who do not complete the study treatment and reasons for not completing the study will 
be summarized for each treatment sequence as Treatment Disposition and Subject Disposition, 
respectively. All percentages will be based on the number of subjects randomized. Subject 
disposition data will be listed as well. 
5.3. Protocol Deviations 
Protocol deviations will be tracked by the clinical team on an on-going basis. Specific criteria for 
what constitutes a significant protocol deviation will be determined by the clinical team. A 
blinded review of the deviation log collected by the clinical group will be conducted prior to 
database lock. All deviations will be listed. 
Protocol violations, which disqualify a subject from the per-protocol set, will also be tracked on 
an on-going basis. These violations will be categorized and summarized by treatment sequence 
within each treatment period and listed by subject. 
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6. Demographics and Baseline Characteristics 
6.1. Demographics 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
Demographic infonnation and baseline characteristics collected at screening will be summarized 
for the ITT, PP, and Safety populations. Continuous variables, including age (years), baseline 
weight (kg), baseline height ( cm), and baseline body mass index (BMI) (kg/m2) will be 
summarized using descriptive statistics for each treatment sequence and overall. Categorical 
variables including sex (Male, Female), ethnicity (Hispanic or Latino, Not Hispanic or Latino), 
race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Multiple, and Other), and native language (English, Spanish, 
Chinese, Tagalog, Vietnamese, Arabic, French, Korean, Russian, Getman, Other) will be 
summarized by reporting the number and percentage of subjects in each category for each 
treatment sequence and overall. All demographic and baseline characteristics will be listed for all 
subjects in the Safety set. 
' 
Age will be calculated as (date of Screening visit- date ofbirth)/365.25. 
BMI is calculated as (body weight in kilograms) / (height in meters )2. 
In addition, baseline (pre-dose) BASS score and post-STEPP NRS for each treatment period will 
be summarized using descriptive statistics for each treatment sequence and overall. 
6.2. Alcohol, Tobacco and Drug Usage 
Descriptive statistics will be provided by treatment sequence for subject alcohol history (Yes, 
No), tobacco usage (Current, Previous, Never), and whether illegal drug use history was 
discussed with the subject (Yes, No). Percentages will be based on the total number of subjects 
in the ITT, and results will be listed by subject. 
6.3. Medical History 
6.3.1. General Medical History 
Medical history will be collected in the Electronic Case Repmi Form ( eCRF) at the screening 
and baseline visits and verbatim te1ms will be coded classified on the basis of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology, which will be updated whenever 
possible throughout the life of the study. Medical history will be summarized by the number and 
percentage of subjects with any medical history repmied by coded system organ class, prefe1rnd 
term, and treatment sequence for the Safety population. A subject listing will also be included 
with stmi date and end date or ongoing status. 
6.4. Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria deviations noted in the eCRF will be presented for the all 
subjects in a data listing. 
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7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
Any medicinal product, prescribed or over-the-counter (OTC), including herbal products, 
vitamins, and minerals is considered a concomitant medication. Any medications used during the 
study will be coded with the World Health Organization Drug Dictionary (WHODD), version 
dated September 2018. 
Prior/concomitant medication use will be recorded in the eCRF beginning at Screening visit 
before the first dose of study medication and will be recorded at the subsequent visits as well. 
Any changes in prior or concomitant medications will also be recorded in the subject's. eCRF. 
Summary of prior and concomitant medications by treatment group and preferred tenn will be 
· provided. All prior and concomitant medications will be presented in data listings. Prior and 
concomitant medications will be summarized for the safety set. Rescue medications will be 
flagged in the listing. 
7.2. Study Treatments 
Subjects will follow the dosing schedule as outlined in Table I. The blister package will be 
blinded to the specific treatments in the sequence. All subjects will randomly receive one drug 
treatment (A, B, C or D) during each dosing period. Depending upon which treatment in the 
sequence, they could be taking naproxen sodium, acetaminophen ER, celecoxib or placebo. 
Subjects will administer the drug with a full glass of non-refrigerated, non-carbonated water 
(about 8 ounces or 240 mL). 
· 
7 .2.1. Extent of Exposure and Compliance 
The distribution of the study medication will be supervised by a member of the Investigator's 
team. The subject will bring their dosing blister package (Med-ic®) with them to each visit. The 
Med-ic blister electronically records the date and time when the subject depresses the blister to 
take a dose ofIMP. The study center will download and review the dosing data from the Med-ic 
blister package for compliance. Any deviations related to dosing outside of a ± I hour window 
will be documented in the subject's medical record. A dose will be considered compliant ifit is 
taken within a± 2 hour window of the expected time. Total exposure and percent compliance 
will be summarized for the Safety and ITT sets, and a by-subject listing will be included on the 
Safety set. Subject use of rescue medication will also be summarized along with IMP and 
included in a listing. 
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Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
8. Efficacy Analysis 
Efficacy data will be analyzed utilizing the PP set, with ITT set used as a sensitivity analysis. 
Data imputation may occur ifthere are any missing BASS scores during the study. They will be 
imputed using linear interpolation (trapezoid rule - for between periods) or extrapolation (last 
observation caiTied forward within treatment period) approach depending on availability of data 
smTounding the missing value. For instances where a patient only partially answers some 
questions in the WOMAC questionnaire (left some answers blank) the standard WOMAC 
method (12) will be used, where the mean of non-missing sub-scale items is imputed for the 
missing ones when no more than 1 stiffness question, 2 pain questions, and 4 physical function 
questions are missing. The following key pairwise comparisons may be tested for endpoints as 
described in sections below: naproxen versus placebo, celecoxib versus placebo, acetaminophen 
versus placebo, naproxen versus acetaminophen and naproxen versus celecoxib. 
8.1. Primary Efficacy Endpoint 
The daily BASS is designed to measure the severity of any stiffness experienced in the target 
knee over a 24-hour period. Subjects who had stiffness over the 24-hour period, ai·e asked four 
questions on a 0-10 scale, with O representing no stiffness and 10 representing worst stiffness 
imaginable: 
The primary efficacy endpoint is the sum of change from baseline (Day 1 of the Treatment 
Period) in BASS over the 4-day treatment period. It will be calculated by summing the values of 
all four questions scale on the BASS questionnaire and summing the change-from-baseline 
calculations at each post-baseline time point. 
3 
(1) 2li+1 -ti 
i=1 
Where f1 is BASS score (sum of four questions, 0-40 scale) at the baseline (Day 1) time point, 
and (fi+1 -f1) represents the change in baseline from BASS score at each day post-baseline. The 
subjects complete the BASS on Day 1 prior to first dose in the treatment period, and at Day 2, 
Day 3, and Day 4 in each treatment period. 
8.1.1. Primary Analysis 
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8.2. Secondary Efficacy Endpoint 
8.2.1. Absolute BASS Score at Each Time Point 
8.2.2. Day 4 Change from Baseline in BASS Score 
8.3. Exploratory Efficacy Endpoints 
8.3.1. Day 1 and Day 4 Post-STEPP Sum of Pain Intensity Difference (SPID) at 4, 
6, and 8 Hours Post-Dose 
On Days l and 4 of each treatment period after dosing, subjects will undergo the STEPP 
procedure at 2, 4, 6, and 8 hours. The NRS is a numeric scale from 0-10 (0= no pain and 
l0=extreme pain) which measures pain at Baseline (pre-Dose), both before and after the STEPP 
procedure, as well as after the STEPP procedure at 2, 4, 6, and 8 hours. 
Pain intensity differences (PID) will be derived by subtracting the pain intensity (using NRS 0-
10, 0=no pain and 1 0=extreme pain) at the baseline (post-STEPP) time point from the post dose 
intensity score (baseline score - post-baseline score). A positive difference is indicative of 
improvement. Summed Pain Intensity Difference will be calculated as follows: 
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n 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
(2) SPID = _L (fo - [;)(t; - t;-1) 
i 
Where fi is the NRS score at i hours after dose ofIMP, fo represents the baseline post-STEPP 
NRS score, and (ti -ti-1) represents the duration in hours since the last time point, with to 
representing the baseline time point. The post-baseline time points will be at 2, 4, 6, and 8 hours. 
Sum of Pain Intensity Difference will be calculated at n=4, 6, and 8 hours and surmnarized 
descriptively by period and total in a table. At 8 hours on Day 1 and Day 4, the key pahwise 
comparisons will be perfonned without multiplicity adjustment, with confidence intervals and 
nominal p-values reported. 
8.3.2. Day 1 and Day 4 Post-STEPP Sum of Pain Intensity (SPI) at 4, 6, and 8 
Hours Post-Dose 
Sum of pain intensi_ty will be derived by summing the NRS scores at each post-dose time point 
multiplied by the interval between measurements. Sum of Pain Intensity will be calculated as 
follows: 
n 
(3) SP!== _L(f;)(t; - t;-1) 
i 
Where fi is the NRS score at i hours after dose ofIMP, fo represents the baseline post-STEPP 
NRS score, and (ti -ti-I) represents the duration in hours since the last time point, with to 
representing the baseline time point. The post-baseline time points will be at 2, 4, 6, and 8 hours. 
Sum of Pain Intensity will be calculated at n=4, 6, and 8 hours and summarized descriptively in a 
table. 
8.3.3. Day 1 and Day 4 Post-STEPP Pain Intensity Difference (PID) at 2, 4, 6, and 8 
Hours Post-Dose 
Pain intensity differences will be calculated as indicated in Error! Reference source not 
found., and measured at 2, 4, 6, and 8 hours post-dose. The results will be displayed in a 
summary table by visit, plotted and listed by subject. 
8.3.4. Day 1 and Day 4 Post-STEPP Pain Intensity (PI) at 2, 4, 6, and 8 Hours Post-
Dose 
The pain intensity scores based on the 0-10 NRS will be presented at 2, 4, 6, and 8 hours post-
dose, and the results will be displayed in a summary table by visit and listed by subject. 
8.3.5. Current Hourly PI Using the 0-10 NRS Pre-Dose, and from 1 to 8 Hours 
Post-Dose 
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Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
The pain intensity scores based on 0-10 NRS will be measured every hour for eight hours 
following first dose on Days 1 and 4. We will summarize all NRS scores on Days 1 and 4 by 
time point in a summary table, figure and list by subject. 
8.3.6. Mean Change from Baseline to End of,Treatment Period on the WOMAC 
Pain Subscale, 48-Hour Recall Version 
The WOMAC consists of24 items divided into 3 subscales: Pain (5 items), Stiffness (2 items), 
and Physical Function (17 items). Each item is on a 0-10 NRS scale. All questions are based on 
48-hour recall. The pain questions .are: 
The results of the questions on a 0-10 scale (0= no pain and I0=extreme pain) will be summed 
(0-50 scale for sum) and change from baseline (Day I of treatment period) to Day 4 will be 
measured across all treatment groups, and comparison of mean change from baseline will be 
tested using the ANCOV A model, with key pairwise comparisons. 
8.3.7. Mean Change from Baseline to End of Treatment Period on the WOMAC 
Stiffness Subscale, 48-Hour Recall Version 
The WOMAC stiffness subscale consists of2 questions: 
The results of the questions on a 0-10 scale (0=no stiffness and 1 0=extreme stiffness) will be 
summed (0-20 scale for sum) and change from baseline (Day 1 of treatment period) to Day 4 will 
be measured across all treatment groups, and comparison of mean change from baseline will be 
tested using the ANCOV A model, with key pairwise comparisons. 
8.3.8. Absolute WOMAC Stiffness Subscale Scores, 48-Hour Recall Version, at 
Each Time Point 
The sum of WOMAC stiffness subscale results (0-20) will also be measured at each time point, 
and summarized descriptively by period and total in a table. 
8.3.9. Mean Change from Baseline to End of Treatment Period on the WOMAC 
Physical Function Subscale, 48 Hour Recall Version 
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The WOMAC physical function subscale consists of 17 questions (see Appendix Error! 
Reference source not found. for details) and the results of the questions on a 0-10 scale (0=no 
difficulty and 1 0=extreme difficulty) will be summed (0-170 scale for sum) and change from 
baseline (Day 1 of treatment period) to Day 4 will be measured across all treatment groups, and 
comparison of mean change from baseline will be tested using the ANCOV A model, with key 
pairwise comparisons 
8.3.10. Patient Global Impression of Change (PGIC) on Day 4 of Each Treatment 
Period 
Approximately 8 hours after dosing, prior to leaving the study center on Day 4 of each Treatment 
Period, subjects will complete two Patient Global Impression of Change (PGIC) scales: the PGIC 
for OA Pain, and the PGIC for OA Symptoms. Each is a 7-point scale and the subject may only 
choose one response. The responses will be summarized in frequency tables and listed by 
subject. 
8.3.11. Subject Preference for Treatment Assessed at the End of the Study 
After treatment period 4 of 4 is completed, or if the subject is withdrawn from the study prior to 
completion, subjects will be asked to choose which treatment they felt gave the most pain relief. 
Responses will be summarized in frequency tables and listed by subject. 
8.3.12. Level of Activities During Days 1 (Partial), 2 and 3 as Measured by the 
Accelerometer 
The following activity level outcomes will be measured by the accelerometer: 
• 
Number of steps per day 
• 
Minutes active vs. inactive per day 
• 
Percent time in low, medium or high activity 
• 
Peak performance of the day (30 minutes) 
• 
Maximum performance (1, 5, 20, 60 minutes) 
• 
Cadence 
Some endpoints mentioned in protocol (stride length, stride velocity, total distance) were not 
captured by the accelerometer and will not be presented. The results for each of these outcomes 
for the complete days (Day 2 and Day 3) will be summarized in a table and presented in a figure. 
Listings will be produced by subject. 
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9. Safety Analysis 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
Safety parameters include monitoring of TEAEs, physical examination findings, vital sign 
measurements, and laboratory examinations. All safety summaries and analyses will be 
summarized by actual treatment group within the Safety set. 
9.1. Adverse Events 
All AEs that occur during the study will be recorded and classified on the basis of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology version 20.1. Treatment-emergent 
AEs (TEAEs) are defined as AEs with an onset on or after the date of the first IMP dose. 
Adverse events noted prior to the first IMP administration that worsen after baseline will also be 
reported as TEAEs and included in the summaries 
All info1mation pertaining to an AE noted during the study will be listed by subject, detailing 
verbatim term, preferred te1m, system organ class (SOC), onset date, resolution date, intensity, 
seriousness, action taken, outcome, drng relatedness, and relatedness to protocol-required 
procedures. The event onset will also be shown relative to IMP initiation (in number of days). 
Listings will be provided for all TEAEs. 
TEAEs will be presented on the Safety set and displayed by treatment period and group unless 
noted. 
9.1.1. Incidence of TEAEs 
Adverse events will be deemed treatment emergent if the onset date is on or after the date of first 
treatment, Day 1 in each period. An overall summary of incidence of TEAEs (subject/event 
counts) including drng relation, serious adverse events (SAE), TEAEs leading to drug 
discontinuation and fatal AEs will be presented. 
The number and percentage of subjects with at least one TEAE and the number of events overall 
will be presented by SOC and PT. 
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9.1.2. Relationship of Adverse Events to IMP 
Draft Statistical Analysis Plan, Version 1,0 
Date Issued :25SEP2019 
A summary ofTEAEs by relationship to IMP will be presented in a table by total number of 
TEAE and incidence of occurrence. The investigator will provide an assessment of the 
relationship of the event to the IMP as.Related or Not Related. If a subject reports multiple 
occurrences of the same TEAE, only the most closely related occurrence will be presented in the 
incidence count. Treatment-emergent AEs that are missing a relationship will be presented in the 
summary table as "Related" but will be presented in the data listing with a missing relationship. 
Percentages will be calculated based on the number of subjects in the safety set. 
The TEAE data will be categorized and presented by SOC, PT, and relationship in a manner 
similar to that described in Section 9 .1.1. 
9.1.3. Intensity of Adverse Event 
A summary of TEAEs by intensity will be presented in a table by total number of TEAE and 
incidence of occurrence. The intensity that will be presented represents the most extreme 
intensity captured on the eCRF page. The possible intensities are "Mild," "Moderate," and 
"Severe." In the TEAE intensity table, if a subject reported multiple occurrences of the same 
TEAE, only the most severe will be presented in the incidence count. Treatment-emergent AEs 
that are missing intensity will be presented in tables as "Severe" but will be presented in the data 
listing with a missing intensity. Percentages will be calculated based on the nwnber of subjects in 
the safety set. 
The TEAE data will be categorized and presented by SOC, PT, and intensity in a manner similar 
to that described in Section 9 .1.1. 
9.1.4. Serious Adverse Events 
The treatment-emergent SAE data will be categorized and presented by SOC and PT in a manner 
similar to that described in Section 9.1.1. At each level of subject summarization, a subject is 
counted once for the incidence if the subject reported one or more events. 
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9.1.5. Deaths, Adverse Events Leading to Treatment Discontinuation/Study 
Discontinuation 
A listing of all Serious TEAEs (including deaths) and/or AEs leading to treatment or study 
discontinuation will be presented. Additionally, a separate listing of any deaths will be presented. 
Deaths and discontinuations will be assessed based on data recorded in the AE eCRF page. 
Subject deaths will be identified as AEs where the outcome is "Fatal". Adverse events leading to 
treatment discontinuation will be identified as AEs where the action taken with IMP is "Drug 
Withdrawn". Adverse events leading to study discontinuation will be identified as AEs where the 
caused study discontinuation field is marked as "Yes". 
9.2. Clinical Laboratory Evaluations 
9.2.1. Hematology 
The following hematology tests will be performed at screening: Hemoglobin, Hematocrit, RBC 
count, Platelet count, WBC count. The test results will be summarized and listed. 
9.2.2. Serum Chemistry 
The following serum chemistry tests will be performed at screening: BUN, Creatinine, Glucose, 
Ca++, Na+, K+, Cl-, Total CO2 (Bicarbonate), AST, ALT, Total Bilirubin, Alkaline 
phosphatase, Albumin, Total protein. The test results will be summarized and listed. 
9.2.3. Urinalysis 
The following urinalysis tests will be perfonned at screening: Specific gravity, pH, Glucose 
( qua!), Protein ( qua!), Blood ( qua!), Ketones, Leukocyte Esterase, Nitrite, Bilirubin, 
Urobilinogen. The test results will be summarized and listed. 
9.2.4. Urine Drug Screen 
A screen for drugs of abuse will be performed at Screening (Visit I) and Visit 2 of each 
treatment period. A by-subject list of urine drug screen will be presented. Subjects will be tested 
for the following drugs: methamphetamines, amphetamines, cannabinoids, cocaine, opiates, 
benzodiazepines, barbiturates, methylenedioxymethamphetamine, methadone, oxycodone, 
adulterants. 
9.2.5. Breath/Saliva Alcohol Test 
An alcohol test, administered via breath or saliva will be performed at Screening and Visit 2 of 
each treatment period for inclusion/exclusion purposes. A by-subject listing of results will be 
presented. 
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9.2.6. Urine Pregnancy Test 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued :25SEP2019 
At screening and Visit 2 of each treatment period all females of child bearing potential must perform 
a urine pregnancy test and verify that the results are negative (not pregnant). Subjects with a verified 
positive pregnancy test will be withdrawn from the study. Pregnancy test results will be listed by 
subject. 
9.3. Vital Sign Measurements 
The vital sign summary and analysis will be based on the recordings of the variables blood 
pressure ( systolic and diastolic [ mm Hg]), oral body temperature (F), heart rate (beats/min), and 
respiratory rate (breaths/min). Notable abnonnal values will be flagged in the data listings. The 
conversion between conventional unit to SI unit for temperature and weight and definitions for 
notable abnormal values are listed in the appendix (Section Error! Reference source not 
found.). After screening assessment, vital signs assessments will consist of heart rate and blood 
pressure only. Observed values at Screening and Visits 2 and 3 and change from Baseline values 
to Visit 3 for vital sign measurements will be summarized descriptively by treatment group. 
All summaries will be done for the Safety set and all vital sign data will be listed. 
9.4. Physical Examination 
The physical examination (by means of inspection, palpation, auscultation) will be performed by a 
physician (or appropriately licensed designee) at the study site covering at least the organs of the 
cardiovascular, respiratory, and abdominal system. 
Abnormal physical examination findings are recorded either as medical history or as adverse events. 
Physical examination results will be listed. 
10. Interim Analysis 
There is no interim analysis scheduled for this study. 
11. References 
1. Altman, R. Osteoarthritis (OA). In Merck manual online. Retrieved from 
http://www.merckmanuals.com/home/bone,-joint,-and-muscle-disorders/joint-
disorders/osteoarthritis-%28oa%29 Accessed on April 11, 2016. 
2. Centers for Disease Control and Prevention (CDC). Prevalence of doctor diagnosed 
arthritis and aiihritis attributable activity limitation-. United States, 20072009. Morb 
Mortal Wkly Rep. 2013; 59(39):1261-5. 
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3. Zhang Y, Jordan, M. Epidemiology ofOsteoartln·itis. Clin Geriatr Med. 2010; 26(3): 
355-369. 
. 
4. Bannurn, R. et al. Comparative Effectiveness of Phaimacologic Interventions for Knee 
Osteoarthritis. Ann Intern Med, 2015; 162:46-54. 
5. Altman, R. et al. Tln·ee-Month Efficacy and Safety of Acetaininophen Extended-Release 
for Osteoaitln·itis Pain of the Hip or Knee: A Randomized, Double-Blind, Placebo-
Controlled Study. Osteoarthritis Cartilage. 2007; 15, 454-461. 
6. Golden, HE, Moskowitz, RW, and Minic, M. Analgesic efficacy and safety of 
nonprescription doses of naproxen sodium compai·ed with acetaininophen in the 
treatment of osteoaiiln·itis of the knee. Am J Ther. 2004; 11 :85-94. 
7. Schiff, Mand Minic, M. Comparison of the analgesic efficacy and safety of 
nonprescription doses of naproxen sodium and Ibuprofen in the treatment of osteoartln·itis 
of the knee. Journal of Rheumatology. 2004;31: 1373-1383. 
8. Cuoto A, Troullos E, Moon J, Pai·edes-Diaz A. Analgesic efficacy & safety of 
nonprescription doses of naproxen sodium in the treatment of osteoaiihritis of the lmee or 
hip. Osteoarthritis and Cartilage 2017;25 (supplement 1): S420 Abstract #692. 
9. Puljak L, Mai-in A, Vrdoljak D, Markotic F, Utrobicic A, Tugwell P. Celecoxib for 
osteoaiihritis. Cochrane Database of Systematic Reviews 2017, Issue 5. Ali. No.: 
CD009865. DOI: 10.1002/1465 l 858.CD009865.pub2. 
10. Bellamy N, Buchanan W, Goldsmith C, Campbell J, Stitt L. Validation Study of 
WOMAC: A Health Status Instrument for Measuring Clinically Important Patient 
Relevant Outcomes to Antirheumatic Drug Therapy in Patients with Osteoartln·itis of the 
Hip or Knee. J Rheumatol. 1988 Dec; 15(12): 1833-40. 
11. Dixon SJ, Hinman RS, Creaby MW, Kemp G, Crossley KM. Knee Joint Stiffness 
During Walking in Knee Osteoaiiln·itis. Arthritis Care Res. 2010 Jan 15;62(1):38-44. 
12. Ghonn·awi I-IM, Mandi LA, Rutledge J, Alexiades MM, Mazumdar M. Is there a role for 
expectation maximization imputation in addressing missing data in research using 
WOMAC questionnaire? Comparison to the standai·d mean approach and tutorial. BMC 
Musculoskeletal Disorders. 2011; 12(109): DOI: 10.l 186/1471-2474-12-109. 
13. Kenward MG, Roger JH. The use of baseline covariates in crossover studies. 
Biostatistics, Jan 2010; 1-17. 
14. Choi K, Hong T, Lee J. On compai-ison of SAS Codes with GLM and MIXED for the 
crossover studies with QT interval data. Transl Clin Pharamcol, 2014; 78-82. 
15. Yai·andi, HN. Paper SD04- Crossover Designs and Proc Mixed in SAS. 
http:// analytics .ncsu.edu/ sesug/2004/SD04-Y ai·andi. pdf 
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12. Appendices 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued: 25SEP2019 
12.1. 
Notable Abnormal Vital Signs 
Table 2 
Notable Abnormal Vital Signs 
Parameter 
Actual Value 
Change from Baseline 
Pulse 
<40bpm 
>= 15 bpm increase from baseline 
> 120bpm 
>= 15 bpm decrease from baseline 
Systolic blood 
<80mmHg 
>= 20 mmHg increase from baseline 
nressure 
> 180mmHg 
>= 20 mmHg decrease from baseline 
Diastolic blood 
<50mmHg 
>= 15 mmHg increase from baseline 
pressure 
> 105mmH.g 
>= 15 mmHg decrease from baseline 
Temperature 
NA 
>= 2 F increase from baseline 
>= 2 F decrease from baseline 
12.2. 
Schedule of Study Procedures 
Treatment Phase 
Screening 
These events are repeated during each of the 4 Treatment Periods. 
Trial Procedure 
Visitl 
Washout 
Treatment Periods will be seoarated bv a washout of3 to 7 davs 
Screening 
Phase 
Visit2 
Continue 
Visit3 
Start of 
Treatment Period 
End of 
Treatment Period 
Outsubiect 
Treatment Period 
Day-4 to-1 
Day-18 to -5 
(+3 d) 
Day 1 
2,4, 6, 8hrs 
Day2-3 
Day4 
2, 4, 6 hrs 
Signed Informed Consent 
X 
Inclusion/Exclusion criteria review 
X 
X 
X 
Subject demographics 
X 
. 
Medic.al history 
X 
Prior/Concomitant medications 
X 
X 
X 
History of drug, alcohol and tobacco use 
X 
Body weigh~ height and BM! 
X 
Physical examination 
X 
30 
End of Study 
(Phone call) 
7-1 0 days after 
8hrs 
Treatment Period 
4 of4 
X 
. 


Bayer HealthCare 
19783 
QA assessment of the knee 
(includes radio9Tilnh) 
Vital signs:i. 
Clinical Laboratory Tests 
chemi<mv, urinalysis) 
Alcohol breath/saliva test 
Urine drug screen 
(hematology, 
Urine pregnancy test (if applicable) 
Accurate pain reporting training 
Appropriate expectations training 
Regional Pain Scale 
48 hour WOMAC Pain 
48 hour WOMAC Stiffuess 
48 hour WOMAC Function 
24 hour Average Pain Intensity NRS 
Baseline Sti:ffhess questionnaire 
Joint Stiffuess SeverityNRS 
Washout from analgesic medications 
Daily BASS 
Accelerometer Setup 
Accelerometer Use 
Accelerometer Data Download 
Accelerometer Battery Charge 
Current Pain Intensity NRS 
STEPP 
10 point pain NRS 
Randomization 
IMP self-administration 
IMP compliance review 
Subject Global hnpression of Change 
Subject treatment preference 
Qualitative interview 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
. 
X 
X' 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued: 25SEP2019 
X 
X 
X 
X 
X 
X 
X" 
X 
X 
X 
X 
X 
X 
X 
X 
X' 
X' 
X' 
X' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X' 
X 
X 
X 
X' 
X' 
X' 
X' 
X' 
X 
X 
X' 
X' 
X 
X 
X 
X 
a Vital signs (blood pressure, respiratory rate, heart rate and body temperature after 5 minutes of rest in a sitting position). After the screening assessment, vital signs assessments will consist of heart rate and 
blood pressure 
11 WOMAC pain subscale average score must be ~4.0 on 0-10 scale to be eligible for Randomization on Day 1 of Treatment Period 1 of 4 
c Screening STEPP is to confirm subject is capable of petforming the exercise and completing the pre-STEPP and post-STEPP NRS 
d A washout period of 3 to 7 days will occur at the start of Treatment Periods: 2 of 4, 3 of 4, and 4 of 4. During each washout, only acetaminophen ER will be allowed as rescue therapy (as needed up to 2000 
mg/day) 
c Current pain intensity performed immediately prior to the pre-dose STEPP and hourly at 1, 3, 5 and 7 hours after dosing 
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19783 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued: 25SEP20!9 
r Subjects will complete the 0-10-point NRS pain scale pre-dose (time 0) and immediately before (at rest) and then 2-5 minutes after completing the STEPP at 2, 4, 6 and 8 hours post-dose. Additionally, 
subjects will complete hourly current pain intensity rating 1, 3, 5, and 7 hours post-dose when not completing the STEPP 
i; Subjects will be randomized to a treatment sequence at Treatment Period 1 of 4 
h Subjects will only take the 8 AM dose that day 
i Completed at Visit 3, Treatment Period 4 of 4 only or if the subject is withdrawn prior to completion 
32 


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Draft Statistical Analysis Plan, Version 1.0 
19783 
Date Issued: 25SEP2019 
12.3. 
WOMAC Function Subscale Questions 
33 
CCI


Bayer HealthCare 
19783 
Draft Statistical Analysis Plan, Version 1.0 
Date Issued: 25SEP2019 
34 
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19783 
Draft Statistical Analysis Plan, VcrsiOn 1.0 
Date Issued: 25SEP2019 
35 
CCI