Randomized, Controlled, Double-blind, Placebo-controlled, Multi-center Hypothesis-finding Trial to Compare the Efficacy and Safety of a 10% Naproxen Gel vs. a 2.32% Diclofenac Diethylamine Gel and Placebo in the Treatment of Acute Soft Tissue Injuries of the Lower Extremities
Phase: PHASE2
Conditions: Soft Tissue Injury
Sponsor: Bayer

 
Document Type: 
Clinical Study Protocol 
Official Title: 
Randomized, Controlled, Double-blind, Placebo-controlled, 
Multi-center Hypothesis-finding Trial to Compare the 
Efficacy and Safety of a 10% Naproxen Gel vs. a 2.32% 
Diclofenac Diethylamine Gel and Placebo in the Treatment 
of Acute Soft Tissue Injuries of the Lower Extremities 
NCT Number: 
NCT05026320 
Document Date: 
09-Nov-2021 
 

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Title Page 
Protocol Title: Randomized, Controlled, Double-blind, Placebo-controlled, Multi-center 
Hypothesis-finding Trial to Compare the Efficacy and Safety of a 10% Naproxen Gel vs. a 
2.32% Diclofenac Diethylamine Gel and Placebo in the Treatment of Acute Soft Tissue Injuries 
of the Lower Extremities 
Protocol Number: 21559 
 
Amendment Number: 3 
Compound Number: BAY H6689 
Study Phase: 2 
 
 
Sponsor Name: Bayer Healthcare LLC. 
Legal Registered Address: 100 Bayer Boulevard, Whippany NJ 07981-0915, USA 
Regulatory Agency Identifier Number(s): EudraCT 2020-004343-92 
 
Approval Date: 09 Nov 2021 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
performance 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 

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Sponsor Signatory - amended 
 
 
 
 
 
 
 
Global Medical Category Pain 
Medical and Clinical Affairs 
Bayer Healthcare LLC. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Medical Monitor name and contact information will be provided separately. 
 
 
 
PPD
PPD
PPD

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Protocol Amendment Summary of Changes Table 
 
Protocol Amendment (Version 2.0) 
 
The following sections were amended from Version 1.0 to Version 2.0.  Also modified were the  
BAY No., version number, date and Table of Contents. 
 
Section 1.3  Schedule of Activities – amended (changes only reflected here) 
 
Trial Procedure 
Screening Phase 
Treatment Phase 
Screening  Baseline 
Day 1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Visit 1 
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Visit 11 
Hours Post First Dose  
12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs 108 hrs 120 hrs 
Prior and Concomitant / Medication 
History and Diary Reviewa 
X 
 
 
X 
X 
X 
X 
X 
    X 
X 
X 
X 
X 
Vital signs (incl. temperature)b 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Physical examination (injury 
assessment)c 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine pregnancy test 
Xf 
 
 
 
 
 
 
 
 
 
 
Xf 
 
Randomization/Kit assignment 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
IMP administratione 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Global Assessments 
 
 
 
 
Xg 
 
Xg 
 
Xg 
 
 
 
Xg 
a Diary review begins at Visit 2 
b Vital signs (blood pressure, respiratory rate, heart rate and body temperature after 5 minutes of rest in a sitting position). 
c Full physical exam and injury assessment at Visit 1, limited exam (injury assessment) at all other visits 
d Randomization to treatment occurs only for eligible patients. 
e All topical IMP treatments must be weighed on a digital scale, then applied by the unblinded study staff at the site.  Patient will wear a blindfold when being treated. 
f Urine pregnancy test must be performed (for female patients) and the results must be negative (not pregnant) before dosing and at Visit 10  
g Assessments by the patient will be completed before first rescue medication is taken.  If between visits, then the investigator will complete assessments at the next scheduled visit. 
 
 
 
 

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Protocol Amendment 2 (Version 3.0) 
 
The following sections were amended from Version 2.0 to Version 3.0.   
 
Type of Amendment: Substantial 
Significant Changes: 
Changes which are considered significant or substantial have been made to the following sections 
 reflected below: 
 
Page 
Number 
Section 
Number 
Paragraph or Bullet point/number 
21 
5.2 
Exclusion Criteria 15 
15. Ice and compression are prohibited from the time of injury 
through the final evaluation. Application of standard care by 
rest, ice, compression (non-occlusive bandage) or elevation 
(RICE) may be considered at the discretion of the 
investigator 
41 
9.1 
Statistical Hypotheses 
The purpose of the study is to gather preliminary data for the 
efficacy and safety of the IMP.  Therefore, there is no statistical 
hypotheses to be formulated. 
For the comparison of the test gel vs. placebo, the primary 
efficacy hypothesis to be tested is the equality of Algometry 
AUC 0-72; the second is the POM VAS AUC 0-72. 
41 
9.2 
Sample Size Determination 
The study is not statistically powered. From feasibility point of 
view, sufficient number of participants will be randomized to 
study intervention in order to achieve an estimated total of 30 
evaluable participants for each active treatment (naproxen gel or 
diclofenac gel) and 15 evaluable participants for placebo gel. 
This is a proof of concept study and therefore a specific 
statistical power calculation cannot be applied, however, 
assuming a comparable effect of the test gel vs. diclofenac – 
as suggested by pharmacological studies-, reference is made 
to  similar studies (Predel, Br J Sports Med 2004;38:318–
323), in which the standardized effect sizes of Algometry 
AUC 0-72 and POM VAS AUC 0-72 were over 1; with 30:15 
Protocol Amendment Summary of Changes Table 

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patients, a drop out rate of 10%, and a two-sided significance 
level α = 5%, a power 1 – β of about 80% is reached.  
44 
9.3 
Analysis Sets – Per Protocol 
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 and 
other efficacy endpoints to assess the robustness of the results 
based on PP Population. 
44 
9.4 
Statistical Analysis  
This section is a summary of the planned statistical analyses of 
the most important endpoints including primary and secondary, 
and other key endpoints. 
 
 
Additional Changes:  
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Amendment 3 (Version 4.0) 
 
The following sections were amended from Version 3.0 to Version 4.0.    
 
Type of Amendment: Substantial 
Significant Changes: 
Changes which are considered significant or substantial have been made to the following sections 
 reflected below: 
 
Sponsor Signatory – amended  
 
  
, Global Medical Affairs 
Bayer Healthcare LLC. 
 
 
 
Global Medical Category Pain 
Medical and Clinical Affairs 
Bayer Healthcare LLC. 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Amendment Summary of Changes Table 
PPD
PPD
PPD
PPD

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Table of Contents 
Title Page ................................................................................................................................... 1 
Sponsor Signatory - amended ................................................................................................. 2 
Protocol Amendment Summary of Changes Table ............................................................... 3 
1. 
Protocol Summary ........................................................................................................... 10 
1.1 
Synopsis ......................................................................................................................... 10 
1.2 
Scheme ........................................................................................................................... 13 
1.3 
Schedule of Activities (SoA) - amended ....................................................................... 14 
2. 
Introduction ..................................................................................................................... 15 
2.1 
Study Rationale .............................................................................................................. 15 
2.2 
Background .................................................................................................................... 15 
2.3 
Benefit/Risk Assessment ............................................................................................... 16 
2.3.1 
Risk Assessment ......................................................................................................... 17 
2.3.2 
Benefit Assessment ..................................................................................................... 19 
2.3.3 
Overall Benefit: Risk Conclusion ............................................................................... 19 
3. 
Objectives and Endpoints ............................................................................................... 20 
4. 
Study Design .................................................................................................................... 21 
4.1 
Overall Design ............................................................................................................... 21 
4.1.1 
Study Design Phases ................................................................................................... 21 
4.1.1.1 
Screening/Baseline Phase ........................................................................................ 21 
4.1.1.2 
Treatment Phase ...................................................................................................... 21 
4.1.1.3 
Follow-up Phase ...................................................................................................... 22 
4.2 
Scientific Rationale for Study Design ............................................................................ 22 
4.3 
Justification for Dose ..................................................................................................... 22 
4.4 
End of Study Definition ................................................................................................. 22 
5. 
Study Population ............................................................................................................. 23 
5.1 
Inclusion Criteria ........................................................................................................... 23 
5.2 
Exclusion Criteria - Amended........................................................................................ 23 
5.3 
Lifestyle Considerations ................................................................................................ 25 
5.4 
Screen Failures ............................................................................................................... 25 
5.5 
Criteria for Temporarily Delaying Study Intervention Administration ......................... 25 
6. 
Study Intervention(s) and Concomitant Therapy ........................................................ 26 
6.1 
Study Intervention Administered ................................................................................... 26 
6.2 
Identity of Study Interventions ...................................................................................... 28 
6.3 
Preparation/Handling/Storage/Accountability ............................................................... 28 
6.4 
Measures to Minimize Bias: Randomization and Blinding ........................................... 29 
6.5 
Study Intervention Compliance ..................................................................................... 30 
6.6 
Dose Modification ......................................................................................................... 30 
6.7 
Stopping Rules ............................................................................................................... 31 
6.8 
Continued Access to Study Intervention after the End of the Study ............................. 31 
6.9 
Treatment of Overdose................................................................................................... 31 
6.10 Concomitant Therapy ..................................................................................................... 31 
6.10.1 Rescue Medicine ......................................................................................................... 32 
7. 
Discontinuation of Study Intervention and Participant .............................................. 33 
7.1 
Discontinuation of Study Intervention ........................................................................... 33 

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7.2 
Participant Discontinuation/Withdrawal from the Study ............................................... 33 
7.3 
Lost during the Treatment Phase ................................................................................... 33 
8. 
Study Assessments and Procedures ............................................................................... 34 
8.1 
General Procedures ........................................................................................................ 34 
8.1.1 
Screening Phase Visit 1 - (Day 1)............................................................................... 34 
8.1.2 
Baseline Visit 1 - (Day 1) ........................................................................................... 35 
8.1.3 
Visit 2 (Day 2 morning) .............................................................................................. 35 
8.1.4 
Visit 3 (Day 2 evening)............................................................................................... 36 
8.1.5 
Visit 4 (Day 3 morning) .............................................................................................. 36 
8.1.6 
Visit 5 (Day 3 evening)............................................................................................... 37 
8.1.7 
Visit 6 (Day 4 morning) .............................................................................................. 37 
8.1.8 
Visit 7 (Day 4 evening)............................................................................................... 38 
8.1.9 
Visit 8 (Day 5 morning) .............................................................................................. 38 
8.1.10 Visit 9 (Day 5 evening)............................................................................................... 39 
8.1.11 Visit 10 (Day 6 morning) ............................................................................................ 39 
8.1.12 Visit 11 (Day 6 evening, End of Study) ..................................................................... 40 
8.2 
Efficacy Assessments ..................................................................................................... 40 
8.2.1 
Assessment of Pain on Movement .............................................................................. 40 
8.2.2 
Algometry ................................................................................................................... 40 
8.2.3 
Global Assessments of Efficacy and Tolerability ...................................................... 41 
8.2.4 
Sensory Questions ...................................................................................................... 42 
8.3 
Safety Assessments ........................................................................................................ 42 
8.3.1 
Physical Examinations ................................................................................................ 42 
8.3.2 
Vital Signs .................................................................................................................. 43 
8.3.3 
Pregnancy Testing ...................................................................................................... 43 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting .. 43 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ....................... 43 
8.4.2 
Method of Detecting AEs and SAEs .......................................................................... 44 
8.4.3 
Follow-up of AEs and SAEs....................................................................................... 44 
8.4.4 
Regulatory Reporting Requirements for SAEs........................................................... 44 
8.4.5 
Pregnancy ................................................................................................................... 44 
8.5 
Pharmacokinetics ........................................................................................................... 45 
8.6 
Genetics or Pharmacogenomics ..................................................................................... 45 
8.7 
Biomarkers ..................................................................................................................... 45 
8.8 
Immunogenicity Assessments ........................................................................................ 45 
8.9 
Health Economics .......................................................................................................... 45 
9. 
Statistical Considerations ............................................................................................... 46 
9.1 
Statistical Hypotheses - Amended ................................................................................. 46 
9.2 
Sample Size Determination - Amended ......................................................................... 46 
9.3 
Analysis Set - Amended ................................................................................................. 46 
9.4 
Statistical Analyses - Amended ..................................................................................... 46 
9.4.1 
General Considerations ............................................................................................... 47 
9.4.2 
Primary Endpoint ........................................................................................................ 47 
9.4.3 
Secondary Endpoint .................................................................................................... 47 
9.4.4 
Other Endpoints .......................................................................................................... 47 
9.4.5 
Safety Analysis ........................................................................................................... 48 
9.5 
Interim Analysis ............................................................................................................. 48 
10. Supporting Documentation and Operational Considerations .................................... 49 

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10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........................ 49 
10.1.1 Regulatory and Ethical Considerations ...................................................................... 50 
10.1.2 Financial Disclosure ................................................................................................... 50 
10.1.3 Funding ....................................................................................................................... 50 
10.1.4 Informed Consent Process .......................................................................................... 51 
10.1.5 Data Protection and Confidentiality ........................................................................... 52 
10.1.6 Compensation for Health Damage of Participants/Insurance ..................................... 52 
10.1.7 Committees Structure ................................................................................................. 52 
10.1.8 Dissemination of Clinical Study Data ........................................................................ 52 
10.1.9 Data Quality Assurance .............................................................................................. 53 
10.1.10 Source Documents ...................................................................................................... 53 
10.1.11 Missing Data ............................................................................................................... 54 
10.1.12 Audit and Inspection ................................................................................................... 54 
10.1.13 Archiving .................................................................................................................... 54 
10.1.14 Study and Site Start and Closure ................................................................................ 55 
10.1.15 Publication Policy ....................................................................................................... 55 
10.2 Appendix 2: Clinical Laboratory Tests .......................................................................... 56 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures ............................................. 56 
10.3.1 Definition of AE ......................................................................................................... 56 
10.3.2 Definition of SAE ....................................................................................................... 58 
10.3.3 Recording and Follow-Up of AE and/or SAE ............................................................ 59 
10.3.4 Reporting of SAEs ...................................................................................................... 61 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ......... 61 
10.5 Appendix 5: Abbreviations ............................................................................................ 63 
11. References ........................................................................................................................ 65 
 
Table of Tables 
Table 1 – Dosing Example ....................................................................................................... 27 
Table 2 – Study Interventions .................................................................................................. 28 
 
 

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1. 
Protocol Summary 
1.1 
Synopsis 
 
Protocol Title: Randomized, Controlled, Double-blind, Placebo-controlled, Multi-center 
Hypothesis-finding Trial to Compare the Efficacy and Safety of a 10% Naproxen Gel vs. a 
2.32% Diclofenac Diethylamine Gel and Placebo in the Treatment of Acute Soft Tissue Injuries 
of the Lower Extremities 
 
Rationale: Proof of concept study to determine the effectiveness of naproxen gel 10% in 
participants with lower extremity injuries. 
 
 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
 
To assess the effectivenss of a 
naproxen gel 10%,diclofenac  
diethylamine gel 2.32% and placebo for 
relieving tenderness to pressure in 
subjects with acute soft tissue injuries 
of the lower extremities.  
 
Tenderness (Algometry) over the initial 
72 hours (Algometry AUC 0-72). 
Secondary 
 
 
To assess the safety of a naproxen gel 
10%,diclofenac  diethylamine gel 2.32% 
and placebo during a 5 day treatment 
period.  
 
To assess adverse events. 
 
Safety (percentage of subjects with at 
least one TEAE); 
 
Incidence of adverse events. 

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Objectives 
Endpoints 
Other 
 
 
To evaluate pain on movement and 
tenderness to pressure over various 
time periods and at individual time 
points. 
 
VAS POM over the initial 12-hours (VAS 
AUC 0-12), 24-hours (VAS AUC 0-24), 
36-hours (VAS AUC 0-36), 48-hours (VAS 
AUC 0-48), 60-hours (VAS AUC 0-60), 
72-hours (VAS AUC 0-72), and 120 hours 
(VAS AUC 0-120); 
 
Change of VAS POM at hours 12,  24, 36, 
48, 60, 72 and 120 from baseline; 
 
Change of Algometric Tenderness 
(N/cm2) at hours 12, 24, 36, 48, 60, 72 
and 120 from baseline; 
 
Algometric Tenderness (N/cm2)  over the 
initial 12-hours (N/cm2 AUC 0-12), 24-
hours (N/cm2 AUC 0-24), 36-hours (N/cm2 
AUC 0-36), 48-hours (N/cm2 AUC 0-48) 
60-hours (N/cm2 AUC 0-60) and 120 
hours (N/cm2AUC 0-120); 
 
Ratio of algometry injured/contralateral 
sites over 72 hours and 120 hours (N/cm2 
Ratio AUC 0-72 and N/cm2 Ratio AUC 0-
120); 
 
Percent of subjects with no (zero) VAS 
POM at 120 hours; 
 
Global assessment of treatment efficacy 
at 24 hours, 48 hours, 72 hours and 120 
hours by patients using a 5-point scale 
(0=none, 1=poor, 2=fair, 3=good, 
4=excellent); 
 
Global assessment of treatment efficacy 
at 24 hours, 48 hours, 72 hours and 120 
hours by investigators using a 5-point 
scale (0=none, 1=poor, 2=fair, 3=good, 
4=excellent). 
 
Overall Design: This is a randomized (2:2:1/naproxen:diclofenac:placebo), stratified by injury 
(contusion or sprain/strain) active- and placebo-controlled (vehicle), double-blind, multi-center 
(3 sites), parallel study. 
 
Brief Summary: 
This is a 6-day clinical trial to test the hypothesis that naproxen gel 10% safely and effectively 
relieves tenderness to pressure in subjects with acute soft tissue injuries of the lower extremities.   
Subjects who present to the study within 3 hours of injury will be recruited for the study. In order 
to assure adequate representation of different types of soft tissue injuries, subjects may enter the 
study with a lower extremity sprain/strain injury or a lower extremity contusion injury.  Eligible 
subjects will be selected immediately following screening/baseline evaluations. Following 
selection, subjects will enter the Treatment Phase and will be randomly assigned to one of the 
three treatment groups- naproxen topical gel 10% (test); diclofenac diethylamine topical gel 
2.32% (active comparator); or placebo gel.   The randomization assignment is such that there is a 

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1 in 5 chance of receiving the placebo treatment. Treatment consists of a twice daily application 
(approximately 12 hours apart) of the assigned topical gel over 5 consecutive days, beginning on 
the evening of Day 1 and ending (last application) on the morning of Day 6 (total of 10 
applications).  All treatment applications will be performed by study staff at the site. After the 
first treatment, two visits each day for five consecutive days are required.  Patients who 
experience a treatment failure can have the option of taking rescue medication for pain relief. 
During the screening/baseline and follow-up treatment visits, tenderness will be measured by the 
pressure required to elicit a response. Pain on movement will also be rated by the subject using a 
100 mm visual analogue scale.  
Approximately 100 participants will be screened to achieve 75 randomized to study intervention 
for an estimated total of 30 evaluable participants per each active treatment and 15 participants in 
the placebo treatment. 
Study Duration: 6 days 
Treatment Duration: 6 days 
Visit Frequency: After the first treatment, two visits each day for five consecutive days 
Condition/Disease: Soft tissue injury, either a sprain/strain or contusion 
Study Hypothesis: Topical naproxen gel, 10% effectively relieves tenderness to pressure in 
patients with acute soft tissue injuries 
Health Measurement/Observation: Algometry measurements for tenderness and Visual 
Analog Scales for pain will occur pre and post topical treatment. 
Number of Participants: Approximately 100 participants will be screened to achieve 75 
randomized to study intervention for an estimated total of 30 evaluable participants per each 
active cohort and 15 participants in the placebo cohort. 
Intervention Groups: Participants will be randomized in 2:2:1 fashion and stratified by injury 
type with at least 25 participants in the Sprain/Strain cohort and at least 50 participants in the 
Contusion cohort. 
Data Monitoring/Other Committee: No 

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1.2 
Scheme 
Pre-
screening 
Screening 
Baseline 
Treatment Phase 
Trial 
Days 
Day -1 
Day 1 
Injury 
Assessment 
Day 1  
Visit 1  
Day 2 
Visit 2 
Day 2 
Visit 3 
Day 3 
Visit 4 
Day 3      
Visit 5 
Day 4 
Visit 6 
Day 4 
Visit 7    
Day 5    
Visit 8 
Day 5    
Visit 9 
Day 6 
Visit 10 
Day 6 
Visit 11 
Clinic 
Visit 
NA 
Evening (6pm – 10pm) Morning 
Evening 
Morning 
Evening 
Morning 
Evening 
Morning Evening Morning 
Evening 
 
Sports 
related 
lower 
extremity 
injury within  
3 hours of 
screening 
            Post first dose  12 Hours 
24 Hours 
36 Hours 
48 Hours 
60 Hours 
72 Hours 
84 Hours 96 Hours 108 Hours 120 Hours 
Contusion 
Cohort 
 
n≥50 
 
 
 
POM  
VAS 
 
Algometry 
 
 
 
 
 
POM     
VAS 
 
Algometry 
 
Global 
Assessment 
 
 
 
POM  
VAS 
 
Algometry 
 
 
 
POM      
VAS 
 
Algometry 
 
Global 
Assessment 
 
 
 
POM   
VAS 
 
Algometry 
 
 
 
 
POM      
VAS 
 
Algometry 
 
Global 
Assessment 
 
 
 
 
POM      
VAS 
 
Algometry 
 
Global 
Assessment 
 
Patient 
Discharged 
POM  
VAS 
 
Algometry 
 
 
-------------------------- Dosing every 12 hours (nominal time ± 1 hour) ----------------------------- 
 
 
Sprain/Strain 
Cohort 
 
n≥25 
 
 
 
POM  
VAS 
 
Algometry 
 
 
 
POM  
VAS 
 
Algometry 
 
 
 
POM     
VAS 
 
Algometry 
 
Global 
Assessment 
 
 
 
 
POM  
VAS 
 
Algometry 
 
 
 
POM      
VAS 
 
Algometry 
 
Global 
Assessment 
 
 
 
 
POM    
VAS 
 
Algometry 
 
 
 
 
POM      
VAS 
 
Algometry 
 
Global 
Assessment 
 
 
 
 
 
POM      
VAS 
 
Algometry 
 
Global 
Assessment 
 
Patient 
Discharged 
 = Injury stratification (contusion or sprain/strain cohort) after  
 
 
 assessment and prior to randomization 
 = Randomization at Visit 1 into one of three treatments and first dose:         
 naproxen gel 10% 
 diclofenac diethylamine gel 2.32% 
 placebo 
 
Nominal dosing times (am and pm) established at Visit 1 
 
= Patient to take IMP at the site (am and pm)  
 
 
 
POM = Pain on movement 
VAS = Visual analog scale (100 mm) 
 
Patient to keep a daily diary for concomitant/rescue medications and 
adverse events 

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1.3 
Schedule of Activities (SoA) - amended 
Trial Procedure 
Screening Phase 
Treatment Phase 
Screening  Baseline 
Day 1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Visit 1 
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Visit 11 
Hours Post First Dose  
12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs 108 hrs 120 hrs 
Signed Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant / Medication 
History and Diary Reviewa 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
History of drug, alcohol and tobacco 
use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, height, and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (incl. temperature)b 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Physical examination (injury 
assessment)c 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Injury Stratification (cohort) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
Xf 
 
 
 
 
 
 
 
 
 
 
Xf 
 
Diary distribution/training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization/Kit assignment 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
IMP administratione 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense rescue medication 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Rescue medicine accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Algometry 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
POM VAS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Global Assessments 
 
 
 
 
Xg 
 
Xg 
 
Xg 
 
 
 
Xg 
Sensory Questions 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Diary and rescue medicine return 
 
 
 
 
 
 
 
 
 
 
 
 
X 
End of Study (pt. discharged) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Diary review begins at Visit 2 
b Vital signs (blood pressure, respiratory rate, heart rate and body temperature after 5 minutes of rest in a sitting position). 
c Full physical exam and injury assessment at Visit 1, limited exam (injury assessment) at all other visits 
d Randomization to treatment occurs only for eligible patients. 
e All topical IMP treatments must be weighed on a digital scale, then applied by the unblinded study staff at the site.  Patient will wear a blindfold when being treated. 
f Urine pregnancy test must be performed (for female patients) and the results must be negative (not pregnant) before dosing.  
g Assessments by the patient will be completed before first rescue medication is taken.  If between visits, then the investigator will complete assessments at the next scheduled visit. 

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2. 
Introduction 
 
 The product is to be used for the temporary relief of minor aches & pains of 
muscles & joints.  This proof-of-concept trial will assess the efficacy and safety of a newly 
developed 10% naproxen gel formulation compared to a commercially available topical 
nonsteroidal anti-inflammatory drug (NSAID) gel and placebo in the treatment of common 
sports related, acute traumatic injuries. 
 
2.1 
Study Rationale 
This is a proof of concept study to guide decision-making for the naproxen topical gel 
development program.  Bayer needs information on the product’s attributes to help determine 
whether to support further clinical development of this topical gel formulation.  Assuming this 
pilot study is successful, the data will provide supportive data for future clinical studies and a 
regulatory submission. 
 
2.2 
Background 
NSAIDs effectively reduce the pain and disability associated with acute ankle sprain and 
other soft tissue traumas (1,2,3).  In some patients however, non-selective NSAIDs, which 
inhibit both cyclooxygenase (COX)-1 and COX-2, may cause significant adverse events 
including upper gastrointestinal intolerance and have been associated with serious adverse 
events such as ulcers and bleeding.  Risk of gastrointestinal bleeding is reduced with 
decreasing dose and treatment duration of non-selective NSAIDs (4). 
Topical delivery of an NSAID that is efficacious and limits systemic exposure might offer an 
improvement over an oral formulation (5) in patients with acute musculoskeletal pain.  Minor 
aches and pains of muscles and joints are amenable to treatment with topical products as the 
site of injury is closely to the overlying skin where the topical products can be applied. 
Topical NSAIDs have been shown to be effective in the treatment of aches and pains of 
muscles and joints (1,6,7,8,9,10).  Although skin reactions have been reported with the use of 
locally delivered NSAIDs, reports of systemic adverse events from the use of these topical 
products are infrequent.  A systematic review found that local and systemic adverse events 
with topical NSAIDs had a low incidence and are not different from placebo (7).  There does 
not appear to be any significant association of these formulations with gastrointestinal or renal 
side effects (11,12,13).  A recent systematic review and meta-analysis of topical NSAID 
safety in osteoarthritis found no significant difference in the odds for gastrointestinal 
disorders between topical NSAIDs and placebo (odds ratio 0.96, 95% CI 0.73–1.27, 14). 
Naproxen and naproxen sodium have been commercially available in a variety of dosage 
forms for decades.   Naproxen gel 10% is an OTC topical analgesic gel currently marketed in 
several countries where it is indicated for a variety of conditions, characterized by pain and 
inflammation.  It has been shown to reduce pain and inflammation in patients with acute soft 
tissue injuries (15). 
Based on this body of evidence supporting topical NSAIDs for acute musculoskeletal pain, 
  To date, nonclinical safety 
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studies conducted include the evaluation of skin sensitization potential utilizing the mouse 
local lymph node assay, a seven-day dermal dose-range finding pilot study and a 28-day 
repeated dose study including a four-week recovery period, the latter two studies conducted in 
minipigs (16).  Preclinical studies with the naproxen gel formulation 
 
 
 
2.3 
Benefit/Risk Assessment 
Patients with a sports-related injury to the lower extremities who would typically take over-
the-counter NSAIDs for pain relief will be enrolled in this study.  Patients who experience a 
treatment failure can have the option of taking rescue medication for pain relief. 
 
During the study, patients will be closely monitored for evidence of adverse events.  
Weighing between the potential risks of topical analgesics associated with the study and given 
the ability to mitigate risks through close monitoring, this study is considered clinically and 
ethically acceptable. 
Relevant emerging safety data, e.g., serious adverse events (SAEs), suspected unexpected 
serious adverse reactions (SUSARs), and serious safety-related protocol deviations, will be 
communicated as soon as possible between the sponsor, all study sites and investigators and 
trial subjects according to the requirements of the EMA guideline on strategies to identify 
risks for early clinical trials.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of naproxen gel 10% and diclofenac diethylamine 2.32% may be 
found in the Investigator’s Brochure (IB) and Voltaren Schmerzgel forte Package Leaflet 
respectively (16,17). 
The potential impact of COVID-19 on study participants will be evaluated before the start of 
enrollment and monitored during the study in accordance with European Medicines Agency 
guidance (18). 
 
 
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2.3.1 
Risk Assessment 
 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Intervention 
The risks associated with 
naproxen gel 10% are 
mostly cutaneous and 
nonserious in nature and 
include application site 
reactions such as erythema, 
pruritus, skin irritation, 
burning skin sensation, and 
contact dermatitis. Subjects 
with hypersensitivity to 
naproxen, or to any 
excipient in the test 
products should avoid 
exposure and should be 
excluded from this study.  
 
 
Naproxen Topical Gel IB 
section 5.3.3.5 Adverse 
events 
The exclusion criteria for the 
study and the medical 
oversight of its conduct for 
the detection and treatment 
(if necessary) of adverse 
events are adequate for 
subject safety and no special 
risk mitigation measures are 
necessary. 
The following strategies (as 
numbered below) will be 
employed to mitigate 
adverse event risks: 
 
5.2 Exclusion criteria 
6.6 Dose modification 
6.7 Stopping rules 
6.9 Treatment of overdose 
7.1 Discontinuation of study 
intervention 
7.2 Participant 
discontinuation/ Withdrawal 
from study 
8.3 Safety assessments 
8.4.3 Follow up of AEs and 
SAEs 
 
Study Procedures 
Subject may have an 
underlying medical 
condition uncovered during 
screening and baseline 
procedures. 
 
Investigator will advise 
subject to seek appropriate 
medical attention. 

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Other 
Subject may present to the 
clinic with an injury that is 
more serious than described 
by the inclusion criteria 
Voltaren gel may cause rare 
and very rare side effects 
that may be serious:  
Rare side effects (may 
affect up to 1 in 1,000 
people) 
• Skin inflammation with 
blistering (bullous 
dermatitis) 
Very rare side effects (may 
affect up to 1 in 10,000 
people) 
• wheezing, shortness of 
breath, or tightness in the 
Chest (asthma) 
• Swelling of the face, lips, 
tongue, or throat 
(Angioedema) 
Other side effects with 
Voltaren gel include skin 
reactions, gastrointestinal 
complaints, 
hypersensitivity reactions, 
and photosensitivity  
Voltaren Pain Gel applied 
extensively to the skin and 
used over a longer period of 
time may cause systemic 
side effects (e.g. renal, 
hepatic or gastrointestinal 
side effects, systemic 
hypersensitivity reactions)  
Package leaflet: Information 
for users, Voltaren 
Schmerzgel forte, 23.2 mg/g 
Gel, April 2019. 
 
Investigator will advise 
subject to seek appropriate 
medical attention if the 
injury is more serious than 
allowed by the inclusion 
criteria. 
 
The exclusion criteria for the 
study and the medical 
oversight of its conduct for 
the detection and treatment 
(if necessary) of adverse 
events are adequate for 
subject safety and no special 
risk mitigation measures are 
necessary. 
The following strategies (as 
numbered below) will be 
employed to mitigate 
adverse event risks: 
 
5.2 Exclusion criteria 
7.1 Discontinuation of study 
intervention 
7.2 Participant 
discontinuation/ Withdrawal 
from study 
8.3 Safety assessments 
8.4.3 Follow up of AEs and 
SAEs 
 
Subjects participating in this 
study will have a defined  
dose and short term 
exposure to Voltaren gel and 
will be administered at the 
study site by a professional 
 
 
 
 
 
 

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2.3.2 
Benefit Assessment 
Potential benefits may include: 
 Potential benefit of receiving study intervention during the study duration that may 
result in decreased tenderness and pain of the injured extremity 
 Medical evaluations/assessments associated with study procedures (e.g., physical 
exam, vital signs, etc.). 
 
2.3.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified using a topical medication are justified by the anticipated benefits 
that may be afforded to participants with a soft tissue injury. 
 
 
 

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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
 
To assess the effectivenss of a 
naproxen topical gel 10%,diclofenac  
diethylamine 2.32% and placebo for 
relieving tenderness to pressure in 
subjects with acute soft tissue injuries 
of the lower extremities. 
 
Tenderness (Algometry) over the initial 
72 hours (Algometry AUC 0-72). 
Secondary 
 
 
To assess the safety of a naproxen gel 
10%,diclofenac  diethylamine gel 2.32% 
and placebo during a 5 day treatment 
period; 
 
To assess adverse events. 
 
Safety (percentage of subjects with at 
least one TEAE); 
 
Incidence of adverse events. 
Other 
 
 
To evaluate pain on movement and 
tenderness to pressure over various 
time periods and at individual time 
points. 
 
VAS POM over the initial 12-hours (VAS 
AUC 0-12), 24-hours (VAS AUC 0-24), 
36-hours (VAS AUC 0-36), 48-hours 
(VAS AUC 0-48), 60-hours (VAS AUC 0-
60), 72-hours (VAS AUC 0-72), and 120 
hours (VAS AUC 0-120); 
 
Change of VAS POM at hours 12,  24, 
36, 48, 60, 72 and 120 from baseline; 
 
Change of Algometric Tenderness 
(N/cm2) at hours 12, 24, 36, 48, 60, 72 
and 120 from baseline; 
 
Algometric Tenderness (N/cm2)  over the 
initial 12-hours (N/cm2 AUC 0-12), 24-
hours (N/cm2 AUC 0-24), 36-hours 
(N/cm2 AUC 0-36), 48-hours (N/cm2 AUC 
0-48) 60-hours (N/cm2 AUC 0-60) and 
120 hours (N/cm2AUC 0-120); 
 
Ratio of algometry injured/contralateral 
sites over 72 hours and 120 hours 
(N/cm2 Ratio AUC 0-72 and N/cm2 Ratio 
AUC 0-120); 
 
Percent of subjects with no (zero) VAS 
POM at 120 hours; 
 
Global assessment of treatment efficacy 
at 24 hours, 48 hours, 72 hours and 120 
hours by patients using a 5-point scale 
(0=none, 1=poor, 2=fair, 3=good, 
4=excellent); 
 
Global assessment of treatment efficacy 
at 24 hours, 48 hours, 72 hours and 120 
hours by investigators using a 5-point 
scale (0=none, 1=poor, 2=fair, 3=good, 
4=excellent). 
 
 

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4. 
Study Design 
4.1 
Overall Design 
This is a randomized (2:2:1/naproxen:diclofenac:placebo), stratified by injury (contusion or 
sprain/strain) active- and placebo-controlled (vehicle), double-blind, multi-center (3 sites), 
parallel study. 
The study consists of a Screening/Baseline Phase and a Treatment Phase. 
Subjects who present to the site between 6PM – 10PM and within 3 hours of injury will be 
recruited for the study.  Eligible subjects will be selected immediately following 
screening/baseline evaluations. Following selection, subjects will enter the Treatment Phase. 
Subjects will be randomized into one of the three treatment groups in a 2:2:1 
(active:active:placebo) allocation. Treatment consists of a twice daily application 
(approximately 12 hours apart) of the assigned topical gel over 5 consecutive days, beginning 
on the evening of Day 1 and ending (last application) on the morning of Day 6 (total of 10 
applications).  In order to assure adequate representation of different types of soft tissue 
injuries, at least 25 randomized subjects must enter the study with a lower extremity 
sprain/strain injury (cohort) and at least 50 randomized subjects with a lower extremity 
contusion injury (cohort). 
4.1.1 
Study Design Phases 
4.1.1.1 
Screening/Baseline Phase  
Subjects will be screened for eligibility according to the inclusion/exclusion criteria.  Basic 
health information will be collected, and the subject’s injury will be examined and assessed 
by the study investigator/designee.  Subjects will be evaluated by the investigator/designee to 
determine if they qualify based on the injury sustained.  Qualified subjects will then be 
stratified into one of two injury cohorts (sprain/strain or contusion) based on the injury and 
prior to randomization.  Subjects will self-report their level of pain on movement using a 100 
mm visual analog scale (VAS).  Tenderness of the injured area will be assessed with an 
algometer and determined as the amount of pressure (N/cm2) required to produce the first 
tenderness reaction by the subject.  Patients who qualify will be randomized to start the 
Treatment Phase. 
4.1.1.2 
Treatment Phase 
All treatment applications will be performed by an unblinded staff at the site. The unblinded 
staff will not be responsible for any pain or tenderness assessments.  The correct location for 
application of the gel will be marked with a water-resistant pen to ensure the gel is applied at 
the same site for each application during the entire study.  The topical investigational 
medicinal product (IMP) will be gently applied without any massaging. 
At site visits on Days 1, 2, 3, 4 and 6, algometric and pain on movement (POM) VAS 
assessments will be performed.  Compliance will be evaluated by the investigator/designee.  
The investigator and patient will give a global assessment of the treatment efficacy and local 
tolerability using a 5-point Likert scale. 
Patients will use a patient diary to record adverse events, concomitant/rescue medication use 
on Days 1, 2, 3, 4, 5 and 6. 

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The algometry/tenderness will be measured such that the greater the algometry value (N/cm2), 
the greater the pressure required to produce the first tenderness reaction. Therefore, greater 
algometry values indicate less pain at the site of interest. 
4.1.1.3 
Follow-up Phase 
Not applicable for this study. 
The duration of each patient’s participation will be approximately 6 days. For an overview on 
the trial design and trial procedures see Section 1.2. 
 
4.2 
Scientific Rationale for Study Design 
The study model for this study is based on published literature (19,20).  Both systemic and 
topical NSAID treatments have been shown to be effective for both contusions and 
sprains/strains (1).  Since pain is subjective, a placebo treatment arm is very important in 
assessing the effectiveness of the treatment and the sensitivity of the study model.  Inclusion 
of placebo represents no harm to the subject as these studies are of short duration, and because 
rescue medication is available to any subject who so requests. The primary endpoint, 
tenderness to pressure, was selected because it has been shown to be both sensitive to 
treatment effect and a meaningful measure in patients with acute soft tissue injury (19,20).  
4.3 
Justification for Dose 
Preclinical studies have shown that the 10% formulation provides effective penetration to the 
underlying tissue layers at the site of application and is efficacious in the rat paw carrageenan 
model (16).  The amount of product (
) applied at each dosing time is in line with 
dosing directions of currently approved topical NSAIDS (17).  In the case of the naproxen 
topical gel, 10%, each 
 application delivers 
 of naproxen.  This amount falls 
within currently recommended single doses of naproxen for systemic delivery, with an 
important caveat.  Due to poor systemic absorption of topical NSAIDs, the amount absorbed 
into systemic circulation is expected to be less than 10% of the amount contained in the 
product (21). 
 
 
4.4 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if he/she has completed all phases of 
the study up to Visit 6 as shown in the Schedule of Activities. 
 
 
 
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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions are not permitted. 
5.1 
Inclusion Criteria 
 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 18 to 60 years of age inclusive, at the time of signing the 
informed consent. 
 
Type of Participant and Disease Characteristics 
2. Participants with a primary diagnosis of acute sports-related acute soft tissue injuries 
of the lower extremities that do not require hospitalization and that occurred within 3 
hours of enrollment. 
3. Participants with a baseline algometric measurement values on the injured site of 
≤50% of the respective value at the contralateral site. 
4. Participants with a baseline (POM) of ≥50 mm on a visual analog scale (VAS) (0–
100 mm). 
5. Participant’s absolute sensitivity to tenderness on the contralateral site is at least 2.5 
N/cm2 as measured by algometry. 
6. Participant’s size of trauma is between 25 and 150 cm2. 
 
Informed Consent 
7. Capable of giving signed informed consent as described in Section 10.1.4 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
 
5.2 
Exclusion Criteria - Amended 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Heart surgery within 2 weeks of enrollment in the study. 
2. Suspected bone fracture or torn ligaments related to the injury. 
3. Open wounds to the area to be treated. 
4. Current skin disorders or localized infection in the area to be treated. 
5. Injured area is too hairy for proper assessments. 
6. Suspected head injury. 
7. History of blood coagulation disorders. 

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8. Current or past history of gastrointestinal ulceration, gastrointestinal bleeding or 
other bleeding disorder(s). 
9. Relevant concomitant disease such as asthma (exercise induced asthma is 
permitted). 
10. History of significant disease deemed by the investigator to render the patient 
unsuitable for inclusion, including evidence or history of clinically significant (in the 
judgment of the investigator) hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular (including hypertension and cardiac arrhythmia), 
hepatic, psychiatric, neurologic diseases, or malignancies within the last 5 years. 
11. Participants with a medical disorder, condition, or history of such that could impair 
the participant’s ability to participate or complete this trial in the opinion of the 
investigator. 
12. Significant ongoing painful condition other than that associated with the sports-
related injury/contusion. 
13. Any ongoing condition that might interfere with the absorption, distribution, 
metabolism, or excretion of the study medication. 
14. Females who are planning to become pregnant, are pregnant or lactating. 
Prior/Concomitant Therapy 
15. Application of standard care by rest, ice, compression (non-occlusive bandage) or 
elevation (RICE) may be considered at the discretion of the investigator. 
16. Physical therapy or other comfort measures, or herbal preparations for bruises from 
the time of injury through the final evaluation. 
17. Use of any medications within 5 days of enrollment until discharge from the study 
site (except oral contraceptives, prophylactic antibiotics, synthetic thyroid hormones, 
methylphenidate or medications to treat benign conditions such as antibiotics to treat 
acne). 
18. Any other treatment or medication (oral or topical), that could interfere with the trial 
(e.g. corticosteroids) up to 3 days prior to the trial. 
19. Participants with the following medical conditions may be eligible at the discretion 
of the investigator: ADHD on a stable dose regimen of methylphenidate/(dextro) 
amphetamine for at least 6 months; participants with hypothyroidism on a stable 
dose of synthetic thyroid hormone for at least 6 months. 
20. Have received any form of treatment in the form of medication for depression in the 
past 6 months or any form of psychotropic agent (including selective serotonin 
uptake inhibitors [SSRI] but excluding ADHD medications described above) within 
the last 6 months. 
21. Any previous history of allergy or known intolerance to naproxen, diclofenac, 
paracetamol or any of the drugs or formulation constituents which, in the 
investigator’s opinion, might preclude use of an NSAID, including aspirin-sensitive 
asthma or a previous allergic response to a NSAID, including bronchospasm, 
urticaria, angioedema, and rhinitis; participation in a clinical trial in the previous 30 
days. 
22. Use of any over the counter (OTC) or prescription medications with which the 
administration of naproxen, acetaminophen, any other NSAID, is contraindicated. 

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23. Habituation to analgesic drugs including opioids (i.e., routine use of oral analgesics 
5 or more times per week for greater than 3 weeks within the past 2 years). 
 
Other Exclusions 
24. More than low-risk alcohol consumption (>24 g (males) or ˃12 g (females) of 
alcohol regularly per day). Amount corresponds to 0.6 L of beer/day or 0.24 L of 
wine/day or 3 glasses (at 2 cL) of liquor/day for males and 0.3 L of beer/day or 0.12 
L of wine/day or 1 glass (at 2 cL) of liquor/day for females. 
25. Self-reported drug abuse within two years prior to screening. 
26. Member or first-degree relative of study staff or the Sponsor directly involved in the 
study. 
27. Unwilling or unable to comply with all requirements outlined in the protocol. 
 
Prior/Concurrent Clinical Study Experience 
28. Previous enrollment in this study. 
 
5.3 
Lifestyle Considerations 
No lifestyle restrictions are required. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, and eligibility criteria. 
Individuals who do not meet the criteria for participation in this study (screen failure) cannot 
be rescreened. 
5.5 
Criteria for Temporarily Delaying Study Intervention Administration 
Not applicable 
 
 
 

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6. 
Study Intervention(s) and Concomitant Therapy 
The study center will dispense a blinded treatment after successfully completing screening 
and baseline assessments. The tubes of investigational medicinal product (IMP) for each 
treatment will be dispensed using a computer generated randomization schedule.  Participants 
will get the same randomized treatment for the duration of the study. 
 
6.1 
Study Intervention Administered 
During screening and injury assessment, 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: 
 
10 = country code (Germany) 
 = site number (for site ) 
 = randomization number 
Whereas the “ s” will be replaced with a four digit sequentially assigned number as each 
subject enters the study (e.g., first subject number at Site 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 baseline assessments, subjects enter the Treatment 
Phase and are randomized into one of three blinded treatments: 
 Naproxen Topical Gel, 10%, bid for 5 days (final application on morning of Day 6); 
 Diclofenac Diethylamine Gel, 2.32% bid for 5 days (final application on morning of Day 6); 
 Placebo Gel bid for 5 days (final application on morning of Day 6). 
Approximately 
 of IMP will be dispensed and weighted at the site on a 
digital scale with an allowance of no more than 
.  The weight of the 
gel will be recorded on the source documents and case report form and then be applied at each 
treatment by an unblinded site staff depending upon the location of the injury.  Study staff 
should make their best attempt to weigh and dispense the topical gel as close as possible 
to the target of 
 for each application.  The first treatment will start on Day 1 (after 
being randomized).  The topical IMP will be applied in a thin layer over the affected area and 
lightly rubbed in without using pressure or any massaging.  The maximum daily dose is 
approximately 
 on Days 2, 3, 4 and 5.  The maximum dose for 
Days 1 and 6 are approximately 
.  The total dose for each participant is approximately 
. 
The patient will not see the specific treatment and will be blindfolded during the application 
of the topical gel.   Nominal dosing times will be established after the patient is randomized 
PPD
P
P
D
PPD
P
P
D
P
P
D
PPD
PPD
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(evening of Day 1) with the next application being approximately 12 hours apart from the 
previous application.  A dosing window of ± 1 hour from the established nominal dosing time 
from Day 1 is allowed (see example). 
Table 1 – Dosing Example 
 
Day 1 
PM 
Day 2 
AM 
Day 2 
PM 
Day 3 
AM 
Day 3 
PM 
Day 4 
AM 
Day 4 
PM 
Day 5 
AM 
Day 5 
PM 
Day 6 
AM 
Day 6 
PM 
Dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
dose 
applied 
Dosing 
Time 
19:40 
7:40 
19:40 
7:40 
19:40 
7:40 
19:40 
7:40 
19:40 
7:40 
Dosing 
Window 
18:40   
to      
20:40 
6:40    
to      
8:40 
18:40   
to      
20:40 
6:40    
to      
8:40 
18:40   
to      
20:40 
6:40    
to      
8:40 
18:40   
to      
20:40 
6:40    
to      
8:40 
18:40   
to      
20:40 
6:40    
to      
8:40 
Note: All dosing times are in military time. 
Any dosing-related deviations outside of the allowable window (± 1 hour) will be documented 
in the subject’s medical record, source documents and/or diary. 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 

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6.2 
Identity of Study Interventions 
Table 2 – Study Interventions 
Intervention 
Naproxen gel 
Diclofenac gel 
Placebo gel 
UI Number 
1614000-268 
NA 
1614000-272 
Type  
Drug 
Drug 
Vehicle 
Dose 
Formulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Strength 
10% 
2.32% 
NA 
Dosage 
 
 
 
Route of 
Administration 
Topical 
Topical 
Topical 
Use 
Test 
Comparator       
Placebo               
Packaging and 
Labeling 
Study Intervention will 
be provided in tubes. 
Each tube will be labeled 
as required per country 
requirements 
Study Intervention will        
be provided in tubes.        
Each tube will be labeled     
as required per country 
requirements 
Study Intervention will 
be provided in tubes. 
Each tube will be labeled 
as required per country 
requirements 
Batch Number 
available in the study file 
available in the study file 
available in the study file 
Manufacturer 
Formulated Solutions 
Largo, Florida USA 
GlaxoSmithKline Consumer 
Healthcare GmbH & Co. KG 
Munich, Germany 
Formulated Solutions 
Largo, Florida USA 
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. 
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. 
6.3 
Preparation/Handling/Storage/Accountability 
Only participants randomized in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored in 
a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
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The investigator or the head of the institution (where applicable) is responsible for study 
intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in a separate document.  
 
6.4 
Measures to Minimize Bias: Randomization and Blinding 
Study using 
Pre-Coded 
Randomization 
provided to the 
site 
On Day 1 participants will be assigned a unique number 
(randomization number) in ascending numerical order at each study 
site. The randomization number encodes the participant’s 
assignment to one of the 3 arms of the study, according to the 
randomization schedule generated prior to the study by the 
Statistics Department at Bayer. Each participant will be dispensed 
blinded study intervention, labeled with his/her unique 
randomization number, throughout the study. 
Blind Break 
(Envelopes) 
A sealed envelope that contains the study intervention assignment 
for each participant will be provided to the investigator. The sealed 
envelope will be retained by the investigator (or representative) in a 
secured area. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If 
the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s intervention assignment unless this could 
delay emergency treatment of the participant. If a participant’s 
intervention assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. Once the study is 
complete, all envelopes (sealed and opened) must be inventoried 
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Blinded study with 
unblinded site 
staff who is 
dispensing study 
intervention 
Participants will be randomly assigned in a 2:2:1 ratio to receive 
study intervention. Investigators and designated staff will remain 
blinded to each participant’s assigned study intervention throughout 
the course of the study. To maintain the blind, the participant will 
wear a blindfold so they cannot see the topical treatment applied to 
the injured area.  Additionally, the unblinded staff at the site will be 
responsible for the dispensing, weighing and topical application to 
the injured area of all study interventions and will endeavor to 
ensure that there are no differences in time taken to dispense 
following randomization.  The unblinded staff at the site is not 
responsible for adverse events, global assessments, pain and 
tenderness measurements.   
 
This unblinded study staff will instruct the participant to avoid 
discussing the smell, color, texture or packaging of the study 
intervention with the investigator and other blinded staff at the site. 
Prior to presenting to the investigator for assessment, the treated 
area will be cleaned with water at room temperature to eliminate 
residual gel quantity and the smell related to the gel.  
 
In the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to unblinded study intervention records at the site(s) 
to verify that randomization/dispensing has been done accurately. 
If necessary, Bayer Pharmacovigilance may unblind the intervention assignment for any 
participant with an SAE. If the SAE requires that an expedited regulatory report be sent to one 
or more regulatory agencies, a copy of the report, identifying the participant’s intervention 
assignment, may be sent to investigators in accordance with local regulations and/or sponsor 
policy. 
 
6.5 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date, time and weight (in grams) of 
each dose administered at the site will be recorded in the source documents. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. 
 
6.6 
Dose Modification 
Dose modification (increase or decrease) from the standard 
 is not 
permitted.  Randomized participants will receive ten (10) consecutive topical treatments over 
6 days. 
 
CCI

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6.7 
Stopping Rules 
Dosing will be stopped for all subjects under the following conditions: 
 A serious adverse reaction considered related to IMP administration in one subject. 
 Severe non-serious adverse reactions related to IMP administration in two subjects, 
within the skin and subcutaneous tissue system, or gastrointestinal system organ 
classes. 
Restart of the study is possible if the review/investigation leads to a conclusion that the 
adverse reaction was not related to the IMP administration.  The subject(s) in whom the 
adverse reaction occurred may not restart. 
 
6.8 
Continued Access to Study Intervention after the End of the Study 
No study intervention will be available after Visit 6 (Day 11). 
 
6.9 
Treatment of Overdose 
For this study, any dose of study intervention greater than 
 within a 24-hour time 
period will be considered an overdose (17). 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
 
Contact the Medical Monitor immediately. 
 
Evaluate the participant to determine, in consultation with the Medical Monitor, 
whether study intervention should be interrupted or whether the dose should be 
reduced. 
 
Closely monitor the participant for any AE/SAE until study intervention can no 
longer be detected systemically (at least 7 days). 
 
Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
 
6.10 
Concomitant Therapy 
Any medication (including OTC or prescription medicines, recreational drugs, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with: 
 Reason for use 
 Dates of administration including start and end dates 
 Dosage information including dose and frequency 
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The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
 
6.10.1 
Rescue Medicine 
The study site will supply paracetamol (Paracetamol HEXAL® 500 mg tablets) with a maximum 
daily dose of 1000 mg as rescue medication during the study, except 6 hours prior to the next 
site visit.  Rescue medication will be provided by the investigator and documented on the source 
documents. 
If the participant decides to take rescue medication during the study, the patient will be 
instructed to complete the Global Assessments (both efficacy and tolerability) prior to taking 
the rescue medication. 
 
 

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7. 
Discontinuation of Study Intervention and Participant 
7.1 
Discontinuation of Study Intervention  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in 
the study to be evaluated for efficacy and safety. See the SoA for data to be collected at the 
time of discontinuation of study intervention for any further evaluations that need to be 
completed. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
7.3 
Lost during the Treatment Phase 
A participant will be considered lost if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the site for a required 
study visit: 
 The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
 Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 2 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
 Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
 
 

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8. 
Study Assessments and Procedures 
8.1 
General Procedures 
 Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
 Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
 Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
 Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
 
8.1.1 
Screening Phase Visit 1 - (Day 1) 
At the Screening visit, the Principal Investigator or appropriate designee will discuss with 
each patient the nature of the trial, its requirements and its restrictions.  Written informed 
consent will be obtained prior to performance of any protocol-specific procedures.  Patients 
will present with a lower extremity injury within 3 hours of screening between 6 pm and 10 
pm.   
 
The following will be conducted during the Screening Visit to determine eligibility: 
 
 Signed Informed Consent; 
 Review Inclusion and Exclusion Criteria; 
 Patient demographics; 
 Medical History (lower extremity injury is a self-reported history)  
 Medication history of all prescription and OTC drugs (including topicals, herbal 
products, vitamins and nutritional supplements), use of topical heat or cold, and other 
products of topical application and investigational drugs, taken within 30 days prior to 
screening; 
 History of drug, alcohol and tobacco use; 
 Height, weight, and Body Mass Index (BMI); 
 Physical examination (general routine and injury-related assessment); 
 Urine pregnancy test (female patients only); 
 Vital signs (blood pressure, heart rate, respiratory rate and body temperature after 5 
minutes in a sitting position); 
 Discuss the procedure to report adverse events; 
 Diary distribution and training; 
 

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The Principal Investigator or his/her designee must review all screening results before 
proceeding to the Treatment phase of the study.  Patients must have a lower extremity injury 
within 3 hours of Screening for participation into the study.  Patients with the appropriate 
sports-related lower extremity injury will be designated into one of two cohorts for baseline 
testing. 
 
8.1.2 
Baseline Visit 1 - (Day 1) 
Patients will undergo baseline pain and tenderness testing to determine eligibility for 
randomization.  All patients must score at least 50 on the 0 – 100 mm visual analog scale 
(VAS) for POM and have algometric measurement values on the injured site of ≤50% of the 
respective value at the contralateral site in order to qualify for treatment.  Additionally, the 
absolute tenderness sensitivity of the contralateral site must be  at least 2.5 N/cm2.  The 
investigator will stratify patients into 2 injury cohorts.  One cohort is contusion cohort and the 
other is the sprain/strain cohort.  The contusion cohort will enroll at least 50 patients and the 
sprain/strain cohort will enroll at least 25 patients.  
 
The site will randomize Investigational Medicinal Product (IMP or treatment kit) based on 
computer generated randomization schedule stratified by injury type (either contusion or 
sprain/strain cohorts). 
Patients entering the Treatment Phase are randomized in a 2:2:1 fashion into one of three 
blinded treatments: 
 Naproxen Topical Gel, 10%, every 12 hours for 5 days 
 Diclofenac Diethylamine Topical Gel, 2.32% every 12 hours for 5 days 
 Placebo Topical Gel every 12 hours for 5 days 
Patients will be reminded to discontinue use of all pain medications including supplements, 
use of topical heat or cold, and other products of topical application once the patient is 
deemed eligible to participate. 
The investigator or designee will mark the injured lower extremity with a water-resistant pen 
so that the treatment area is consistently targeted through the Treatment Phase.  After 
randomization, the first topical treatment will be applied the evening of Day 1.  The topical 
treatment will be weighed on a digital scale, then applied by an unblinded study staff at the 
site who is not responsible for adverse events, global assessments, pain and tenderness 
measurements.  Patients will wear a blindfold during treatment so that the identity of the IMP 
is blinded.  Patients will be instructed to return approximately 12 hours to the site for their 
second treatment.  The nominal repeat dosing times will be established for the rest of the 
study that conform to the dosing time established on Day 1. 
Rescue medication will be dispensed.  If the patient decides to take rescue medication prior to 
the next treatment, the patient will be instructed to complete the Global Assessments prior to 
taking the rescue medication. 
8.1.3 
Visit 2 (Day 2 morning) 
Patients will return to the site approximately 12 hours after Day 1 dosing.  The following 
activities will be performed: 

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 Cleaning of the treated area by the unblinded staff 
 Limited physical exam (injured extremity); 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 
 Adverse Event assessment; 
 POM VAS; 
 Algometry measurements. 
Patients will undergo the second topical treatment at the site weighed on a digital scale, then 
applied by an unblinded study staff at the site who is not responsible for adverse events, 
global assessments, pain and tenderness measurements.  Patients will wear a blindfold during 
treatment so that the identity of the IMP is blinded.  Patients will be instructed to return 
approximately 12 hours to the site for the third treatment based on their established nominal 
time.   
If the patient decides to take rescue medication prior to the next treatment, the patient will be 
instructed to complete the Global Assessments prior to taking the rescue medication. 
8.1.4 
Visit 3 (Day 2 evening) 
Patients will return to the site approximately 12 hours after Day 2 morning dosing.  The 
following activities will be performed: 
 
 Cleaning of the treated area by the unblinded staff 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 
 Adverse Event assessment; 
 POM VAS; 
 Algometry measurements. 
 Global assessments for efficacy and tolerability; 
 
Patients will undergo the third topical treatment at the site weighed on a digital scale, then 
applied by an unblinded study staff at the site who is not responsible for adverse events, 
global assessments, pain and tenderness measurements.  Patients will wear a blindfold during 
treatment so that the identity of the IMP is blinded.  Patients will be instructed to return 
approximately 12 hours to the site for the fourth treatment based on their established nominal 
time. 
If the patient decides to take rescue medication prior to the next treatment, the patient will be 
instructed to complete the Global Assessments prior to taking the rescue medication. 
8.1.5 
Visit 4 (Day 3 morning) 
Patients will return to the site approximately 12 hours after Day 2 evening dosing.  The 
following activities will be performed: 
 
 Cleaning of the treated area by the unblinded staff 
 Limited physical exam (injured extremity); 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 

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 Adverse Event assessment; 
 POM VAS; 
 Algometry measurements. 
Patients will undergo the fourth topical treatment at the site weighed on a digital scale, then 
applied by an unblinded study staff at the site who is not responsible for adverse events, 
global assessments, pain and tenderness measurements.  Patients will wear a blindfold during 
treatment so that the identity of the IMP is blinded.  Patients will be instructed to return 
approximately 12 hours to the site for the fifth treatment based on their established nominal 
time.   
If the patient decides to take rescue medication prior to the next treatment, the patient will be 
instructed to complete the Global Assessments prior to taking the rescue medication. 
8.1.6 
Visit 5 (Day 3 evening) 
Patients will return to the site approximately 12 hours after Day 3 morning dosing.  The 
following activities will be performed: 
 
 Cleaning of the treated area by the unblinded staff 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 
 Adverse Event assessment; 
 POM VAS; 
 Algometry measurements; 
 Global assessments for efficacy and tolerability. 
 
Patients will undergo the fifth topical treatment at the site weighed on a digital scale, then 
applied by an unblinded study staff at the site who is not responsible for adverse events, 
global assessments, pain and tenderness measurements.  Patients will wear a blindfold during 
treatment so that the identity of the IMP is blinded.  Patients will be instructed to return 
approximately 12 hours to the site for their sixth treatment based on their established nominal 
time. 
If the patient decides to take rescue medication prior to the next treatment, the patient will be 
instructed to complete the Global Assessments prior to taking the rescue medication. 
8.1.7 
Visit 6 (Day 4 morning) 
Patients will return to the site approximately 12 hours after Day 3 evening dosing.  The 
following activities will be performed: 
 
 Cleaning of the treated area by the unblinded staff 
 Limited physical exam (injured extremity); 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 
 Adverse Event assessment; 
 POM VAS; 
 Algometry measurements. 
 

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Patients will undergo the sixth topical treatment at the site weighed on a digital scale, then 
applied by an unblinded study staff at the site who is not responsible for adverse events, 
global assessments, pain and tenderness measurements.  Patients will wear a blindfold during 
treatment so that the identity of the IMP is blinded.  Patients will be instructed to return 
approximately 12 hours to the site for the seventh treatment based on their established 
nominal time.   
If the patient decides to take rescue medication prior to the next treatment, the patient will be 
instructed to complete the Global Assessments prior to taking the rescue medication. 
8.1.8 
Visit 7 (Day 4 evening) 
Patients will return to the site approximately 12 hours after Day 4 morning dosing.  The 
following activities will be performed: 
 
 Cleaning of the treated area by the unblinded staff 
 Vital signs (blood pressure, heart rate, respiratory rate and body temperature after 
5 minutes in a sitting position); 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 
 POM VAS; 
 Algometry measurements; 
 Adverse Event assessment; 
 Global assessments for efficacy and tolerability. 
 
Patients will undergo the seventh topical treatment at the site weighed on a digital scale, then 
applied by an unblinded study staff at the site who is not responsible for adverse events, 
global assessments, pain and tenderness measurements.  Patients will wear a blindfold during 
treatment so that the identity of the IMP is blinded.  Patients will be instructed to return 
approximately 12 hours to the site for the eighth treatment based on their established nominal 
time. 
If the patient decides to take rescue medication prior to the next treatment, the patient will be 
instructed to complete the Global Assessments prior to taking the rescue medication. 
8.1.9 
Visit 8 (Day 5 morning) 
Patients will return to the site approximately 12 hours after Day 4 evening dosing.  The 
following activities will be performed: 
 
 Cleaning of the treated area by the unblinded staff 
 Limited physical exam (injured extremity); 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 
 Adverse Event assessment. 
 
Patients will undergo the eighth topical treatment at the site weighed on a digital scale, then 
applied by an unblinded study staff at the site who is not responsible for adverse events, 
global assessments, pain and tenderness measurements.  Patients will wear a blindfold during 
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approximately 12 hours to the site for their ninth treatment based on their established nominal 
time.   
If the patient decides to take rescue medication prior to the next treatment, the patient will be 
instructed to complete the Global Assessments prior to taking the rescue medication. 
8.1.10 
Visit 9 (Day 5 evening) 
Patients will return to the site approximately 12 hours after Day 5 morning dosing.  The 
following activities will be performed: 
 
 Cleaning of the treated area by the unblinded staff 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 
 Adverse Event assessment. 
 
Patients will undergo the ninth topical treatment at the site weighed on a digital scale, then 
applied by an unblinded study staff at the site who is not responsible for adverse events, 
global assessments, pain and tenderness measurements.  Patients will wear a blindfold during 
treatment so that the identity of the IMP is blinded.  Patients will be instructed to return 
approximately 12 hours to the site for the tenth and final treatment based on their established 
nominal time. 
If the patient decides to take rescue medication prior to the next treatment, the patient will be 
instructed to complete the Global Assessments prior to taking the rescue medication. 
8.1.11 
Visit 10 (Day 6 morning) 
Patients will return to the site approximately 12 hours after Day 5 evening dosing.  The 
following activities will be performed: 
 
 Cleaning of the treated area by the unblinded staff 
 Limited physical exam (injured extremity); 
 Urine pregnancy test (female patients only); 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 
 Adverse Event assessment. 
 
Patients will undergo the tenth topical treatment at the site weighed on a digital scale, then 
applied by an unblinded study staff at the site who is not responsible for adverse events, 
global assessments, pain and tenderness measurements.  Patients will wear a blindfold during 
treatment so that the identity of the IMP is blinded.  Patients will be instructed to return 
approximately 12 hours to the site based on their established nominal time for final 
assessments. 
If the patient decides to take rescue medication prior to the next treatment, the patient will be 
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8.1.12 
Visit 11 (Day 6 evening, End of Study) 
Patients will return to the site approximately 12 hours after Day 6 morning dosing.  The 
following activities will be performed: 
 
 Cleaning of the treated area by the unblinded staff 
 Vital signs (blood pressure, heart rate, respiratory rate and body temperature after 
5 minutes in a sitting position); 
 Review diary for rescue/concomitant medications; 
 Rescue medicine drug accountability; 
 Adverse Event assessment; 
 POM VAS; 
 Algometry measurements; 
 Global assessments for efficacy and tolerability; 
 Sensory questions related to smell and touch; 
 Return of diary and rescue medication. 
 
No topical treatment is performed for this visit.  Upon return of all study materials and 
completion of all study procedures, the patient will be discharged from the study. 
8.2 
Efficacy Assessments  
 
8.2.1 
Assessment of Pain on Movement 
Pain on Movement will be assessed using a 100 mm visual analogue scale at baseline and at 
each subsequent study visit. 
 
Place a line on the ‘Scale’ that best characterizes how your injured extremity feels when it’s moved now. 
 
  No Pain      
Severe Pain 
 
 
8.2.2 
Algometry 
Algometry will be performed at baseline and at each study visit.  Algometric measurements 
will be performed using a calibrated caliper with digital pressure recording).  Increases in 
pressure during measurement will be kept constant at 10 N/cm2/s. The site of measurement will 
be marked with a water resistant marker, and measurements will be repeated at the same site. 
The measurements will be performed in such a way that the patient and the investigator cannot 
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which is then recorded on the case report form. A tenderness reaction is defined as the pressure 
that, under the above conditions, produced a painful sensation. 
Additional information related to the algometry procedures will be detailed in a separate 
document. 
8.2.3 
Global Assessments of Efficacy and Tolerability 
At 24 hours, 48 hours, 72 hours and 120 hours post dose, the patient and the investigator will 
rate global assessment of the treatment efficacy using a 5-point Likert scale. 
Global Efficacy 
How would you rate the study medication you received as a pain-reliever? 
 0 = poor 
 1 = fair  
 2 = good  
 3 = very good  
 4 = excellent 
 
At 24 hours, 48 hours, 72 hours and 120 hours post dose, the patient and the investigator will 
rate global assessment of tolerability (quality of life) using a 5-point Likert scale. 
Global Tolerability 
Considering all the ways this treatment has affected you since you started in the clinical trial, 
how well are you doing? 
 0 = poor 
 1 = fair  
 2 = good  
 3 = very good  
 4 = excellent 
 
If the patient completes the Global Assessment not at the time of the scheduled clinic visit (or 
between visits), then the investigator will complete the Global Assessment at the next scheduled 
visit. 
Planned time points for all efficacy assessments are provided in the SoA and Section 8.1. 
 
 
 

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8.2.4 
Sensory Questions 
 
During the final visit of the study (Visit 11), patients will be asked two sensory questions 
related to the IMP they received. 
 
What is your opinion of the scent of the product? 
 Strongly liked 
 Liked 
 Neutral 
 Didn’t like 
 Strongly disliked 
 Did not notice a scent 
 
How do you feel about the appearance of the product on your skin post application? 
 There is no difference in the appearance of my skin 
 Strongly like 
 Like 
 Neutral  
 Dislike 
 Strongly dislike 
 
8.3 
Safety Assessments  
All safety assessments are detailed in Sections 8.3.1, 8.3.2 and 8.3.3.  Planned visits for all 
safety assessments are provided in the SoA. 
 
8.3.1 
Physical Examinations 
A general physical examination will include the injured extremity and assessments of the 
Dermatological, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems at 
Screening (Visit 1). Height and weight will also be measured and recorded. 
A limited physical examination of the injured extremity will be performed at Visits 2, 4, 6, 8 
and 10.  Changes related to the physical exam will be documented on the source documents 
and case report form. 
 

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8.3.2 
Vital Signs 
Blood pressure, heart rate, respiratory rate and body temperature (oral) will be assessed.  
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest in a 
sitting position for the participant in a quiet setting without distractions (e.g., television, cell 
phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded. 
 
8.3.3 
Pregnancy Testing 
Female participants of child bearing potential will undergo urine pregnancy testing at Visit 1 
(prior to first dose) and Visit 10 (prior to last dose). 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 10.3.  The definition of unsolicited and solicited AEs can be found in Section 10.3.  
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the informed consent form (ICF)] at the time 
points specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning of the event, as indicated in Section 
10.3. The investigator will submit any updated SAE data to Bayer Pharmacovigilance within 
24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study intervention or study participation, the investigator 
must promptly notify the sponsor.  
 

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8.4.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in Section 
10.3.  
 
8.4.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements. 
For all studies except those using medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary. 
 
8.4.5 
Pregnancy 
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.  
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the female 
participant pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs, and will be reported as such. 

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Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 8.4.4. 
While the investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
For all reports, the forms provided are to be used.  The investigator should submit them within 
the same timelines as an SAE (see Section 10.3.4.).  Send the completed pregnancy forms to: 
bv-med-ams@bayer.com or phone +49 21 43 05 1699 (Germany) 
 
8.5 
Pharmacokinetics 
PK and pharmacodynamic parameters are not evaluated in this study. 
 
8.6 
Genetics or Pharmacogenomics 
Genetics are not evaluated in this study. 
 
8.7 
Biomarkers 
Biomarkers are not evaluated in this study. 
 
8.8 
Immunogenicity Assessments 
Not Applicable 
 
8.9 
Health Economics 
Health Economics parameters are not evaluated in this study. 
 
 
 

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9. 
Statistical Considerations  
9.1 
Statistical Hypotheses - Amended 
For the comparison of the test gel vs. placebo, the primary efficacy hypothesis to be tested is 
the equality of Algometry AUC 0-72; the second is the POM VAS AUC 0-72. 
9.2 
Sample Size Determination - Amended 
This is a proof of concept study and therefore a specific statistical power calculation cannot be 
applied, however, assuming a comparable effect of the test gel vs. diclofenac – as suggested 
by pharmacological studies-, reference is made to  similar studies (Predel, Br J Sports Med 
2004;38:318–323), in which the standardized effect sizes of Algometry AUC 0-72 and POM 
VAS AUC 0-72 were over 1; with 30:15 patients, a drop-out rate of 10%, and a two-sided 
significance level α = 5%, a power 1 – β of about 80% is reached.  
 
9.3 
Analysis Set - Amended 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Intent To Treat (ITT) 
All subjects who are randomized and provide at least one 
measure of primary efficacy parameters after the first 
application of IMP. 
Per Protocol (PP) 
The Per Protocol population will include all subjects in 
ITT who complete the study and do not have any major 
protocol violations. 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 and other efficacy endpoints to 
assess the robustness of the results based on PP 
Population. 
Safety 
All randomized subjects who take at least one 
application of IMP. Safety analyses will be conducted on 
the safety population. 
9.4 
Statistical Analyses - Amended 
The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary, secondary, and other key endpoints. 
 

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9.4.1 
General Considerations 
Statistical analysis will be performed using statistical analysis system 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. 
All endpoints will be summarized descriptively by treatment.  Statistical testings may be 
conducted at significance level of 0.05 if deemed necessary and no multiplicity adjustment 
will be made. 
 
9.4.2 
Primary Endpoint 
The primary efficacy variable is:  
 Tenderness (Algometry) over the initial 72 hours (Algometry AUC 0-72). 
 
The primary efficacy endpoint will be analyzed if deemed necessary using analysis of 
covariance (ANCOVA) with treatment as the factor and baseline tenderness (algometry) as 
the covariance. Pair-wise comparisons may be made from above model. 
9.4.3 
Secondary Endpoint 
 Safety (percentage of subjects with at least one TEAE). 
 
 The secondary endpoint will be summarized descriptively by body system and 
preferred term. 
 
9.4.4 
Other Endpoints 
 VAS POM over the initial 12-hours (VAS AUC 0-12), 24-hours (VAS AUC 0-
24), 36-hours (VAS AUC 0-36), 48-hours (VAS AUC 0-48), 60-hours (VAS AUC 
0-60), 72-hours (VAS AUC 0-72), and 120 hours (VAS AUC 0-120); 
 Change of VAS POM at hours 12,  24, 36, 48, 60, 72 and 120 from baseline; 
 Change of Algometric Tenderness (N/cm2) at hours 12, 24, 36, 48, 60, 72 and 120 
from baseline; 
 Algometric Tenderness (N/cm2)  over the initial 12-hours (N/cm2 AUC 0-12), 24-
hours (N/cm2 AUC 0-24), 36-hours (N/cm2 AUC 0-36), 48-hours (N/cm2 AUC 0-
48) 60-hours (N/cm2 AUC 0-60) and 120 hours (N/cm2AUC 0-120); 
 Ratio of algometry injured/contralateral sites over 72 hours and 120 hours (N/cm2 
Ratio AUC 0-72 and N/cm2 Ratio AUC 0-120); 
 Percent of subjects with no (zero) VAS POM at 120 hours; 
 Global assessment of treatment efficacy at 24 hours, 48 hours, 72 hours and 120 
hours by patients using a 5-point scale (0=none, 1=poor, 2=fair, 3=good, 
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 Global assessment of treatment efficacy at 24 hours, 48 hours, 72 hours and 120 
hours by investigators using a 5-point scale (0=none, 1=poor, 2=fair, 3=good, 
4=excellent). 
 
9.4.5 
Safety Analysis 
Safety will be measured by adverse events (AEs) and vital signs.  Only descriptive analyses 
will be conducted on the Safety Population. No imputation will be made for missing safety data. 
Quantitative data for safety variables will be described by summary statistics for the original 
data as well as for the differences to baseline when it is appropriate. Frequency tables will be 
provided for qualitative data. No statistical test will be planned regarding the safety analyses. 
 
Only treatment-emergent AEs will be included in the summary analysis, i.e., AEs that begin or 
worsen after the first application of Investigational Medicinal Product (IMP).  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 group. Tables will also be 
produced by severity and relationship to IMP. Seriousness, severity, relationship to IMP 
duration, and outcome will also be listed. 
 
Listings of individual data will be presented. 
 
9.5 
 Interim Analysis 
No interim analysis is planned for this study. 
 
 

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10. 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
Investigator(s) and other study personnel 
Sponsor’s medical expert for the study 
Name: 
  
Title: 
 Global Medical Affairs 
Address: Bayer Healthcare 
 
100 Bayer Boulevard 
 
Whippany NJ 07981-0915 USA 
 
Phone: 
 
Email: 
 
Coordinating investigator for the study (LKP) 
Name: 
Prof. Dr. Hans Georg Predel 
Title: 
Physician 
Address: Deutsche Sporthochschule Köln 
Am Sportpark Müngersdorf 6 50933 Köln  Germany 
 
 
Phone: 
 
Fax: 
 
Email: 
 
CRO and 
 for the study 
Name 
 
CRO: 
Clinsearch GmbH 
Address: 
Zugerstrasse 80 a 
 
Walchwil, Zug, Switzerland 
 
 
Phone: 
 
Email: 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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10.1.1 
Regulatory and Ethical Considerations 
 
 This study will be conducted in accordance with the protocol and with the 
following: 
 Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
 Applicable ICH Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
 The protocol, protocol amendments, ICF, Investigator Brochure and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
 Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. Any substantial 
modification of the protocol will be submitted to the competent authorities as 
substantial amendments for approval, in accordance with ICH Good Clinical 
Practice and national and international regulations. 
 Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
 The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
 
10.1.3 
Funding 
This study will be funded by the sponsor. 
 

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10.1.4 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. Each participant 
will be informed about the following aspects of premature withdrawal: 
 Each participant has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
 The participant’s consent covers examinations as specified in the visit description 
described in Section 8.1.12 to be conducted after withdrawal of consent. 
 The participant’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan. 
 Participant-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 participant 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 participant’s oral objection may be documented in the participant’s source data. 
Each participant will have ample time and opportunity to ask questions. 
Only if the participant 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 
participant will receive a second original of the informed consent form. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be consented to the most current version of the ICF(s) during their 
participation in the study.  
The informed consent form and any other written information provided to participants will be 
revised whenever important new information becomes available that may be relevant to the 
participant’s consent, or there is an amendment to the protocol that necessitates a change to 
the content of the participant information and / or the written informed consent form.  The 
investigator will inform the participant of changes in a timely manner and will ask the 
participant to confirm his/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. 
A copy of the ICF(s) must be provided to the participant.  Participants who are rescreened are 
required to sign a new ICF. 
 

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10.1.5 
Data Protection and Confidentiality 
Participants will be assigned a unique identifier by the sponsor. Any participant records, 
datasets or biological samples that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
All records identifying the participant will be kept confidential and, to the extent permitted 
by the applicable laws and/or regulations, will not be made publicly available. 
Participant names will not be supplied to the sponsor.  Only the participant numbers (SNR 
and RNR) will be recorded in the CRF/eCRF data collection system, and if the participant 
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 participants 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 participant’s identity will remain confidential. 
The investigator will maintain a list to enable participants to be identified. 
 
10.1.6 
Compensation for Health Damage of Participants/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. 
 
10.1.7 
Committees Structure 
Not applicable 
 
10.1.8 
Dissemination of Clinical Study Data 
The sponsor has made the information regarding the study protocol 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. 

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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.   
 
10.1.9 
Data Quality Assurance 
Participant data necessary for analysis and reporting will be provided to the Sponsor in 
CDISC (Clinical Data Interchange Standards Consortium) standards. 
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).  
Guidance on completion of CRFs will be provided with the paper case report forms. 
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used. 
Reasons for missing data, especially inability to perform a test, must be documented. 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  The investigator must maintain accurate documentation 
(source data) that supports the information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan or applicable monitoring SOP. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  The sponsor assumes accountability for actions delegated to 
other individuals (e.g., Contract Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for  15 years  after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
 
10.1.10 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.   

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Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
 
10.1.11 
Missing Data 
Reasons for missing data, especially inability to perform a test, must be documented. 
 
10.1.12 
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 IEC(s)/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. 
 
10.1.13 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
Participant files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice.  Where the 
archiving procedures do not 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 (eg 
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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10.1.14 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first subject screened and is considered the first act of 
recruitment and will be the study start date. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
 Discontinuation of further study intervention development 
For site termination: 
 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
 Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
 Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
 
10.1.15 
Publication Policy 
 The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
 The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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10.2 
Appendix 2: Clinical Laboratory Tests 
Not applicable 
 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures 
10.3.1 
Definition of AE 
 
AE Definition 
 An AE is any untoward medical occurrence in a clinical study participant, 
associated with the use of study intervention, whether or not considered related to 
the study intervention. 
 NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention. 
 
Definition of Unsolicited and Solicited AE 
 An unsolicited adverse event is an adverse event that was not solicited using a 
Participant Diary and that is communicated by a participant who has signed the 
informed consent. Unsolicited AEs include serious and non-serious AEs. 
 Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalisation, or emergency room visit, or visit to/by a health care 
provider). The participants will be instructed to contact the site as soon as possible 
to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant concern. Detailed information about reported 
unsolicited AEs will be collected by qualified site personnel and documented in the 
participant’s records. 
 Unsolicited AEs that are not medically attended nor perceived as a concern by 
participant will be collected during interview with the participants and by review of 
available medical records at the next visit. 
 Solicited AEs are predefined local at the application site and systemic events for 
which the participant is specifically questioned, and which are noted by the 
participant in their diary.  
 
Events Meeting the AE Definition  
 Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital 
signs measurements), including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator 
(i.e., not related to progression of underlying disease). 

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 Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected intervention-
intervention interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study intervention or a concomitant medication. Overdose per se will not be 
reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
 The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition  
 Any clinically significant abnormal laboratory findings or other abnormal 
safety assessments which are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s 
condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social 
and/or convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
 
 

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10.3.2 
Definition of SAE 
 
An SAE is defined as any AE that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
 The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the participant 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. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. 
Results in persistent or significant disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
 This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
 Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
 

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10.3.3 
Recording and Follow-Up of AE and/or SAE 
 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the investigator to review 
all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE information. 
 It is not acceptable for the investigator to send photocopies of the participant’s 
medical records in lieu of completion of the required form. 
 There may be instances when copies of medical records for certain cases are 
requested. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission. 
 The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 
Assessment of Intensity 
 The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories:  
 Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities. 
 Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe. 
 
 

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Assessment of Causality 
 The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE. 
 A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and 
other risk factors, as well as the temporal relationship of the event to study 
intervention administration will be considered and investigated. 
 The investigator will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data. 
 The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
 The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
 New or updated information will be recorded in the originally submitted 
documents. 
 The investigator will submit any updated SAE data within 24 hours of receipt 
of the information. 
 

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10.3.4 
Reporting of SAEs 
 
SAE Reporting to Bayer Pharmacovigilance via Paper Data Collection Tool 
 Email transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to Bayer Pharmacovigilance.   
 In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
 Initial notification via telephone does not replace the need for the investigator 
to complete and sign the SAE data collection tool within the designated 
reporting time frames. 
 Contacts for SAE reporting: 
bv-med-ams@bayer.com or phone +49 21 43 05 1699 (Germany) 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
 

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3. Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
 Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
 
Contraception Guidance: 
 
Female participants who become pregnant  
 The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy.  
 The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
 A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
 Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.4.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting.  
 Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
 
 
 

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10.5 
Appendix 5: Abbreviations 
ADHD 
attention deficit hyperactivity disorder 
AE 
adverse event 
AUC 
area under the curve 
BAY no. 
BAY number is the main identifier for compounds within the Bayer HealthCare 
Organization 
bid 
twice a day 
BMI 
body mass index: weight [kg] / (height [m])² 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
cm 
centimeter 
COX 
cyclooxygenase 
CRO 
contract research organization 
CV 
coefficient of variation 
(e)CRF 
(electronic) case report form 
e.g. 
exempli gratia (for example) 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
g 
grams 
GCP 
good clinical practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
HRT 
hormonal replacement therapy 
i.e. 
id est (that is) 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
kg 
kilogram 
(c)L 
(centi)liter 
MedDRA 
medical dictionary for regulatory activities 
mm 
millimeter 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over the counter 
POM 
pain on movement 
QA 
quality assurance 
RNR 
randomization number 

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SoA 
schedule of events 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SNR 
screening number 
SoA 
Schedule of Activities 
SOP 
standard operating procedure 
SSRI 
selective serotonin uptake inhibitors 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
UI 
unique identifier (drug formula) 
USA 
United States of America 
VAS 
visual analog scale 
WOCBP 
woman of childbearing potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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