A Randomized, Double-Blind, Single-Dose, Parallel, Placebo-Controlled Pivotal Trial to Confirm the Efficacy of a Fixed Dose Combination Tablet of Naproxen Sodium and Caffeine to Effectively Alleviate Postsurgical Dental Pain
Phase: PHASE3
Conditions: Postoperative Dental Pain
Sponsor: Bayer

 
Document Type: 
Clinical Study Protocol 
Official Title: 
A Randomized, Double-Blind, Single-Dose, Parallel, Placebo-
Controlled Pivotal Trial to Confirm the Efficacy of a Fixed 
Dose Combination Tablet of Naproxen Sodium and Caffeine 
to Effectively Alleviate Postsurgical Dental Pain 
NCT Number: 
NCT05485805 
Document Date:  
13-Mar-2023 
 
 

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Title Page 
Protocol Title: A Randomized, Double-Blind, Single-Dose, Parallel, Placebo-Controlled 
Pivotal Trial to Confirm the Efficacy of a Fixed Dose Combination Tablet of Naproxen 
Sodium and Caffeine to Effectively Alleviate Postsurgical Dental Pain 
Protocol Number: 22093 
Amendment Number:  3  
Compound Number: BAY 2880376 
Study Phase: Phase 3 
 
 
Sponsor Name: Bayer HealthCare LLC, Consumer Health 
Legal Registered Address: 100 Bayer Boulevard 
 
Whippany, NJ 07981-0915, USA 
 
Regulatory Agency Identifier Number(s): IND 140798 
 
Approval Date: 13-Mar-2023 
 
 
 
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
 Global Medical Affairs Pain
Bayer Consumer Health
Date
13-Mar-2023
PPD
PPD
PPD

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Protocol Amendment Summary of Changes Table 
 
Protocol Amendment 1 (Version 2.0) 
 
The following sections were amended from Version 1.0 to Version 2.0.  Pagination 
was updated in this table to align with Amendment 2. 
 
Type of Amendment: Substantial 
 
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 
28 
6.1.1 
Study intervention assignment 
At the beginning of the first treatment period, after 
completion of the pre-treatment baseline 
procedures/assessments, participants who meet the entry 
criteria will be sequentially assigned to a unique number in 
sequential order (randomization number, RNR) according to 
the randomization schedule 2:2:2:1:1  3:3:3:1:1(naproxen 
sodium/caffeine 220/65 mg; naproxen sodium/caffeine 
440/130 mg; naproxen sodium 220 mg; caffeine 100 mg; 
placebo) prepared prior to the study.  
 
 
Protocol Amendment 2 (Version 3.0) 
 
The following sections were amended from Version 2.0 to Version 3.0.  Pagination 
and headers were updated in this table to align with Amendment 2. 
 
Type of Amendment: Substantial 
 
Page 
Number 
Section 
Number 
Paragraph or bullet point/number 
2 
Sponsor 
Signatory 
 
 Global Medical Affairs 
 
 Global Medical Affairs Pain 
Bayer Consumer Health 
 
 
PPD
PPD
PPD
PPD

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12 
Objectives and 
Endponts 
x 
Pain Intensity Difference (PID) and Pain Relief scores at 
0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, (16, 18, 20 
if awake), 22 and 24 hours post-dose  
15 
1.3 
Footnote c - Pain Intensity NRS to be completed at baseline 
(predose), and Pain Intensity NRS and Categorical Pain Relief 
will be assessed 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 
(16, 18, 20 if awake), 22 and 24 hours (+/-5 minutes over the 
first 8 hours; +/-8 minutes from hours 9 through 24) post-
dose.  If rescue occurs, scales/questions will be completed 
immediately each time rescue medication is taken 
19 
3 
x Pain Intensity Difference (PID) and Pain Relief scores at 
0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, (16, 18, 20 
if awake), 22 and 24 hours post-dose  
x Peak PID and peak pain relief  
x Time and cumulative proportion of achieving 
complete pain relief 
25 
5.2 
17. Use of Nicotine containing products from midnight 24 
hours prior to surgery until discharge from the study site 
or longer if so directed by the oral surgeon; 
27 
6 
The study center will dispense a single-dose (2 tablets) of an 
assigned treatment within 4.5 hours post-surgery.  The tablets 
and placebo will be administered based on a computer-
generated randomization schedule (section 6.1.1) and 
stratified by the severity of pain experienced (moderate or 
severe).  Moderate participants will use the lowest 
randomization number available and severe participants 
will use the highest randomization number available. 
 
 

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28 
6.1.1 
At the beginning of the first treatment period, after 
completion of the pre-treatment baseline 
procedures/assessments, participants who meet the entry 
criteria will be randomized in the study. The 
randomization will be stratified by baseline pain intensity 
(moderate vs severe) according to the randomization 
schedule 3:3:3:1:1 (naproxen sodium/caffeine 220/65 mg; 
naproxen sodium/caffeine 440/130 mg; naproxen sodium 
220 mg; caffeine 100 mg; placebo) prepared prior to the 
study. Participants sequentially assign will be assigned 
sequentially to a unique number in sequential order the 
lowest available number or highest available number 
(randomization number, RNR) for those with moderate or 
severe baseline pain intensity, respectively according to the 
randomization scheduled 3:3:3:1:1 (naproxen sodium/caffeine 
220/65 mg; naproxen sodium/caffeine 440/130 mg; naproxen 
sodium 220 mg; caffeine 100 mg; placebo) prepared prior to 
the study to assure treatment balance between each 
stratum. 
29 
6.1.1 
Participants will be numbered according to the following 
scheme: 
 
Whereas the “Xs” will be replaced with a four five digit 
sequentially assigned number as each participant enters the 
study (e.g., first participant number will be 
 
29 
6.1.2 
Participants must be nil per os (NPO) from midnight prior to 
surgery until completion of surgery. If participants ingest 
clear liquids during this time, they may be eligible as per 
investigator discretion.  Each participant will continue 
fasting, with the exception of clear liquids, until after study 
drug administration. 
30 
6.1.2 
The Sponsor will provide sufficient quantity of the study 
intervention to the study site.  The study center will dispense 
study intervention according to the randomization schedule 
and stratify randomization by the participant’s categorical 
pain intensity (moderate or severe) post-surgery.   
 
 
PPD
PPD

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32 
6.5.1 
Rescue medication will be dispensed in a hierarchical 
method starting with ibuprofen 400 mg.  Should the 
participant not experience adequate pain relief, 
Hydrocodone 5 mg/Acetaminophen 325 mg tablets or other 
appropriate analgesics (such as an additional ibuprofen 
dose) may be used at the discretion of the Investigator.  
Rescue medication is also available on return of pain and the 
time of rescue medication will be recorded in the source 
documents.  Pain assessments will be performed immediately 
before the first dose of rescue medication. 
36 
8.1.6 
After the baseline (pre-dose) pain intensity is determined, pain 
intensity and pain relief will be rated by participants at 0.5, 1, 
1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, (16, 18, 20 if awake), 
22 and 24 hours (+/-5 minutes over the first 8 hours; +/-8 
minutes from hours 9 through 24) post-dose, and immediately 
prior to the use of the first dose rescue medication. 
37 
8.1.6 
Participants would be encouraged not to sleep before 
midnight and if needed, woken for assessments (up to hour 
14). Participants will be allowed a 6 hour rest period 
during the overnight hours of the 24-hour evaluation period 
and woken for the 22 hour assessment.  The order of the 
pain assessments is Pain Intensity, then Pain Relief, then 
query about any AEs.  At hour 24 or immediately prior to the 
first dose of rescue medication (if prior to hour 24), study 
participants will be asked to provide a Global Assessment of 
investigational product after completion of the other 
assessments.  Additionally, participants will have vital signs 
taken after surgery, then at 1, 12 and 24 hours post-dose. 
43 
9.3 
All participants in the Safety Population who provide at least 
one pain assessment after the first dose of the investigational 
product.  ITT population will be used as the primary 
analysis for the efficacy parameters will be used as 
secondary to conduct the sensitivity analysis for the selected 
parameters. 
PP population will include all participants in ITT who do not 
have any major protocol violations and complete the 24 hour 
assessments. PP population will be used as secondary to 
conduct the sensitivity analysis for the selected 
parameters will be used as primary analysis for the efficacy 
parameters. 
 
 

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44 
9.4.1 
A positive difference is indicative of improvement.  Time-
weighted Sum of Pain Intensity Differences (SPIDs) will be 
calculated for 2, 4, 6, 8, 12, 16, 20 and 24 hours by 
multiplying the PID score at each post-dose time point by the 
duration (in hours) since the preceding time point and then 
summing these values over 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 
11, 12, 14, (16, 18, 20 if awake), 22 and 24 hours, 
respectively.   
44 
9.4.1 
The primary efficacy analyses population will be based on the 
ITT PP population. 
45 
9.4.1 
Pain Intensity Difference (PID) and Pain Relief scores at 0.5, 
1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, (16, 18, 20 if 
awake), 22 and 24 hours post-dose. Descriptive statistics for 
each time point and graphical illustrations of the time effect 
curves will be presented. 
 
Time to achieve complete pain relief will be analyzed 
similarly as for the time to first use of rescue medication.  
 
Cumulative percent of participants with ‘at least a 2-point 
PID’ and cumulative percent of participants achieving 
complete pain relief will be plotted over time and will be 
analyzed using Chi-square tests. 
 
 
Protocol Amendment 3 (Version 4.0) 
 
The following sections were amended from Version 3.0 to Version 4.0.  Pagination 
was updated in this table to align with Amendment 3. 
 
 
Type of Amendment: Substantial 
 
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 
16 
1.3 
Footnote a - Vital signs (blood pressure, pulse rate, and 
respiration after sitting for at least 5 minutes). On Day 1, vital 
signs are due pre-operatively, post-surgery, at 1 hour, 12 
hours and on Day 2, 24 hours (-30 minutes pre-surgery; +30 
minutes post-surgery; +/- 30 minutes from hours 1 
through 24) after study medication dosing 
 
 

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37 
8.1.2 
Participants will arrive at the unit at their assigned time and 
will have the following activities completed prior to dental 
surgery: 
x Vital signs consisting of sitting blood pressure (in 
triplicate with one min in between), respiratory rate and 
pulse after sitting for at least 5 minutes (-30 minutes); 
38 
8.1.6 
Participants who have not met the randomization criteria 
within 4.5 hours from last suture or 14:30 h (+/- 15 minutes) 
will not be randomized and may be discharged from the 
clinic, once deemed eligible by an Investigator. 
 
Additionally, participants will have vital signs taken after 
surgery, then at 1, 12 and 24 hours (+30 minutes post-
surgery; +/-30 minutes from hours 1 through 24) post-
dose. 
40 
8.2.2 
Blood pressure is to be taken in triplicates, one minute apart 
to enhance accuracy as suggested in the FDA guidance 
(Assessment of Pressor Effect of Drugs, May, 2018). Pre-
surgery vitals may be collected up to 30 minutes prior to 
time of surgery. 

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Table of Contents 
Title Page ............................................................................................................................... 1 
Sponsor Signatory ................................................................................................................ 2 
Protocol Amendment Summary of Changes Table ........................................................... 3 
Study intervention assignment ............................................................................................... 3 
Table of Contents ................................................................................................................. 9 
Table of Tables ................................................................................................................... 11 
1. 
Protocol Summary ...................................................................................................... 12 
1.1 
Synopsis ..................................................................................................................... 12 
1.2 
Schema ....................................................................................................................... 15 
1.3 
Schedule of Activities (SoA) ..................................................................................... 16 
2. 
Introduction ................................................................................................................. 17 
2.1 
Study Rationale .......................................................................................................... 17 
2.2 
Background ................................................................................................................ 17 
2.3 
Benefit/Risk Assessment ........................................................................................... 18 
3. 
Objectives and Endpoints ........................................................................................... 20 
4. 
Study Design ................................................................................................................ 21 
4.1 
Overall Design ........................................................................................................... 21 
4.2 
Scientific Rationale for Study Design ....................................................................... 22 
4.3 
Justification for Dose of Active Treatment Groups ................................................... 22 
4.4 
End of Study (EOS) Definition .................................................................................. 24 
5. 
Study Population ......................................................................................................... 24 
5.1 
Inclusion Criteria ....................................................................................................... 24 
5.2 
Exclusion Criteria ...................................................................................................... 25 
5.3 
Lifestyle Considerations ............................................................................................ 27 
5.3.1 
Meals and Dietary Restrictions .............................................................................. 27 
5.3.2 
Alcohol ................................................................................................................... 27 
5.4 
Screen Failures ........................................................................................................... 27 
5.5 
Run-in Failures .......................................................................................................... 27 
5.6 
Dropouts ..................................................................................................................... 27 
5.7 
General Procedures .................................................................................................... 27 
6. 
Study Intervention ...................................................................................................... 28 
6.1 
Study Intervention(s) Administered ........................................................................... 28 
6.1.1 
Study intervention assignment ............................................................................... 29 
6.1.2 
Participant Administration ...................................................................................... 30 
6.2 
Preparation/Handling/Storage/Accountability ........................................................... 30 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....................................... 31 
6.3.1 
Unblinding .............................................................................................................. 32 
6.3.2 
Emergency unblinding by the investigator ............................................................. 32 
6.4 
Study Intervention Compliance ................................................................................. 32 
6.5 
Prior and Concomitant Therapy ................................................................................. 32 
6.5.1 
Rescue Medicine..................................................................................................... 33 
6.6 
Dose Modification ..................................................................................................... 33 

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6.7 
Intervention after the End of the Study ...................................................................... 33 
7. 
Discontinuation of Study Intervention and Participant .......................................... 33 
7.1 
Discontinuation of Study Intervention ....................................................................... 33 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................... 34 
7.3 
Lost to Follow Up ...................................................................................................... 34 
8. 
Study Assessments and Procedures ........................................................................... 35 
8.1 
Efficacy Assessments ................................................................................................ 35 
8.1.1 
Screening Period ..................................................................................................... 35 
8.1.2 
Pre-surgery ............................................................................................................. 36 
8.1.3 
Impaction Score ...................................................................................................... 36 
8.1.4 
During Surgery ....................................................................................................... 37 
8.1.5 
Surgical Trauma Score ........................................................................................... 37 
8.1.6 
Postsurgery ............................................................................................................. 37 
8.2 
Safety Assessments .................................................................................................... 39 
8.2.1 
Physical Examinations ............................................................................................ 39 
8.2.2 
Vital Signs .............................................................................................................. 39 
8.2.3 
Clinical Safety Laboratory Assessments ................................................................ 40 
8.2.4 
Other Procedures and Variables ............................................................................. 40 
8.3 
Adverse Events and Serious Adverse Events ............................................................ 40 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information................... 40 
8.3.2 
Expected Adverse Events ....................................................................................... 41 
8.3.3 
Method of Detecting AEs and SAEs ...................................................................... 41 
8.3.4 
Follow-up of AEs and SAEs .................................................................................. 41 
8.3.5 
Regulatory Reporting Requirements for SAEs ...................................................... 41 
8.3.6 
Pregnancy ............................................................................................................... 42 
8.4 
Treatment of Overdose .............................................................................................. 42 
8.5 
Pharmacokinetics ....................................................................................................... 42 
8.6 
Pharmacodynamics .................................................................................................... 42 
8.7 
Genetics ..................................................................................................................... 42 
8.8 
Biomarkers ................................................................................................................. 42 
8.9 
Health Economics ...................................................................................................... 43 
9. 
Statistical Considerations ........................................................................................... 43 
9.1 
Statistical Hypotheses ................................................................................................ 43 
9.2 
Sample Size Determination ....................................................................................... 43 
9.3 
Populations for Analyses ........................................................................................... 44 
9.4 
Statistical Analyses .................................................................................................... 44 
9.4.1 
Efficacy Analyses ................................................................................................... 44 
9.4.2 
Safety Analyses ...................................................................................................... 47 
9.5 
Interim Analyses ........................................................................................................ 47 
10. Supporting Documentation and Operational Considerations ................................ 47 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .................... 47 
10.1.1 Regulatory and Ethical Considerations .................................................................. 47 
10.1.2 Financial Disclosure ............................................................................................... 48 
10.1.3 Funding ................................................................................................................... 48 
10.1.4 Informed Consent Process ...................................................................................... 48 
10.1.5 Data Protection and Confidentiality ....................................................................... 49 
10.1.6 Compensation for Health Damage of Participants / Insurance............................... 50 

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10.1.7 Committees Structure ............................................................................................. 50 
10.1.8 Dissemination of Clinical Study Data .................................................................... 50 
10.1.9 Data Handling and Quality Assurance ................................................................... 50 
10.1.10 Source Documents .................................................................................................. 51 
10.1.11 Missing Data ........................................................................................................... 51 
10.1.12 Audit and Inspection ............................................................................................... 51 
10.1.13 Archiving ................................................................................................................ 52 
10.1.14 Study and Site Closure ........................................................................................... 52 
10.1.15 Publication Policy ................................................................................................... 52 
10.2 Appendix 2: Clinical Laboratory Tests ...................................................................... 53 
10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .......................................................................................... 53 
10.3.1 Definition of AE ..................................................................................................... 53 
10.3.2 Definition of SAE ................................................................................................... 54 
10.3.3 Recording and Follow-Up of AE and/or SAE ........................................................ 56 
10.3.4 Reporting of SAEs .................................................................................................. 59 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ..... 60 
10.5 Appendix 5: Participant Assessments ........................................................................ 63 
10.6 Appendix 6: Abbreviations ........................................................................................ 65 
11. References .................................................................................................................... 66 
 
Table of Tables 
Table 1 – Treatments administered ...................................................................................... 28 
Table 2 – Identity of study treatment ................................................................................... 29 
 
Table of Figures 
Figure 1 – Design Overview ................................................................................................ 15 
 
 
 
 
 

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1. 
Protocol Summary 
1.1 
Synopsis 
The post-impaction dental pain model has been widely used in the evaluation of OTC and 
prescription analgesics for a number of reasons. Dental surgical procedures can be easily 
standardized, and the population of participants undergoing a given procedure is usually 
relatively healthy and homogeneous. In addition, there is extensive data substantiating the 
usefulness of the dental pain model in predicting the relative efficacy of a wide range of 
analgesic medications. The model has been found to be very useful for comparing several 
measures of analgesic efficacy, including onset, peak effect, and duration of analgesic activity 
(Cooper and Beaver 1976, Cooper, Desjardins et al. (2016)).  This study will use the dental 
pain model to compare the efficacy of naproxen sodium 220mg/caffeine 65 mg with respect 
to its components caffeine and naproxen sodium as well as placebo. 
Protocol Title: A Randomized, Double-Blind, Single-Dose, Parallel, Placebo-Controlled 
Pivotal Trial to Confirm the Efficacy of a Fixed Dose Combination Tablet of Naproxen 
Sodium and Caffeine to Effectively Alleviate Postsurgical Dental Pain 
 
Rationale: 
 
 
BHC intends to continue the development of a fixed dose combination (FDC) product of 
naproxen sodium and caffeine. The product is intended to temporary relieve minor aches and 
pains due to minor pain of arthritis, muscular aches, backache, menstrual cramps, headache, 
and toothache.  The clinical development program will provide evidence in accordance to the 
combination drug rule set forth in 21CFR 330.10(a)(4)(iv), which includes, in part, that each 
active ingredient makes a contribution to the claimed effect. 
Naproxen sodium was approved on March 11, 1976 as a prescription product and on January 
11, 1994 as an over-the-counter medication under NDA 20-204.  In the US, it is indicated as a 
pain reliever/fever reducer and marketed over the counter by BHC as Aleve® tablets, gelatin-
enrobed tablets, and liquid-filled capsules (under NDA 21-920, owned by BionPharma Inc.). 
It is indicated for adults and children over 12 years of age, with one tablet to be taken every 8-
12 hours while symptoms persist. The first dose may be taken as 2 tablets within the first 
hour, but should not exceed 2 tablets in any 8- to 12-hour period and no more than 3 tablets in 
any 24-hour period. The maximum daily limit for naproxen sodium is 660 mg for up to 10 
days. 
Caffeine is included in three different OTC drug monographs: internal analgesic, antipyretic, 
and anti-rheumatic OTC drug products (21 CFR 343); stimulant OTC drug products (21 CFR 
340); and menstrual OTC drug products (21 CFR 357).  The internal analgesics monograph is 
in the Tentative Final Monograph (TFM) state since 1998.  However, subsequent FDA 
correspondence (1995) in response to Industry  Docket Submissions permits analgesics, such 
as aspirin and acetaminophen, to be combined with 65 mg of caffeine, which functions as an 
adjuvant, potentiating the effect of the analgesic active ingredient to provide stronger relief as 
compared to its therapeutic dose in monotherapy.  When used as an analgesic adjuvant in 
adults and children 12 years and older, caffeine dose can be up to 130 mg per single dose and 
up to 4 doses in 24 hours, which can reach 520 mg of caffeine per day.  The stimulant 
monograph allows for products to have 100-200 mg of caffeine per dose. These products are 
to be taken no more than every 3-4 hours, for a total of 1600 mg of caffeine per day by adults 
and children 12 years and older. The menstrual drug products monograph allows for 100-200 
mg of caffeine every 3 to 4 hours when used as a diuretic in adults. 

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This study is intended to compare the efficacy of a single tablet of naproxen sodium 
220/caffeine 65 mg with respect to the single ingredients as well as placebo.  This study will 
also examine the analgesic efficacy of two tablets of the FDC. 
Objectives and Endpoints: 
 
Overall Design: 
This is a single center, randomized, double-blind, parallel, placebo-controlled study in 
participants experiencing moderate to severe postoperative dental pain. The study will consist 
Objectives 
Endpoints 
Primary 
 
x 
To compare a single oral dose of the FDC 
naproxen sodium 220mg/caffeine 65mg relative 
to naproxen sodium 220mg, caffeine 100 mg and 
placebo  
x 
Sum of Pain Intensity Difference over 8 hours 
(SPID0-8)  
Secondary 
 
x 
To compare a single oral dose of the FDC relative 
to naproxen sodium 220mg, caffeine 100 mg and 
placebo.  The assessments are made in terms of: 
o 
Pain intensity differences  
o 
Measures of pain relief  
o 
Duration of analgesic efficacy  
o 
Onset of pain relief as determined by the 
time of perceptible relief 
o 
Onset of pain relief as determined by the 
time to meaningful relief  
o 
Overall relief from pain based on measures 
of pain intensity and pain relief  
o 
Global assessment of the investigational 
product 
x 
To assess the safety and tolerability of the 
investigational product in terms of adverse events 
(AEs) and clinical parameters 
x 
Sum of pain intensity differences from 0 to 2, 4, 6, 
12 and 24 hours post-dose (SPID0-2, SPID0-4, 
SPID0-6, SPID6-12, SPID0-12, SPID12-16, 
SPID16-20, SPID12-24, SPID16-24, SPID0-24) 
x 
Total pain relief from 0 to 2, 4, 6, 8, 12 and 24 
hours post-doseTOTPAR0-2, TOTPAR0-4, 
TOTPAR0-6, TOTPAR 6-12, TOTPAR0-8 
TOTPAR0-12, TOTPAR12-16, TOTPAR16-20, 
TOTPAR 12-24, TOTPAR16-24 and TOTPAR0-
24) 
x 
Time to first use of rescue medication 
x 
The cumulative proportion of participants taking 
rescue medication over the 24 hour period. 
x 
Time to first perceptible relief measured by a 
stopwatch, time to meaningful relief measured by a 
stopwatch, and time to first perceptible relief 
confirmed by meaningful relief defined as the time 
to perceptible pain relief (the first stopwatch time) 
for those participants who had meaningful pain 
relief (the second stopwatch time)  
x 
Pain Intensity Difference (PID) and Pain Relief 
scores at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 
14, (16, 18, 20 if awake), 22 and 24 hours post-
dose  
x 
Peak PID and peak pain relief  
x 
Cumulative percent of participants with ‘at least a 
2-point PID’ over time  
x 
Global assessment of the investigational product 
x 
Collect AE and clinical paramaeters  

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of a Prescreening telephone call, a Screening Visit, a one day Treatment Period and a Post-
Operative phone call or visit.  Eligible participants who have undergone surgical extraction of 
three or four third molars, two of which must be mandibular partial or full bony impacted, 
will be randomized into one of five treatment groups and kept in-house and evaluated for 
efficacy and safety at the study site through completion of all trial procedures. 
Disclosure Statement: This is a parallel group treatment study with 5 arms that is participant 
and investigator blinded. 
Intervention Model: Parallel 
Primary Purpose: Treatment 
Number of Arms: 5 
Masking: No masking 
Number of Participants:  
Approximately 750 participants will be screened to achieve 540 randomly assigned to study 
intervention and 528 evaluable participants for an estimated total of 144 evaluable 
participants per active intervention group with 48 participants in the caffeine 100 mg arm and 
48 participants for placebo (total of 5 groups). 
Intervention Groups and Duration: 
Participants will receive a single dose of study intervention of either: 
x naproxen sodium/caffeine 220/65 mg 
x naproxen sodium/caffeine 2 x 220/65 mg 
x naproxen sodium 220 mg 
x caffeine 100 mg 
x or placebo 
with pain intensity, pain relief and onset of pain relief assessments performed over the next 24 
hours. 
 
Data Monitoring Committee: No 
 
 

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1.2 
Schema 
Figure 1 – Design Overview 
 
Screening 
Phase 
Treatment Phase 
 
Follow up 
Phase 
Trial 
Days 
Day -28 to -1 
Day 1 
Pre-surgery 
Day 1 
Surgery 
Day 1 
Post-surgery 
Day 1 
Day 2 
2-5 days after 
discharge 
 
 
Check-in to 
study site     
Surgical 
teeth 
extraction 
Categorical 
pain 
NRS pain 
Stopwatch 
method 
NRS pain,    
Pain relief 
Stopwatch 
method 
NRS pain 
Pain relief 
Global 
assessment 
Phone call or 
visit 
 
  
  
= randomized study intervention of:  
naproxen sodium/caffeine 220/65 mg; 
naproxen sodium/caffeine 2 x 220/65 mg; 
naproxen sodium 220 mg; 
caffeine 100 mg; 
or placebo. 
 
 
 
 
 
 
 
 
  
  

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1.3 
Schedule of Activities (SoA) 
 
Protocol Activities 
Screening Visit    
(within 28 days prior 
to oral surgery) 
Dosing Period  
Inpatient 
End of Trial 
Call or Visit 
(2-5 days after 
discharge) 
Day 1 
Day 2 
Written Informed Consent 
x 
 
 
 
Inclusion/Exclusion Reviewed 
x 
x 
 
 
Medical/Medication History (incl. caffeine consumption) 
x 
x 
 
 
Physical and Oral Examination  
x 
 
 
 
Vital Signs a 
x 
x 
x 
 
Urine  for Drug Screen 
x 
x 
 
 
Breath or saliva alcohol test 
x 
x 
 
 
Dental x-ray examination 
x 
 
 
 
Urine Pregnancy Test (if applicable) 
x 
x 
 
 
Admission to Unit  
 
x 
 
 
Oral surgery (between 0530 h and 1030 h) 
 
x 
 
 
Randomization Number Assigned 
 
x 
 
 
Investigational Product Administration                 
 
x 
 
 
Surgical Trauma Rating 
 
x 
 
 
Stop watch method (perceptible and meaningful relief) 
 
x 
x 
 
Categorical Pain Rating Scale b   
 
x 
x 
 
Pain Intensity Numerical Rating Scale (NRS) c      
 
x 
x 
 
Categorical Pain Relief Rating Scale c 
 
x 
x 
 
Global Assessment of Pain Relief d 
 
 
x 
 
Concomitant Medications  
 
x 
x 
x 
Adverse Events Assessed 
x 
x 
x 
x 
Discharge from Unit the afternoon/evening of Day 2 
 
 
x 
 
a vital signs (blood pressure, pulse rate, and respiration after sitting for at least 5 minutes).  On Day 1, vital signs are due pre-operatively, 
post-surgery,  at 1 hour, 12 hours and on Day 2, 24 hours (-30 minutes pre-surgery; +30 minutes post-surgery; +/- 30 minutes from 
hours 1 through 24) after study medication dosing 
b to be completed prior to dosing 
c Pain Intensity NRS to be completed at baseline (predose), and Pain Intensity NRS and Categorical Pain Relief will be assessed 0.5, 
1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, (16, 18, 20 if awake), 22 and 24 hours (+/-5 minutes over the first 8 hours; +/-8 minutes 
from hours 9 through 24) post-dose.  If rescue occurs, scales/questions will be completed immediately each time rescue medication 
is taken 
 d assessment will be completed immediately before first rescue medication is taken or at 24 hours post-dose 
 
 

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2. 
Introduction 
In addition to the information provided below, please also refer to the Aleve Drug Facts Label 
(DFL) and the DFL of caffeine for any additional data on these products. 
 
2.1 
Study Rationale 
BHC intends to continue the development of a fixed dose combination (FDC) product of 
naproxen sodium and caffeine. The product is to be used for the temporary relief of minor 
aches and pains due to minor pain of arthritis, muscular aches, backache, menstrual cramps, 
headache, and toothache. 
Naproxen sodium was approved on March 11, 1976 as a prescription product and on January 
11, 1994 as an over-the-counter medication under NDA 20-204.  In the US, it is indicated as a 
pain reliever/fever reducer and marketed over the counter by BHC as Aleve tablets, gelatin-
enrobed tablets, and liquid-filed capsules (under NDA 21-920, owned by BionPharma Inc.). It 
is indicated for adults and children over 12 years of age, with one tablet to be taken every 8-
12 hours while symptoms persist. The first dose may be taken as 2 tablets within the first 
hour, but should not exceed 2 tablets in any 8- to 12-hour period and no more than 3 tablets in 
any 24-hour period. The maximum daily limit for naproxen sodium is 660 mg for up to 10 
days. 
Caffeine is included in three different OTC drug monographs: internal analgesic, antipyretic, 
and anti-rheumatic OTC drug products (21 CFR 343); stimulant OTC drug products (21 CFR 
340); and menstrual OTC drug products (21 CFR 357). The internal analgesics monograph is 
in the Tentative Final Monograph (TFM) stage since 1998.  However, subsequent FDA 
correspondence (1995) in response to Industry  Docket Submissions now permits analgesics, 
such as aspirin and acetaminophen, to be combined with 65 mg of caffeine, which functions 
as an adjuvant, potentiating the effect of the analgesic active ingredient to provide stronger 
relief as compared to its therapeutic dose in monotherapy.  When used as an analgesic 
adjuvant, in adults and children 12 years and older, caffeine dosing can be up to 130 mg per 
single dose and up to 4 doses in 24 hours, which can reach 520 mg of caffeine per day. The 
stimulant monograph allows for products to have 100-200 mg of caffeine per dose. These 
products are to be taken no more than every 3-4 hours, for a total of 1600 mg of caffeine per 
day by adults and children 12 years and older. The menstrual drug products monograph 
allows for 100-200 mg of caffeine every 3 to 4 hours when used as a diuretic in adults. 
The clinical development program will provide evidence in accordance to the combination 
drug rule set forth in 21CFR 330.10(a)(4)(iv), which includes, in part, that each active 
ingredient makes a contribution to the claimed effect. 
This study will also examine the analgesic efficacy of two tablets of the FDC vs. one tablet. 
2.2 
 Background 
Naproxen sodium is the sodium salt of naproxen, an aryl propionic acid derivative in the 
nonsteroidal anti-inflammatory drugs (NSAID) class. Naproxen exerts its analgesic, 
antipyretic and anti-inflammatory effects by inhibition of prostaglandin synthesis through its 
non-selective, reversible inhibition of the cyclo-oxygenase (COX) enzymes. Naproxen 
inhibits the formation of COX-1 dependent thromboxane synthase, A2 (TXA2), which 
reduces platelet aggregation, and the COX-2 dependent prostacyclin (PGI2) which play a role 

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in vasodilation associated with inflammation and prostaglandins (i.e. PGE2) which  contribute 
to sensation of pain (Capone, Tacconelli et al. 2004, Grosser, Theken et al. 2017). 
In the United States, naproxen has been marketed as a prescription medication since 1976 under 
the brand name Naprosyn®.  Its sodium salt, naproxen sodium, was first sold under the trade 
name Anaprox® in 1980.  In 1994, the US FDA approved naproxen sodium tablets (using the 
brand name Aleve®), 220 mg for over-the-counter (OTC) use. Aleve® is indicated for the 
temporary relief of minor aches and pains due to minor pain of arthritis, muscular aches, 
backaches, menstrual cramps, headaches, toothaches, and the common cold.  It also temporarily 
reduces fever.  As an OTC medication, Aleve® should not be taken for longer than 10 days for 
pain or 3 days for fever unless otherwise directed by a physician. 
Caffeine is a methyl xanthine, found in plants and is generally consumed as coffee, tea, or 
cocoa. It is a central nervous system and metabolic stimulant, used to reduce fatigue and 
enhance mental alertness. It can also stimulate the respiratory center, thereby increasing the 
rate and depth of respiration. It can also facilitate the performance of muscles. Caffeine has 
been shown to enhance the effectiveness of various pain relievers, so it is accepted as an 
adjuvant to analgesics such as acetaminophen, ibuprofen and aspirin (Laska, Sunshine et al. 
1984, Sawynok and Yaksh 1993, Diener, Pfaffenrath et al. 2005, Derry, Derry et al. 2014, 
Derry, Wiffen et al. 2015, Lipton, Diener et al. 2017). 
While caffeine may affect various physiological processes, its main mode of action as an 
analgesic adjuvant is through antagonism of adenosine receptors in the brain. The reduction in 
adenosine activity results in reduced perception of pain. Caffeine can also exhibit mood 
enhancing and stimulatory properties (Sawynok and Yaksh 1993). 
This proposed product is intended to be a tablet with a fixed dose combination of 220 mg 
naproxen sodium and 65 mg caffeine based on the recently completed dose ranging study. 
The purpose of this product is to provide temporary relief of minor aches and pains due to 
minor pain of arthritis, muscular aches, backache, menstrual cramps, headache, and toothache 
for adults and children over 12 years of age. Its posology will be similar to Aleve®, with one 
tablet to be taken every 8-12 hours while symptoms persist. The first dose may be taken as 2 
tablets within the first hour, but should not exceed 2 in any 8 to 12 hours period and no more 
than 3 in any 24 hour period. Thus, the maximum daily limit will be 660 mg naproxen sodium 
and 195 mg caffeine. 
This pivotal efficacy study is intended to examine the analgesic effect of this FDC compared 
to its components, naproxen sodium and caffeine to satisfy the combination rule set forth in 
21CFR 330.10(a)(4)(iv). 
 
2.3 
Benefit/Risk Assessment 
Participants who need to have third molar extraction will be solicited to participate in this study.  
Participants who consent to participate may benefit by receiving a medical exam, dental 
radiographs and no-cost surgical procedures for teeth extraction. Furthermore, post-surgical 
participants will be provided continuous nursing care for approximately 24 hours after surgery.  
Potential risks of the surgical procedure include pain, dry socket, infection, swelling, bleeding, 
trismus, and lip or tongue numbness.  Potential risks related to local anesthesia and mild 
sedation include paresthesia and drowsiness.  Participants who experience a treatment failure 
can have the option of taking a standard rescue medication commonly used for post-operative 
pain relief.  Potential study medication benefit will be relief of postsurgical pain, which is highly 

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prevalent following extraction of wisdom teeth.  Potential risks of a single dose of OTC study 
medication are low and described in the Drug Facts Label. 
During the study, participants will be closely monitored for evidence of adverse events.  
Weighing between the potential risks associated with the study, and given the ability to mitigate 
risks through close monitoring and routine peri-operative care, this study is considered 
clinically and ethically acceptable. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events may be found in the naproxen sodium Investigator’s Brochure and 
Aleve® Drug Facts Label. 
Caffeine has been proven to act as an analgesic adjuvant, providing up to 40% more relief 
than analgesics alone (Laska, Sunshine et al. 1984). While the analgesia-enhancing effect of 
caffeine has not been extensively studied with naproxen sodium, a preliminary study (Fricke 
1994) showed a positive effect analogous to the results of studies with ibuprofen, another 
member of the aryl propionic acetic acid family of NSAIDs (Derry, Wiffen et al. 2015). The 
results of a recently completed dose ranging study with the proposed FDC also showed the 
beneficial effect of caffeine in enhancing the analgesic effect of naproxen sodium. 
In regards to safety, caffeine is included in the monographs for stimulant OTC drug products 
(21 CFR 340) and for internal analgesic, antipyretic, and anti-rheumatic OTC drug products 
(21 CFR part 343) as analgesic adjuvant. Although it is generally accepted that 300 mg to 400 
mg of caffeine daily may be safely taken by the general population (McGuire 2014), several 
potentially vulnerable populations have been identified. After a review of available data, 
Health Canada recommended that women of reproductive age restrict caffeine intake to no 
more than 300 mg daily, and that children up to 12 years restrict intake to no more than 2.5 
mg per kilogram of bodyweight. During pregnancy, the American College of Obstetrics and 
Gynecology has recommended no more than 200 mg caffeine intake daily (ACOG 2010). 
Finally, consumers (particularly children) on anticonvulsants or sympathomimetics, as well as 
consumers with known cardiovascular disease should probably limit caffeine intake. 
Risks to vulnerable populations identified above will be addressed through labeling. For 
example, the proposed label will restrict the product to the same population as the current 
Aleve® product, which is not indicated for children younger than 12 years old and instructs 
women to avoid taking NSAIDs around 20 weeks or later in pregnancy. Similarly, the 
proposed label instructs consumers on any prescription drugs or with any concurrent disease 
(which includes cardiovascular conditions and seizure disorders) also to consult a physician 
before use. Finally, the proposed label will include all the necessary instructions for safe and 
effective use including contraindications, applicable warnings and precautions, and 
undesirable effects. No further risk-minimization measures are considered necessary for this 
new product, and its benefit-risk balance is expected to be positive. 
 
 

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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
x 
To compare a single oral dose of the FDC 
relative to naproxen sodium 220mg, Caffeine 
100 mg and placebo 
x 
Sum of Pain Intensity Difference over 8 hours 
(SPID 0-8)  
Objectives 
Endpoints 
Secondary 
 
x 
To compare a single oral dose of the FDC 
relative to naproxen sodium 220mg, caffeine 100 
mg and placebo.  The assessments are made in 
terms of: 
o 
Pain intensity differences  
o 
Measures of pain relief  
o 
Duration of analgesic efficacy  
o 
Onset of pain relief as determined by the 
time of perceptible relief 
o 
Onset of pain relief as determined by the 
time to meaningful relief  
o 
Overall relief from pain based on 
measures of pain intensity and pain relief  
o 
Global assessment of the investigational 
product 
x 
To assess the safety and tolerability of the 
investigational product in terms of adverse 
events (AEs) and clinical parameters 
x Sum of pain intensity differences from 0 to 2, 4, 
6, 12 and 24 hours post-dose (SPID0-2, SPID0-
4, SPID0-6, SPID6-12, SPID0-12,  SPID12-16, 
SPID16-20, SPID12-24,  SPID16-24, SPID0-24) 
x Total pain relief from 0 to 2, 4, 6, 8, 12 and 24 
hours post-doseTOTPAR0-2, TOTPAR0-4, 
TOTPAR0-6, TOTPAR6-12, TOTPAR0-8 
TOTPAR0-12, TOTPAR12-16, TOTPAR16-20, 
TOTPAR12-24, TOTPAR16-24, and 
TOTPAR0-24) 
x Time to first use of rescue medication 
x The cumulative proportion of participants taking 
rescue medication over the 24 hour period. 
x  Time to first perceptible relief measured by a 
stopwatch, time to meaningful relief measured 
by a stopwatch, and time to first perceptible 
relief confirmed by meaningful relief defined as 
the time to perceptible pain relief (the first 
stopwatch time) for those participants who had 
meaningful pain relief (the second stopwatch 
time)  
x Pain Intensity Difference (PID) and Pain Relief 
scores at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 
12, 14, (16, 18, 20 if awake), 22 and 24 hours 
post-dose  
x Peak PID and peak pain relief  
x Time and cumulative proportion of achieving 
complete pain relief 
x Cumulative percent of participants with ‘at least 
a 2-point PID’ over time  
x Global Assessment of the investigational product 
x Collect AE and clinical paramaeters 

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4. 
Study Design 
4.1 
Overall Design 
Design Overview 
This is a single center, randomized, double-blind, parallel, placebo-controlled study in 
participants experiencing moderate to severe postoperative dental pain. The study will consist 
of a Prescreening telephone call, a Screening Visit, a one day Treatment Period and a Post-
Operative phone call or visit.  Eligible participants who have undergone surgical extraction of 
three or four third molars, 2 of which were mandibular partial or full bony impacted third 
molars will be kept in-house and evaluated for efficacy and safety at the study site through 
completion of all trial procedures. 
Qualified participants will then be randomized into one of five treatments. Approximately 750 
participants will be screened prior to surgery.  Approximately 540 will have surgery and 
approximately 528 will be randomized to a specific treatment. 
Screening Phase 
Eligible participants will be screened and selected up to 28 days prior to oral surgery and 
dosing with investigational product (study intervention). 
Treatment Phase 
Following selection, qualified participants will enter the Treatment Phase and be scheduled 
for their surgical teeth extractions.  After completion of the surgical teeth extractions, 
participants will remain at the study site for observation. Participants with appropriate pain 
requirement will be randomized into one of five (5) treatment groups receiving study 
intervention.  Participants will rate their pain severity and pain relief over the next 24 hours.  
Onset of analgesia will be measured using a two stopwatch approach. The first stopwatch will 
be used to capture the time when any pain relief is first perceived.  The second stopwatch will 
be used to capture the time when pain relief becomes meaningful to the participant.  After 
completion of all trial procedures, participants will be discharged from the study site. 
All participants are required to remain at the study center and complete all relevant 
assessments regardless of rescue. 
Follow-Up Phase 
Participants will be evaluated at a post-operative visit/call approximately 2-5 days after 
discharge for follow up for any adverse events or medications not known at the time of 
treatment. 
The duration of each participant’s participation will be approximately 37 days. For an 
overview on the study design and study procedures (see Figure 1). 
 

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4.2 
Scientific Rationale for Study Design 
The study is designed specifically to measure the analgesic effectiveness and capture side 
effect profiles of naproxen sodium and caffeine FDC compared to the individual active 
ingredients on acute post-surgical dental pain in healthy participants who could benefit from 
the administration of an analgesic medication. The molar impaction dental pain model has 
been widely employed with OTC and prescription pain medications, since it is easily 
standardized, and the participants are relatively healthy and homogeneous. In addition, there 
are extensive data substantiating the usefulness of the dental pain model in predicting the 
relative efficacy of a wide range of analgesic medications by comparing several measures of 
analgesic efficacy, including onset, peak effect, and duration of analgesic activity (Cooper, 
2010, Cooper 1976, Kleinert, 2008). 
Time to onset will be measured using a double stopwatch method.  The double-stopwatch 
method for measuring first perceptible relief and meaningful relief was developed using the 
dental pain model (Desjardins 2002).  After ingesting the study medication, the participant is 
asked to depress a stopwatch button when first perceiving any relief (First Perceptible Relief).  
If and when this stopwatch is depressed, the participant is then given a second stopwatch and 
asked to depress the button when the relief is perceived as meaningful (Meaningful Relief). 
Using this method, onset to First Perceptible and Meaningful Relief can be quantified to the 
nearest minute. This method has been proven to be sensitive and reliable for measuring 
analgesic onset (Cooper 2010).  
The endpoints and study design are consistent with most recent Guidance by FDA and 
methods advocated by experts (Cooper 2016 and Singla 2014). Additionally, if a participant 
does not get sufficient pain relief, then rescue medication approved for treating acute pain 
(e.g., hydrocodone/acetaminophen) may be requested and will be provided under the 
supervision of the study site staff. 
4.3 
Justification for Dose of Active Treatment Groups 
Participants will receive a single dose of study intervention, in order to provide an analgesic 
effect in participants who experience post-surgical dental pain.  
The recommended amount of naproxen sodium in the new fixed dose combination product is 
based on currently marketed Aleve®. Its safety and efficacy is well characterized throughout 
more than 20 years of use in the over-the-counter setting. 
The amount of caffeine to be tested in this pivotal efficacy study is 65 mg per unit dose based 
on the results of our dose ranging study which matches the dose permitted in the OTC 
monograph for adjuvant products. Moreover, in the written response at the End of Phase 2 the 
FDA was in agreement with BCH to investigate the use of 65 mg of caffeine in the proposed 
FDC.    
The dose ranging study was submitted to the IND on September 15, 2020 (seq. 0013). This 
single center, single dose, randomized, double blind, parallel study in post-surgical dental 
pain compared one and two tablet doses of the FDC with naproxen sodium 220 mg and 65 or 
100 mg caffeine against 220 mg naproxen sodium, 100 mg caffeine and placebo. The 
participants were healthy male and females subjects 16 years of age and older who were 
scheduled to have 3 or 4 third molars extracted. A total of 193 participants were randomized 
(n=32 in each naproxen sodium containing treatment arms, 16 in caffeine-only arm and 17 in 
placebo group) and 191 participants completed the study per protocol. 

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The primary endpoint was the sum of pain intensity differences over 8 hours (SPID0-8). 
Secondary endpoints included other SPID values as well as total pain relief values including 
TOTPAR 0-8, TOTPAR 0-12. Other efficacy measures were pain intensity differences (PID) 
and pain relief scores at every timepoint and at peak. Duration of analgesic effect, onset of 
action (using a double watch method) and Global assessment and safety variables as adverse 
events were also collected in the study. 
All FDC treatment groups had higher SIPD0-8 than the single ingredient arms, and placebo. 
The differences in SPID0-8 between the FDCs and naproxen sodium was higher for the FDC
containing 65 mg caffeine than the FDC with 100 mg caffeine (6.44 and 0.84, respectively). 
For both caffeine doses (65 and 100 mg/tablet), the 2-tablet dose provided greater efficacy 
than the corresponding 1 tablet dose. Secondary efficacy endpoints showed a similar trend for 
a greater enhancement of efficacy for both 1 tablet and 2 tablet doses of the NapS/Caff FDC 
with 65 mg caffeine.
Figure 2. Summed Pain Intensity Difference from 0-8 hours
Current marketed analgesic combination products of caffeine with acetaminophen or aspirin 
(e.g. Excedrin), recommend a dose of 2 tablets up to three to four times daily, i.e. the dose of 
caffeine is up to 130 mg per single dose (2 tablets) and can reach 520 mg daily (up to 8 tablets 
per day. Newly marketed fixed dose combination ibuprofen plus caffeine products in Europe 
(Thomopyrin Tension Duo and Iprafeine: ibuprofen 400mg and caffeine 100 mg) allow for 
daily dosage of up to three tablets totaling 1200 mg Ibuprofen and 300 mg Caffeine.
Taking 1-2 tablet of the proposed product with 65 mg of caffeine per tablet will add up to 
only 130 mg caffeine if the consumer takes two tablets as the initial dose. A limit of 3 tablets 
per 24 hours will equal 195 mg of caffeine per day. Therefore, the total daily intake of 

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caffeine as proposed in this fixed dose combination product is well below the currently 
permitted limits in the relevant OTC drug monographs and should not pose any safety 
concerns.  Moreover, the efficacy and safety of this FDC product will be evaluated through 
the proposed studies in addition to those completed. 
 
4.4 
End of Study (EOS) Definition 
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities.  Trial 
site will have the option of either contacting participants within 2 to 5 days after surgery (by 
phone) or scheduling participants for an office appointment, depending on their standard of 
care policies, to assess the occurrence or persistence of AEs, any medications taken, and for 
adequate treatment and follow up.   
Primary completion 
The primary completion is defined as the date of the last visit of the last participant for the 
primary outcome. 
5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
The participant population will consist of healthy individuals who are status post extraction of 
three or four third molars, two of which were mandibular partial or full bony impactions. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Healthy, ambulatory, male or female volunteers 16 years of age or older; 
2. Body mass index 18.5 to 35.0 kg/m2 inclusive as measured by the NIH BMI 
Calculator; 
3. Participants will undergo surgical extraction of three or four third molars, two of 
which must be mandibular molars. Maxillary third molars may be removed regardless 
of impaction level.  The mandibular extractions must have a trauma rating of mild or 
moderate and meet one of the following scenarios: 
x two full bony impactions 
x two partial bony impactions 
x one full bony impaction in combination with one partial bony impaction 
Supernumerary teeth present may also be removed at the discretion of the oral 
surgeon; 

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4. Have not taken any form of medication, nutritional supplements with analgesic 
properties (e.g. GABA, turmeric) or herbal supplements (i.e., St. John’s Wort) within 
5 days of admission (except for oral contraceptives, prophylactic antibiotics, 
multivitamin supplements, or other routine medications to treat benign conditions 
(such as antibiotics to treat acne), and agree not to take any medication (other than that 
provided to them) throughout the study;    
5. Female participants of childbearing potential must: a) be using a medically acceptable 
form of birth control [e.g., hormonal contraceptives (oral, patch, injectable or vaginal 
ring), implantable device (implantable rod or intrauterine device), or a double barrier] 
for at least 1 month prior to screening (3 months on oral contraceptives); b) abstain 
from sexual intercourse for at least 1 month prior to screening; or c) participate 
exclusively in a same sex relationship for at least 1 month prior to screening.  In 
addition, female participants of childbearing potential must have a negative pregnancy 
test at Screening and prior to study drug administration.  Female participants of non-
childbearing potential must be amenorrheic for at least two years or have undergone 
surgical sterilization (i.e. tubal ligation/occlusion, hysterectomy and/or bilateral 
oophorectomy); 
6. Have not consumed alcoholic beverages, or foods and beverages containing caffeine 
(examples; coffee, tea, chocolate, and colas) for 24 hours and for 2 days prior to 
surgery, respectively and agree not to consume any of these foods or beverages 
throughout their stay at the study site;    
7. Use of only short-acting local anesthetic (e.g., mepivacaine or lidocaine) 
preoperatively, with or without a vasoconstrictor and nitrous oxide at the discretion of 
the Investigator; 
8. Have moderate to severe postoperative pain on the Categorical Pain Intensity Scale (a 
score of at least 2 on a 4 point scale) and a score of ≥ 5 on the 0-10 pain intensity NRS 
within 4.5 hours post-surgery; 
9. Ability to understand and follow study-related instructions; 
10. Be willing and able to participate in all scheduled visits, treatment plan, and trial 
procedures according to the clinical protocol; 
11. 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  
Participants are excluded from the study if any of the following criteria apply: 
1. History of hypersensitivity to naproxen sodium, caffeine, ibuprofen, NSAIDS, aspirin, 
similar pharmacological agents, local anesthetics, rescue medication or components of 
the investigational products; 
2. 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;    

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3. 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; 
4. 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; 
5. Relevant concomitant disease such as asthma (exercise induced asthma is permitted); 
6. Current or past history of gastrointestinal ulceration, gastrointestinal bleeding or other 
bleeding disorder(s); 
7. Acute illness or active local infection prior to surgery that can interfere with the 
conduct of the study in the judgment of the investigator; 
8. Use of any OTC or prescription medications with which the administration of 
naproxen, acetaminophen, ibuprofen, any other NSAID, (e.g., tramadol) or if a 
medication is contraindicated; 
9. Use of any medications within 5 days of surgery 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); 
10. Use of caffeine within 2 days prior to the study 
11. Habits of high consumption of caffeine (>400 mg/day equivalent to about 3-4 cups of 
coffee per day) 
12. Females who are planning to become pregnant, are pregnant or lactating; 
13. 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); 
14. Alcoholism or drug abuse within 2 years prior to the Screening Visit or routine 
consumption of 3 or more alcohol containing beverages per day; Alcohol containing  
beverages are defined as one beer (5%), one glass of wine (11%) and one shot (40%) 
hard liquor; 
15. Positive urine drug screen or alcohol test on day of surgery; 
16. Surgeon’s trauma rating of severe following surgery; 
17. Use of Nicotine containing products from 24 hours prior to surgery until discharge 
from the study site or longer if so directed by the oral surgeon; 
18. Member or first-degree relative of study staff or the Sponsor directly involved in the 
study; 
19. Unwilling or unable to comply with all requirements outlined in the protocol; 
20. 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; 
21. Previous enrollment in this study. 

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5.3 
Lifestyle Considerations 
No lifestyle restrictions are required. 
 
5.3.1 
Meals and Dietary Restrictions 
Participants will be instructed not to consume food that contains caffeine (e.g., chocolate, ice 
cream) two days prior to surgery. 
 
5.3.2 
Alcohol 
Participants will be instructed not to consume alcohol beverages 24 hours prior to surgery. 
 
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 to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) due to 
scheduling surgery may be rescreened.  A previous dental x-ray if taken during the original 
screening visit can be used when rescreened.  Rescreened participants should be assigned a 
new participant number. 
5.5 
Run-in Failures 
A participant who, for any reason terminates the study after surgery and prior to the start of 
study drug administration (e.g., not meeting pain threshold) is regarded as a “Run-in failure”. 
 
5.6 
Dropouts 
A participant who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the participant has been randomized and administered at least one dose of study 
drug. 
 
5.7 
General Procedures 
In all cases, the reason for withdrawal must be recorded on the screening log and in the 
participant's medical records.  
The participant may object to the generation and processing of post-withdrawal data as 
specified in Section 10.1.8. 
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 10.1.14 (Premature termination of the Study). 
 

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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
The study center will dispense a single-dose (2 tablets) of an assigned treatment within 4.5 
hours post-surgery.  The tablets and placebo will be administered based on a computer-
generated randomization schedule (section 6.1.1) and stratified by the severity of pain 
experienced (moderate or severe).  Moderate participants will use the lowest randomization 
number available and severe participants will use the highest randomization number available. 
Participants who characterize their pain severity as mild and have a NRS <5 will not receive 
treatment and will be discharged from the study site with a prescription for pain medication, if 
deemed safe, by the Investigator.   
 
6.1 
Study Intervention(s) Administered 
Table 1 – Treatments administered 
Treatment (condition) 
Dose / route 
Amount / 
form 
Frequency of 
administration 
Naproxen sodium and caffeine 220/65 mg (postsurgery)  
220/65 mg / orally  
1 / tablet* 
single dose 
Naproxen sodium and caffeine 440/130 mg (postsurgery) 440/130 mg / orally  
2 / tablets 
single dose 
Naproxen sodium 220 mg (postsurgery) 
220 mg / orally 
1 / tablet* 
single dose 
Caffeine 100 mg (postsurgery) 
100 mg / orally 
1 / tablet* 
single dose 
Placebo (postsurgery) 
NA / orally 
2 / tablets 
single dose 
*participants assigned to these study interventions will also receive a second tablet of placebo so that blinding is maintained. 
 
 
 

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Table 2 – Identity of study treatment 
Treatment (UI) 
Naproxen / 
Caffeine 
(1614204-029) 
Naproxen 
(1600169) 
Caffeine 
(not applicable) 
Placebo 
(1614204-027) 
Dose 
one or           
two tablets 
one  tablet 
one tablet 
two  tablets 
Pharmaceutical 
Form 
tablet 
tablet 
tablet 
tablet 
Strength 
220/65 mg 
220 mg 
100 mg 
not applicable 
Formulation 
naproxen sodium  
caffeine 
microcrystalline 
cellulose       
copovidone       
talc      
magnesium 
stearate          
blue film coating 
naproxen sodium 
FD&C blue #2 
lake 
hypromellose 
magnesium 
stearate 
microcrystalline 
cellulose 
polyethylene 
glycol 
povidone 
talc 
titanium dioxide 
caffeine 
calcium stearate 
lactose 
microcrystalline 
cellulose 
silicon dioxide 
dibasic calcium 
phosphate 
dihydrate 
magnesium 
stearate 
microcrystalline 
cellulose         
blue film coating 
Route of 
administration 
orally with a full 
glass of water 
(i.e. about 8 
ounces or 240 
mL) 
orally with a full 
glass of water 
(i.e. about 8 
ounces or 240 
mL) 
orally with a full 
glass of water 
(i.e. about 8 
ounces or 240 
mL) 
orally with a full 
glass of water 
(i.e. about 8 
ounces or 240 
mL) 
Batch Number 
see study file 
see study file 
see study file 
see study file 
Trade Name and 
Manufacturer 
Bayer 
Morristown, NJ 
USA 
Aleve® 
Bayer            
Bitterfeld, 
Germany 
Bell 
Pharmaceuticals 
Belle Plaine, MN 
USA 
Bayer 
Morristown, NJ 
USA 
 
6.1.1 
Study intervention assignment 
At the beginning of the first treatment period, after completion of the pre-treatment baseline 
procedures/assessments, participants who meet the entry criteria will be randomized in the 
study.  The randomization will be stratified by baseline pain intensity (moderate vs severe) 
according to the randomization schedule 3:3:3:1:1 (naproxen sodium/caffeine 220/65 mg; 
naproxen sodium/caffeine 440/130 mg; naproxen sodium 220 mg; caffeine 100 mg; placebo) 
prepared prior to the study. Participants will be assigned sequentially to the lowest available 
number or highest available number (randomization number, RNR) for those with moderate 
or severe baseline pain intensity, respectively to assure treatment balance between each 
stratum. 
Participants will be numbered according to the following scheme: 
 
PPD

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Whereas the “Xs” will be replaced with a five digit sequentially assigned number as each 
participant enters the study (e.g., first participant number will be 
 
The unique participant identifier number will be assigned in numerical order prior to dosing.  
Participants who characterize their pain severity as mild and <5 on the NRS will not receive 
treatment and be withdrawn from the study. 
Once a number has been assigned to a participant, it cannot be reassigned to another 
participant.   
Participants completing the Screening Visit, if not scheduled for surgery the same day,  will 
return to the trial site within 28 days, and if they continue to meet inclusion/exclusion criteria 
post-surgery will be randomized to one of five treatment groups: 
x naproxen sodium/caffeine 220/65 mg (1 tablet plus 1 tablet of placebo) 
x naproxen sodium/caffeine 220/65 mg (2 tablets) 
x naproxen sodium 220 mg (1 tablet plus 1 tablet of placebo) 
x caffeine 100 mg (1 tablet plus 1 tablet of placebo) 
x placebo (2 tablets) 
Participants will be assigned to treatment groups in accordance with the randomization 
schedule.  The Sponsor will provide a randomization schedule to the study site. 
 
6.1.2 
Participant Administration 
Each participant will receive a single dose of the study intervention.  Participants receive the 
study intervention with a full glass of non-refrigerated, non-carbonated water (about 8 ounces 
or 240 mL). Study intervention will be administered using dosing cups. Selection and 
preparation of the proper dose will be performed by an unblinded study team member using 
the provided randomization schedule (see Section 6.3).  The Investigator or a designee will 
supervise the study intervention administration in a manner, which maintains the masking 
conditions (blinding of the participant).   
Participants must be nil per os (NPO) from midnight prior to surgery until completion of 
surgery. If participants ingest clear liquids during this time, they may be eligible as per 
investigator discretion.  Each participant will continue fasting, with the exception of clear 
liquids, until after study drug administration. 
6.2 
Preparation/Handling/Storage/Accountability 
All study drugs will be labeled according to the requirements of local law and legislation.  
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 Good 
Manufacturing Practice (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. 
PPD

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The source of test and reference products will be documented in the clinical supply file. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.  Only participants enrolled 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.  The investigator, 
institution, or the head of the medical institution (where applicable) is responsible for study 
intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
The Sponsor will provide sufficient quantity of the study intervention to the study site.  The 
study center will dispense study intervention according to the randomization schedule and 
stratify randomization by the participant’s categorical pain intensity (moderate or severe) 
post-surgery.  Study intervention will be supplied to the study center in multi-dose bottles and 
dispensed by an unblinded member of the study team. 
All study drugs will be stored at the investigational site in accordance with GCP requirements 
and the instructions given by the clinical supplies department of the sponsor (or its 
affiliate/CRO), and will be inaccessible to unauthorized personnel. Special storage conditions 
and a complete record of batch numbers and expiry dates can be found in the Sponsor’s study 
file; the site-relevant elements of this information will be available in the investigator site file. 
On the day of receipt, the responsible site personnel will confirm receipt of study 
investigational products in writing. The personnel will use the study investigational products 
only within the framework of this clinical study and in accordance with this protocol. Receipt, 
distribution, return and destruction (if any) of the study drug must be properly documented 
according to the sponsor’s agreed and specified procedures. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
On Day 1, participants will be assigned a unique number (randomization number) in 
ascending numerical order at the study site. The randomization number encodes the 
participant’s assignment to one of the five (5) arms of the study, according to the 
randomization schedule generated prior to the study by the Sponsor. Each participant will be 
dispensed blinded study intervention, labeled with his/her unique randomization number, 
throughout the study. 
Participants enrolled in the trial, investigators and their staff involved in protocol procedures 
or who are involved in data collection, data entry and data analysis will be blinded to the 
identity of the treatments until the database is locked. The study monitor will conduct product 
accountability after database lock. To preserve blinding, participants will be blindfolded 
during administration of study medication.  Study drug will be dispensed by an unblinded 
study team member based on the randomization schedule.  That team member may have no 
other role in the study conduct and may not reveal the study drug’s identity to any members 
of the blinded study team. 
Sponsor will supply study medication in bulk containers.  Selection of the proper dose for an 
individual participant will be performed by an unblinded study team member using the 
provided randomization schedule.  The unblinded study team member will withdraw the 
appropriate study medication from the bulk container and transfer it to a dispensing cup.  All 

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study interventions must be administered as 2 tablets per participant.  Some study 
interventions require the addition of a placebo tablet.  The unblinded study team member will 
then bring the study medication to the treatment room where it will be dispensed to the 
participant by the study team member.  The unblinded study team member should have no 
other responsibilities in the study. 
6.3.1 
Unblinding 
In the case of a medical emergency, such as serious adverse events (SAE), breaking the blind 
may become necessary during the trial 
In compliance with applicable regulations, in the event of a serious unexpected adverse event 
(SUSAR) related to the blinded treatment, the participant’s treatment code will usually be 
unblinded before reporting to the health authorities, ethic committees and investigators (see 
Section 8.3.5). 
 
6.3.2 
Emergency unblinding by the investigator 
The investigator must report the blind break in conjunction with a SAE within 24 hours of 
becoming aware of the effect as defined in Section 10.3.1.  Participants who have been 
unblinded will not be included in the ITT or PP efficacy analysis. 
6.4 
Study Intervention Compliance 
The administration of the study medication will be supervised by an unblinded member of the 
Investigator’s team. This person will perform the oral cavity inspection after study drug 
administration and document that the participant receives the treatment as planned. 
6.5 
Prior and Concomitant Therapy 
The following treatments are prohibited from screening and during the study:  
 
x Use of any form of medication or herbal supplements, including GABA and turmeric, 
or curcumin, within 5 days of surgery that would confound the evaluation of the study 
product, until discharge from the study site; 
x Use of acetaminophen, naproxen, hydrocodone/acetaminophen, ibuprofen, aspirin, or 
other NSAIDs or any other pain reliever (OTC or prescription) within 5 days before 
surgery; 
x Use of alcoholic beverages after midnight prior to surgery and throughout the 
evaluation period; 
All medications (prescription and nonprescription products, vitamin and herbal products) 
taken by the participant from 30 days prior to Screening to End of Trial (EOT) will be 
documented.  The reported medications will be reviewed and evaluated by the Principal 
Investigator or designee to determine if they affect the participant’s eligibility to participate in 
the study. 
 

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6.5.1 
Rescue Medicine 
If adequate pain relief was not achieved, then participants are permitted to take rescue 
medication, although they will be encouraged to wait 2 hours to allow the investigational 
product time to take effect.  The study site will supply the rescue medication that will be 
obtained locally.  Rescue medication will be dispensed in a hierarchical method starting with 
ibuprofen 400 mg.  Should the participant not experience adequate pain relief, Hydrocodone 5 
mg/Acetaminophen 325 mg tablets or other appropriate analgesics (such as an additional 
ibuprofen dose) may be used at the discretion of the Investigator.  Rescue medication is also 
available on return of pain and the time of rescue medication will be recorded in the source 
documents.  Pain assessments will be performed immediately before the first dose of rescue 
medication. 
x Rating of Pain Intensity (NRS); 
x Rating of Pain Relief (Categorical); 
x Global Assessment of investigational product as a pain reliever. 
All active stopwatch elapsed time(s) will be stopped at the time of rescue administration and 
recorded on the case report form. 
Participants will be queried in a nonspecific fashion for any adverse events.  All observed and 
reported AEs will be collected and recorded on the case report form.  The information 
recorded will be based on signs and symptoms reported by the participant or observed by the 
research coordinator during clinical evaluation. 
6.6 
Dose Modification 
The dosing schedule cannot be modified. 
6.7 
Intervention after the End of the Study 
This study is a single dose administration after surgery and there is no additional treatment 
allocated.  Participants who randomize into the study will be discharged from the study center 
after the final (24 hour post dosing) assessments, regardless of whether rescue medication had 
been taken or not. 
7. 
Discontinuation of Study Intervention and Participant  
 
7.1 
Discontinuation of Study Intervention  
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed. 

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7.2 
Participant Discontinuation/Withdrawal from the Study 
Withdrawal criteria 
Participants must be withdrawn from the study if any of the following occurs: 
x 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, 
compliance, or administrative reasons. This is expected to be uncommon. 
x 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. 
x The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
x 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. 
x Participant’s pain intensity post-surgery at pre-dose does not exceed ‘mild’ and the NRS 
is <5 (see Section 10.5); 
x If, in the Investigator's opinion, continuation of the study would be harmful to the 
participant's well-being; 
 
Participants may be withdrawn from the study if any of the following occurs: 
x Participant experiences one or more serious adverse events; 
x At the specific request of the Sponsor and in consultation with the Investigator (e.g., 
obvious non-compliance, safety concerns); 
x Protocol violation: if the participant develops conditions, which would have prevented 
his/her entry into the study according to the inclusion/exclusion criteria, he/she must be 
withdrawn immediately if safety is concerned; in other cases, the investigator will 
decide whether there is a conflict with the study objectives. 
7.3 
Lost to Follow Up 
A participant will be considered lost to follow-up 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 clinic for a required 
study visit: 
x 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. 
x 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, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 

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or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
x Should the participant continue to be unreachable, he/she will be considered lost to 
follow up. 
8. 
Study Assessments and 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 
Efficacy Assessments 
If not stated otherwise, the measures / actions listed in the following Sections 8.1.1 to 8.1.6 
will be performed by a designated study team member as designated by the Principal 
Investigator. 
8.1.1 
Screening Period 
Note: No screening procedures may be performed unless participants have been 
provided an IRB-approved written informed consent which participants have read, 
understood, and signed.  
 
The Screening Period will be up to 28 days long.  The following will be determined during 
the Screening Visit: 
x Signed Informed Consent Form (ICF); 
x Review inclusion and exclusion criteria; 
x Participant demographics; 
x Medical/surgical history including history of drug, alcohol, tobacco and caffeine 
use; 
x Medication history of all prescription, OTC products including vitamins or 
dietary/herbal supplements, taken during the past 30 days; 
x Vital signs consisting of sitting blood pressure (in triplicate with one min in 
between), respiratory rate and pulse after sitting for at least 5 minutes; 

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x Physical and oral examination; 
x Dental x-ray examination and interpretation including impaction score; 
Note: The medical interpretation may occur after the screening visit provided a 
diagnosis of impaction is determined prior to surgery. 
x Urine tests for illicit drugs; 
x Breath or saliva alcohol test; 
x Urine pregnancy test (if applicable). 
Upon satisfying the inclusion/exclusion criteria, eligible participants will be instructed to return 
to the trial site within 28 days for oral surgery.  Participants will be instructed to refrain from 
the use of all medications (prescription, nonprescription, herbal supplements) unless in the 
opinion of the Investigator or Sponsor, the medication will not interfere with study procedures, 
data integrity, or compromise the safety of the participants. 
Participants will be instructed not to consume alcohol or use any nicotine containing products 
24 hours prior to surgery.  Surgery will be scheduled between 0530 h and 1030 h. 
The Principal Investigator or his/her designee must review participant’s study records before 
qualifying the participant for the trial. 
 
8.1.2 
Pre-surgery 
Participants are instructed to be nil per os (NPO) from midnight prior to surgery.  If a participant 
had something to eat or drink after midnight, the surgeon must determine if surgery may 
proceed.  Participants will arrive at the unit at their assigned time and will have the following 
activities completed prior to dental surgery: 
x Review changes in the participant’s medical/medication history and 
inclusion/exclusion criteria since previous visit; 
x Urine tests for illicit drugs; 
x Breath or saliva alcohol test; 
x Vital signs consisting of sitting blood pressure (in triplicate with one min in 
between), respiratory rate and pulse after sitting for at least 5 minutes (-30 
minutes); 
x Urine pregnancy test (if applicable); 
x Review pain assessment process and procedures. 
 
8.1.3 
Impaction Score 
An Impaction Score will be used to assess each tooth based on the radiographic appearance and the 
intraoral examination.  Each tooth will be rated from 1 to 4 using the following criteria: 
(1) erupted in tissue (2) soft tissue impaction (3) partial bony impaction, and (4) full bony 
impaction.  Only participants whose mandibular impactions are scored (3) or (4) will be eligible to 
participate in the study. 
 

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8.1.4 
During Surgery 
During surgery, participants will be administered a short acting local anesthetic (lidocaine or 
mepivacaine with or without vasoconstrictor) and nitrous oxide; at the discretion of the oral 
surgeon.  Topical anesthetics may also be used prior to the administration of the short acting 
local anesthetic.  Long duration local anesthetics like bupivacaine are not permitted.  No other 
perioperative analgesic or anesthetic agents are permitted. Perioperative corticosteroids are 
not permitted.  
 
8.1.5 
Surgical Trauma Score 
At the completion of the procedure, the surgeon will rate the degree of surgical trauma on a  
of (1) mild, (2) moderate or (3) severe.  Only individuals with a surgical trauma rating of mild 
(1) or moderate (2) will be eligible to participate in the study. 
 
8.1.6 
Postsurgery 
During the post-surgery recovery period, participants will rest quietly, but will be encouraged 
not to fall asleep.  Participants will be permitted to drink clear liquids following surgery.  
Participant may incorporate foods according to a soft diet following dosing beginning 60 
minutes after dosing.  Participants will not be allowed to eat 30 minutes prior to any planned 
assessments. 
In order to qualify for randomization and continue in the trial, participants must have 
‘moderate’ or ‘severe’ postoperative pain intensity on the Categorical Pain Rating Scale and a 
score of ≥5 on the NRS within 4.5 hours of the last suture. 
Eligible participants will be assigned a participant randomization number and investigational 
products will be administered according to a generated randomization schedule (see Section 
6.1.1). 
Participants who have not met the randomization criteria within 4.5 hours from last suture or 
14:30 h (+/- 15 minutes) will not be randomized and may be discharged from the clinic, once 
deemed eligible by an Investigator. Prior to being released from the clinic, discharge procedures 
will be reviewed with the participant. When discharged, all participants will need to make prior 
arrangements for travel and should not drive themselves home. 
After the baseline (pre-dose) pain intensity is determined, pain intensity and pain relief will be 
rated by participants at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, (16, 18, 20 if awake), 22 
and 24 hours (+/-5 minutes over the first 8 hours; +/-8 minutes from hours 9 through 24) post-
dose, and immediately prior to the use of the first dose rescue medication.   
Instructions will be provided for use of the two stopwatches.  A double-stopwatch method 
will be used to record time up to 24 hours after dosing for time to “first perceptible pain 
relief” (stopwatch A) and time to “meaningful pain relief determined” (stopwatch B). When 
the participant is administered study medication (following mouth inspection), the Study 
Coordinator or designee will start two stopwatches (one designated A and one designated B).  
The faces of the stopwatches will be covered so that the participant remains blinded to the 
exact time.  To determine the time when the participant begins to perceive pain relief, the 
participant will be given stopwatch A after dosing and will be instructed to: 

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"Stop the stopwatch when you first begin to feel any pain-relieving effect whatsoever of the 
drug. That is, when you first feel a little relief. This does not necessarily mean that you feel 
completely better, although you might, but when you first feel any difference in the pain 
that you have now." 
 
The participant will notify the Study Coordinator as soon as this stopwatch is stopped. The 
elapsed time on stopwatch A will be recorded in the case report form as the time to first 
perceptible pain relief.  The participant will then be asked: 
 
"Do you consider the relief you experienced meaningful?"  
 
This answer will be recorded by the study coordinator in the case report form.  If the 
participant answers “Yes” to this question, then meaningful pain relief is confirmed.  The time 
recorded in the case report form for time to meaningful pain relief confirmed will be the 
same time recorded as first perceptible pain relief. The participant will not be given the 
second stopwatch. If the participant does not consider the relief to be meaningful, (by stating 
No), the participant will be given a second, covered stopwatch with instructions to: 
 
"Stop this stopwatch when you have meaningful relief, that is, when the relief from the 
pain is meaningful to you.” 
 
The elapsed time on stopwatch B will be recorded in the case report form as time to 
meaningful pain relief determined.  Unless meaningful pain relief is achieved, the 
participant will always have an active stopwatch in front of them.   
 
If the participant never experiences first perceptible pain relief, they will retain stopwatch A 
for the entire 24-hour evaluation period.  If the participant experiences first perceptible pain 
relief but not any meaningful pain relief (confirmed or determined), they will retain stopwatch 
B for the remainder of the 24-hour evaluation period. 
 
Participants would be encouraged not to sleep before midnight and if needed, woken for 
assessments (up to hour 14). Participants will be allowed a 6 hour rest period during the 
overnight hours of the 24-hour evaluation period and woken for the 22 hour assessment.  The 
order of the pain assessments is Pain Intensity, then Pain Relief, then query about any AEs.  
At hour 24 or immediately prior to the first dose of rescue medication (if prior to hour 24), 
study participants will be asked to provide a Global Assessment of investigational product 
after completion of the other assessments.  Additionally, participants will have vital signs 
taken after surgery, then at 1, 12 and 24 hours (+30 minutes post-surgery; +/-30 minutes from 
hours 1 through 24) post-dose. 
 
Throughout the treatment period, the participants will be monitored for the occurrence of 
adverse events.  Symptoms will be assessed by spontaneous reporting of AEs and by asking the 
participants to respond to a non-leading question such as “How do you feel?” or “Are you 
experiencing any other effects?”  All reported or observed AEs will be collected and recorded 
on the case report form.  The information will be based on signs and symptoms reported by the 
participant or observed by the study personnel staff during clinical evaluation. 
 

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If a participant has any clinically significant, trial-related abnormalities at the conclusion of the 
treatment period, the clinical monitor (or designated representative) should be notified and the 
participant should be asked to remain at the trial site until such abnormalities are stabilized or 
resolve.  If the participant is unable or unwilling to remain at the trial site, the clinical monitor 
(or designated representative) should be notified, and the Investigator should make every effort 
to arrange follow-up evaluations at appropriate intervals to document the course of the 
abnormalities. 
 
Participants will be allowed the use of ice following the use of rescue medication.  Ice will not 
be permitted for participants prior to randomization until after they have been administered 
rescue medication (if applicable).  If participant has been administered rescue, ice will be given 
as requested by the participant for 20 minute increments.  Upon completion of all trial 
procedures, participants will be discharged from the trial site.  Participants will need to make 
prior arrangements for travel and should not drive themselves home. 
8.2 
Safety Assessments  
Safety measures will be analyzed for all participants in the safety population.   
Adverse events will be collected throughout the treatment and safety follow-up periods and 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  
Only treatment-emergent AEs will be included, i.e., AEs that begin or worsen after the first 
dose of the investigational products in the treatment period.  The number and percent of 
participants who experience any event, by System Organ Class (SOC), and by Preferred Term 
will be displayed by treatment group.  Tables will also be produced by severity and 
relationship to investigational product. Seriousness, severity, relationship to investigational 
product, duration, and outcome will also be listed. 
Planned time points for all safety assessments are provided in the SoA. 
 
8.2.1 
Physical Examinations 
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by qualified medical staff (e.g., a physician, oral surgeon, nurse practitioner or physician 
assistant) at the study site covering at least the organs of the head/neck, cardiovascular, and 
respiratory systems. 
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 10.3.1). 
 
8.2.2 
Vital Signs 
Systolic and diastolic blood pressure and heart rate will be measured (in triplicates allowing 
one minute in between measurements) by a member of the investigator’s team under the 
following conditions: 
x Systolic blood pressure (after resting for at least 5 min in sitting position); 
x Diastolic blood pressure (after resting for at least 5 min in sitting position); 
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x Measuring site: cuff to be placed on the right / left upper arm (if possible, the same arm 
will be used for all measurements in one participant); cuff location will be documented; 
x Method: oscillometric by automatic measurement device. 
Blood pressure is to be taken in triplicates, one minute apart to enhance accuracy as suggested 
in the FDA guidance (Assessment of Pressor Effect of Drugs, May, 2018). Pre-surgery vitals 
may be collected up to 30 minutes prior to time of surgery. 
 
8.2.3 
Clinical Safety Laboratory Assessments 
Urine samples will be collected by a member of the investigator’s team, for time points and 
parameters see Section 1.3. 
 
8.2.4 
Other Procedures and Variables 
Eligible participants will undergo an oral examination and a dental x-ray (radiograph) exam to 
confirm that impacted third molar teeth are present. 
 
8.3 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 10.3. 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative or health care professional not involved in the 
study).  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, or AEs considered related to the study intervention or study procedures, 
or those that caused the participant to discontinue the study. 
 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs and SAEs will be collected from the signing of the ICF until the follow up visit at the 
time points specified in the SoA (Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF) not the AE section. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstances should this exceed 24 hours, as indicated in Section 10.3.2. The investigator 
will submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE 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 
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8.3.2 
Expected Adverse Events 
For this study, the applicable reference document is the most current version of the DFL and 
IB for naproxen and caffeine.  If relevant new safety information is identified, the information 
will be integrated into an update of the safety information and distributed to all participating 
sites. 
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations. 
 
8.3.3 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
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.  
8.3.4 
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 given in Section 10.3.  
 
8.3.5 
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. 
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. 
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.  Send the SAE CRF pages and complementary forms to: 
cc-consreldept@bayer.com (in the USA) 
 

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8.3.6 
Pregnancy 
A participant’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 study 
participant 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.  Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
For a pregnancy in the partner of a male study participant, all efforts will be made to obtain 
similar information on course and outcome, participant to the partner’s consent. 
For all reports, the forms provided are to be used.  The investigator should submit them within 
the same timelines as a SAE (see Section 8.3.5).  Send the completed pregnancy forms to: 
cc-consreldept@bayer.com (in the USA) 
8.4 
Treatment of Overdose 
For this study, any dose of study intervention greater than single dose study intervention 
within a 12-hour time period will be considered an overdose. 
The sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator/treating physician should: 
x Contact the Medical Monitor immediately; 
x Closely monitor the participant for any AE/SAE; 
x Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
8.5 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
 
8.6 
Pharmacodynamics 
Pharmacodynamic biomarker parameters are not evaluated in this study. 
 
8.7 
Genetics 
Genetic testing is not performed in this study. 
 
8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
 

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8.9 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.  
9. 
Statistical Considerations 
Statistical analysis will be performed using statistical analysis software (SAS) and the version 
used will be specified in the Statistical Analysis Plan (SAP) and placed on file.  The SAP will 
contain a more comprehensive explanation than described below of the methodology used in 
the statistical analyses.  The SAP will also contain the rules and data handling conventions 
used to perform the analyses, and the procedure used for accounting for missing data. 
 
9.1 
Statistical Hypotheses 
The primary efficacy endpoint is the sum of change in pain intensity from 0 to 8 hours 
(SPID0-8). The treatment comparisons will be made in the following sequential order for 
SPID0-8 (each at 0.05 level of significance) in order to protect overall type 1 error at 0.05: 
x Naproxen sodium/caffeine 220/65 mg versus Naproxen sodium 220 mg  
x Naproxen sodium/caffeine 440/130 mg versus Naproxen sodium 220 mg  
x Naproxen sodium/caffeine 220/65 mg versus Naproxen sodium/caffeine 440/130 mg  
 
Once a comparison is statistically non-significant, the subsequent comparisons will be 
technically ineligible to be declared significant.  However, all pairwise comparisons will be 
presented to provide a complete picture. 
 
9.2 
Sample Size Determination  
Assuming that the treatment difference between the combo and naproxen alone of 6.5 and 
common standard deviation of 16.9 with respect to SPID0-8, a total of approximately 528 
subjects (144 subjects per active treatment arm and 48 in the caffeine and placebo using a 
3:3:3:1:1 ratio) are required to achieve 90% of power with the type I error of 0.05, a total of  
approximately 556 subjects will be randomized into the study if a drop-out rate of 5% is 
assumed. 
 
 
 

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9.3 
Populations for Analyses  
For purposes of analysis, the following populations are defined: 
Population 
Description 
Safety 
All participants who are randomized and take at least one 
dose of investigational product.  Safety measures will be 
analyzed for all participants in the safety population. 
Intent-To-Treat (ITT) 
All participants in the Safety Population.  ITT population 
will be used as the primary analysis for the efficacy 
parameters.   
Per Protocol (PP) Population 
PP population will include all participants in ITT who do 
not have any major protocol violations and complete the 
24 hour assessments. PP population will be used as 
secondary to conduct the sensitivity analysis for the 
selected parameters. 
 
Major protocol deviations will be identified prior to 
database lock and may include but are not limited to 
significant violations of inclusion/exclusion criteria, 
noncompliance of the trial treatment taken, conditions 
such as vomiting and diarrhea or use of prohibited 
medications, and not following clinical trial protocol 
procedures.  Any participant who rescues or vomits at or 
prior to 60 minutes after ingesting study medication will 
be excluded from the PP population. 
 
9.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock and 
will describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints. 
 
9.4.1 
Efficacy Analyses 
For each post-dose time point, Pain Intensity Differences (PID) will be derived by subtracting 
the pain intensity at the post-dose time point from the baseline intensity score (baseline score 
– post-baseline score).  A positive difference is indicative of improvement.  Time-weighted 
Sum of Pain Intensity Differences (SPIDs) will be calculated for 2, 4, 6, 8, 12, 16, 20 and 24 
hours by multiplying the PID score at each post-dose time point by the duration (in hours) 

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since the preceding time point and then summing these values over 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 
8, 9, 10, 11, 12, 14, (16, 18, 20 if awake), 22 and 24 hours, respectively.   
Similarly, Total Pain Relief Scores (TOTPARs), will be calculated by multiplying the pain 
relief score at each post-dose time point by the duration (in hours) since the preceding time 
point and then summing these values. 
In all analyses for participants who take rescue medication, all pain intensity scores after 
intake of rescue medication will be imputed by the worse of the baseline or the score assessed 
immediately before taking rescue medication. All pain relief after intake of rescue medication 
will be imputed by “no relief” (0). 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary efficacy analyses population will be based on the ITT 
population. 
 
Sum of Pain Intensity Difference over 8 hours: SPID0-8 be analyzed 
using an analysis of covariance model (ANCOVA) with treatment as 
fixed effect and baseline pain intensity score as the covariate.  A 95% 
of confidence interval (CI) for the treatment differences and pairwise 
p-values will be calculated based on the above mentioned model. 
Secondary 
Total Pain Relief over 8 hours: TOTPAR0-8 will be analyzed 
similarly as for the primary endpoint. 
 
Time to first use of rescue medication.  If a participant did not take 
the rescue medication during the treatment period, (s)he will be 
censored at the time of last assessment. Time to first use of rescue 
medication will be estimated and plotted using Kaplan-Meier method 
and analyzed using log-rank test. 
 
 

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Secondary 
The SPID0-2, 0-4, 0-6, 6-12, 0-12, 12-16, 16-20, 12-24, 16-24 and 0-
24 will be analyzed using the same methodology as for SPID0-8. 
 
TOTPAR0-2, 0-4, 0-6, 6-12, 0-8, 0-12, 12-16, 16-20, 12-24, 16-24 
and 0-24 will be analyzed using the same methodology as for SPID0-8. 
 
Pain Intensity Difference (PID) and Pain Relief scores at 0.5, 1, 1.5, 
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, (16, 18, 20 if awake), 22 and 24 
hours post-dose. Descriptive statistics for each time point and 
graphical illustrations of the time effect curves will be presented. 
 
Time to first perceptible relief measured by a stopwatch, time to 
meaningful relief measured by a stopwatch, and time to first 
perceptible relief confirmed by meaningful relief defined as the time 
to perceptible pain relief (the first stopwatch time) for those 
participants who had meaningful pain relief (the second stopwatch 
time) will be analyzed similarly as for the time to first use of rescue 
medication.  
 
Time to achieve complete pain relief will be analyzed similarly as for 
the time to first use of rescue medication.  
 
The cumulative proportion of participants taking rescue medication 
over time will be analyzed using Chi-square tests and curves over 
time will be plotted.  Frequency tables will be tabulated for the 
number of times that the participant took rescue medication over the 
24 hour period. 
 
Peak PID and peak pain relief will be analyzed descriptively. 
 
Cumulative percent of participants with ‘at least a 2-point PID’ and 
cumulative percent of participants achieving complete pain relief will 
be plotted over time and will be analyzed using Chi-square tests. 
  
Global Assessment of the investigational product will be analyzed 
using CMH method with modified ridit score. 
 
 
 

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9.4.2 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Endpoint 
Statistical Analysis Methods 
Secondary 
AEs produced by severity and relationship to study intervention. 
Seriousness, severity, relationship to each study intervention 
duration, and outcome will also be listed. 
 
Quantitative data for blood pressure, heart rate, body weight, body 
temperature will be described by summary statistics for the original 
data as well as for the change from baseline.  Frequency tables will 
be provided for qualitative data. Laboratory data outside the 
reference range will be listed and highlighted with ‘L’ for low and 
‘H’ for high. An additional table with all abnormal values will be 
presented. 
 
9.5 
Interim Analyses  
No interim analysis will be performed. 
10. 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
 
10.1.1 
Regulatory and Ethical Considerations 
x This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o 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.  
The investigator will be responsible for the following: 
x 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 
x Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 

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x Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), 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 its sponsor. 
 
10.1.4 
Informed Consent Process 
All relevant information on the study will be summarized in an integrated participant 
information sheet and informed consent form provided by the sponsor or the study center.  
Sample participant information and informed consent/assent forms are provided as a 
document separate to this protocol.  Participants 16 to 17 years old who cannot legally give 
informed consent for research participation must use an IRB-approved assent form and a 
Parental/Guardian informed consent form.  Informed consent must first be obtained from the 
child’s parent or legal guardian before assent may be obtained from the child. 
Based on this participant information sheet, 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. 
The investigator will also mention that written approval of the IRB has been obtained. 
Each participant will be informed about the following aspects of premature withdrawal: 
x 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;   
x The participant’s consent covers EOT examinations as specified in the visit 
description described in Section 7.2 to be conducted after withdrawal of consent; 
x 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; 
x 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 

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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 copy of the signed and dated 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.  In the event 
that informed consent is obtained on the date that baseline study procedures are performed, 
the study record or participant´s clinical record must clearly show that informed consent was 
obtained prior to these procedures. 
For minors or adults under legal protection, consent shall be given by the legal guardian(s). 
The consent of a minor or adult under legal protection shall also be requested where such a 
person is able to express his/her own will. His/her refusal or the withdrawal of his/her consent 
may not be disregarded. 
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. 
Participants who are rescreened are required to sign a new ICF. 
 
10.1.5 
Data Protection and Confidentiality 
Any participant records or datasets 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.  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 national or international 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 

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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 will make the information regarding the study publicly available on the internet 
at www.clinicaltrials.gov as applicable to local regulations. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators. 
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.  
 
10.1.9 
Data Handling and Quality Assurance 
The data collection tool for this study will be a validated electronic data capture system to be 
used at the study site. 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). 
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, except operative medications will be recorded on a 
CRF/eCRF data collection system 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.  

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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 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 10 years (US), 25 years (Canada) 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. 
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. 
 
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. 

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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. 
 
10.1.14 
Study and Site Closure 
The sponsor 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: 
x 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 
x Inadequate recruitment of participants by the investigator 
x Discontinuation of further study intervention development 
 
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. 

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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.2 
Appendix 2: Clinical Laboratory Tests 
Urine samples will be collected by a member of the investigator’s team, for time points and 
parameters see Section 1.3.  Additional tests may be performed at any time during the study as 
determined necessary by the investigator or required by local regulations. 
 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE  
 
AE Definition 
x An AE is any untoward medical occurrence in a patient or clinical study 
participant, associated with the use of study intervention, whether or not considered 
related to the study intervention. 
x 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. 
 
Events Meeting the AE Definition  
x 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. 
x Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
x 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. 
x  “Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE.  
 

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Events NOT Meeting the AE Definition  
x 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. 
x 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. 
x Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x 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. 
 
10.3.2 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
x 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 
x In general, hospitalization signifies that the participant has been detained (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. 
x Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. 
Results in persistent disability/incapacity 
x The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
x 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. 

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e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
x Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
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. 
x Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
 
 
 

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10.3.3 
Recording and Follow-Up of AE and/or SAE  
 
AE and SAE Recording 
x 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. 
x The investigator will then record all relevant AE/SAE information in the CRF. 
x It is not acceptable for the investigator to send photocopies of the participant’s 
medical records in lieu of completion of the AE/SAE CRF page. 
x There may be instances when copies of medical records for certain cases are 
requested by the sponsor. 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. 
x 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 one of the following categories:  
x Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
x Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
x 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. 
x 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. 
Assessment of Causality 
x The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
x 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. 
x Possible answers are “yes” or “no” 
x An assessment of “no” would include: 
o The existence of a highly likely alternative explanation, e.g., mechanical 
bleeding at surgical site. 
or 

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o Non-plausibility, e.g., the participant is struck by an automobile when there 
is no indication that the drug caused disorientation that may have caused 
the event; cancer developing a few days after the first drug administration. 
An assessment of “yes” indicates that that the AE is reasonably associated with the use of 
the study treatment. 
x The investigator will use clinical judgment to determine the relationship. 
x 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. 
x The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
x 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. 
x 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. 
x 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. 
x The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Causal relationship to protocol-required procedure(s) 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” 
to protocol-required procedure(s). 
Possible answers are “yes” or “no” 
Action taken with study intervention 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
The study treatment action should be recorded separately for each study treatment as 
detailed in the CRF/eCRF data collection system. 
x Drug withdrawn 
x Drug interrupted 
x Not applicable 
x Unknown 
 
 

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Other specific treatment(s) of adverse event 
x None 
x Remedial drug therapy 
x Other 
Outcome of adverse event 
The outcome of the AE is to be documented as follows:  
x Recovered/resolved 
x Recovering/resolving 
x Recovered/resolved with sequelae 
x Not recovered/not resolved 
x Fatal 
x Unknown 
Follow-up of AEs and SAEs 
x The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated 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. 
x New or updated information will be recorded in the originally completed CRF. 
x The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information. 
 
 
 

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10.3.4 
Reporting of SAEs 
 
SAE Reporting to the Sponsor via Paper CRF/Complementary pages 
x 
Email or facsimile transmission of the SAE paper CRF as well as the 
complementary pages provided is the preferred method to transmit this 
information to Bayer’s Pharmacovigilance department (see Section 
8.3.5). 
x 
In rare circumstances and in the absence of facsimile equipment, 
notification by telephone is acceptable with a copy of the SAE data 
collection tool sent by overnight mail or courier service. 
x 
Initial notification via telephone does not replace the need for the 
investigator to complete and sign the SAE CRF and complementary 
pages within the designated reporting time frames. 
 
 
 

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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: 
x Documented hysterectomy 
x Documented bilateral salpingectomy 
x 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. 
 
1. 
Postmenopausal female 
x A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, confirmation with more than one FSH measurement [insert 
threshold if required (>40 IU/L or mIU/mL) or remove to allow for flexibility with 
different local thresholds for defining postmenopausal state] is required.  
x 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. 
x The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy.  

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x 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, after 
obtaining the signed informed consent from both parents, unless local law or specific 
circumstances of the respective case allow otherwise, 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. 
x While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion 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 8.3.5. 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.  
x Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
 
Collection of Pregnancy Information: 
Male participants with partners who become pregnant  
x The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention. 
x After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Participants who become pregnant  
x The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy.  

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x 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, after 
obtaining the signed informed consent from both parents, unless local law or specific 
circumstances of the respective case allow otherwise, 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. 
x While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion 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 8.3.6. 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.  
x 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: Participant Assessments 
 
Categorical Pain Intensity Scale (predose) 
 
Finish the statement: “My pain at this time is” by checking the appropriate box. 
 
⁭ No Pain (0) 
⁭ Mild Pain (1) 
⁭ Moderate Pain (2) 
⁭ Severe Pain (3) 
 
 
Numerical Rating Scale (pre-dose and post-dose) 
 
Circle a number to indicate level of pain (from 0 to 10) below to indicate the severity of the 
pain you are experiencing at this time. 
 
No  
pain 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst 
possible 
pain 
 
 
 
Categorical  Pain Relief Rating Scale (post-dose) 
 
Finish the statement: “ My relief from my starting pain is”” by checking the appropriate 
box. 
 
 
܆No Relief (0) 
܆  A Little Relief (1) 
܆Some Relief (2) 
܆A Lot of Relief (3) 
܆Complete Relief (4) 
 
 
 
 
 
 

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Global Assessment of Pain (post-dose) 
 
Finish the statement: “ What is your overall rating of the study medication you received?” 
by checking the appropriate box. 
 
 
܆Poor (0) 
܆Fair (1) 
܆Good (2) 
܆Very Good (3) 
܆Excellent (4) 
 
 
 
 

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10.6 
Appendix 6: Abbreviations 
 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CDER 
Center for Drug Evaluation and Research 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
COX 
Cyclooxygenase 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
(e)CRF 
(electronic) Case Report Form  
EOT 
End of Trial 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NPO 
nil per os 
NRS 
Numerical Rating Scale 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
OTC 
Over-the-Counter 
PID 
Pain Intensity Differences 
PP 
Per Protocol 
QA 
Quality Assurance 
RNR 
Randomization Number 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SNR 
Screening Number 
SSRI 
Selective Serotonin Uptake Inhibitors 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SPID 
Summed Pain Intensity Difference 
SUSAR 
Serious Unexpected Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TOTPAR 
Total Pain Relief 
UI 
Unique Identification (formulation) 

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