Clinical trial NCT04447040
Conditions: Pain
Keywords: Analgesics Dental Pain Acetaminophen Naproxen Sodium Pain Fixed-Dose
Sponsor: Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division
Start date: 2020-11-09; Completion date: 2021-05-03
Enrollment: 304 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study assessing the relative efficacy of five strengths of a fixed combination of acetaminophen and naproxen sodium is being investigated to help inform selection of dose(s) for further development and to evaluate the safety of a fixed combination of naproxen sodium and acetaminophen.

Detailed description:
This is a randomized, double-blind, placebo-controlled study to evaluate the analgesic efficacy and safety profile of the following doses of a fixed combination of Acetaminophen (APAP)/Naproxen sodium (NPX) administered as a single two-tablet dose:\[Acetaminophen/Naproxen Sodium Dose A, Acetaminophen/Naproxen Sodium Dose B, Acetaminophen/Naproxen Sodium Dose C, Acetaminophen/Naproxen Sodium Dose D, Acetaminophen/Naproxen Sodium Dose E and Placebo\] following surgical extraction of four third molars.

Arms: arm 1: Acetaminophen/naproxen sodium Dose A administered as a single two-tablet dose. arm 2: Acetaminophen/naproxen sodium Dose B administered as a single two-tablet dose. arm 3: Acetaminophen/naproxen sodium Dose C administered as a single two-tablet dose. arm 4: Acetaminophen/naproxen sodium Dose D administered as a single two-tablet dose. arm 5: Acetaminophen/naproxen sodium Dose E administered as a single two-tablet dose. arm 6: Placebo tablets administered as a single two-tablet dose.
Interventions: intervention 1: Acetaminophen/naproxen sodium Dose A intervention 2: Acetaminophen/naproxen sodium Dose B intervention 3: Acetaminophen/naproxen sodium Dose C intervention 4: Acetaminophen/naproxen sodium Dose D intervention 5: Acetaminophen/naproxen sodium Dose E intervention 6: Placebo
Intervention descriptions: intervention 1: Acetaminophen/naproxen sodium Dose A administered as a single two-tablet dose. intervention 2: Acetaminophen/naproxen sodium Dose B administered as a single two-tablet dose. intervention 3: Acetaminophen/naproxen sodium Dose C administered as a single two-tablet dose. intervention 4: Acetaminophen/naproxen sodium Dose D administered as a single two-tablet dose. intervention 5: Acetaminophen/naproxen sodium Dose E administered as a single two-tablet dose. intervention 6: Placebo tablets administered as a single two-tablet dose.

Protocol documents:
Prot_000.pdf: 
Acetaminophen/Naproxen sodium
Protocol Number: CCSPAA002398
Amendment #2, Version 3 (Final) 25 November 2020
Company Confidential
Page 1 of 66
This document contains privileged and confidential information belonging to the Sponsor. Except 
as otherwise agreed to in writing, by accepting or reviewing this document, you agree to hold the 
information contained herein in confidence and not copy or disclose it to others (except where 
required by applicable law) or use it for unauthorized purposes. In the event information is 
disclosed to others, as required by applicable law, they must be informed that the information is 
privileged and confidential and may not be further disclosed by them. These restrictions on 
disclosures will apply equally to all future information supplied to you that is indicated as 
privileged and confidential. You agree that no unpublished information contained herein will be 
published or disclosed without the prior written approval of Sponsor. In the event of any actual or 
suspected breach of this obligation, Sponsor must be promptly notified.
CLINICAL STUDY PROTOCOL
AMENDMENT #2
CCSPAA002398
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO 
EVALUATE FIVE STRENGTHS OF A FIXED COMBINATION OF 
ACETAMINOPHEN/NAPROXEN SODIUM IN POSTOPERATIVE DENTAL PAIN
Investigational Product Name
Acetaminophen/Naproxen sodium
Protocol Number
CCSPAA002398
IND / IDE / EudraCT number
145,058
Phase
II
Version and Date
Amendment 2, Version 3, 25 November 2020
Amendment #1, Version 2 (Final), 08 October
2020
Version 1 (Final), 10 July 2020
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Protocol Number: CCSPAA002398
Amendment #2, Version 3 (Final) 25 November 2020
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
 mg Acetaminophen/
 mg Naproxen sodium

 mg Acetaminophen/
 mg Naproxen sodium

 mg Acetaminophen/
 mg Naproxen sodium

 mg Acetaminophen/
 mg Naproxen sodium

Placebo
Subjects will undergo dental extraction of three or four third molars. Supernumerary teeth 
may also be removed. Judgment of impaction level will be made by the oral surgeon 
based on visual examination of the panorex x-ray. Maxillary third molars may be 
removed regardless of impaction level. The mandibular extractions must meet one of the 
following scenarios:

Two full bony impactions

Two partial bony impactions

One full bony impaction in combination with one partial bony impaction
Post-surgery trauma assessment will be done on the day of surgery (Baseline visit). 
Subjects will be excluded from the study if the mandibular extraction results in a trauma 
rating of “severe” on a mild, moderate, or severe scale on the categorical and numerical 
pain intensity scale.
Approximately 300 subjects who meet the randomization criteria (post-surgical pain of 
moderate to severe on the four-point categorical pain scale, and at least a score of 5 on 
the 11-point [0-10] pain intensity-numerical rating scale [PI-NRS] at Baseline within 
4.5 hours of last stitch from dental extractions) will be assigned to one of the following 
six treatment groups, with equal allocation among the treatment groups:

 mg Acetaminophen/
 mg Naproxen sodium (administered as two tablets 
of Acetaminophen/Naproxen Sodium 
)

mg Acetaminophen/
mg Naproxen sodium (administered as two tablets of 
Acetaminophen/Naproxen sodium 
) 

mg Acetaminophen/
 mg Naproxen sodium (administered as two tablets of 
Acetaminophen/Naproxen sodium 
) 

 mg Acetaminophen/
 mg Naproxen sodium (administered as two tablets of 
Acetaminophen/Naproxen sodium
)

 mg Acetaminophen/
 mg Naproxen sodium (administered as two tablets of 
Acetaminophen/Naproxen sodium 
)

Placebo (administered as two placebo tablets)
All treatments will be administered as a single dose. Rescue analgesic medication 
(oxycodone immediate release 5 mg every four to six hours as needed for pain; not to 
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Protocol Number: CCSPAA002398
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
two full bony impactions

two partial bony impactions

one full bony impaction in combination with one partial bony impaction.
5. Indicate at least moderate pain on a categorical scale ranging from (0) none, (1) 
mild, (2) moderate, or (3) severe AND at least a score of 5 on the 11-point (0-10) 
PI-NRS at Baseline within 4.5 hours of the last stitch from oral surgery.
6. Are able to comprehend and follow the requirements of the study (including 
pre-surgical instructions provided by the site and availability on scheduled visit 
dates) based upon research site personnel’s assessment.
7. Provide written informed consent (for subjects who are below the age of legal 
consent, parent or legally authorized representative provides written informed 
consent and the subject provides written assent).
8. Females of childbearing potential and males agree to the contraceptive 
requirements.
9. Are willing for this to be the only investigational product used during the study.
10. Have a negative urine drug screen at Screening, and on day of surgical procedure.
Exclusion Criteria
Subjects will be excluded if they:
1. Are female and are pregnant, breastfeeding, or currently trying to become 
pregnant.
2. Are male with a pregnant partner or a partner who is currently trying to become 
pregnant.
3. Have extraction of mandibular third molars resulting in a trauma rating of 
“severe” on a mild, moderate, or severe scale.
4. Have a known allergy or hypersensitivity to naproxen or other nonsteroidal 
anti-inflammatory drugs, including aspirin, acetaminophen, oxycodone or other 
opioids.
5. Have presence or a history of major medical condition that in the Investigator’s 
opinion may jeopardize the subject’s safety or well-being (e.g., hepatic, renal, 
pancreatic, gastrointestinal, cardiovascular, cerebrovascular, or thyroid diseases as 
well as a history of head injury or seizures, history of respiratory depression or 
lung problems such as but not limited to asthma or chronic obstructive pulmonary 
disease, psychiatric disorders, problems urinating, a history of blockage or 
narrowing of the stomach or intestines, uncontrolled hypertension indicated as 
systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg, or 
uncontrolled diabetes in the last 6 months) or the integrity of the study.
6. Have a history of a confirmed or suspected Coronavirus Disease 2019 (COVID-
19) infection in the last 30 days or contact with COVID-19-infected person within 
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14 days prior to any site visit.
7. Have any international travel within 14 days prior to any site visit including 
members in the same household.
8. Have self-reported symptoms within 14 days prior to any site visit:

Unexplained cough, shortness/difficulty breathing, fatigue, body aches 
(headaches, muscle pain, stomach aches), conjunctivitis, loss of smell, loss 
of taste, poor appetite, nausea, vomiting, diarrhea, palpitations, or chest 
pain/tightness; 

Temperature ≥37.5C/99.5F, within 14 days prior to any site visit or 
when measured upon arrival at any site visit; 

Use of fever or pain reducers within the past three days prior to any site
visit.
9. Are not able to swallow whole large tablets or capsules.
10. Routinely use oral analgesics ≥5 times per week.
11. Have a history of chronic tranquilizer use, heavy drinking, or substance abuse, as 
judged by the Investigator site staff, in the last five years. Heavy drinking is 
defined as the use of more than four standard drinks daily or more than 14 drinks 
a week for men, and more than three standard drinks daily or more than seven
standard drinks in a week for women. Standard drink refers to 14 g (0.6 oz.) of 
pure alcohol, which is approximately 12 oz. of beer, 8 oz. of malt liquor, 5 oz. of 
wine, 1.5 oz. or “shot” of 80-proof distilled spirits or liquor (e.g., gin, rum, vodka, 
or whiskey).
12. Have a history of endoscopically documented peptic ulcer disease or bleeding 
disorder in the last two years.
13. Used oral over-the-counter or prescription products (except contraceptive 
medications and those required for use during the oral surgical procedure), within 
five half-lives before the oral surgical procedure.
14. Used vitamins, dietary or herbal supplements within five days before the oral 
surgical procedure.
15. Used
any immunosuppressive drugs, corticosteroids (except for topical 
corticosteroids), or injectable or oral anticoagulants (e.g., heparin, Lovenox, 
Xarelto, Eliquis, Pradaxa, Coumadin, Miradon) within two weeks of Screening.
16. Used alcohol within three days before the oral surgical procedure.
17. Consumed methylxanthine-containing products (e.g., chocolate bars or chocolate 
beverages, coffee, tea, cola or caffeinated energy drinks), tobacco, or nicotine 
containing products (e.g., cigarettes, cigars, nicotine replacement therapies) 
<12 hours before the oral surgical procedure.
18. Used monoamine oxidase inhibitors within 14 days prior to surgery.
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Protocol Number: CCSPAA002398
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19. Have a positive test for human immunodeficiency virus (HIV) antibody, hepatitis 
B surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV).
20. Have participated in any interventional clinical trials within 30 days before
Screening.
21. Are related to those persons involved directly or indirectly with the conduct of 
this study (i.e., Principal Investigator, sub-investigators, study coordinators, other 
site personnel, employees of Johnson & Johnson [J&J] subsidiaries, contractors of 
J&J, and the families of each).
Test Products, Dosage and Mode of Administration: 

 mg Acetaminophen/
 mg Naproxen Sodium (administered as two tablets 
of Acetaminophen/Naproxen Sodium 
), to be taken orally with up 
to 180 mL water

 mg Acetaminophen/
 mg Naproxen Sodium (administered as two tablets of  
Acetaminophen/Naproxen Sodium 
), to be taken orally with up to 
180 mL water

 mg Acetaminophen/
 mg Naproxen Sodium (administered as two tablets of 
Acetaminophen/Naproxen Sodium 
), to be taken orally with up 
to 180 mL water

 mg Acetaminophen/
 mg Naproxen Sodium (administered as two tablets of 
Acetaminophen/Naproxen Sodium 
), to be taken orally with up to 
180 mL water

 mg Acetaminophen/
 mg Naproxen Sodium (administered as two tablets of  
Acetaminophen/Naproxen Sodium 
), to be taken orally with up to 
180 mL water
Comparator Product, Dosage and Mode of Administration: 

Placebo (administered as two placebo tablets), to be taken orally with up to 
180 mL water
Duration of Study per Subject: Ten days, including Baseline (Day 1 [day of surgery]) 
and follow-up (Days 7 to 10), and excluding Screening (Day -30 to Day 1).
Duration of Treatment: Twenty four (24) hours. Subjects will be observed at the study 
site for at least 24 hours after dosing with study medication, regardless of whether or not 
the subject rescues, vomits, or experiences other AEs.
Criteria for Efficacy Evaluation:
Primary Efficacy Endpoint:

Time weighted sum of pain intensity difference from 0-12 hours after dosing 
(SPID 0-12)
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Protocol Number: CCSPAA002398
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3.
TABLE OF CONTENTS 
1.
SYNOPSIS ...................................................................................................................2
2.
ACTIVITY SCHEDULE............................................................................................10
3.
TABLE OF CONTENTS ...........................................................................................12
3.1.
List of Tables..............................................................................................................16
3.2.
List of Figures.............................................................................................................16
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17
5.
ETHICS ......................................................................................................................19
5.1.
Institutional Review Board (IRB) / Independent Ethics Committee (IEC)................19
5.2.
Ethical and Regulatory Considerations ......................................................................19
5.3.
Subject Information and Consent ...............................................................................19
5.4.
Subject Written Assent ...............................................................................................20
6.
STUDY ADMINISTRATIVE STRUCTURE ...........................................................21
7.
INTRODUCTION......................................................................................................22
8.
STUDY OBJECTIVES ..............................................................................................22
8.1.
Primary Objective.......................................................................................................22
8.2.
Secondary Objective...................................................................................................23
8.3.
23
8.4.
Primary Endpoint........................................................................................................23
8.5.
Secondary Endpoints ..................................................................................................23
8.6.
23
9.
INVESTIGATIONAL PLAN.....................................................................................24
9.1.
Overall Study Design and Plan...................................................................................24
9.2.
Discussion of Study Design........................................................................................26
9.3.
Sponsor Discontinuation Criteria ...............................................................................26
10.
STUDY POPULATION.............................................................................................27
10.1.
Subject Eligibility.......................................................................................................27
10.1.1.
Subject Inclusion Criteria ...........................................................................................27
10.1.2.
Subject Exclusion Criteria..........................................................................................28
10.1.3.
Subject Withdrawal/Termination Criteria ..................................................................29
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11.
STUDY INTERVENTION ........................................................................................30
11.1.
Treatment Administration...........................................................................................30
11.2.
Description and Administration of Investigational Products......................................30
11.3.
Packaging and Labeling..............................................................................................32
11.4.
Preparation, Handling and Disposal ...........................................................................32
11.5.
Storage and Accountability.........................................................................................34
11.6.
Randomization/Treatment Allocation ........................................................................34
11.7.
Blinding and Unblinding ............................................................................................34
11.8.
Treatment Compliance................................................................................................35
11.9.
Previous and Concomitant Medications.....................................................................35
11.9.1.
Permitted Therapies....................................................................................................35
11.9.2.
Prohibited Therapies...................................................................................................35
11.10.
Rescue Therapy ..........................................................................................................36
11.11.
Product Quality Complaints .......................................................................................36
12.
STUDY PROCEDURES............................................................................................36
12.1.
Overview.....................................................................................................................36
12.2.
Screening Visit............................................................................................................36
12.3.
Study Visits (Periods).................................................................................................37
12.3.1.
Baseline Visit (Day of Surgery) .................................................................................37
12.3.2.
Post-dose Assessments (0-24 Hours)..........................................................................37
12.3.3.
Follow-Up Phone Call (Days 7 to 10)........................................................................39
12.4.
End of Study for Subject.............................................................................................39
12.5.
COVID-19 Pandemic Response Plan .........................................................................39
12.6.
Life Style Restrictions ................................................................................................39
12.6.1.
Meals and Dietary Restrictions...................................................................................39
12.6.2.
Alcohol, Caffeine and Tobacco Restrictions..............................................................39
12.6.3.
Physical Activity Requirements/Restrictions .............................................................40
12.6.4.
Contraception for Females..........................................................................................40
12.6.5.
Contraception for Males .............................................................................................41
13.
ASSESSMENTS.........................................................................................................41
13.1.
Efficacy Assessments .................................................................................................41
13.2.
Safety Assessments.....................................................................................................42
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13.2.1.
Physical Examination .................................................................................................42
13.2.2.
Vital Signs ..................................................................................................................42
13.2.3.
Clinical Laboratory Tests ...........................................................................................42
14.
ADVERSE EVENT REPORTING ............................................................................42
14.1.
Reporting Period.........................................................................................................43
14.2.
Definitions ..................................................................................................................43
14.2.1.
Definition of Adverse Event.......................................................................................43
14.2.1.1.
Abnormal Test Findings .............................................................................................44
14.2.2.
Definition of Serious Adverse Events (SAE) for Drugs.............................................44
14.2.2.1.
Hospitalization............................................................................................................45
14.3.
Adverse Event Assessments .......................................................................................46
14.3.1.
Severity Assessment ...................................................................................................46
14.3.2.
Causality Assessment .................................................................................................46
14.3.3.
Resolution...................................................................................................................47
14.4.
Adverse Event Reporting............................................................................................47
14.4.1.
Time Period ................................................................................................................47
14.4.2.
Process for Reporting .................................................................................................48
14.4.2.1.
Serious Adverse Event Reporting...............................................................................48
14.4.2.2.
Contacts for Serious Adverse Event Reporting..........................................................49
14.5.
Suspected Unexpected Serious Adverse Reaction .....................................................49
14.6.
Special Situations........................................................................................................49
14.6.1.
Exposure In Utero.......................................................................................................50
14.7.
Withdrawal Due to Adverse Events ...........................................................................51
15.
STATISTICS ..............................................................................................................51
15.1.
Determination of Sample Size....................................................................................51
15.2.
Analysis Sets...............................................................................................................51
15.2.1.
Efficacy Analysis Sets ................................................................................................51
15.2.2.
Safety Analysis Population.........................................................................................51
15.3.
Baseline and Demographics .......................................................................................52
15.4.
Previous and Concomitant Medications.....................................................................52
15.5.
Efficacy Analysis........................................................................................................52
15.5.1.
Efficacy Endpoints......................................................................................................52
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15.5.1.1.
Primary Efficacy Endpoint .........................................................................................52
15.5.1.2.
Secondary Efficacy Endpoints....................................................................................52
15.5.1.3.
52
15.5.2.
Statistical Hypotheses.................................................................................................53
15.5.3.
Data Computations and Handling of Missing Values ................................................54
15.5.3.1.
Endpoints Relating to Pain Intensity and Pain Relief.................................................54
15.5.3.2.
Time to First Rescue...................................................................................................54
15.6.
Analysis Methods .......................................................................................................55
15.6.1.
Analysis of Primary Endpoint ....................................................................................55
15.6.2.
Analysis of Secondary Endpoints...............................................................................55
15.6.3.
56
15.6.4.
Subgroup Analysis......................................................................................................56
15.6.5.
57
15.7.
Safety Analysis ...........................................................................................................57
15.7.1.
Adverse Events ...........................................................................................................57
15.7.2.
Vital Signs ..................................................................................................................57
15.8.
Interim Analysis..........................................................................................................57
16.
STUDY MONITORING ............................................................................................57
16.1.
Direct access to source data/documents .....................................................................58
17.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................58
17.1.
Audits and Inspections................................................................................................59
18.
DATA HANDLING AND RECORDKEEPING.......................................................59
18.1.
Case Report Forms/Electronic Data Capture..............................................................59
18.2.
Source Documents......................................................................................................59
18.3.
Inspection of Records .................................................................................................60
18.4.
Retention of Records ..................................................................................................60
19.
PUBLICATION POLICY ..........................................................................................60
20.
LIST OF REFERENCES............................................................................................61
21.
APPENDICES ............................................................................................................62
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3.1.
List of Tables
Table 1:
Activity Schedule........................................................................................................10
Table 2:
Abbreviations and Specialist Terms...........................................................................17
Table 3:
Investigational Products..............................................................................................31
3.2.
List of Figures
Figure 1:
Schematic Study Design.............................................................................................26
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5.
ETHICS
5.1.
Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC)
It is the responsibility of the Sponsor and Investigator to have prospective approval of the 
study protocol, protocol amendments, informed consent forms/assent, and other written 
information to be provided to subjects, e.g., advertisements and diaries if applicable, from the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). All correspondence 
with the IRB/IEC should be retained in the Investigator File (Site Master File). Copies of 
IRB/IEC approvals obtained by the Investigator should be forwarded to the Sponsor.
The only circumstance in which a protocol amendment may be initiated prior to IRB/IEC 
approval is where the change is necessary to eliminate apparent immediate hazards to the 
subjects. In that event, the Investigator must notify the IRB/IEC and the Sponsor in writing 
within five working days after implementation.
5.2.
Ethical and Regulatory Considerations
The study will be performed in accordance with the protocol, International Council for
Harmonization Good Clinical Practice guidelines (ICH GCP E6), the latest version of the
Declaration of Helsinki,5 and applicable local regulatory requirements and laws.
Before initiating the clinical study, the Sponsor should submit any required application(s) to 
the appropriate authority (ies) for review, acceptance, and/or and/or permission to begin the 
study. Any notification/submission should be dated and contain sufficient information to 
identify the protocol.
Amendments to the protocol that are considered as substantial, i.e., are likely to have an 
impact on the safety of the study subjects, to change the interpretation of the scientific 
documents in support of the conduct of the study, or if they are otherwise significant, must be 
reviewed and approved by the appropriate authority(ies).
5.3.
Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or subject initials on any forms, reports, publications, or in any other disclosures. Each 
subject will be assigned a subject number that is used in the electronic Case Report Form 
(eCRF) in lieu of the subject’s name. In case of data transfer, the Sponsor will maintain high 
standards of confidentiality and protection of subject personal data.
The informed consent form must be agreed upon by the Sponsor and the IRB/IEC. It must be 
in compliance with current regulatory requirements (e.g., ICH E6), and legal requirements,
and be in a language that the subject can read and understand with compliance to the 
International Standard and any regional or national regulations, as appropriate.
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The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation in the study. Subjects 
must consent to informing the site if they develop symptoms of Coronavirus disease 2019 
(COVID-19). The Investigator, or a person designated by the Investigator, will obtain written 
informed consent from each subject before any study-specific activity is performed. The 
informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and the Sponsor before use. The 
Investigator will retain the original of each subject's signed consent form. A copy of the 
signed and dated consent form will be provided to subjects.
Prior to a subject’s participation in the study, the written informed consent form should be 
signed and personally dated by the subject or by the subject's legally acceptable 
representative, and by the person who conducted the informed consent discussion.
Only subjects who provide informed consent will be permitted to participate in the study.
5.4.
Subject Written Assent
After the informed consent form is signed and dated by the parents or legally authorized 
representatives and witnessed by a member of the Investigator’s clinical team, written assent 
to participate in the study must be obtained from prospective subjects who are below the age 
of legal consent yet old enough to understand details of the study as required by the site’s
IRB/IEC or Principal Investigator (PI), or local requirements. During the Assent process, the
PI or designee will provide the minor with an assent document that explains, in terms
appropriate to the child’s age, experience, maturity and condition, any discomfort and 
inconveniences the child may expect to experience if he or she agrees to participate. The 
subject should also be made aware of his or her rights to decline participation or to withdraw 
from the study at any time.
The assent document will focus on the risks, benefits and alternatives to research 
participation as well as confidentiality of information obtained as a result of their 
participation. The minor should be given an opportunity to ask questions prior to signing the 
approved assent form or designated assent signature line within the Informed Consent Form. 
An impartial witness must also sign and date the assent form.
The original signed assent form will be retained by the Investigator as part of the source 
documents/study files and will be available for review by the Monitor and the Sponsor. A 
copy of the signed and dated assent form will be given to the subject. Assent by the subject 
acknowledges willingness to participate, but does not necessarily ensure a thorough
understanding of the procedures, risks, and benefits of the study.
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6.
STUDY ADMINISTRATIVE STRUCTURE
Details on the administrative structure of the study (e.g., PI/study site personnel, the 
Sponsor’s study team, and the external service providers) will be included in the study 
contact list. The study contact list will also include contact information for the Sponsor, 
Investigator(s), Monitor(s), Clinical and Bioanalytical Laboratories, and IRB/IEC(s), as well 
as the names and titles of the person(s) authorized to sign the protocol and the protocol 
amendment(s) for the Sponsor. The complete contact list will be maintained in the trial
master file throughout the study for inclusion in the clinical study report.
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9.
INVESTIGATIONAL PLAN
9.1.
Overall Study Design and Plan
This will be a randomized, double-blind, placebo-controlled study to evaluate the analgesic 
efficacy and safety profile of the following doses of a fixed combination of 
acetaminophen/naproxen sodium (Figure 1):

 mg Acetaminophen/
 mg Naproxen sodium

mg Acetaminophen/
 mg Naproxen sodium

 mg Acetaminophen/
 mg Naproxen sodium

 mg Acetaminophen/
 mg Naproxen sodium

 mg Acetaminophen/
 mg Naproxen sodium

Placebo
Subjects will undergo dental extraction of three or four third molars. Supernumerary teeth 
may also be removed. Judgment of impaction level will be made by the oral surgeon based 
on visual examination of the panorex x-ray. Maxillary third molars may be removed 
regardless of impaction level. The mandibular extractions must meet one of the following 
scenarios:

Two full bony impactions

Two partial bony impactions

One full bony impaction in combination with one partial bony impaction
Post-surgery trauma assessment will be done on the day of surgery (Baseline visit). Subjects 
will be excluded from the study if the mandibular extraction results in a trauma rating of 
“severe” on a mild, moderate, or severe scale on the categorical and numerical pain intensity 
scale.
Approximately 300 subjects who meet the randomization criteria (post-surgical pain of 
moderate to severe on the four-point categorical pain scale, and at least a score of 5 on the 
11-point [0-10] pain intensity-numerical rating scale [PI-NRS] at Baseline within 4.5 hours 
of last stitch from dental extractions) will be assigned to one of the following six treatment 
groups, with equal allocation among the treatment groups:

mg Acetaminophen/
 mg Naproxen sodium (administered as two tablets 
of Acetaminophen/Naproxen sodium
)

mg Acetaminophen/
 mg Naproxen sodium (administered as two tablets of 
Acetaminophen/Naproxen sodium
) 
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10.
STUDY POPULATION
10.1.
Subject Eligibility
This clinical study can fulfill its objectives only if appropriate subjects are enrolled. The 
following eligibility criteria are designed to select subjects for whom protocol treatment is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject. No 
waivers to inclusion or exclusion criteria will be permitted at point of enrollment.
10.1.1.
Subject Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Males or females who are 17 to 50 years of age (inclusive) at the time of Screening.
2. If female and of childbearing potential have a negative urine pregnancy at Screening 
and at Baseline.
3. Weigh (100) pounds or greater and have a body mass index (BMI) of 17.5 to 30.4
(inclusive) at Screening.
4. Have undergone dental extraction of three or four third molars. Maxillary third 
molars may be removed regardless of impaction level. Supernumerary teeth may also 
be removed. The mandibular extractions must meet one of the following scenarios
(and must not result in a trauma rating of “severe” on a mild, moderate, or severe
scale):

two full bony impactions

two partial bony impactions

one full bony impaction in combination with one partial bony impaction.
5. Indicate at least moderate pain on a categorical scale ranging from (0) none, (1) mild, 
(2) moderate, or (3) severe AND at least a score of 5 on the 11-point (0-10) PI-NRS 
at Baseline within 4.5 hours of the last stitch from oral surgery.
6. Are able to comprehend and follow the requirements of the study (including 
pre-surgical instructions provided by the site and availability on scheduled visit dates) 
based upon research site personnel’s assessment.
7. Provide written informed consent (for subjects who are below the age of legal 
consent, parent or legally authorized representative provides written informed consent 
and the subject provides written assent).
8. Females of childbearing potential and males agree to the contraceptive requirements 
as outlined in Section 12.6.4 and 12.6.5.
9. Are willing for this to be the only IP used during the study.
10. Have a negative urine drug screen at Screening, and on day of surgical procedure.
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10.1.2.
Subject Exclusion Criteria
Subjects will be excluded if they:
1. Are female and are pregnant, breastfeeding or currently trying to become pregnant.
2. Are male with a pregnant partner or a partner who is currently trying to become
pregnant.
3. Have extraction of mandibular third molars resulting in a trauma rating of “severe” on 
a mild, moderate, or severe scale.
4. Have a known allergy or hypersensitivity to naproxen or other NSAIDs, including 
aspirin, acetaminophen, oxycodone, or other opioids.
5. Have presence or a history of major medical condition that in the Investigator’s 
opinion may jeopardize the subject’s safety or well-being (e.g., hepatic, renal, 
pancreatic, gastrointestinal, cardiovascular, cerebrovascular, or thyroid diseases as 
well as a history of head injury or seizures, history of respiratory depression or lung 
problems such as but not limited to asthma or chronic obstructive pulmonary disease, 
psychiatric disorders, problems urinating, a history of blockage or narrowing of the 
stomach or intestines, uncontrolled hypertension indicated as systolic blood pressure 
≥160 mm Hg or diastolic blood pressure ≥100 mm Hg, or uncontrolled diabetes in the 
last 6 months) or the integrity of the study.
6. Have a history of a confirmed or suspected COVID-19 infection in the last 30 days or 
contact with COVID-19-infected person within 14 days prior to any site visit.
7. Have any international travel within 14 days prior to any site visit including members 
in the same household.
8. Have self-reported symptoms within 14 days prior to any site visit:

Unexplained cough, shortness/difficulty breathing, fatigue, body aches 
(headaches, muscle pain, stomach aches), conjunctivitis, loss of smell, loss of 
taste, poor appetite, nausea, vomiting, diarrhea, palpitations, or chest 
pain/tightness; 

Temperature ≥37.5C/99.5F, within 14 days prior to any site visit or when 
measured upon arrival at any site visit; 

Use of fever or pain reducers within the past three days any site visit.
9. Are not able to swallow whole large tablets or capsules.
10. Routine use of oral analgesics ≥5 times per week.
11. Have a history of chronic tranquilizer use, heavy drinking, or substance abuse, as 
judged by the Investigator site staff, in the last five years. Heavy drinking is defined 
as the use of more than four standard drinks daily or more than 14 drinks a week for 
men, and more than three standard drinks daily or more than seven standard drinks in 
a week for women. Standard drink refers to 14 g (0.6 oz.) of pure alcohol, which is 
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approximately 12 oz. of beer, 8 oz. of malt liquor, 5 oz. of wine, 1.5 oz. or “shot” of 
80-proof distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey).
12. Have a history of endoscopically documented peptic ulcer disease or bleeding 
disorder in the last two years.
13. Used oral OTC or prescription products (except contraceptive medications and those 
required for use during the oral surgical procedure), within five half-lives before the 
oral surgical procedure.
14. Used vitamins, dietary or herbal supplements within five days before the oral surgical 
procedure.
15. Used any immunosuppressive drugs, corticosteroids (except for topical 
corticosteroids), or injectable or oral anticoagulants (e.g., heparin, Lovenox, Xarelto, 
Eliquis, Pradaxa, Coumadin, Miradon) within two weeks of Screening.
16. Used alcohol within three days before the oral surgical procedure.
17. Consumed methylxanthine-containing products (e.g., chocolate bars or chocolate 
beverages, coffee, tea, cola or caffeinated energy drinks), tobacco, or nicotine 
containing products (e.g., cigarettes, cigars, nicotine replacement therapies) <12 hours 
before the oral surgical procedure.
18. Used monoamine oxidase inhibitors within 14 days prior to surgery.
19. Have a positive test for human immunodeficiency virus (HIV) antibody, hepatitis B 
surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV).
20. Have participated in any interventional clinical trials within 30 days before Screening.
21. Are related to those persons involved directly or indirectly with the conduct of this 
study (i.e., PI, sub-investigators, study coordinators, other site personnel, employees 
of Johnson & Johnson [J&J] subsidiaries, contractors of J&J, and the families of 
each).
10.1.3.
Subject Withdrawal/Termination Criteria
Subjects have the right to withdraw from the study at any time for any reason without 
compromising their rights to receive further treatment. The Investigator and/or the Sponsor
may terminate a subject from investigational treatment and/or study follow-up in the event of 
any of the following:

Medical reasons considered significant by the subject, Investigator and/or the 
Sponsor, which may include, an adverse event (AE), inter-current illness or 
medical reasons unrelated to the study

Nonmedical reasons (e.g., subject request or noncompliance with the treatment 
procedure as determined by the Investigator, the Sponsor and/or subject)

Pregnancy

Non-eligibility or on-study violation of the protocol
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
Administrative or other reasons (e.g., lost to follow-up, non-compliance)
Should a subject decide to withdraw from the study at any point, all efforts should be made to 
complete all end of study assessments (see Section 12.3.3 for details). In case of questions 
surrounding the circumstances that a subject needs to be withdrawn from the study (e.g.,
protocol deviation), the Sponsor, or the Sponsor representative should be consulted. The
reason for withdrawal should be documented in the subject’s source document and in the 
Subject Disposition eCRF.
If a subject is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal 
before considering the subject to be lost to follow-up. Such efforts should include repeated 
telephone calls, certified letters, and email requests. The measures taken to follow-up must be 
documented.
11.
STUDY INTERVENTION
11.1.
Treatment Administration
All study treatments will be taken orally with up to 180 mL water.
11.2.
Description and Administration of Investigational Products
A description of the IPs are provided in Table 3.
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Table 3:
Investigational Products
Product
APAP/NPX
APAP/NPX
APAP/NPX
APAP/NPX
APAP/NPX
Placebo
Dosage Form
Tablet
Tablet
Tablet
Tablet
Tablet
Tablet
Route of Administration
Oral
Oral
Oral
Oral
Oral
Oral
Unit Dose
NA
Physical Description
 
 tablet, debossed 
with double circular 
arrows with lightning 
bolt inside the circle, on 
one side; opposite side 
plain
 
 tablet, debossed 
with double circular 
arrows with lightning 
bolt inside the circle, on
one side; opposite side 
plain
 
 tablet, debossed 
with double circular 
arrows with lightning 
bolt inside the circle, on 
one side; opposite side 
plain
 
 tablet, debossed 
with double circular 
arrows with lightning 
bolt inside the circle, on 
one side; opposite side 
plain
 
 tablet, debossed 
with double circular 
arrows with lightning 
bolt inside the circle, on 
one side; opposite side 
plain
White oval 
shaped tablet
Manufacturer/Brand
Johnson & Johnson 
Consumer Inc
Johnson & Johnson 
Consumer Inc
Johnson & Johnson 
Consumer Inc
Johnson & Johnson 
Consumer Inc
Johnson & Johnson 
Consumer Inc
Patheon Inc. 
Manatai, PR
Abbreviations: APAP=acetaminophen; NA=not applicable; NPX=naproxen sodium
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11.3.
Packaging and Labeling
Product will be provided in subject specific wallets containing two count blisters. Each 
subject specific wallet will be labeled with two panel Sponsor study label. The second panel 
will contain an unblinding panel. The unblinding panel should be removed prior to subject 
dispensation and stored with the site’s Pharmacy (IP) binder.
11.4.
Preparation, Handling and Disposal
Investigational products and placebo will be packaged in blister packs. Each pack will have a 
sufficient supply for the duration of the study for one subject. The Sponsor will label the 
blister packs for use per the standard operating procedures (SOPs). The pack will have a two
panel label with a perforation between Panels I and II. Panel I will provide study-related 
information, instructions for use, storage conditions, and randomization number. Panel II will 
include a concealed scratch off sticker containing the treatment assignment for each subject. 
Panel II of the label should be removed at the perforation line and attached to the site’s 
Pharmacy (IP) binder prior to dispensing the kit to the subject. The scratch off unblinding 
panel should not be removed from the label and the integrity of the scratch off surface should 
be preserved. In order to maintain the double-blind status of the study, the site must adhere to 
the following general storage, dispensing, and dosing procedures:

The site will delegate a qualified third party and back-up staff member(s) who 
will be responsible for dispensing and administering study medication and who 
will have no other direct or indirect role in the execution of this study.
Investigational product preparation and dispensing will be performed on Day 1, following 
dental surgery (within 4.5 hours of last stitch from dental extractions). For subjects who meet 
the randomization criteria, an independent dispenser will administer one of the following 
study treatments with up to 180 mL of water at ambient temperature to blindfolded subjects:

mg Acetaminophen/
 mg Naproxen sodium (administered as two tablets 
of Acetaminophen/Naproxen sodium
)

 mg Acetaminophen/
mg Naproxen sodium (administered as two tablets of 
Acetaminophen/Naproxen sodium
) 

mg Acetaminophen/
mg Naproxen sodium (administered as a two tablets 
of Acetaminophen/Naproxen sodium
) 

 mg Acetaminophen/
 mg Naproxen sodium (administered as a two tablets 
of acetaminophen/naproxen sodium
)

 mg Acetaminophen/
mg Naproxen sodium (administered as two tablets of 
Acetaminophen/Naproxen sodium
)

Placebo (administered as two placebo tablets)
Baseline pain assessments and drug administration will be completed in the subject’s room. 
The unblinded dispenser will bring the assigned blister pack to the designated dispensing 
room. Study medication will be dispensed at the time that the subject’s pain level is 
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determined to be eligible by verbal assessment, just prior to the completion of the baseline 
categorical pain severity scale and the baseline 11-point (0-10) PI-NRS. The blinded study 
coordinator will communicate the subject’s pain severity and gender to the unblinded team. 
The unblinded team (unblinded dispenser and unblinded witness) will pull the Pharmacy (IP) 
Binder & prepare the IP. The unblinded team assigns the appropriate randomization number 
from the IP Binder. The unblinded dispenser will take out a total of one blister pack 
(containing two tablets, per assigned treatment group), remove Panel II from the blister pack 
and dispense the appropriate study treatment. The double-blind label with the randomization 
number will be affixed to the blister packs and the tear-off portion of the label will be placed 
in the site’s Pharmacy (IP) binder. The unblinded dispenser will complete the study drug 
dispensing record. The study drug dispensing record will remain in a secure and locked area, 
with access limited to the unblinded team, back-up staff member, and unblinded Monitor. A 
second individual, with no other study involvement, will witness the preparation and 
dispensing process. No other study personnel will be present in the designated dispensing 
room at the time of study drug dispensing. 
The unblinded team will inform the blinded study coordinator once the study drug is ready to 
be administered to the subject. Following completion of the baseline categorical pain severity 
scale and baseline PI-NRS, the study coordinator will blindfold the subject and then exit the 
subject’s room to inform the unblinded team that the pain assessments are completed and 
confirm that the pain severity has not changed from the verbal assessment used to determine 
the appropriate randomization, and that the PI-NRS score qualifies the subject for 
randomization. If the baseline categorical pain severity has changed, randomization numbers 
will not be re-used and an undispensed treatment previously prepared will be quarantined. If 
the severity has changed and the original treatment prepared is not administered, then the 
unblinded team will check the box: No, Quarantined under the Dosed column on the IP 
Dispensing and Accountability Log. The unblinded team will complete the quarantined log
for the applicable treatment group. The unblinded dispenser will deliver the study drug from 
the designated dispensing room to the subject’s room. No other study personnel, other than 
the unblinded witness and dispenser, will be present in the subject’s room at the time of 
dosing.
After entering the blindfolded subject’s room and while the subject is sitting up, the 
dispenser will empty the contents of the blister pack into a dosing cup and hand the dosing 
cup containing the study treatment to the blindfolded subject and instruct the subject to 
empty the contents of the dosing cup directly into his/her mouth and then swallow the study 
medication immediately with up to 180 mL of water at ambient temperature. The dispenser 
will inspect the subject’s oral cavity to ensure that the study treatment was swallowed. The 
time at which the subject swallows all study medication will be recorded as Time 0. Study 
drug will be administered to the subject within five minutes of the completion of the baseline 
pain assessments. Subjects that have received rescue medication will be prohibited from 
operating a motor vehicle when leaving the investigational site for any reason, and will be 
advised to avoid driving a motor vehicle within 24 hours of the last dose of rescue 
medication.
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Representative or designee for consultation about breaking the study blind. If there is a 
medical emergency and the Investigator deems it necessary to know the subject’s study 
treatment urgently for the subject’s proper medical care, the Investigator may break the 
treatment code immediately, and then contact the Designated Physician Representative or 
designee as soon as possible afterward.
In the event of a medical emergency that necessitates breaking the code, the third-party 
person(nel) will be permitted to inform the Investigator what study drug the subject was 
given.
When the blind is broken, the Investigator will notify the Sponsor within 24 hours after 
determining that it is necessary to unblind the treatment assignment and document the reason 
and date of the unblinding. The event will also be recorded in the eCRF and in the source 
document. Any AE or serious adverse event (SAE) associated with breaking the blind must 
be recorded and reported as specified in this protocol.
Once the treatment is unblinded, the subject must be discontinued from the study and 
followed until the event is resolved. The rationale, date, time, and attempts to contact the 
Sponsor must be documented in the source document. The study site should take the 
necessary measures to maintain the treatment blind throughout the study and prevent any 
unintended or premature unblinding.
11.8.
Treatment Compliance 
All subjects randomized to treatment in this study will be in compliance with treatment if 
they take the dose of study medication.
11.9.
Previous and Concomitant Medications 
Medications and other treatments that are taken from 30 days prior to Screening until the end 
of the 24-hour assessment period will be recorded in the source documents and eCRF. 
Additional postsurgical medications (e.g., antibiotics or analgesic prescriptions) and other 
treatments or therapies (e.g., ice packs) that are taken after the 24-hour assessment period 
through the follow-up interview will be captured on the source documents, but not in the 
eCRF. However, concomitant medications and other treatments taken for or associated with 
an AE will be recorded on the eCRF and the source documents.
11.9.1.
Permitted Therapies
Female subjects taking hormonal contraceptives will be instructed to continue before, during, 
and after the study as per protocol. All subjects will be permitted a short-acting local 
anesthetic, lidocaine with or without epinephrine, and/or nitrous oxide during dental surgery. 
Topical benzocaine is also allowed.
11.9.2.
Prohibited Therapies
Long-acting anesthetics are prohibited during the dental surgery. Other medications 
prohibited before entry into the study are listed under Exclusion Criteria.
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
Vital signs: resting blood pressure, heart rate, respiratory rate, and oral 
temperature

Physical examination: height, weight and BMI assessment

A serum sample will be collected to test for HIV antibody, hepatitis B surface 
antigen (HBsAg) and hepatitis C virus antibody (anti-HCV)

Urine drug screen test

Urine pregnancy test for females with childbearing potential

Safety monitoring
Subjects who meet all study entry requirements per the inclusion/exclusion criteria will be 
scheduled for the dental procedure within 30 days after Screening.
12.3.
Study Visits (Periods)
12.3.1.
Baseline Visit (Day of Surgery)
The following will be re-evaluated prior to the surgical procedure, and the evaluations will be 
recorded in the source documents and the CRF. For data collected on both Screening and 
Baseline Visits, only the data collected at Baseline will be recorded on the eCRF.

Inclusion and exclusion criteria

Any changes to medical and surgical history

Any changes to prior and concomitant therapies

Vital signs: resting blood pressure, heart rate, respiratory rate, oral temperature

Postsurgical trauma assessment

Categorical and Numerical Pain Intensity

Urine drug screen test. A negative urine drug screen must be obtained on the same 
day as the surgical procedure

Urine pregnancy test on females with childbearing potential. A negative urine 
pregnancy test (for women of childbearing potential) must be obtained on the 
same day as the surgical procedure

Investigational product administration

Safety monitoring
12.3.2.
Post-dose Assessments (0-24 Hours)
Post-dose assessments includes the following procedures (please refer to Section 13 for 
details):

Randomization

Pain intensity and pain relief ratings
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12.3.3.
Follow-Up Phone Call (Days 7 to 10)
Subjects will be interviewed by telephone to follow-up on appropriate postsurgical medical 
care and changes in their health, including any emergent or existing AEs. The interview will 
occur between Days 7 to 10. At least three attempts should be made to contact the subject by 
phone. If the subject cannot be contacted by phone by Day 10, then a certified letter should 
be mailed to the subject. Every effort will be made by the Investigator or designated study 
staff to adhere to the schedule.
During the follow-up call, a follow-up interview will be conducted and information 
pertaining to safety monitoring (AEs) and concomitant medications will be collected.
12.4.
End of Study for Subject
End of Study for each subject is defined as the follow-up phone call or early termination. For 
subjects whose participation is discontinued during this study, end of study evaluations will 
be completed as soon as possible after discontinuation.
12.5.
COVID-19 Pandemic Response Plan
Regulatory authorities have recognized that the COVID-19 pandemic may impact the 
conduct of clinical studies of medical products. Challenges may arise, e.g., from quarantines, 
site closures, travel limitations, interruptions to the supply chain for the IP(s), or other 
considerations if site personnel or study participants become infected with COVID-19. These 
challenges may lead to difficulties in meeting protocol-specified procedures, including 
administering 
or 
using 
the 
IP 
or 
adhering 
to 
protocol-mandated 
visits 
and 
laboratory/diagnostic testing. To accommodate these challenges and mitigate safety risks 
associated with COVID-19, protocol modifications will be required.
Johnson & Johnson COVID-19 guideline document entitled, “Guidelines for Resuming 
Clinical and Consumer Science Studies” will be shared with the Investigator for review and 
sign off prior to study start. Any changes to the guidelines during the conduct of the study
will also require sign off by the Investigator. The signed version(s) of these guidelines will be
maintained by the site and a copy will be included in the Trial Master File.
12.6.
Life Style Restrictions 
12.6.1.
Meals and Dietary Restrictions 
Only clear, non-caffeinated liquids may be consumed from the time of surgery until two 
hours following administration of the IP. After two hours, subjects may consume soft foods 
consistent with having dental surgery.
12.6.2.
Alcohol, Caffeine and Tobacco Restrictions
Use of alcoholic beverages within three days before the oral surgical procedure and during 
the study is prohibited. In addition, subjects must refrain from the use of any 
methylxanthine-containing products (e.g., chocolate bars or beverages, coffee, tea, colas, or 
caffeinated energy drinks) and tobacco or nicotine containing products (e.g., cigarettes, 
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cigars, nicotine replacement therapies) within 12 hours before surgery and during the study 
while confined at the site.
12.6.3.
Physical Activity Requirements/Restrictions
Walking at a normal pace will be permitted. Subjects will remain sitting upright or 
semi-reclining for dosing and should remain in the study area under observation for at least 
four hours immediately following treatment administration, except for short durations to use 
the restroom.
12.6.4.
Contraception for Females
Female subjects with reproductive potential must agree to practice a medically acceptable 
form of birth control throughout the study and for 30 days following the last dose of IP, 
whichever is later. 
Medically acceptable forms of birth control that may be used by the subject and/or his/her 
partner include: 

Sexually active female subjects who use hormonal contraception must have used 
a stable dose for 30 days before surgery. If hormonal contraception has been used 
for less than 30 days or if the dose has changed within the past 30 days, subjects 
must agree to also use a barrier method during the study and up to 30 days after 
taking the IP

Barrier methods of contraception with spermicide: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/ film/ cream/ 
suppository

Intrauterine device (IUD) or intrauterine system

Surgical sterilization (e.g., vasectomy that has been confirmed effective by sperm 
count check, tubal occlusion, hysterectomy, bilateral salpingectomy)

Abstinence from heterosexual intercourse: When this is in line with the preferred 
and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception
Female subjects are not considered of childbearing potential if they meet at least one of the 
following criteria:

Had a hysterectomy and/or bilateral oophorectomy at least six months prior to 
product administration

Had sterilization surgery (e.g., hysteroscopic sterilization/tubal implants or tubal 
ligation) at least six months prior to Screening; tubal implants must have been 
confirmed effective by medical assessment as reported by the subject

Are postmenopausal (i.e., amenorrheic for at least 12 consecutive months, without 
an alternative medical cause, prior medical Screening by a healthcare provider)
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AEs, the Investigator or medically qualified individual (MD/DO/DMD/DDS) must pursue 
and obtain adequate information to make the appropriate assessments.  
14.1.
Reporting Period
All AEs, whether serious or non-serious, observed or spontaneously reported will be 
recorded on the eCRF in the AE section beginning from the time the informed consent/assent
is signed and dated. Subject’s participation in the clinical study begins at signing the 
informed consent. All AEs are recorded even if the AE occurs prior to the subject’s 
participating in any study-related procedure and/or receiving IP. Nonserious AEs will be 
reported through the subject’s last study visit (or termination if the subject terminates early 
from the study for any reason). Spontaneous reports of SAEs will be collected through and 
including 30 calendar days after administration of the subject’s last dose or exposure to IP. 
Serious adverse events require immediate notification to the Sponsor or its designated 
representative. Any SAE occurring any time after the reporting period (30 calendar days post 
IP exposure or last dose) must be promptly reported if a causal relationship to study product 
is suspected.
14.2.
Definitions
14.2.1.
Definition of Adverse Event
An AE is any untoward medical occurrence that occurs in a subject after they have signed an 
informed consent for a study. The event does not need to have a suspected causal relationship
with the IP. Therefore, an AE can be any unfavorable and unintended sign, symptom, disease 
or injury temporally associated with the subject’s participation in the study. Examples of AEs 
include, but are not limited to:

Abnormal test findings

Clinically important signs and symptoms

Changes in physical examination findings

Hypersensitivity

Progression/worsening of underlying disease
Additionally, they may include the signs or symptoms resulting from:

Overdose

Withdrawal

Abuse

Drug misuse

Drug interactions

Medication errors
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
Product dependency

Exposure in utero

Study related procedure
14.2.1.1.
Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as
an AE are as follows:

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention
beyond ordering a repeat (confirmatory) test, and/or

Test result leads to a discontinuation from the study, significant additional 
concomitant treatment, or other therapy, and/or

Test result is considered to be an AE by the medically qualified Investigator or 
designee or the Sponsor
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
14.2.2.
Definition of Serious Adverse Events (SAE) for Drugs
An AE or suspected adverse reaction is considered “serious” for a drug study if, in the view 
of either the medically qualified Investigator or designee (MD/DO/DMD/DDS) or the 
Sponsor, it results in any of the following outcomes:

Results in death

Is life-threatening (immediate risk of death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions

Results in congenital anomaly/birth defect

Is considered medically significant (medical and scientific judgment should be
exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not result in death, be 
life-threatening or require hospitalization but may be considered a serious adverse 
drug experience when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent 
one of the other outcomes listed above). Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an Emergency Room or at 
home, blood dyscrasia, or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse, or malignancy, or
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
Is a suspected transmission of any infectious agent via a medical product 
(medically significant) and should be reported as an SAE in the category “Other 
medically important conditions”
14.2.2.1.
Hospitalization
AEs reported from clinical studies associated with hospitalization or prolonging
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a
healthcare facility meets these criteria. Admission also includes transfer within the hospital to
an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit). Hospitalization does not 
include the following:

Rehabilitation facilities 

Hospice facilities 

Respite care (e.g., caregiver relief)

Skilled nursing facilities 

Nursing homes

Emergency room visits (unless the reason for the emergency room visit meets one 
of the other outcomes in the definition of serious)

Same day surgeries (as outpatient/same day/planned procedures)

Hospitalization or prolongation of hospitalization in the absence of a 
precipitating, clinical AE is not in itself an SAE. Examples include: 

Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition 
(e.g., for work-up of persistent pre-treatment lab abnormality)

Social admission (e.g., subject has no place to sleep)

Administrative admission (e.g., for yearly physical exam)

Protocol-specified admission during a clinical study (e.g., for a procedure 
required by the study protocol)

Optional admission not associated with a precipitating clinical AE (e.g., or 
elective cosmetic surgery)
Pre-planned treatments or surgical procedures should be noted in the baseline documentation 
for the entire protocol and/or for the individual subject.

Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs. However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of an AE. 
For example, an acute appendicitis that begins during the AE reporting period 
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should be reported as the AE and the resulting appendectomy should be recorded 
as treatment of the AE.
14.3.
Adverse Event Assessments 
Sufficient information should be obtained for each AE to allow the Investigator or medically 
qualified individual to make assessments as described below.
14.3.1.
Severity Assessment
The severity of AEs will be assessed by the medically qualified Investigator or designee
using the following general categorical descriptors:
MILD:
Awareness of symptoms that are easily tolerated, causing minimal
discomfort and not interfering with the subject's usual function or normal
everyday activities.
MODERATE:
Sufficient discomfort is present to cause interference to some extent with
the subject's usual function or normal everyday activity.
SEVERE: 
Extreme distress, causing significant impairment of functioning or
incapacitation; interferes significantly with subject's usual function; 
prevents normal everyday activities.
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious event. For example, a headache may be severe (interferes significantly 
with the subject's usual function) but would not be classified as serious unless it met one of 
the criteria for SAEs listed above.
14.3.2.
Causality Assessment
The medically qualified Investigator’s assessment of causality to IP (i.e., relationship to IP) 
must be provided for all AEs (serious and non-serious). The causality assessment is the 
determination of whether there exists a reasonable possibility that the IP caused or 
contributed to an AE.

Not Related - An AE that is not related to the use of the drug.

Doubtful - An AE for which an alternative explanation is more likely, e.g.,
concomitant drug(s), concomitant disease(s), or the relationship in time suggests 
that a causal relationship to IP is unlikely.

Possible - An AE that might be due to the use of the drug. An alternative
explanation, e.g., concomitant drug(s), concomitant disease(s), is inconclusive. 
The relationship in time is reasonable; therefore, the causal relationship to IP
cannot be excluded.

Probable - An AE that might be due to the use of the drug. The relationship in 
time is suggestive (e.g., confirmed by dechallenge) and an alternative 
explanation is less likely, e.g., concomitant drug(s), concomitant disease(s).
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
Very Likely - An AE that is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., concomitant drug(s),
concomitant disease(s). The relationship in time is very suggestive (e.g., it is
confirmed by dechallenge and rechallenge) for a causal relationship to the drug.  
Any AE that occurs after the informed consent has been signed, until first usage of IP, will be 
considered non-treatment emergent and cannot (by virtue of time of occurrence) have a 
causal relationship with the IP.
If the Investigator determines an AE is associated with study procedures, the Investigator 
must record this suspected causal relationship in the source documents and the SAE form, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
14.3.3.
Resolution
The medically qualified Investigator or designee will be required to assess the outcome of the 
AE for IP as one of the following:

Resolved

Not Resolved

Fatal

Resolved with sequelae

Resolving

Unknown
Any causally-related AEs that are not resolved upon completion of the last study visit will be
followed up by the study staff until the event or its sequelae resolve or stabilize at a level
acceptable to the medically qualified Investigator or designee, and recorded on the eCRF. An 
event that is assessed as resolved with sequelae or resolving indicates that the subject has
stabilized to a level acceptable to the medically qualified Investigator or designee and has 
concurrence by the Sponsor.
14.4.
Adverse Event Reporting 
14.4.1.
Time Period
All AEs, whether serious or non-serious, will be collected starting from the time a subject 
signs and dates an informed consent until the completion of the subject’s last study-related
procedure, which may include contact for follow-up of safety. Spontaneous reports of serious 
AEs will be collected through and including 30 calendar days after subject’s last dose of IP.
Any SAE occurring any time after the reporting period must be promptly reported if a causal 
relationship to study product is suspected.
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If a subject develops COVID-19 during the conduct of the study, it will be considered an AE. 
The subject will be instructed to inform the site if diagnosed with COVID-19 during the 
conduct of the study.
14.4.2.
Process for Reporting
The Investigator is to report all AEs whether directly observed or spontaneously reported by 
the study subject. In addition, each study subject will be questioned in general about any 
AEs.
All AEs, serious or non-serious, will be recorded on the source documents; e.g., written 
documentation, electronic medical records, subject diaries, or journals. Adverse events will 
be entered into eCRFs for screen failure subjects as well as randomized subjects. AEs should 
be reported using concise medical terminology on the eCRFs. Each AE is to be assessed to 
determine if it meets the criteria for an SAE. If an SAE occurs, expedited reporting is 
required.
14.4.2.1.
Serious Adverse Event Reporting 
A Clinical SAE Report Form must also be completed if the event is considered to be serious. 
Where the same data are collected, the Clinical SAE Report Form and the AE eCRF must be 
completed in a consistent manner. For example, the same AE term should be used on both 
forms. 
If an SAE occurs, the Sponsor or designee must be notified by telephone, email or fax 
immediately upon awareness of the event by the Investigator’s site and the SAE documented 
on the source document. Within 24 hours of the Investigator site’s awareness of the event, 
the study site must send the Sponsor the Clinical SAE Report Form (via a secure e-mail or 
fax). This timeframe also applies to additional new information (follow-up) on previously 
reported SAEs as well as to the initial and follow-up reporting of Exposure In Utero (EIU)
cases. In the rare event that the Investigator’s site does not become aware of the occurrence 
of an SAE immediately (e.g., in a telephone contact, in a subject diary or journal, or if an 
outpatient study subject initially seeks treatment elsewhere), the Investigator’s site is to 
report the event immediately after learning of it as described, and document the date and time 
of the study site’s first awareness of the AE in the Subject’s file.  
For all SAEs, the Investigator is obligated to pursue and provide information to the Sponsor 
in accordance with the timeframes for reporting specified above. In addition, an Investigator 
may be requested by the Sponsor to obtain specific additional follow-up information in an 
expedited fashion. This information may be more detailed than that captured on the AE
eCRF. In general, this will include a description of the AE in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible 
causality. Information on other possible causes of the event, such as concomitant medications 
and illnesses must be provided. In the case of a subject death, a summary of available 
autopsy findings (if available) and death certificate should be collected if permission is 
obtained from the subject’s family. For a hospitalization, a copy of the hospital discharge 
summary should be requested. If obtained, these documents (with subject’s personal 
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identifiers redacted) should be submitted as soon as possible to the Sponsor or its designated 
representative.
Appropriate SAE forms will be provided to the study site at the initiation of the study.
14.4.2.2.
Contacts for Serious Adverse Event Reporting 
Study Contacts for reporting can be found on the Study Contact List kept in the Site Master 
File.
All nonserious AEs are to be reported on the AE eCRFs and will be submitted to the 
Sponsor.
14.5.
Suspected Unexpected Serious Adverse Reaction
If the Sponsor judges an SAE to be a Suspected Unexpected Serious Adverse Reaction 
(SUSAR), the Sponsor will report it to the Regulatory Authority(ies) and the Investigator (or 
Sponsor) must report to the IRB/IEC as required and in accordance with the Sponsor’s SOPs
for safety reporting.
14.6.
Special Situations
Special Situations are safety events that may not meet the definition of an AE; however, from 
a policy perspective, they are treated in the same manner as AE and recorded in the source 
document. Examples include:

Pregnancy exposure (maternal and paternal) to a J&J product, see next section.

Off-label use of a J&J product.  Note: Off-label use of a product without an 
associated AE should be collected only when it is specifically and voluntarily 
brought to the attention of the company in an unsolicited manner by a reporter 
(e.g., Patient or Health Care Professional), or data obtained from databases 
where off-label use may be systematically collected (e.g., reimbursement database 
in US), and in accordance with local procedure in compliance with local laws 
and regulations.

Overdose of a J&J product.

Exposure to a J&J product from breastfeeding.

Suspected abuse/misuse of a J&J product.

Inadvertent, accidental exposure, or occupational exposure to a J&J product.

For marketed products, any failure of expected pharmacological/therapeutic
action (i.e., lack of effect) of a J&J product. Lack of effect/Lack of efficacy 
defined as any failure that a product did not achieve expected pharmacological 
action/therapeutic benefit when used in accordance with the Reference Safety 
Information or equivalent. In the context of complaint intake, lack of effect shall 
be reported if there is specific evidence that the reporter did not think the product 
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achieved expected pharmacological action/therapeutic benefit evidenced by 
statements such as or similar to “the product did not work/perform as expected”.

Medication error involving a J&J product (with or without subject exposure to the 
J&J product, e.g., product name confusion).

Unexpected therapeutic or clinical benefit from use of a J&J product.
14.6.1.
Exposure In Utero
An exposure in utero (EIU) occurs if:
1. A woman is exposed to the IP at any time between her last menses prior to conception 
through the delivery of the baby. 
2. There is a possibility of intrauterine exposure to IP via semen from the male partner 
who is taking/using the IP at the time of conception, thereby possibly exposing the 
fetus to the product. 
If an EIU occurs, the Investigator or designee should inform the Sponsor immediately. This 
must be done irrespective of whether an AE has occurred. The site must complete a 
Pregnancy Notification and Update Form and send it securely to the Sponsor within 24 hours 
of the site’s awareness. The information submitted should include the anticipated date of 
delivery (see below for information related to induced termination of pregnancy). This 
reporting requirements include environmental exposure to the IP in a pregnant woman (e.g., a 
nurse reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage). If a male participant informs about a partner’s pregnancy, the site must obtain 
consent to follow that pregnancy.   
Follow-up should be conducted to obtain pregnancy outcome information on all EIU reports. 
The Investigator will follow the pregnancy until completion or until the pregnancy 
terminated (i.e., induced abortion) and then notify the Sponsor of the outcome. The 
Investigator will provide any updated information as a follow-up using the Pregnancy 
Notification and Update Form, and will report the outcome on the End of Pregnancy 
Collection Form. The reason(s) for an induced abortion should be specified. An EIU report is
not created when an ectopic pregnancy report is received since this pregnancy is not usually
viable. Rather, an SAE case is created with the event of ectopic pregnancy.  
The medically qualified Investigator or designee (MD/DO/DMD/DDS) should follow the 
procedures for reporting SAEs if the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e., spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly [including that in an aborted fetus, stillbirth, or neonatal death]). In the 
case of a live birth, the “normality” of the newborn can be assessed at the time of birth (i.e.,
no minimum follow-up period of a presumably normal infant is required before an End of 
Pregnancy Collection Form can be completed). The “normality” of an aborted fetus can be 
assessed by gross visual inspection, unless pre-abortion test findings are suggestive of a 
congenital anomaly.  
Additional pregnancy outcomes that are classified as SAEs and should be reported as such 
include:
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
“Spontaneous abortion” includes miscarriage and missed abortion. 

All neonatal deaths that occur within 1 month of birth, without regard to 
causality.

Any infant death after 1 month that the Investigator assesses as possibly related 
to EIU to the IP.
14.7.
Withdrawal Due to Adverse Events
When a subject withdraws due to AEs, whether serious or not the AEs must be reported in 
accordance with the reporting requirements defined below.
15.
STATISTICS
The Sponsor will be responsible for the statistical analysis of study data. Detailed 
methodology for the statistical analysis of the data will be documented in a Statistical 
Analysis Plan finalized and approved prior to database lock and release of randomization 
codes.
15.1.
Determination of Sample Size
The total sample size of 300 subjects (50 per treatment group) provides 90% probability that 
the model-based estimated SPID 0-12 for at least one of the combination doses included in 
the study design will be statistically significantly higher than the estimate for each
corresponding monotherapy, based on one-sided α=0.01 for each comparison and a 
regression model accounting for acetaminophen, naproxen, and acetaminophen-by-naproxen 
interaction effects. Power was estimated using simulations assuming an Emax dose response 
for the monotherapies, maximum effect sizes of 0.6 for acetaminophen and 1.4 for naproxen 
over the doses in this study, and an interaction index that provides for slightly less than an 
additive effect for each monotherapy component. Effect size is defined here as the difference 
between the active and placebo means divided by the standard deviation. Maximum effect 
sizes and assumptions regarding interaction were based on a previous proof-of-concept study 
and acetaminophen and naproxen monotherapy studies.
15.2.
Analysis Sets
15.2.1.
Efficacy Analysis Sets
The primary efficacy analyses will be based on the Intent-to-Treat analysis set, which will 
include all randomized subjects. As a secondary analysis, the primary endpoint will be 
analyzed based on the per-protocol analysis set, if the per-protocol analysis set differs from 
the Intent-to-Treat analusisset by at least 5% of the subjects. The final per-protocol analysis 
set will be determined before unblinding.
15.2.2.
Safety Analysis Population 
The Safety Analysis Set will include all subjects who are randomized and take IP.
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∶: 	 = 	
∶: 	 ≠ 	
where 	 is the population mean for the strength of the fixed combination and 	 is the 
population mean for placebo.
For time-to-event endpoints (time to first use of rescue analgesic
), each 
fixed combination will be compared with placebo by testing the following hypotheses:
)
(
)
(
:
2
1
0
t
S
t
S
H

(all t) 
)
(
)
(
:
2
1
t
S
t
S
H A

(at least some t)
where S1(t) is the survival function for the fixed combination and S2(t) is the survival 
function for placebo.
Each pairwise comparison with placebo will be performed at α=0.05, two-sided.
15.5.3.
Data Computations and Handling of Missing Values
15.5.3.1.
Endpoints Relating to Pain Intensity and Pain Relief
The PID at each time point will be derived by subtracting the pain intensity from the baseline 
pain intensity. A higher value is indicative of a greater improvement.
The SPID scores will be derived by first multiplying each PID score by the time from the 
previous time point, and adding these time-weighted PID scores together over the intervals 
from 
 0-12, 6-12 
hours. The TOTPAR for each specified interval will be similarly
derived.
Pain intensity and pain relief ratings provided at times differing from the intended times by 
more than ±5 minutes for the scores up to 90 minutes post-dose, and by more than 
±15 minutes for the remaining measurements will be estimated by linear interpolation. For 
subjects who use rescue medication, the last reported pain score before taking rescue 
medication or baseline pain score, whichever is worse, will be carried forward to the 
remaining time points; pain relief scores after rescue medication will be set to zero. For 
subjects who discontinue the study early, the same imputation approach will be used.
15.5.3.2.
Time to First Rescue
Time to first use of rescue medication will be measured as the elapsed time from when the IP
was given until the time, rescue medication was first given. Subjects who discontinue from 
the study before 24 hours, but do not use rescue medication, will be censored at the time of 
discontinuation. Subjects who do not use rescue medication during the 24-hour study period 
will have their time to first rescue set to 24 hours and be censored at 24 hours.
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
Discuss with the Investigator(s) and other personnel their responsibilities the site's 
responsibility with regard to protocol adherence as well as the study and 
monitoring responsibilities of J&J or its representatives. These responsibilities 
will be documented in a Clinical Study Agreement between J&J and the 
Investigator.
During the study, a Monitor from J&J or representative will have regular contacts with the 
investigational site, for the following:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the rights and well-being of subjects are taken care of

Confirm that the investigational team is adhering to the protocol, that data are 
being accurately recorded in the case report forms, and that IP accountability 
checks are being performed

Perform source data verification. This includes a comparison of the data in the 
case report forms with the subject’s source documents, e.g., written medical 
records, electronic medical records at the hospital or practice, subject 
diaries/journals and other records relevant to the study. This will require direct 
access to all original records for each subject (e.g., clinic charts).

Record and report all protocol deviations not previously sent to J&J. The 
Investigator should not deviate from the protocol except if specified by the 
Sponsor or within the protocol. 

Confirm AEs and SAEs have been properly documented on eCRFs and confirm 
any SAEs have been forwarded to J&J and those SAEs that met criteria for 
reporting to Regulatory Authority/Competent Authority and/or IRB/IEC, as 
applicable, have been forwarded to the required authorities. The Monitor will be 
available between visits if the Investigator(s) or other staff needs information or 
study-related direction.
16.1.
Direct access to source data/documents
The Sponsor should ensure that it is specified in the protocol or other written agreement that 
the Investigator(s)/institution(s) shall permit study-related monitoring, audits, IRB/IEC 
review, and regulatory inspection(s) by providing direct access to source data/documents.
17.
QUALITY CONTROL AND QUALITY ASSURANCE
The clinical study will be executed and reported following GCPs, all applicable regulatory 
requirements and applicable SOPs, including quality control of documents. Deviations will 
be analyzed and documented. To ensure compliance, the Sponsor may conduct one or several 
quality assurance audit(s). Please see Section 17.1 for more details regarding the audit 
process.
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17.1.
Audits and Inspections
Authorized representatives of J&J, a regulatory/competent authority, an IRB/IEC 
representative may visit the site to perform audits or inspections, including source data 
verification. The purpose of a J&J audit or inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH E6, and any applicable regulatory requirements. The 
Investigator should notify the Sponsor (e.g., Study Manager, Monitor) listed within the 
protocol or other contacts provided immediately if contacted by a regulatory agency about an
inspection.
18.
DATA HANDLING AND RECORDKEEPING
18.1.
Case Report Forms/Electronic Data Capture
All data will be collected on source documents first and then recorded in an Electronic Data 
Capture (EDC) system. The EDC system is the database where pertinent study data are 
collected such as demography, subject randomization, efficacy assessments, AEs, and subject 
disposition. EDC eCRFs should be completed for each included subject. The completed 
pages of the EDC system are the sole property of the Sponsor and should not be made 
available in any form to third parties, except for authorized representatives of the Sponsor or
appropriate regulatory authorities, without written permission from the Sponsor.
It is the Investigator's responsibility to ensure completion, review and approval of all 
information captured in the EDC. The subject’s data in the EDC system must be 
electronically signed by the Investigator. These signatures serve to attest that the information 
contained in the EDC system is true. At all times, the Investigator has final personal 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered in 
the EDC. Subject source documents are the Investigator's/physician's subject records
maintained at the study site. In cases where the source documents are the hospital or the 
physician's chart, the information collected in the EDC must match those charts. All final 
data recorded in EDC system will be copied into files and kept by the Sponsor. A copy of 
these files will also be kept at the clinical site. All data provided in the eCRF must be 
supported by source documents.
18.2.
Source Documents
The Investigator/institution should maintain adequate and accurate source documents and 
study records that include all pertinent observations on each of the site’s study subjects. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original entry, 
and should be explained if necessary (e.g., via an audit trail).
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18.3.
Inspection of Records
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the 
Investigator agrees to keep records including the identity of all participating subjects 
(sufficient information to link records, e.g., eCRFs and hospital records), all original signed 
informed consent forms, copies of all eCRFs, SAE forms, source documents, and detailed 
records of treatment disposition.
18.4.
Retention of Records
The PI must maintain all documentation relating to the study according to ICH/GCP
guidelines or as specified in the Clinical Study Agreement for a period of two years after the 
last marketing application approval or per local requirements if longer than two years, or if 
not approved two years following the discontinuance of the test article for investigation. If it 
becomes necessary for J&J or the Regulatory Authority to review any documentation relating 
to the study, the Investigator must permit access to such records.
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor 
should be prospectively notified. The study records must be transferred to an acceptable 
designee, e.g., another Investigator. The Investigator must obtain Sponsor's written 
permission before disposing of any records, even if retention requirements have been met.
19.
PUBLICATION POLICY
Publication of study results by the Investigator is discussed in the Clinical Study Agreement, 
as appropriate. Results from this study may be published in the form of oral or written 
presentations at scientific meetings or as one or more peer-reviewed journal articles. In these 
cases, no information on individual subjects will be revealed.
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Amendment #2, Version 3 (Final) 25 November 2020
Company Confidential
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21.
APPENDICES
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Protocol Number: CCSPAA002398
Amendment #2, Version 3 (Final) 25 November 2020
COMPANY CONFIDENTIAL
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APPENDIX 1.
PAIN RATING SCALES/ CATEGORICAL PAIN 
INTENSITY SCALE
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)
0-10 PAIN INTENSITY - NUMERICAL RATING SCALE (PI-NRS)
Circle the number that best represents your pain.
No pain   0  1  2  3  4  5  6  7  8  9  10   Very severe pain
0-10 PAIN RELIEF – NUMERICAL RATING SCALE (PR-NRS)
Circle the number that shows your amount of pain relief.
No relief   0  1  2  3  4  5  6  7  8  9  10   Complete relief
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APPENDIX 2.
 
 
 
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Amendment #2, Version 3 (Final) 25 November 2020
COMPANY CONFIDENTIAL
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APPENDIX 3B. 
  
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SAP_001.pdf: 
Protocol CCSPAA002398
Statistical Analysis Plan
Company Confidential
Page 1 of 23
Protocol CCSPAA002398
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE FIVE 
STRENGTHS OF A FIXED COMBINATION OF 
ACETAMINOPHEN/NAPROXEN SODIUM IN 
POSTOPERATIVE DENTAL PAIN
Statistical Analysis Plan
(SAP)
Version Date: 5/17/2021
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Protocol CCSPAA002398
Statistical Analysis Plan
Company Confidential
Page 8 of 23
2
INTERIM ANALYSES
No interim statistical analysis is planned for this trial. 
3
ANALYSIS SETS
3.1
Primary Analysis Set
The primary analysis set will be based on the Intent-to-Treat analysis set, which will 
include all randomized subjects
3.2
Per-Protocol Set 
As a secondary analysis, the primary endpoint will be analyzed based on the per-protocol 
analysis set, if the per-protocol analysis set differs from the Intent-to-Treat analysis set by 
at least 5% of the subjects. The final per protocol analysis set will be determined before 
unblinding. The per-protocol set will exclude subjects who vomited within 60 minutes after 
dosing, and those with major protocol deviations. The final per-protocol set will be 
determined before unblinding.
3.3
Safety Analysis Set
The Safety Analysis Set will include all subjects who are randomized and take 
investigational product. Safety analysis will be based on the actual received treatment. 
4
EFFICACY ASSESSMENTS AND ENDPOINTS 
4.1
Efficacy Assessments
Primary Efficacy Endpoint

Time weighted sum of pain intensity difference from 0-12 hours after dosing 
(SPID 0-12)
Secondary Efficacy Endpoint

Time weighted sum of pain relief from 0 to 12 hours (TOTPAR 0-12)

Time weighted sum of pain intensity difference from 6 to 12 hours (SPID 6-12)

Time to first use of rescue analgesic (duration of relief after dosing)

Proportion of subjects who require rescue analgesic 
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Statistical Analysis Plan
Company Confidential
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Medications taken after the 24-hour assessment through the follow-up call that were not 
taken for an AE will not be collected on the CRF or summarized. Previous medications 
and concomitant medications will be summarized by treatment in separate tables. 
Number and percentage of subjects receiving each coded medication will be presented by 
treatment. Additionally, concomitant medications taken by greater than or equal to 5% of 
subjects in at least one treatment group will be presented.
5.6
SAFETY ANALYSIS 
5.6.1
Adverse Events 
Treatment-emergent AEs are those with a start date and time at or after the time of study 
drug administration. All summaries described below are for treatment-emergent AEs 
except where noted. Non- treatment-emergent AEs will be provided in a listing.
The number and percentage of subjects experiencing AEs will be tabulated by treatment, 
system organ class and preferred term using the MedDRA coding dictionary. The number 
and percentage of subjects experiencing treatment-related AEs will also be presented by 
system organ class and preferred term. Treatment-related AEs will include events marked 
as being at least possibly related to study treatment. The number and percentage of subjects 
with AEs will be presented by severity. Subjects will be counted only once for each system 
organ class and preferred term by selecting the most severe event. The number of subjects 
with the most commonly reported adverse events (those reported by 5% or more in any one 
treatment group) will be summarized by treatment, system organ class and preferred term. 
The number of subjects with adverse events will also be summarized by demographic 
characteristics: age group (<18 years, ≥18 years), gender, and race. 
The number and percentage of subjects experiencing SAEs or who discontinued the study 
due to an AE will be presented by system organ class and preferred term. These displays 
will include all AEs, not just treatment-emergent AEs.
5.6.2
Vital Signs 
Vital signs (temperature, respiratory rate, heart rate, and blood pressure) collected at 
baseline will be summarized (number of subjects, mean, standard deviation, median, 
minimum and maximum) by treatment group.
6. CHANGES FROM PROTOCOL
For proportion of subjects requiring rescue analgesics, the protocol-specified analysis 
includes adjustment for baseline pain and gender, and the intention was to combine 
across strata using inverse variance weighting.  However, based on the high overall 
proportion of subjects requiring rescue analgesics based on the blinded data, and the 
relatively small number of subjects per stratum, there was concern with the risk that the 
variance for the treatment difference within a stratum could be zero, which would result 
in division by zero for the weighting for that stratum.  For this reason, stratification by 
gender and baseline pain was removed from the Kaplan-Meier analysis method.
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Statistical Analysis Plan
Company Confidential
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Cochran-Mantel-Haenszel tests were added as a sensitivity analysis, and as the primary 
methodology in the event of computational difficulties using the Kaplan-Meier method.  
The CMH tests will stratify by baseline pain (moderate or severe) and gender, and 
consider as having received rescue those subjects who discontinued prior to the end of 
the 24-hour observation period and did not have rescue medication usage recorded.
7. REFERENCES
None. 
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Statistical Analysis Plan
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APPENDIX 3: 
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