Conditions: Pain, Postoperative
Keywords: Postsurgical pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 387
Healthy volunteers: no

Brief summary:
To compare the duration of analgesic efficacy as determined by the time to rescue medication of a single oral dose of naproxen sodium 440 mg (2 x 220 mg tablets) relative to ibuprofen 400 mg (2 x 200 mg tablets) and placebo over 24 hours in subjects experiencing moderate to severe post-impaction surgery dental pain.

To compare the overall analgesic effect (SPID 0-24) of a single dose of naproxen sodium 440 mg (2 x 220 mg tablets) relative to ibuprofen 400 mg (2 x 200 mg tablets) and placebo.

To compare the overall relief from pain (TOTPAR 0-24) of a single dose of naproxen sodium 440 mg (2 x 220 mg tablets) relative to ibuprofen 400 mg (2 x 200 mg tablets) and placebo.

Detailed description:

Arms:
arm 1: Participants received one single dose of 440 mg naproxen sodium tablets (200 mg x 2 tablets, oral) after randomization arm 2: Participants received one single dose of 400 mg ibuprofen tablets (200 mg x 2 tablets, oral) after randomization arm 3: Participants received one single dose of matching placebo tablets (2 tablets, oral) after randomization

Interventions: intervention 1: Naproxen Sodium (Aleve, BAY117031) intervention 2: Ibuprofen (Advil) intervention 3: Placebo
Intervention descriptions: intervention 1: 220 mg x 2 tablets, oral, single dose intervention 2: 200 mg x 2 tablets, oral, single dose intervention 3: Matching placebo, 2 tablets, oral, single dose

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Study Protocol  
Official Title: 
A Randomized, Double-Blind, Placebo-Controlled Trial to Compare 
the Duration of Analgesic Efficacy and Safety of Naproxen Sodium 
Tablets and Ibuprofen Tablets in Postsurgical Dental Pain 
NCT Number: 
NCT03404206 
Document Date: 
15-Feb-2018 
 


Clinical Study Protocol 19762 
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Reference Number: BHC-RD-OI-107 
Supplement: Version 5 
1. Title page 
 
A Randomized, Double-Blind, Placebo-Controlled Trial to Compare the Duration of Analgesic 
Efficacy and Safety of  Naproxen Sodium Tablets and Ibuprofen Tablets in Postsurgical Dental 
Pain 
Test drugs: 
BAY 117031 / Naproxen Sodium 
Study purpose: 
Clinical efficacy 
Clinical study phase: 
Phase 4 
Date: 
15-Feb-2018 
Registration: 
Not Applicable 
Version no.: 
3.0 
IMPACT Number: 
19762 
 
 
Sponsor: 
Bayer HealthCare LLC, Consumer Health 
100 Bayer Boulevard 
Whippany, NJ 07981-0915, USA 
Sponsor’s medical expert: 
  
 
Bayer HealthCare LLC, Consumer Health 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical investigation 
or its use for any other purpose without the prior written consent of the sponsor is not 
permitted. 
 
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.   
Hence, the appearance of product names without these symbols does not imply that these names are not protected. 
 
 
 
PPD


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Reference Number: BHC-RD-OI-107 
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Signature of the sponsor’s medically responsible person 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
  
Role:   
 
 
 
 
Date: 
 
 
Signature: 
 
 
 
 
PPD
PPD
PPD


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Signature of principal investigator 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
 
Affiliation:  
Date: 
 
 
Signature:  
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file. 
In the protocol document, this page may remain unsigned. 
 
 
PPD


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Reference Number: BHC-RD-OI-107 
Supplement: Version 5 
2. 
Synopsis 
 
Title 
A Randomized, Double-Blind, Placebo-Controlled Trial to Compare the 
Duration of Analgesic Efficacy and Safety of  Naproxen Sodium Tablets and 
Ibuprofen Tablets in Postsurgical Dental Pain 
IMPACT 
19762 
Clinical study phase 
4 
Study objective(s) 
To compare the duration of analgesic efficacy as determined by the time to 
rescue medication of a single oral dose of naproxen sodium 440  mg (2 x 220 mg 
tablets)  relative to ibuprofen 400 mg (2 x 200 mg tablets) and placebo over 24 
hours in subjects experiencing moderate to severe post-impaction surgery dental 
pain. 
To compare the overall analgesic effect (SPID 0-24) of a single dose of naproxen 
sodium 440 mg (2 x 220 mg tablets) relative to ibuprofen 400 mg (2 x 200 mg 
tablets) and placebo. 
To compare the overall relief from pain (TOTPAR 0-24) of a single dose of 
naproxen sodium 440 mg (2 x 220 mg tablets) relative to ibuprofen 400 mg (2 x 
200 mg tablets) and placebo. 
Test drug(s) 
Name of active ingredient 
Naproxen sodium tablet 
Dose(s) 
220 mg naproxen sodium (x2) 
Route of administration 
Oral 
Duration of treatment 
Single dose with pain/relief assessments for up to 24 hours 
Reference drug(s) 
 
Name of active ingredient 
Ibuprofen tablet 
Dose(s) 
200 mg ibuprofen (x2) 
Route of administration 
Oral 
Duration of treatment 
Single dose with pain/relief assessments for up to 24 hours 
Reference drug(s) 
 
Name of active ingredient 
Placebo tablet 
Dose(s) 
Placebo  (x2) 
Route of administration 
Oral 
Duration of treatment 
Single dose with pain/relief assessments for up to 24 hours 
Background treatment 
not applicable 
Indication 
pain relief 
 
 


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Diagnosis and main criteria for 
inclusion /exclusion 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria 
• 
Healthy, ambulatory, male or female volunteers 16-40  years of age; 
• 
Body mass index 18.5 to 30.0 kg/m2 inclusive; 
• 
Scheduled to undergo surgical removal of at least 2 mandibular partial or full bony 
impacted third molars. Up to two maxillary third molars may be removed 
regardless of impaction level.  Supernumerary teeth present may also be removed 
at the discretion of the oral surgeon; 
• 
Mandibular molars must demonstrate modified Demirjian root classification stage, 
D, E, F, G or H; 
• 
Have not taken any form of medication or herbal supplements (i.e., St. Johns 
Wort) within 5 days of admission (except for oral contraceptives, prophylactic 
antibiotics, or other routine medications to treat benign conditions, such as 
antibiotics to treat acne) and agree not to take any medication (other than that 
provided to them) throughout the study;    
• 
Female subjects of childbearing potential must be using a medically acceptable 
form of birth control for at least 1 month prior to screening (3 months on oral 
contraceptives) [e.g., hormonal contraceptives (oral, patch, injectable or vaginal 
ring), implantable device (implantable rod or intrauterine device), or a double 
barrier], abstinence or in same sex relationship and have a negative pregnancy test 
at Screening and prior to study drug administration.  Female subjects of non-
childbearing potential must be amenorrheic for at least two years or have 
undergone surgical sterilization (i.e. tubal ligation/occlusion, hysterectomy and/or 
bilateral oophorectomy)  
• 
Have not consumed alcoholic beverages, or foods and beverages containing 
caffeine  (examples; coffee, tea, chocolate, and colas) after midnight prior to 
surgery and agree not to consume any of these foods or beverages throughout 
their stay at study site 
• 
Use of only short-acting local anesthetic (e.g., mepivacaine or lidocaine) 
preoperatively, with a vasoconstrictor and nitrous oxide at the discretion of the 
Investigator; 
• 
Have moderate to severe postoperative pain on the Categorical Pain Intensity 
Scale (a score of at least 2 on a 4 point scale) and a score of ≥ 5 on the 0-10 pain 
intensity NRS within 4.5 hours postsurgery, but no later than 14:30 hours +/- 15 
minutes. 
 
Exclusion Criteria 
• 
History of hypersensitivity to naproxen sodium, ibuprofen, NSAIDS, aspirin, 
similar pharmacological agents, local anesthetics, rescue medication or 
components of the investigational products; 
• 
Evidence or history of clinically significant (in the judgment of the investigator) 
hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, 
hepatic, psychiatric, neurologic diseases, or malignancies within the last 5 years; 
• 
Relevant concomitant disease such as asthma (exercise induced asthma is 
permitted); 
• 
Current or past history of gastrointestinal bleeding or other bleeding disorder(s); 
• 
Acute illness or active local infection prior to surgery that can interfere with the 
conduct of the study in the judgment of the investigator; 
• 
Use of any OTC or prescription medications with which the administration of 
naproxen, acetaminophen, ibuprofen or any other NSAIDs, Hydrocodone 
bitartrate and acetaminophen is contraindicated or use of any medications within 5 
days of surgery until discharge from the study site (except oral contraceptives, 
prophylactic antibiotics or medications to treat benign conditions such as 
antibiotics to treat acne); 
• 
Females who areplanning to become pregnant, pregnant or lactating; 
• 
Habituation to analgesic drugs including opioids (i.e., routine use of oral 
analgesics 5 or more times per week for greater than 3 weeks within the past 2 
years); 
• 
Alcoholism or drug abuse within 2 years prior to the Screening Visit or routine 
consumption of 3 or more alcohol containing beverages per day.  Alcohol 
containing beverages are defined as one beer (5%, one glass of wine (11%) and 
one shot hard liquor (40%);    
• 
Positive urine drug screen, alcohol breathalyser or urine cotinine test on day of 
surgery;                  
• 
Have received any form of treatmentin the form of medication for depression in 
the past 6 months or any form of psychotropic agent (selective serotonin uptake 
inhibitors [SSRI]) within the last 6 months. 


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Reference Number: BHC-RD-OI-107 
Supplement: Version 5 
Study design 
This is a single center, randomized, stratified by baseline pain, double-blind, 
parallel, placebo-controlled study in subjects experiencing moderate to severe 
postoperative dental pain. 
Methodology 
Subjects desiring elective third molar surgery will be solicited to participate.  
Subject who consent and meet all the inclusion and exclusion criteria will be 
scheduled for surgical removal of impacted teeth under local anesthesia +/- light 
sedation with nitrous oxide/oxygen.  When subjects report “moderate” to 
“severe” post-operative pain, they will be dosed with one of the three study 
treatments as determined by a predetermined randomization schedule. Pain 
assessments (Pain Intensity, Pain Relief, Pain Half Gone and Global Assessment) 
will be performed at scheduled intervals post-drug for 24 hours.  
For each postdose timepoint, pain intensity differences (PID) will be derived by 
subtracting the pain intensity at the postdose timepoint from the baseline 
intensity score (baseline score – post-baseline score).  A positive difference is 
indicative of improvement.  Time-weighted sum of pain intensity differences 
(SPIDs) will be calculated by multiplying the PID score at each postdose 
timepoint by the duration (in hours) since the preceding timepoint and then 
summing these values over the desired time interval.  Similarly, total pain relief 
scores (TOTPARs), will be calculated by multiplying the pain relief score at each 
postdose timepoint by the duration (in hours) since the preceding timepoint and 
then summing these values. 
Type of control 
Reference product (positive control) and placebo (negative control) 
Data Monitoring Committee 
No 
Number of subjects 
385 
Primary variable(s) 
Time to first use of rescue medication  
Time point/frame of 
measurement for primary 
variable(s) 
Pain intensity and pain relief will be rated by subjects at baseline (predose), 0.5, 
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, and 24 hours postdose, and 
immediately prior to the use of any rescue medication. 
Plan for statistical analysis 
Time to first use of rescue medication will be estimated and plotted using 
Kaplan-Meier method and analyzed using log-rank test stratified by center and 
baseline pain intensity. 
Additional parameters calculated for SPID 0-4, SPID 0-8, SPID 0-12, SPID 0-24, 
SPID 6-12, TOTPAR 0-4, TOTPAR 0-8, TOTPAR 0-12, TOTPAR 0-24 and 
TOTPAR 6-12 analyzed using an analysis of covariance model (ANCOVA) with 
treatment as fixed effect and baseline pain intensity score as the covariate.  A 
95% of confidence interval (CI) for the treatment difference (naproxen-placebo; 
naproxen-ibuprofen; ibuprofen-placebo) will be calculated based on the above 
mentioned model. 
 


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Reference Number: BHC-RD-OI-107 
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Table of contents 
1. 
Title page ............................................................................................................................. 1 
2. 
Synopsis .............................................................................................................................. 4 
3. 
Introduction ....................................................................................................................... 11 
4. 
Study objectives ................................................................................................................ 14 
5. 
Study design ...................................................................................................................... 15 
6. 
Study population ............................................................................................................... 17 
6.1 
Inclusion criteria .................................................................................................... 17 
6.2 
Exclusion criteria ................................................................................................... 18 
6.3 
Justification of selection criteria ............................................................................ 19 
6.4 
Withdrawal of subjects from study ....................................................................... 19 
6.4.1 
Withdrawal .............................................................................................. 19 
6.4.2 
Replacement ............................................................................................ 20 
6.5 
Subject identification ............................................................................................. 20 
7. 
Treatment(s) ...................................................................................................................... 21 
7.1 
Treatments to be administered .............................................................................. 21 
7.2 
Identity of study treatment .................................................................................... 22 
7.3 
Treatment assignment ............................................................................................ 23 
7.4 
Dosage and administration .................................................................................... 23 
7.5 
Blinding ................................................................................................................. 24 
7.5.1 
Blinding measures ................................................................................... 24 
7.5.2 
Unblinding ............................................................................................... 24 
7.5.3 
Emergency unblinding by the investigator ............................................. 24 
7.6 
Drug logistics and accountability .......................................................................... 24 
7.7 
Treatment compliance ........................................................................................... 25 
8. 
Non-study therapy ............................................................................................................. 26 
8.1 
Prior and concomitant therapy .............................................................................. 26 
8.2 
Post-study therapy ................................................................................................. 26 
9. 
Procedures and variables ................................................................................................... 27 
9.1 
Tabular schedule of evaluations ............................................................................ 27 
9.2 
Visit description .................................................................................................... 27 
9.2.1 
Screening Period ..................................................................................... 27 
9.2.2 
Presurgery ............................................................................................... 28 
9.2.2.1 
Impaction Score .................................................................... 28 
9.2.3 
During Surgery ........................................................................................ 28 
9.2.4 
Postsurgery .............................................................................................. 28 
9.2.5 
Rescue Medication .................................................................................. 29 
9.2.6 
End of Trial (EOT) .................................................................................. 30 
9.3 
Population characteristics ...................................................................................... 30 
9.3.1 
Demographic ........................................................................................... 30 
9.3.2 
Medical history ........................................................................................ 30 


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9.3.3 
Other baseline characteristics .................................................................. 31 
9.4 
Efficacy Analysis .................................................................................................. 31 
9.4.1 
Safety Analysis ........................................................................................ 31 
9.5 
Pharmacokinetics / pharmacodynamics ................................................................ 31 
9.5.1 
Pharmacodynamics ................................................................................. 31 
9.6 
Safety ..................................................................................................................... 32 
9.6.1 
Adverse events ........................................................................................ 32 
9.6.1.1 
Definitions ............................................................................ 32 
9.6.1.2 
Classifications for adverse event assessment ....................... 33 
9.6.1.2.1 
Seriousness ........................................................................... 33 
9.6.1.2.2 
Intensity ................................................................................ 34 
9.6.1.2.3 
Causal relationship ............................................................... 34 
9.6.1.2.4 
Action taken with study treatment ........................................ 35 
9.6.1.2.5 
Other specific treatment(s) of adverse events ....................... 35 
9.6.1.2.6 
Outcome ............................................................................... 36 
9.6.1.3 
Assessments and documentation of adverse events ............. 36 
9.6.1.4 
Reporting of serious adverse events and pregnancy ............. 36 
9.6.1.5 
Expected adverse events ....................................................... 37 
9.6.2 
Pregnancies ............................................................................................. 37 
9.6.3 
Safety Examinations ................................................................................ 38 
9.7 
Other procedures and variables ............................................................................. 38 
9.8 
Appropriateness of procedures / measurements .................................................... 39 
10. Statistical methods and determination of sample size ....................................................... 40 
10.1 
General considerations .......................................................................................... 40 
10.2 
Analysis sets .......................................................................................................... 40 
10.3 
Efficacy Analysis .................................................................................................. 41 
10.3.1 
Primary Efficacy Parameter .................................................................... 41 
10.3.2 
Secondary Efficacy Parameters ............................................................... 41 
10.3.3 
Other Efficacy Parameters ...................................................................... 41 
10.4 
Determination of sample size ................................................................................ 42 
10.5 
Planned interim analyses ....................................................................................... 42 
11. Data handling and quality assurance ................................................................................. 43 
11.1 
Data recording ....................................................................................................... 43 
11.2 
Monitoring ............................................................................................................. 44 
11.3 
Data processing ..................................................................................................... 44 
11.4 
Missing data .......................................................................................................... 44 
11.5 
Audit and inspection .............................................................................................. 44 
11.6 
Archiving ............................................................................................................... 45 
12. Premature termination of the study ................................................................................... 46 
13. Ethical and legal aspects ................................................................................................... 47 
13.1 
Investigator(s) and other study personnel ............................................................. 47 
13.2 
Funding and financial disclosure ........................................................................... 47 


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13.3 
Ethical and legal conduct of the study ................................................................... 47 
13.4 
Subject information and consent/assent ................................................................ 48 
13.5 
Publication policy and use of data ......................................................................... 49 
13.6 
Compensation for health damage of subjects / insurance ..................................... 49 
13.7 
Confidentiality ....................................................................................................... 50 
14. Reference list ..................................................................................................................... 51 
15. Protocol amendments ........................................................................................................ 52 
16. Appendices ........................................................................................................................ 53 
16.1 
Study Flow Chart ................................................................................................... 53 
16.2 
Subjective Assessments ......................................................................................... 54 
 
Table 1: Treatments administered ............................................................................................ 21 
Table 2: Study treatments ......................................................................................................... 22 
Table 3: Study schema ............................................................................................................. 53 
 
Figure 1 – Design Overview .................................................................................................... 16 


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Reference Number: BHC-RD-OI-107 
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List of abbreviations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CDER 
Center for Drug Evaluation and Research 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
COX 
Cyclooxygenase 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
(e)CRF 
(electronic) Case Report Form  
EOT 
End of Trial 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NPO 
nil per os 
NRS 
Numerical Rating Scale 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
OTC 
Over-the-Counter 
PID 
Pain Intensity Differences 
PP 
Per Protocol 
QA 
Quality Assurance 
RNR 
Randomization Number 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SNR 
Screening Number 
SSRI 
Selective Serotonin Uptake Inhibitors 
SOC 
System Organ Class 
SPID 
Summed Pain Intensity Difference 
SUSAR 
Serious Unexpected Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TOTPAR 
Total Pain Relief 


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Reference Number: BHC-RD-OI-107 
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3. Introduction 
Background 
In addition to the information provided below please also refer to the Package Insert for Aleve 
and Advil or any additional data supplied by the Sponsor. 
 
Naproxen sodium and ibuprofen are nonselective cyclooxygenase (COX) inhibitors. They are 
propionic acid derivatives and members of a drug class s known as nonsteroidal anti-
inflammatory drugs (NSAIDs).  Both naproxen and ibuprofen inhibit COX-1 and COX-2 
isoenzymes.  COX enzymes play a key role in the inflammatory response and the production 
of prostaglandins.  Specifically, COX-1 is expressed in the gastrointestinal epithelium, 
vascular endothelium and kidney, while COX-2 plays a role in induction of inflammation. 
COX-2 inhibition reduces prostaglandin synthesis, leading to pain relief.  
 
In the United States, naproxen has been marketed as a prescription medication since 1976 
under the brand name Naprosyn®.  Its sodium salt, naproxen sodium, was first sold under the 
trade name Anaprox® in 1980.  In 1994, the US FDA approved naproxen sodium tablets 
(using the brand name Aleve®), 220 mg for over-the-counter (OTC) use. Aleve is indicated 
for the temporary relief of minor aches and pains due to: minor pain of arthritis, muscular 
aches, backaches, menstrual cramps, headaches, toothaches, and the common cold.  It also 
temporarily reduces fever.  As an OTC medication, Aleve should not be taken for longer than 
10 days for pain or 3 days for fever unless otherwise directed by a physician.  Similarly, 
Advil® (a branded form of ibuprofen) has been available OTC since 1984.  It carries the same 
indications and duration of use labeling as Aleve. 
 
The labelled dosing interval for over-the-counter naproxen sodium is 8-12 hours due to its 
long elimination half-life (approximately 14 hours) and documented long duration of 
action.[1,2] In contrast, ibuprofen, another propionic acid nonsteroidal anti-inflammatory drug 
available over-the-counter, has a  labeled dosing interval of 4-6 hours and a short elimination 
half-life, 2-4 hours.[2]  These two agents have been compared in single dose dental pain 
studies.[3,4] The analgesic effectiveness of naproxen sodium was greater than ibuprofen at 
later time points in both of these 12 hour studies but the duration of the studies was relatively 
short and the evaluations were performed at home.  The ability to assess relative differences 
in the later hours may have been limited by the outpatient nature of those earlier studies which 
used at-home diaries.    
 
The duration of analgesia in acute pain studies is  generally assessed by the time to 
remedication.[5] At both low OTC doses and high OTC doses, naproxen sodium showed a 
numerically longer duration of action compared to ibuprofen although the difference did not 
achieve the level of statistical significance.[3,4]  However, the sample size in these two 
studies was not estimated based on this secondary outcome parameter. 
 
The post-impaction dental pain model chosen for this study has been widely used in the 
evaluation of OTC and prescription analgesics for a number of reasons. Dental surgical 
procedures can be easily standardized, and the population of subjects undergoing a given 
procedure is usually relatively healthy and homogeneous. In addition, there is extensive data 
substantiating the usefulness of the dental pain model in predicting the relative efficacy of a 
wide range of analgesic medications. The model has been found to be very useful for 
comparing several measures of analgesic efficacy, including onset, peak effect, and duration 


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of analgesic activity. [6,7,8] Therefore, the purpose of this investigation is to use the post-
impaction dental pain model to compare the duration of action of naproxen sodium to 
ibuprofen at over-the-counter doses. 


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Benefit-risk assessment 
 
Subjects who desire to have third molar extraction will be solicited to participate in this study.  
Subjects who consent to participate may benefit by receiving a medical exam, dental 
radiographs and no-cost surgical procedures for teeth extraction. Furthermore, post-surgical 
subjects will be provided continual nursing care for approximately 24 hours after surgery.  
Potential risks of the surgical procedure include pain, dry socket, infection, swelling, 
bleeding, trismus, and lip or tongue numbness.  Potential risks related to local anesthesia and 
mild sedation include paresthesia and drowsiness.  Subjects who experience a treatment 
failure can have the option of taking a standard rescue medication commonly used for post-
operative pain relief.  Potential study medication benefit will be relief of postsurgical pain 
which is highly prevalent following extractions of wisdom teeth.  Potential risks of a single 
dose of OTC study medication are low and described in the Drug Facts Label. 
 
During the study, subjects will be closely monitored for evidence of adverse events.  
Weighing between the potential risks associated with the study, and given the ability to 
mitigate risks through close monitoring and routine peri-operative care, this study is 
considered clinically and ethically acceptable. 
 
 


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4. 
Study objectives 
The primary objective of this trial is: 
• 
To compare the duration of analgesic efficacy as determined by the time to 
rescue medication of a single oral dose of naproxen sodium 440  mg (2 x 220 
mg tablets)  relative to ibuprofen 400 mg (2 x 200 mg tablets) and placebo (2 x 
tablets) over 24 hours in subjects experiencing moderate to severe post-
impaction surgery dental pain. 
 
The secondary objectives of this trial are:  
• 
To compare  the overall analgesic effect (SPID 0-24) of a single dose of 
naproxen sodium 440  mg (2 x 220 mg tablets)  relative to ibuprofen 400 mg (2 
x 200 mg tablets) and placebo; 
• 
To compare  the overall relief from starting pain (TOTPAR 0-24) of a single 
dose of naproxen sodium 440  mg (2 x 220 mg tablets)  relative to ibuprofen 
400 mg (2 x 200 mg tablets) and placebo. 
Other  objectives of this trial are: 
• 
To compare the efficacy of naproxen 440 mg, ibuprofen 400 mg and placebo 
for the following measures: 
o SPID 0-4, SPID 0-8, SPID 0-12, SPID 6-12; 
o TOTPAR 0-4, TOTPAR 0-8, TOTPAR 0-12 and TOTPAR 6-12; 
o Peak Pain Intensity; 
o Peak Pain Relief; 
o Sum of Observations with Pain Half Gone; 
o Duration of Pain Relief At Least Half Gone; 
o Total amount of time that subject reported at least a 2-point PID; 
o Global Pain Assessment. 
 


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5. 
Study design 
Design Overview 
This is a single center, randomized, double-blind, parallel, placebo-controlled study, stratified 
by baseline pain, in subjects experiencing moderate to severe postoperative dental pain. The 
study will consist of a Prescreening telephone call, a Screening Visit, a two day Treatment 
Period and a Post-Operative visit.  Eligible subjects who have undergone surgical extraction 
of at least 2 mandibular partial or full bony impacted third molars will be kept in-house and 
evaluated for efficacy and safety at the study site overnight. 
The study consists of a Screening Phase, Treatment Phase and a Follow-Up Phase. During 
Treatment Phase, subjects will be kept in-house at the study site for one overnight stay.  
Qualified subjects will then be randomized into one of two treatments. Approximately 485 
subjects will be screened prior to surgery.  Approximately 397 will have surgery and 
approximately 385 will be randomized to a specific treatment. 
Screening Phase 
Eligible subjects will be screened and selected up to 28 days prior to oral surgery and dosing 
with investigational product. 
Treatment Phase 
Following selection, qualified subjects will enter the Treatment Phase and be scheduled for 
their surgical teeth extraction.  After completion of the surgical teeth extractions, subjects will 
remain at the study site for observation. Subjects with appropriate pain severity for 
randomization will then be stratified by baseline pain intensity and randomized into one of 
three (3) treatment groups.  Subjects will rate their pain severity and pain relief over the next 
24 hours.  After completion of all trial procedures, subjects will be discharged from the study 
site. 
All subjects are required to remain at the study center and complete all assessments regardless 
of rescue. 
Follow-Up Phase 
Subjects will be evaluated at a post-operative visit/call approximately 6-10 days after surgery 
for follow up for any adverse events or medications not known at the time of treatment. 
 
The duration of each subject’s participation will be approximately 38 days. For an overview 
on the study design and study procedures see Figure 1. 
 
 


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Figure 1 – Design Overview  
 
 
Screening 
Phase 
Treatment Phase 
Follow up 
Phase 
Trial 
Days 
Day -28 to -1 
Day 1 
Presurgery 
Day 1 
Surgery 
Day 1 
Postsurgery 
Day 1 
Day 2 
Days 6-10 
 
 
Check-in to 
study site     
(if needed) 
Surgical 
teeth 
extraction 
Categorical 
pain 
NRS pain 
NRS pain  
Pain relief 
Pain half 
gone 
NRS pain       
Pain relief   
Pain half gone 
Global 
assessment 
Phone call 
or visit 
 
 
= randomized to either naproxen (440 mg), ibuprofen (400 mg), or placebo  
 
 
Justification of the design 
The study was designed specifically to capture and measure acute post-surgical dental pain in 
healthy subjects who could benefit from the administration of an OTC pain reliever.  This 
pain model has been widely studied for OTC pain medications; however, should a subject not 
get sufficient pain relief from the IMP, then rescue medication approved for treating acute 
pain (e.g., acetaminophen plus hydrocodone, tramadol, acetaminophen, etc.) may be 
requested. The endpoints and study design are consistent with most recent Guidance by FDA 
and methods advocated by experts.[9,10] 
 
 
  
 


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6. 
Study population 
The subject population will consist of healthy individuals who are status post extraction of 2 
mandibular partial or full bony impactions.  No more than 25% of the enrolled subjects may 
be less than 18 years of age. 
6.1 
Inclusion criteria 
 
Those who inquire about the trial will be allowed to participate in the study if they meet the 
following eligibility criteria: 
1. Healthy, ambulatory, male or female volunteers 16 to 40 years of age; 
2. Body mass index 18.5 to 30.0 kg/m2 inclusive; 
 
3. Scheduled to undergo surgical removal of at least 2 mandibular partial or full bony 
impacted third molars. Up to two maxillary third molars may be removed regardless of 
impaction level.  Supernumerary teeth present may also be removed at the discretion of 
the oral surgeon; 
4. Mandibular molars must demonstrate modified Demirjian root classification stage D, 
E, F,  G or H; [11] 
5. Have not taken any form of medication or herbal supplements (i.e., St. Johns Wort) 
within 5 days of admission (except for oral contraceptives, prophylactic antibiotics, 
multivitamin supplements, or other routine medications to treat benign conditions, such 
as antibiotics to treat acne) and agree not to take any medication (other than that 
provided to them) throughout the study;    
6. Female subjects of childbearing potential must be using a medically acceptable form of 
birth control for at least 1 month prior to screening (3 months on oral contraceptives) 
[e.g., hormonal contraceptives (oral, patch, injectable or vaginal ring), implantable 
device (implantable rod or intrauterine device), or a double barrier], abstinence or in 
same sex relationship and have a negative pregnancy test at Screening and prior to 
study drug administration.  Female subjects of non-childbearing potential must be 
amenorrheic for at least two years or have undergone surgical sterilization (i.e. tubal 
ligation/occlusion, hysterectomy and/or bilateral oophorectomy); 
7. Have not consumed alcoholic beverages, or foods and beverages containing caffeine 
(examples; coffee, tea, chocolate, and colas) after midnight prior to surgery and agree 
not to consume any of these foods or beverages throughout their stay at the study site;    
8. Use of only short-acting local anesthetic (e.g., mepivacaine or lidocaine) 
preoperatively, with or without a vasoconstrictor and nitrous oxide at the discretion of 
the Investigator; 
9. Have moderate to severe postoperative pain on the Categorical Pain Intensity Scale (a 
score of at least 2 on a 4 point scale) and a score of ≥ 5 on the 0-10 pain intensity NRS 
within 4.5 hours postsurgery, but no later than 14:30 hours +/- 15 minutes. 


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10. Ability to understand and follow study-related instructions; 
11. Be willing and able to participate in all scheduled visits, treatment plan, and  trial 
procedures according to the clinical protocol; 
12.  Subject must have signed the IRB-approved Informed Consent. 
6.2 
Exclusion criteria 
Subjects presenting with any of the following will not be included in the trial: 
1. History of hypersensitivity to naproxen sodium, ibuprofen, NSAIDS, aspirin, similar 
pharmacological agents, local anesthetics, rescue medication or components of the 
investigational products; 
2. Evidence or history of clinically significant (in the judgment of the investigator) 
hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 
psychiatric, neurologic diseases, or malignancies within the last 5 years; 
3. Relevant concomitant disease such as asthma (exercise induced asthma is permitted); 
 
4. Current or past history of gastrointestinal bleeding or other bleeding disorder(s); 
5. Acute illness or active local infection prior to surgery that can interfere with the 
conduct of the study in the judgment of the investigator; 
6. Use of any OTC or prescription medications with which the administration of 
naproxen, acetaminophen, ibuprofen or any other NSAIDs, Hydrocodone bitartrate and 
acetaminophen), is contraindicated or use of any medications within 5 days of surgery 
until discharge from the study site (except oral contraceptives, prophylactic antibiotics, 
multivitamin supplements, or medications to treat benign conditions such as antibiotics 
to treat acne); 
7. Females who are planning to become pregnant, pregnant or lactating; 
8. Habituation to analgesic drugs including opioids (i.e., routine use of oral analgesics 5 or 
more times per week for greater than 3 weeks within the past 2 years); 
9. Alcoholism or drug abuse within 2 years prior to the Screening Visit or routine 
consumption of 3 or more alcohol containing beverages per day; Alcohol containing  
beverages are defined as one beer (5%), one glass of wine (11%) and one shot (40%) 
hard liquor.    
10. Positive urine drug screen, alcohol breathylyzer or urine cotinine test on day of 
surgery.    
11. Use of Nicotine containing products within 3 days prior to presurgery to the 
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12. Have received any form of  treatment in the form of medication for depression in the 
past 6 months or any form of psychotropic agent (including selective serotonin uptake 
inhibitors [SSRI]) within the last 6 months.  
13. Member or first-degree relative of study staff or the Sponsor directly involved in the 
study; 
14. Unwilling or unable to comply with all requirements outlined in the protocol; 
15. Subjects with a medical disorder, condition, or history of such that could impair the 
subject’s ability to participate or complete this trial in the opinion of the investigator; 
16. Previous enrollment in this study. 
6.3 
 Justification of selection criteria 
The selection criteria are chosen to ensure that subjects with specific risks for administration 
of either study medication and/or subjects with conditions which may have an impact on the 
outcomes of the study are excluded. 
6.4 
Withdrawal of subjects from study 
6.4.1 
Withdrawal 
Withdrawal criteria 
Subjects must be withdrawn from the study if any of the following occurs: 
• At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further.  The subject will not suffer any disadvantage as a result. 
• Subject’s pain intensity post-surgery at pre-dose does not exceed ‘mild’ and the NRS 
is <5 (see Section 16.2); 
• If, in the Investigator's opinion, continuation of the study would be harmful to the 
subject's well-being; 
•  
Subjects may be withdrawn from the study if any of the following occurs: 
• Subject experiences one or more serious adverse events; 
• At the specific request of the Sponsor and in consultation with the Investigator (e.g., 
obvious non-compliance, safety concerns); 
• Protocol violation: if the subject develops conditions which would have prevented 
his/her entry into the study according to the inclusion/exclusion criteria, he/she must 
be withdrawn immediately if safety is concerned; in other cases, the investigator will 
decide whether there is a conflict with the study objectives. 


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Depending on the time point of withdrawal, a withdrawn subject is referred to as either a 
“screening failure”, “run-in failure” or “dropout” as specified below: 
Screening failure 
A subject who, for any reason (e.g., failure to satisfy the selection criteria), terminates the 
study prior to the start of surgery is regarded as a “Screening failure”. 
Re-starting the defined set of screening procedures to enable the “screening failure” subject’s 
participation at a later time point is not allowed – with the following exceptions: 
• The subject had successfully passed the screening procedures, but could not start 
subsequent surgery/treatment on schedule. 
• Initial screening occurred too early to complete the required washout period after prior 
therapy. 
• The inclusion / exclusion criteria preventing the subject’s initial attempt to participate 
have been changed (via protocol amendment). 
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk. Subjects who  re-screen will  re-sign the 
informed consent form, even if it was not changed after the subject’s previous screening and 
will be assigned a new screening number. 
Run-in failure 
A subject who, for any reason terminates the study after surgery and prior to the start of study 
drug administration (e.g., not meeting pain threshold) is regarded as a “Run-in failure”. 
Dropout 
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has been randomized and administered at least one dose of study 
drug. 
General procedures 
In all cases, the reason for withdrawal must be recorded in the case report form/electronic 
case report form (CRF/eCRF) data collection system and in the subject's medical records.  
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4. 
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (Premature termination of the Study). 
6.4.2 
Replacement 
Subjects will not be replaced. 
6.5 
Subject identification 
Each subject is identified by the study site’s unique subject identification code. After 
informed consent procedure every subject is given a screening number (SNR). At the time 


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point of randomization, subjects who meet the entry criteria will be sequentially assigned to a 
four-digit number in sequential order (randomization number, RNR).  See Section 7.3. 
 
7. Treatment(s) 
The study center will dispense a single-dose of an assigned treatment within 4.5 hours 
postsurgery.  The tablets and placebo will be administered in a 3:3:1 randomization ratio 
(naproxen sodium; ibuprofen; placebo) based on a computer-generated randomization 
schedule and the severity of pain experienced (moderate or severe).  Subjects who 
characterize their pain severity as mild and have a NRS <5 will not receive treatment and will 
be discharged from the study site, if deemed safe by an Investigator.   
7.1 
Treatments to be administered 
The treatments to be administered during the study are displayed in Section 7.2. 
 
Table 1: Treatments administered 
Treatment (condition) 
Dose / route 
Amount / form 
Frequency of 
administration 
Naproxen sodium 440  mg (postsurgery) 
220 mg / orally 
2 / tablets 
single dose 
Ibuprofen 400 mg (postsurgery) 
200 mg / orally 
2 / tablets 
single dose 
Placebo (postsurgery) 
NA / orally 
2 / tablets 
single dose 
 
 
 


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7.2 
Identity of study treatment 
Table 2: Study treatments 
Treatment 
Naproxen 
Ibuprofen 
Placebo 
Dose 
two  tablets 
two  tablets 
two  tablets 
Pharmaceutical Form 
tablet 
tablet 
tablet 
Strength 
220 mg 
200 mg 
not applicable 
Formulation 
naproxen sodium 
FD&C blue #2 lake 
hypromellose 
magnesium stearate 
microcrystalline cellulose 
polyethylene glycol 
povidone 
talc 
titanium dioxide 
ibuprofen 
acetylated monoglycerides 
colloidal silicon dioxide 
corn starch 
croscarmellose sodium 
methylparaben 
microcrystalline cellulose 
pharmaceutical glaze 
pharmaceutical ink 
povidone 
pregelatinized starch 
 propylparaben 
sodium benzoate 
sodium lauryl sulfate 
stearic acid 
sucrose 
synthetic iron oxide 
titanium dioxide 
white wax 
dibasic calcium phosphate 
dihydrate 
magnesium stearate 
microcrystalline cellulose 
Route of 
administration 
orally with a full glass of 
water (i.e. about 8 ounces 
or 240 mL) 
orally with a full glass of 
water (i.e. about 8 ounces 
or 240 mL) 
orally with a full glass of 
water (i.e. about 8 ounces 
or 240 mL) 
Batch Number 
see study file 
see study file 
see study file 
Trade Name  and 
Manufacturer 
Aleve® 
Bayer                    
Bitterfeld, Germany 
Advil® 
Pfizer                    
Madison, NJ USA 
 
Bayer                    
Morristown, NJ USA 
All study drugs will be labeled according to the requirements of local law and legislation.  
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request. 
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk batch of the ingredients.  Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies Quality Assurance (QA) group.  
A complete record of batch numbers and expiry dates of all investigational products as well as 
the labels will be maintained in the clinical supply file. 
The source of test and reference products will be documented in the clinical supply file. 


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7.3 
Treatment assignment 
At the beginning of the first treatment period, after completion of the pre-treatment baseline 
procedures/assessments, subjects who meet the entry criteria will be sequentially assigned to a 
unique number in sequential order (randomization number, RNR) according to the 
randomization schedule 3:3:1 (naproxen sodium: ibuprofen: placebo) prepared prior to the 
study.  
Subjects will be numbered according to the following scheme: 
14001XXXX 
Whereas the “Xs” will be replaced with a four digit sequentially assigned number as each 
subject enters the study (e.g., first subject number will be 140011001). 
The unique subject identifier number will be assigned in numerical order stratified by baseline 
2 or 3 categorical pain level (moderate or severe) prior to dosing (see Section 16.2).  Subjects 
who designate their baseline pain as moderate will use the lowest randomization number 
available with subsequent moderate randomizations using the next available lowest number.  
Subjects who designate their baseline pain as severe will use the highest randomization 
number available with subsequent severe randomizations using the next available highest 
randomization number.  Subjects who characterize their pain severity as mild and <5 on the 
NRS will not receive treatment and be withdrawn from the study. 
Once a number has been assigned to a subject, it cannot be reassigned to another subject.   
Subjects completing the Screening Visit, if not scheduled for surgery the same day,  will 
return to the trial site within 28 days, and if they continue to meet inclusion/exclusion criteria 
postsurgery will be randomized to one of three treatment groups: 
• Naproxen sodium tablets (220 mg x 2 tablets) 
• Ibuprofen tablets (200 mg x 2 tablets) 
• Placebo tablets (2 tablets) 
Subjects will be assigned to treatment groups in accordance with the randomization schedule.  
The Sponsor or designee will provide a randomization schedule to the study site.    
7.4 
Dosage and administration 
Each subject will receive a single dose randomized to naproxen (220 mg x 2 tablets), 
ibuprofen (200 mg x 2 tablets) or placebo (2 tablets).  Subjects receive the study drug with a 
full glass of non-refrigerated, non-carbonated water (about 8 ounces or 240 mL). Study drug 
will be administered using dosing cups. Selection and preparation of the proper dose will be 
performed by an unblinded study team member using the provided randomization schedule 
(see Section 7.5.1).  The Investigator or a designee will supervise the study drug 
administration in a manner which maintains the masking conditions (blinding of the subject).   
Subjects must be NPO from midnight prior to surgery until completion of surgery.  Subject 
will continue fasting, with the exception of clear liquids, until after study drug administration. 


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7.5 
Blinding 
7.5.1 
Blinding measures 
Subjects enrolled in the trial, investigators and their staff involved in protocol procedures or 
who are involved in data collection, data entry and data analysis will be blinded to the identity 
of the treatments until the database is locked. The study monitor will conduct product 
accountability after database lock. To preserve blinding, subjects will be blindfolded.  Study 
drug will be dispensed by an unblinded study team member based on the randomization 
schedule.  That team member may have no other role in the study conduct and may not reveal 
the study drug’s identity to any members of the blinded study team. 
Sponsor will supply study medication in bulk containers.  Selection of the proper dose for an 
individual subject will be performed by an unblinded study team member using the provided 
randomization schedule.  The unblinded study team member will withdraw the appropriate 
study medication from the bulk container and transfer it to a dispensing cup.  The unblinded 
study team member will then bring the study medication to the treatment room where it will 
be dispensed to the subject by  the  unblinded study team member.  The unblinded study team 
member should have no other responsibilities in the study. 
 
7.5.2 
Unblinding  
In the case of a medical emergency, such as serious adverse events (SAE), breaking the blind 
may become necessary during the trial.  Randomization code-break envelopes must be 
securely maintained at the trial site and with the Sponsor. 
In compliance with applicable regulations, in the event of a serious unexpected adverse event 
(SUSAR) related to the blinded treatment, the subject’s treatment code will usually be 
unblinded before reporting to the health authorities, ethic committees and investigators (see 
Section 9.6.1.4). 
7.5.3 
Emergency unblinding by the investigator 
The investigator will be provided code-break envelopes that can be used to break the blinding 
of the study drug.  Any subject who was unblinded using the code-break envelopes must 
document this occurrence in the subject’s medical record.  The investigator must report the 
blind break in conjunction with a SAE within 24 hours of becoming aware of the effect as 
defined in Section 9.6.1.  Subjects that have been unblinded will not be included in the ITT or 
PP efficacy analysis. 
The Sponsor will collect all code-break envelopes at the end of the study. 
7.6 
Drug logistics and accountability 
The Sponsor will provide sufficient quantity of the investigational medicinal product (IMP) to 
the study site.  The study center will dispense IMP according to the randomization schedule 
and the subject’s categorical pain intensity (moderate or severe) postsurgery.  IMP will be 
supplied to the study center in multi-dose bottles and dispensed by an unblinded member of 
the study team. 


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All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate/CRO), and will be inaccessible to unauthorized personnel. Special storage 
conditions and a complete record of batch numbers and expiry dates can be found in the 
Sponsor’s study file; the site-relevant elements of this information will be available in the 
investigator site file. On the day of receipt, the responsible site personnel will confirm receipt 
of study investigational products in writing. The personnel will use the study investigational 
products only within the framework of this clinical study and in accordance with this 
protocol. Receipt, distribution, return and destruction (if any) of the study drug must be 
properly documented according to the sponsor’s agreed and specified procedures. 
7.7 
Treatment compliance 
The administration of the study medication will be supervised by an unblinded member of the 
Investigator’s team. This person will perform the oral cavity inspection after study drug 
administration and document that the subject receives the treatment as planned. 
 
 


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8. 
Non-study therapy 
8.1 
Prior and concomitant therapy 
 
The following treatments are prohibited from screening and during the study:  
• 
Use of any form of medication or herbal supplements within 5 days of surgery 
that would confound the evaluation of the study product, until discharge from the 
study site; 
• 
Use of acetaminophen, naproxen, ibuprofen, aspirin, or other NSAIDs or any 
other pain reliever (OTC or prescription) within 5 days before surgery; 
• 
Use of alcoholic beverages, any food or beverages containing caffeine after 
midnight prior to surgery and throughout the evaluation period; 
• 
No smoking within 3 days prior to presurgery to the completion of the study. 
All medications (prescription and nonprescription products, vitamin and herbal products) 
taken by the subject from 30 days prior to Screening to End of Trial (EOT) will be 
documented.  The reported medications will be reviewed and evaluated by the Principal 
Investigator or designee to determine if they affect the subject’s eligibility to participate in the 
study. 
8.2 
Post-study therapy 
This study is a single dose administration after surgery and there is no additional treatment 
allocated.  Subjects who randomize into the study will be discharged from the study center 
after the final (24 hour post dosing) assessments, regardless of whether rescue medication had 
been taken or not. 
 
 
 


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9. 
Procedures and variables 
9.1 Tabular schedule of evaluations 
See flow chart in Section 16.1 
Regarding protocol deviations, the processes and responsibilities defined by the Sponsor will 
be followed. Respective details (e.g., identification and classification of protocol deviations) 
are described separately. 
9.2 
Visit description 
If not stated otherwise, the measures / actions listed in the following Sections 9.2.1 to 9.2.6 
will be performed by a designated study team member as designated by the Principal 
Investigator. 
9.2.1 
Screening Period 
Note: No screening procedures may be performed unless subjects have been provided an 
IRB-approved written informed consent which subjects have read, understood, and 
signed.  
 
The Screening Period will be up to 28 days long.  The following will be determined during 
the Screening Visit: 
• Signed Informed Consent Form (ICF); 
• Review inclusion and exclusion criteria; 
• Subject demographics; 
• Medical/surgical history including history of drug, alcohol and tobacco use; 
• Medication history of all prescription, OTC products including vitamins or 
dietary/herbal supplements, taken during the past 30 days; 
• Vital signs consisting of sitting blood pressure, respiratory rate and pulse after 
sitting for at least 5 minutes; 
• Physical and oral examination; 
• Dental x-ray examination and interpretation; 
• Urine tests for illicit drugs and cotinine; 
• Breath alcohol test; 
• Urine pregnancy test (if applicable); 
• Impaction score. 
Upon satisfying the inclusion/exclusion criteria, eligible subjects will be instructed to 
return to the trial site within 28 days for oral surgery.  Subjects will be instructed to 
refrain from the use of all medications (prescription, nonprescription, herbal 
supplements) unless in the opinion of the Investigator or Sponsor, the medication will 
not interfere with study procedures, data integrity, or compromise the safety of the 
subjects. 


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Subjects will be instructed not to consume alcohol, any food or beverages containing 
caffeine (e.g., coffee, tea, chocolate, and colas) products after midnight prior to 
surgery.  Surgery will be scheduled between 0630 h and 1000 h (+/- 30 minutes). 
The Principal Investigator or his/her designee must review subject’s study records before 
qualifying the subject for the trial. 
9.2.2 
Presurgery 
Subjects are instructed to be nil per os (NPO) from midnight prior to surgery.  If a subject had 
something to eat or drink after midnight, the surgeon must determine if surgery may proceed.  
Subjects will arrive at the unit at their assigned time and will have the following activities 
completed prior to dental surgery: 
• Review changes in the subject’s medical/medication history and 
inclusion/exclusion criteria since previous visit; 
• Urine tests for illicit drugs and cotinine; 
• Breath alcohol test; 
• Vital signs (sitting blood pressure, pulse rate and respiration after sitting for 
5 minutes); 
• Urine pregnancy test (if applicable); 
• Review pain assessment process and procedures; 
9.2.2.1 
Impaction Score 
An Impaction Score will be used to assess each tooth based on the radiographic appearance and 
the intraoral examination.  Each tooth will be rated from 1 to 4 using the following 
criteria: (1) erupted in tissue (2) soft tissue impaction (3) partial bony impaction, and (4) full bony 
impaction.  Only subjects whose mandibular impactions are scored (3) or (4) will be eligible to 
participate in the study. 
9.2.3 
During Surgery 
During surgery, subjects will be administered a short acting local anesthetic (lidocaine or 
mepivacaine with or without vasoconstrictor) and nitrous oxide; at the discretion of the 
dentist/oral surgeon.  Topical anesthetics may also be used prior to the administration of the 
short acting local anesthetic.  Long duration local anesthetics like bupivacaine are not 
permitted.  No other perioperative analgesic or anesthetic agents are permitted. Perioperative 
corticosteroids are not permitted.  
9.2.4 
Postsurgery 
During the postsurgery recovery period, subjects will rest quietly, but will be encouraged not 
to fall asleep.  Subjects will be permitted to drink clear liquids following surgery until they 
have been dosed.  Subject may incorporate foods according to a soft diet following dosing 
beginning 60 minutes after dosing.  Subjects will not be allowed to eat 30 min prior to any 
planned assessments. 
In order to qualify for randomization and continue in the trial, subjects must have ‘moderate’ 
or ‘severe’ postoperative pain intensity on the Categorical Pain Rating Scale and a score of ≥ 5 
on the NRS within 4.5 hours of the last suture, but no later than 14:30 +/- 15 minutes. 


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Eligible subjects will be assigned a subject randomization number and investigational 
products will be administered according to a generated randomization schedule (see Section 
7.3). 
Subjects who have not met the randomization criteria within 4.5 hours from last suture by 
14:30 h +/- 15 minutes will not be randomized and may be discharged from the clinic, once 
deemed eligible by an Investigator. Prior to being released from the clinic, discharge 
procedures will be reviewed with the subject. When discharged, all subjects will need to make 
prior arrangements for travel and should not drive themselves home. 
After the baseline (pre-dose) pain intensity is determined, pain intensity, pain relief and pain 
half  gone will be rated by subjects at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 
and 24 hours (+/- 5 minutes over the first 6 hours; ±10 minutes from hours 7 through 24) 
postdose, and immediately prior to the use of the first dose rescue medication.  If necessary, 
subjects will be awakened 10 minutes prior to  scheduled pain assessments.  The order of the 
pain assessments is Pain Intensity, then Pain Relief, then Pain Half Gone then query about 
any AEs.  At hour 24 or immediately prior to the first dose of rescue medication (if required),  
study subjects will be asked to provide a Global Assessment of investigational product as a 
pain reliever after completion of the other assessments.  Additionally, subjects will have vital 
signs taken after surgery then 1 and 24 hours postdose. 
Throughout the treatment period, the subjects will be monitored for the occurrence of adverse 
events.  Symptoms will be assessed by spontaneous reporting of AEs and by asking the 
subjects to respond to a non-leading question such as “How do you feel?” or “Are you 
experiencing any other effects?”  All reported or observed AEs will be collected and recorded 
on the case report form.  The information will be based on signs and symptoms reported by 
the subject or observed by the study personnel staff during clinical evaluation. 
If a subject has any clinically significant, trial-related abnormalities at the conclusion of the 
treatment period, the clinical monitor (or designated representative) should be notified and the 
subject should be asked to remain at the trial site until such abnormalities are stabilized or 
resolve.  If the subject is unable or unwilling to remain at the trial site, the clinical monitor (or 
designated representative) should be notified, and the Investigator should make every effort to 
arrange follow-up evaluations at appropriate intervals to document the course of the 
abnormalities. 
Subjects will be allowed the use of ice following the use of rescue medication.  Ice will not be 
permitted for subjects prior to randomization until after they have been administered rescure 
medication (if applicable).  If subject has been administered rescue, ice will be given as 
requested by the subject for 20 min incriments.  Ice will be removed 30 min prior to the 
completion of any pain assessments.  Upon completion of all trial procedures, subjects will be 
discharged from the trial site.  Subjects will need to make prior arrangements for travel and 
should not drive themselves home. 
9.2.5 
Rescue Medication 
If adequate pain relief was not achieved, then subjects are permitted to take rescue 
medication, although they will be encouraged to wait 90 minutes to allow the investigational 
product time to take effect.  Rescue medication will be Hydrocodone 5 mg/Acetaminophen 
325 mg tablets or other appropriate analgesics may be used at the discretion of the 
Investigator.  Subjects will be required to complete pain assessments by rating pain intensity, 


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pain relief and pain half gone at each time point and global assessment immediately before the 
initial dose of rescue medication. 
Rescue medication is also available on return of pain and the time of rescue medication will 
be recorded.  Pain assessments will be performed immediately before the first dose of rescue 
medication. 
• Rating of Pain Intensity (NRS); 
• Rating of Pain Relief (Categorical); 
• Pain Half Gone 
• Global Assessment of investigational product as a pain reliever. 
Subjects will be queried in a nonspecific fashion for any adverse events.  All observed and  
reported AEs will be collected and recorded on the case report form.  The information 
recorded will be based on signs and symptoms reported by the subject or observed by the 
research coordinator during clinical evaluation. 
9.2.6 
End of Trial (EOT) 
After completion of the treatment period the following additional evaluations will be 
performed: 
• Trial sites will have the option of either contacting subjects within 5 to 9 days after 
surgery (by phone) or scheduling subjects for an office appointment, depending on 
their standard of care policies, to assess the occurrence or persistence of AEs, any 
medications taken, and for adequate treatment and follow up.   
9.3 
Population characteristics 
9.3.1 Demographic 
For basic subject assessment prior to screening, some demographic information may be 
collected before obtaining written informed consent: 
• Year of birth (approximate age); 
• Native language; 
• Reported need for third molar surgery. 
Collection of demographic information is subject to all applicable local regulations. 
9.3.2 
Medical history 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator: 
• Started before signing of the informed consent; 
• Considered relevant for the subject’s study eligibility. 
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1. 


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9.3.3 
Other baseline characteristics 
Information on caffeine, smoking, drug and alcohol consumption will be collected.  Surgical 
data (tooth number and diagnosis of each extraction, duration of surgery in minutes (first 
incision to last suture), identity and amount of all surgical medications, will be collected. 
9.4 
Efficacy Analysis 
For each postdose timepoint, Pain Intensity Differences (PID) will be derived by subtracting 
the pain intensity at the postdose timepoint from the baseline intensity score (baseline score – 
post-baseline score).  A positive difference is indicative of improvement.  Time-weighted sum 
of pain intensity differences (SPIDs) will be calculated for 4, 8, 12, 6-12, and 24 hours by 
multiplying the PID score at each postdose timepoint by the duration (in hours) since the 
preceding timepoint and then summing these values over 4, 8, 12, 6-12, and 24 hours, 
respectively.  Similarly, total pain relief scores (TOTPARs), will be calculated by multiplying 
the pain relief score at each postdose timepoint by the duration (in hours) since the preceding 
timepoint and then summing these values. 
In all analyses, for subjects who take rescue medication, all pain intensity scores after intake 
of rescue medication will be replaced by the worse of the baseline or the score assessed 
immediately before taking rescue medication. All pain relief after intake of rescue medication 
will be replaced by “no relief” (0). 
A complete list of primary, secondary and other efficacy parameters can be found in Section 
10.3. 
9.4.1 
Safety Analysis 
Safety measures will be analyzed for all subjects in the safety population.   
Adverse events will be collected throughout the treatment and safety follow-up periods and 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  
Only treatment-emergent AEs will be included, i.e., AEs that begin or worsen after the first 
dose of the investigational products in the treatment period.  The number and percent of 
subjects who experience any event, by System Organ Class (SOC), and by Preferred Term 
will be displayed by treatment group.  Tables will also be produced by severity and 
relationship to investigational product. Seriousness, severity, relationship to investigational 
product, duration, and outcome will also be listed. 
9.5 
Pharmacokinetics / pharmacodynamics 
Not applicable 
 
9.5.1 
Pharmacodynamics 
Not applicable 


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


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


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


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


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9.6.1.2.6 Outcome 
The outcome of the AE is to be documented as follows:  
- Recovered/resolved 
- Recovering/resolving 
- Recovered/resolved with sequelae 
- Not recovered/not resolved 
- Fatal 
- Unknown 
9.6.1.3 
Assessments and documentation of adverse events 
AEs observed, mentioned upon open questioning by a member of the investigator’s team or 
spontaneously reported by the subject will be documented. The observation phase for AEs 
will start with signing the informed consent form and will end in general with the last visit of 
follow-up. After the end of follow-up there is no requirement to actively collect AEs. 
In case of ongoing AEs after the last follow-up visit – especially when related to treatment 
with the study medication – the respective AE will be followed until resolution, if possible. 
The type of information that should be assessed and recorded by the investigator for each AE 
is listed in Section 9.6.1.2. 
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness 
and causal relationship to treatment with the study medication. 
The investigator has to record on the respective CRF/eCRF data collection system all adverse 
events occurring in the period between the signing of the informed consent and the end of the 
Follow-up Visit, there is no requirement to actively collect AEs including deaths.  The type of 
information that should be assessed and recorded by the investigator for each AE is listed in 
Section 9.6.1.2.   
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s). 
For all serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug. 
9.6.1.4 Reporting of serious adverse events and pregnancy 
The definition of serious adverse events (SAEs) is given in Section 9.6.1.1.  Each SAE must 
be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient. 
Investigator’s notification of the sponsor 
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as 
needed.  For clarity it might be useful to state that a pregnancy is to be captured as an SAE 
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
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detailed in the instructions for SAE reporting included in the Investigator File.  For this, an 
AE page in the CRF/eCRF data collection system as well as the complementary pages 
provided in the Investigator File must be completed for each SAE.   
Pregnancy occurring during a clinical investigation, although not considered a serious adverse 
event, must be reported to Bayer within the same timelines as a serious adverse event on a 
Pregnancy Monitoring Form.  The outcome of a pregnancy should be followed up carefully 
and any abnormal outcome of the mother or the child should be reported.  This also applies to 
pregnancies following the administration of the investigational product to the father prior to 
sexual intercourse.  Send the completed SAE or pregnancy forms to: 
 or Fax: 
 (in the USA) 
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations. 
Notification of the IRB 
Notification of the Institutional Review Board (IRB) about all relevant events (e.g., SAEs, 
suspected, unexpected, serious adverse reactions [SUSARs]) will be performed by the 
sponsor and/or by the investigator according to all applicable regulations. 
Notification of the authorities 
The processing and reporting of all relevant events (e.g., SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations. 
Sponsor’s notification of the investigational site 
The sponsor will inform the investigational site about reported relevant events (e.g., SUSARs) 
according to all applicable regulations. 
9.6.1.5 Expected adverse events 
For this study, the applicable reference document is the most current version of the package 
insert for naproxen and ibuprofen.  If relevant new safety information is identified, the 
information will be integrated into an update of the safety information and distributed to all 
participating sites. 
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations. 
9.6.2 
Pregnancies 
A subject’s participation is to be terminated immediately if a pregnancy is supposed (i.e. 
in case her pregnancy test becomes positive).   
The investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study.  The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported. 
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent. 
PPD
PPD


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For all reports, the forms provided are to be used.  The investigator should submit them within 
the same timelines as an SAE (see Section 9.6.1.4.).  Send the completed pregnancy forms to: 
 or Fax: 
 (in the USA) 
9.6.3 
Safety Examinations 
The following safety examinations will be performed at the time points specified in the study 
flowchart, see Section 16.1. 
• Physical examination 
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by qualified medical staff (e.g., a physician, oral surgeon, nurse practitioner or physician 
assistant) at the study site covering at least the organs of the head/neck, cardiovascular, and 
respiratory systems. 
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1). 
• Body weight and height, BMI 
Body weight will be measured by a member of the investigator’s team under the following 
conditions: 
− Subject without shoes after having emptied his / her bladder 
− Physician (column) scale, measurement units 0.1 kg 
The subject’s height will be measured (without shoes) to calculate the BMI. 
• Blood pressure / heart rate 
Systolic and diastolic blood pressure and heart rate will be measured by a member of the 
investigator’s team under the following conditions: 
− Systolic blood pressure (after resting for at least 5 min in sitting position) 
− Diastolic blood pressure (after resting for at least 5 min in sitting position) 
− Heart rate (after resting for at least 5 min in sitting position) 
− Measuring site: cuff to be placed on the right / left upper arm (if possible, the same arm 
will be used for all measurements in one subject); cuff location will be documented 
− Method: oscillometric by automatic measurement device 
• Laboratory examinations 
Urine samples will be collected by a member of the investigator’s team, for time points and 
parameters see Section 16.1 in the appendix. 
 
9.7 
Other procedures and variables 
Eligible subjects will undergo an oral examination and a dental x-ray (radiograph) exam to 
confirm that impacted third molar teeth are present. 
PPD
PPD


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9.8 
Appropriateness of procedures / measurements 
All efficacy and safety parameters, as well as the methods to measure them, are standard 
variables / methods in clinical studies and / or clinical practice. They are widely used and 
generally recognized as reliable, accurate and relevant. 
 
 


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10. 
Statistical methods and determination of sample size 
10.1 
General considerations 
Statistical analysis will be performed using statistical analysis software (SAS) and the version 
used will be specified in the Statistical Analysis Plan (SAP) and placed on file.  The SAP will 
contain a more comprehensive explanation than described below of the methodology used in 
the statistical analyses.  The SAP will also contain the rules and data handling conventions 
used to perform the analyses, and the procedure used for accounting for missing data. 
10.2 
Analysis sets 
Three populations will be identified in this trial.  
Safety Population 
All subjects who are randomized and take at least one dose of investigational product.  Safety 
measures will be analyzed for all subjects in the safety population. 
 
Intent-To-Treat (ITT) 
All subjects in the Safety Population who provide at least one pain assessment after the first 
dose of the investigational product.  ITT population will be used as the sensitivity analysis for 
the selected parameters.   
 
Per Protocol (PP) Population 
PP population will include all subjects in ITT who do not have any major protocol violations. 
PP population will be used as the primary analysis for the efficacy parameters. 
 
Major protocol deviations will be identified prior to database lock and may include but are not 
limited to significant violations of inclusion/exclusion criteria, noncompliance of the trial 
treatment taken, conditions such as vomiting and diarrhea or use of prohibited medications, 
and not following clinical trial protocol procedures.  Any subject who rescues or vomits  at or 
prior to 60 minutes after ingesting study medication will be excluded from the Per Protocol 
analysis. 


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10.3 
Efficacy Analysis 
For each postdose timepoint, Pain Intensity Differences (PID) will be derived by subtracting 
the pain intensity at the postdose timepoint from the baseline intensity score (baseline score – 
post-baseline score).  A positive difference is indicative of improvement.  Time-weighted 
Sum of Pain Intensity Differences (SPIDs) will be calculated for 4, 8, 12, 6-12 and 24 hours 
by multiplying the PID score at each postdose timepoint by the duration (in hours) since the 
preceding timepoint and then summing these values over 4, 8, 12, 6-12 and 24 hours, 
respectively.  Similarly, Total Pain Relief Scores (TOTPARs), will be calculated by 
multiplying the pain relief score at each postdose timepoint by the duration (in hours) since 
the preceding timepoint and then summing these values. 
In all analyses, for subjects who take rescue medication, all pain intensity scores after intake 
of rescue medication will be replaced by the worse of the baseline or the score assessed 
immediately before taking rescue medication. All pain relief after intake of rescue medication 
will be replaced by “no relief” (0). 
10.3.1 
Primary Efficacy Parameter 
The primary efficacy analyses population will be based on the PP population. 
The primary efficacy parameter is defined as:  
• Time to first use of rescue medication.  If a subject did not take the rescue medication 
during the treatment period, (s)he will be censored at the time of last assessment. Time 
to first use of rescue medication will be estimated and plotted using Kaplan-Meier 
method and analyzed using log-rank test stratified by center and baseline pain 
intensity. 
10.3.2 
Secondary Efficacy Parameters 
The secondary efficacy variables include: 
• SPID 0-24 and TOTPAR 0-24 will be analyzed using an analysis of covariance model 
(ANCOVA) with treatment as fixed effect and baseline pain intensity score as the 
covariate.  A 95% of confidence interval (CI) for the treatment differences will be 
calculated based on the above mentioned model. 
10.3.3 
Other Efficacy Parameters 
• The SPID 0-4, 0-8, 0-12, 6-12 will be analyzed using the same methodology as for 
SPID 0-24. 
• TOTPAR 0-4, 0-8, 0-12, and TOTPAR 6-12 will be analyzed using the same 
methodology as for SPID 0-24. 
• Pain Intensity Difference (PID) and Pain Relief scores at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 
10, 11, 12, 14, 16, 18, 20, 22 and 24 hours postdose. Descriptive statistics for each 
timepoint and graphical illustrations of the time effect curves will be presented. 
• The cumulative proportion taking rescue medication by timepoint will be analyzed 
using Chi-square tests and time-effect curves will be generated.  Frequency tables will 
be generated for the number of times the subject took rescue medication over the 24 
hour period by treatment group. 


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• Percent of subjects with Pain Half Gone (Yes / No question) by 24 hours will be 
summarized  descriptively by treatment group. 
• The proportion of subjects with pain at least one-half gone at each time point will be 
summarized descriptively and plotted over time by treatment group; 
• Duration of time that subjects reported their pain was at least half gone; 
• Total amount of time that subject reported at least a 2-point PID; 
• Global Assessment of the investigational product as a pain reliever.  This variable will 
be analyzed using CMH method with modified ridit score.  The proportion of subjects 
in each surgery will also be presented. 
Safety and Tolerability 
AEs will be collected from screening throughout the Treatment Phase and Follow-up Phase 
and will be coded using the Medical Dictionary for Regulatory Activities. Only treatment-
emergent AEs will be included, i.e., AEs that begin or worsen after the first dose of the 
investigational medicinal product (IMP) in the Treatment Phase.  The number and percent of 
subjects who experience any event and the number of events overall, by System Organ Class, 
and by Preferred Term will be displayed by treatment period and treatment group.  Tables will 
also be produced by severity and relationship to each IMP. Seriousness, severity, relationship 
to each IMP duration, and outcome will also be listed. 
Quantitative data for blood pressure, heart rate, body weight, body temperature will be 
described by summary statistics for the original data as well as for the differences to baseline.  
Frequency tables will be provided for qualitative data. Laboratory data outside the reference 
range will be listed and highlighted with ‘L’ for low and ‘H’ for high. An additional table 
with all abnormal values will be presented. 
Listings of individual subject data (e.g., vital signs) will be provided. 
10.4 
Determination of sample size 
The objective of this study is to establish superiority of naproxen sodium 440 mg over 24 
hours compared to  ibuprofen 400 mg over 24 hours with respect to the time to rescue 
medication.   
 
 
 
A total of 385 subjects will be randomized 
into the study if a drop-out rate of 5% is assumed. 
10.5 Planned interim analyses 
No interim analysis is planned for this study. 
 
 
CCI


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11. 
Data handling and quality assurance 
11.1 
Data recording 
Data collection and storage 
The data collection tool for this study will be a validated electronic data capture system to be 
used at the study site. Subject data necessary for analysis and reporting will be provided to the 
Sponsor in CDISC (Clinical Data Interchange Standards Consortium) standards. 
Interface to local laboratory 
Laboratory test results will be received as electronic data files from the local laboratory. They 
will be transferred to the clinical study database at the study site. For easy access and tracking 
by the investigator, the results will be additionally provided in printed form. Test results 
originating directly from the site (e.g., urine drug screen) will be entered into the CRF/eCRF 
data collection system by designated site personnel. 
Analytical results generated by central laboratory / -ies 
The analytical results will be provided as electronic data files using predefined data formats. 
Where appropriate, these data will be supplemented with data already available from the 
CRF/eCRF data collection system (e.g., specific time points, demographic data) before being 
evaluated by the responsible specialist(s). Data relevant for the clinical study report will be 
stored in the sponsor’s validated data repository. 
Source documentation 
Entries made in the CRF/eCRF data collection system must be either verifiable against source 
documents, or have been directly entered into the CRF/eCRF data collection system, in which 
case the entry in the CRF/eCRF data collection system will be considered as the source data 
(e.g., time points of blood sampling).  The site has to ensure the availability of all required 
documentation. 
Data recorded from screening failures 
Data of 'only screened subjects' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable.  At minimum, the following data should be 
recorded in the screening log: 
• 
Demographic information (subject number; year of birth  or age, sex); 
• 
Date of informed consent; 
•   Reason for premature discontinuation; 
•   Date of last visit.   
For screening failures with an SAE, the following data should be collected in the CRF/eCRF 
data collection system in addition to the data specified above: 
• All information related to the SAE such as:  
- Concomitant medication 
- Medical history 
- Other information needed for SAE complementary page 


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11.2 
Monitoring 
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items. 
The sponsor/designee will monitor the site activity to verify that the: 
• Data are authentic, accurate and complete.   
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes); 
• Safety and rights of subjects are being protected; 
• Study is conducted in accordance with the currently approved protocol  
(including study treatment being used in accordance with the protocol); 
• Any other study agreements, GCP, and all applicable regulatory requirements are met. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. 
11.3 
Data processing 
Data will be collected as described in Section 11.1.  Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures.  This is applicable for data recorded on the CRF/eCRF data collection system as 
well as for data from other sources (e.g., laboratory). 
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used. 
11.4 
Missing data  
Reasons for missing data, especially inability to perform a test, must be documented.   
11.5 
Audit and inspection 
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome. 
In addition, inspections by regulatory health authority representatives and IRB(s) are possible.  
The investigator should notify the sponsor immediately of any such inspection. 
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study. 


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11.6 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
Study subject files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the study site.  Where the archiving procedures do not 
meet the minimum timelines required by the sponsor, alternative arrangements must be made 
to ensure the availability of the source documents for the required period. 
The investigator/institution notifies the sponsor if the archival arrangements change (e.g., 
relocation or transfer of ownership). 
The investigator site file is not to be destroyed without the sponsor’s approval. 
The contract with the investigator/institution will contain all regulations relevant for the study 
center. 
 
 


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


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


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the study center/medical institution) must supply to the sponsor, upon request, a list of the 
IEC/IRB members involved in the vote and a statement to confirm that the IRB is organized 
and operates according to GCP and applicable laws and regulations. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.   
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator. 
Details on discontinuation of the entire study or parts thereof can be found in Section 12. 
13.4 
Subject information and consent/assent 
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center.  Sample subject 
information and informed consent/assent forms are provided as a document separate to this 
protocol.  Subjects 16 to 17 years old who cannot legally give informed consent for research 
participation must use an IRB-approved assent form and a Parental/Guardian informed 
consent form.  Informed consent must first be obtained from the child’s parent or legal 
guardian before assent may be obtained from the child. 
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject  prior to his/her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms). 
The investigator will also mention that written approval of the IRB has been obtained. 
Each subject will be informed about the following aspects of premature withdrawal: 
• Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision;   
• The subject’s consent covers EOT examinations as specified in the visit description 
described in Section 9.2.6 to be conducted after withdrawal of consent; 
• The subject’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan; 
• Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g., image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan.  The subject has the right to object to the 
generation and processing of this post-withdrawal data.  For this, he/she needs to sign a 
corresponding declaration of objection; alternatively, the subject’s oral objection may be 
documented in the subject’s source data. 


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Each subject will have ample time and opportunity to ask questions. 
Only if the subject agrees to sign the informed consent form and has done so, may he/she 
enter the study.  Additionally, the investigator will personally sign and date the form.  The 
subject will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the subject’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures. 
For minors or adults under legal protection, consent shall be given by the legal guardian(s). 
The consent of a minor or adult under legal protection shall also be requested where such a 
person is able to express his/her own will. His/her refusal or the withdrawal of his/her consent 
may not be disregarded. 
The informed consent form and any other written information provided to subjects will be 
revised whenever important new information becomes available that may be relevant to the 
subject’s consent, or there is an amendment to the protocol that necessitates a change to the 
content of the subject information and / or the written informed consent form.  The 
investigator will inform the subject of changes in a timely manner and will ask the subject to 
confirm his/her participation in the study by signing the revised informed consent form.  Any 
revised written informed consent form and written information must receive the IRB`s 
approval / favorable opinion in advance of use. 
13.5 
Publication policy and use of data 
The sponsor will make the information regarding the study publicly available on the internet 
at www.clinicaltrials.gov as applicable to local regulations. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators. 
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.   
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.   
13.6 
Compensation for health damage of subjects / insurance 
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed. 


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


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14. 
Reference list  
 
1. Grosser T, Smyth E, FitzGerald GA. Anti-inflammatory, Antipyretic, and Analgesic 
Agents; Pharmacotherapy of Gout. In: Brunton LL, Chabner BA, Knollmann BC. eds. 
Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e New York, 
NY: McGraw-Hill; 2011. 
http://accesspharmacy.mhmedical.com/content.aspx?bookid=1613&sectionid=102161
048. Accessed July 16, 2017. 
2. Kiersch TA, Halladay SC, and Hormel PC. A Single-Dose, Double-Blind Comparison 
of Naproxen Sodium, Acetaminophen, and Placebo in Postoperative Dental Pain. Clin 
Ther 1994;16(3):394-404 
3. Kiersch TA, Halladay SC, and Koschik M. A Double-Blind, Randomized Study of 
Naproxen Sodium, Ibuprofen, and Placebo in Postoperative Dental Pain. Clin Ther 
1993;15(5):845-54. 
4. Fricke JR, Halladay SC, and Francisco CA. Efficacy and Safety of Naproxen Sodium 
and Ibuprofen for Pain Relief After Oral Surgery. Curr Ther Res 1993;54(6):619-27. 
5. U.S. Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research (CDER).  Guidance for Industry Analgesic 
Indications: Developing Drug and Biological Products. February 2014  
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guid
ances/ucm384691.pdf Accessed July 16, 2017. 
6. Cooper SA and Desjardins PJ. The value of the dental impaction pain model in drug 
development.  Methods Mol Biol,  Szallasi A, Ed.   Humana Press  617: 175 – 190, 
2010. 
7. Cooper SA, Beaver WT. A model to evaluate mild analgesics in oral surgery 
outpatients. Clin Pharmacol Ther 1976;20:241–50. 
8. Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P.  Single dose 
analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, 
double-blind, placebo-controlled study.  Anesth Analg. 2008;107:2048-55. 
9. Cooper SA, Desjardins PJ, Turk DC, et al. Research design considerations for single-
dose analgesic clinical trials in acute pain: IMMPACT recommendations.  Pain 
2016;157:288-301. 
10. Singla NK, Desjardins PJ, Chang PD.  A comparison of the clinical and experimental 
characteristics of four acute surgical pain models: dental extraction, bunionectomy, 
joint replacement, and soft tissue surgery. Pain. 2014;155:441-56. 
11. Jung YH, Cho BH.  Radiographic evaluation of third molar development in 6- to 24-
year-olds.  Imaging Science in Dentistry 2014; 44: 185-91. 
 
 
 


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15. 
Protocol amendments 
 
Amendment 1 (dated 25-Jan-2018) is attached to the front of this protocol. 
 
 


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Reference Number: BHC-RD-OI-107 
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16. 
Appendices 
 
16.1 
Study Flow Chart 
Table 3: Study schema 
 
Protocol Activities 
Screening Visit     
(within 28 days prior 
to oral surgery) 
Dosing 
Period  
Inpatient 
End of 
Trial Call 
(2-5 days 
after 
discharge) 
Day 1 
Day 2 
Written Informed Consent 
x 
 
 
 
Inclusion/Exclusion Reviewed 
x 
x 
 
 
Medical/Medication History 
x 
x 
 
 
Physical and Oral Examination  
x 
 
 
 
Vital Signsa 
x 
x 
x 
 
Urine  for Drug Screen and Cotinine test 
x 
x 
 
 
Breath alcohol test 
x 
x 
 
 
Dental x-ray examination 
x 
 
 
 
Urine Pregnancy Test (if applicable) 
x 
x 
 
 
Admission to Unit  
 
x 
 
 
Oral surgery (between 0630 h and 1000 h (+/- 30 minutes) 
 
x 
 
 
Randomization Number Assigned 
 
x 
 
 
Investigational Product Administration                       
 
x 
 
 
Categorical Pain Rating Scale b   
 
x 
 
 
Pain Intensity Numerical Rating Scale (NRS) c      
 
x 
x 
 
Categorical Pain Relief Rating Scale c 
 
x 
x 
 
Starting pain is at least ½ gonec 
 
x 
x 
 
Global Assessment of Pain Relief  d 
 
 
x 
 
Concomitant Medications  
 
x 
x 
x 
Adverse Events Assessed 
x 
x 
x 
x 
Discharge from Unit morning of Day 2 
 
 
x 
 
a vital signs ( blood pressure, pulse rate, and respiration after sitting for at least 5 minutes).  On Day 1, vital signs are due post-surgery 
and 1 hour after study medication dose.  On Day 2, vital signs are due at 24 hours post-dose. 
b to be completed prior to dosing 
c Pain Intensity NRS to be completed at baseline (predose), and Pain Intensity NRS and Categorical Pain Relief will be assessed 0.5, 
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22 and 24 hours postdose.  If rescue occurs, scales/questions (except pain ½ gone) 
will be completed immediately each time rescue medication is taken 
 d assessment will be completed immediately before first rescue medication is taken or at 24 hours post-dose 
 


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16.2 Subjective Assessments 
 
Categorical Pain Intensity Scale (predose) 
 
Finish the statement: “My pain at this time is” by checking the appropriate box. 
 
⁭ No Pain (0) 
⁭ Mild Pain (1) 
⁭ Moderate Pain (2) 
⁭ Severe Pain (3) 
 
 
Numerical Rating Scale (predose and post-dose) 
 
Circle a number to indicate level of pain (from 0 to 10) below to indicate the severity of the 
pain you are experiencing at this time. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No  
pain 
 
 
 
 
 
 
 
Worst 
possible 
pain 
 
 
 
Categorical  Pain Relief Rating Scale (post-dose) 
 
Finish the statement: “ My relief from my starting pain is”” by checking the appropriate 
box. 
 
 
☐ No Relief (0) 
☐  A Little Relief (1) 
☐ Some Relief (2) 
☐ A Lot of Relief (3) 
☐ Complete Relief (4) 
 
 
 
 
 


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Half Way Pain Relief (post-dose) 
 
Finish the statement: “Is your starting pain at least ½ gone?” by checking the appropriate 
box. 
 
 
☐ No (0) 
 
☐ Yes (1) 
 
 
 
Global Assessment of Pain (post-dose) 
How would you rate the study medication you received as a pain-reliever? 
 
☐ Poor (0) 
☐ Fair (1) 
☐ Good (2) 
☐ Very Good (3) 
☐ Excellent (4) 
 
 
 
 

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A Randomized, Double-Blind, Placebo-Controlled Trial to Compare 
the Duration of Analgesic Efficacy and Safety of Naproxen Sodium 
Tablets and Ibuprofen Tablets in Postsurgical Dental Pain 
NCT Number: 
NCT03404206 
Document Date: 
24-Aug-2018 
 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
19762 
 
 
Study Title: 
 
 
A Randomized, Double-Blind, Placebo-Controlled 
Trial to Compare the Duration of Analgesic 
Efficacy and Safety of Naproxen Sodium Tablets 
and Ibuprofen Tablets in Postsurgical Dental Pain 
 
 
Development Phase of Study: 
4 
 
 
Sponsor: 
Bayer HealthCare LLC, Consumer Health 
100 Bayer Boulevard 
Whippany, NJ 07981-0915, USA 
Sponsor Contact: 
 
 
 
Statistical Analysis Plan based on Protocol Version: 
V 3.0 / 15-Feb-2018 
 
 
Statistical Analysis Plan Date: 
August 24, 2018 
Statistical Analysis Plan Version: 
1 


PPD
PPD
PPD
PPD
PPD
PPD
CCI
CCI


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
2. 
INTRODUCTION .................................................................................................................6 
2.1 Background .....................................................................................................................6 
2.2 Rationale of the Study .....................................................................................................7 
3. 
STUDY OBJECTIVES .........................................................................................................7 
4. 
STUDY DESIGN ...................................................................................................................8 
4.1 Overall Study Design ......................................................................................................8 
4.1.1 
Method of Assigning Subjects to Treatment Groups ........................................8 
4.1.2 
Blinding .............................................................................................................9 
5. 
EFFICACY AND SAFETY ENDPOINTS .......................................................................10 
5.1 Efficacy Endpoints ........................................................................................................10 
5.1.1 
Primary Efficacy Endpoint ..............................................................................10 
5.1.2 
Secondary Efficacy Endpoints ........................................................................10 
5.1.3 
Other Efficacy Endpoints ................................................................................10 
5.2 Safety Endpoints ...........................................................................................................11 
6. 
STATISTICAL AND ANALYTICAL PLANS ................................................................11 
6.1 General Methodology ...................................................................................................11 
6.1.1 
Statistical Analysis ..........................................................................................11 
6.1.2 
Baseline Definition ..........................................................................................12 
6.1.3 
Visit Windowing .............................................................................................12 
6.1.4 
Adjustments for Covariates .............................................................................12 
6.1.5 
Handling of Dropouts or Missing Data ...........................................................12 
6.1.6 
Interim Analyses and Data Monitoring ...........................................................12 
6.1.7 
Multicenter Studies ..........................................................................................12 
6.1.8 
Multiple Comparisons / Multiplicity ...............................................................13 
6.1.9 
Use of an Efficacy Subset of Subjects .............................................................13 
6.1.10 Active-Control Studies Intended to Show Equivalence ..................................13 
6.1.11 Examination of Subgroups ..............................................................................13 
6.2 Disposition of Subjects .................................................................................................13 
6.3 Protocol Deviations .......................................................................................................13 
6.4 Analysis Sets .................................................................................................................13 
6.4.1 
Safety Population ............................................................................................13 
6.4.2 
Intent-to-Treat (ITT) Population .....................................................................13 
6.4.3 
Per-Protocol (PP) Population ..........................................................................14 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
6.5 Demographic and Other Baseline Characteristics ........................................................14 
6.6 Prior and Concomitant Medications .............................................................................15 
6.7 Rescue Medications ......................................................................................................15 
6.8 Analysis of Efficacy ......................................................................................................15 
6.8.1 
Primary Efficacy Analysis ...............................................................................15 
6.8.2 
Secondary Efficacy Analysis ...........................................................................16 
6.8.3 
Other Efficacy Analysis ..................................................................................16 
6.9 Safety Evaluation ..........................................................................................................18 
6.9.1 
Extent of Exposure ..........................................................................................18 
6.9.2 
Adverse Events ................................................................................................18 
6.9.3 
Clinical Laboratory Evaluation .......................................................................18 
6.9.4 
Other Observations Related to Safety .............................................................19 
6.9.4.1 
Vital Signs ....................................................................................19 
6.9.4.2 
Physical Examination...................................................................19 
6.9.4.3 
ECG Measurements .....................................................................19 
7. 
DETERMINATION OF SAMPLE SIZE .........................................................................19 
8. 
CHANGES IN THE PLANNED ANALYSES..................................................................19 
9. 
REFERENCES ....................................................................................................................19 
 
 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
1. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE(s) 
adverse event(s) 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
CI 
confidence interval 
COX 
Cyclooxygenase 
FDA 
Food and Drug Administration 
hr(s) 
hour(s) 
ITT 
intent-to-treat 
LOCF 
last observation carried forward 
LSMean 
Least squares mean 
LSSD 
Least squares standard deviation 
max 
maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 
n 
number of observations 
N 
number of subjects (sample size) 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
OTC 
over-the-counter 
PID 
Pain Intensity Differences 
PP 
per-protocol 
PT 
preferred term 
 
 
RNR 
randomization number 
SAE(s) 
serious adverse event(s) 
SAS® 
Statistical Analysis System (SAS® Institute Inc., Cary, NC) 
SD 
standard deviation 
SOC 
system organ class 
SPID 
Summed Pain Intensity Difference 
TEAE(s) 
treatment-emergent adverse event(s) 
TOTPAR 
Total Pain Relief 
US 
United States 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 
 
CCI


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
2. INTRODUCTION 
2.1 
Background 
Naproxen sodium and ibuprofen are nonselective cyclooxygenase (COX) inhibitors. They are 
propionic acid derivatives and members of a drug class s known as nonsteroidal 
anti-inflammatory drugs (NSAIDs). Both naproxen and ibuprofen inhibit COX-1 and COX-2 
isoenzymes. COX enzymes play a key role in the inflammatory response and the production of 
prostaglandins. Specifically, COX-1 is expressed in the gastrointestinal epithelium, vascular 
endothelium and kidney, while COX-2 plays a role in induction of inflammation. COX-2 
inhibition reduces prostaglandin synthesis, leading to pain relief.  
In the United States, naproxen has been marketed as a prescription medication since 1976 under 
the brand name Naprosyn®. Its sodium salt, naproxen sodium, was first sold under the trade 
name Anaprox® in 1980. In 1994, the US FDA approved naproxen sodium tablets (using the 
brand name Aleve®), 220 mg for over-the-counter (OTC) use. Aleve is indicated for the 
temporary relief of minor aches and pains due to: minor pain of arthritis, muscular aches, 
backaches, menstrual cramps, headaches, toothaches, and the common cold. It also temporarily 
reduces fever. As an OTC medication, Aleve should not be taken for longer than 10 days for pain 
or 3 days for fever unless otherwise directed by a physician. Similarly, Advil® (a branded form 
of ibuprofen) has been available OTC since 1984. It carries the same indications and duration of 
use labeling as Aleve. 
The labelled dosing interval for over-the-counter naproxen sodium is 8-12 hours due to its long 
elimination half-life (approximately 14 hours) and documented long duration of action.[1,2] In 
contrast, ibuprofen, another propionic acid nonsteroidal anti-inflammatory drug available 
over-the-counter, has a  labeled dosing interval of 4-6 hours and a short elimination half-life, 2-4 
hours.[2] These two agents have been compared in single dose dental pain studies.[3,4] The 
analgesic effectiveness of naproxen sodium was greater than ibuprofen at later time points in 
both of these 12 hour studies but the duration of the studies was relatively short and the 
evaluations were performed at home.  The ability to assess relative differences in the later hours 
may have been limited by the outpatient nature of those earlier studies which used at-home 
diaries.    
The duration of analgesia in acute pain studies is generally assessed by the time to 
remedication.[5] At both low OTC doses and high OTC doses, naproxen sodium showed a 
numerically longer duration of action compared to ibuprofen although the difference did not 
achieve the level of statistical significance.[3,4] However, the sample size in these two studies 
was not estimated based on this secondary outcome parameter. 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
2.2 
Rationale of the Study 
The post-impaction dental pain model chosen for this study has been widely used in the 
evaluation of OTC and prescription analgesics for a number of reasons. Dental surgical 
procedures can be easily standardized, and the population of subjects undergoing a given 
procedure is usually relatively healthy and homogeneous. In addition, there is extensive data 
substantiating the usefulness of the dental pain model in predicting the relative efficacy of a wide 
range of analgesic medications. The model has been found to be very useful for comparing 
several measures of analgesic efficacy, including onset, peak effect, and duration of analgesic 
activity. [6,7,8] Therefore, the purpose of this investigation is to use the post-impaction dental 
pain model to compare the duration of action of naproxen sodium to ibuprofen at 
over-the-counter doses.  
3. STUDY OBJECTIVES 
The primary objective of this trial is: 
• To compare the duration of analgesic efficacy as determined by the time to rescue 
medication of a single oral dose of naproxen sodium 440 mg (2 x 220 mg tablets) relative 
to ibuprofen 400 mg (2 x 200 mg tablets) and placebo (2 x tablets) over 24 hours in 
subjects experiencing moderate to severe post-impaction surgery dental pain. 
The secondary objectives of this trial are: 
• To compare the overall analgesic effect (SPID 0-24) of a single dose of naproxen sodium 
440 mg (2 x 220 mg tablets) relative to ibuprofen 400 mg (2 x 200 mg tablets) and 
placebo;  
• To compare the overall relief from starting pain (TOTPAR 0-24) of a single dose of 
naproxen sodium 440 mg (2 x 220 mg tablets) relative to ibuprofen 400 mg (2 x 200 mg 
tablets) and placebo. 
Other objectives of this trial are: 
• To compare the efficacy of naproxen 440 mg, ibuprofen 400 mg, and placebo for the 
following measures: 
o SPID 0-4, SPID 0-8, SPID 0-12, SPID 6-12; 
o TOTPAR 0-4, TOTPAR 0-8, TOTPAR 0-12, and TOTPAR 6-12; 
o Peak Pain Intensity; 
o Peak Pain Relief; 
o Sum of Observations with Pain Half Gone; 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
o Duration of Pain Relief At Least Half Gone; 
o Total amount of time that subject reported at least a 2-point PID; 
o Global Pain Assessment.  
4. STUDY DESIGN 
4.1 
Overall Study Design 
This is a single center, randomized, double-blind, parallel, placebo-controlled study, stratified by 
baseline pain, in subjects experiencing moderate to severe postoperative dental pain. The study 
will consist of a Prescreening telephone call, a Screening Visit, a two day Treatment Period and a 
Post-Operative visit.  Eligible subjects who have undergone surgical extraction of at least 2 
mandibular partial or full bony impacted third molars will be kept in-house and evaluated for 
efficacy and safety at the study site overnight. 
The study consists of a Screening Phase, Treatment Phase and a Follow-Up Phase. During 
Treatment Phase, subjects will be kept in-house at the study site for one overnight stay.  
Qualified subjects will then be randomized into one of three treatments. Approximately 397 will 
have surgery and approximately 385 will be randomized to a specific treatment. 
The duration of each subject’s participation will be approximately 38 days. For an overview on 
the study design and study procedures see Figure 1. 
Figure 1 – Design Overview  
 
Screening 
Phase 
Treatment Phase 
Follow up 
Phase 
Trial 
Days 
Day -28 to -1 
Day 1 
Presurgery 
Day 1 
Surgery 
Day 1 
Postsurgery 
Day 1 
Day 2 
Days 6-10 
 
 
Check-in to 
study site     
(if needed) 
Surgical 
teeth 
extraction 
Categorical 
pain 
NRS pain 
NRS pain  
Pain relief 
Pain half 
gone 
NRS pain       
Pain relief   
Pain half gone 
Global 
assessment 
Phone call 
or visit 
 
= randomized to either naproxen (440 mg), ibuprofen (400 mg), or placebo  
 
The schedule of assessments can be found in Section 16.1 of the protocol. 
4.1.1 
Method of Assigning Subjects to Treatment Groups 
At the beginning of the first treatment period, after completion of the pre-treatment baseline 
procedures/assessments, subjects who meet the entry criteria will be sequentially assigned to a 
 
 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
unique number in sequential order (randomization number [RNR]) according to the 
randomization schedule 3:3:1 (naproxen sodium: ibuprofen: placebo) prepared prior to the study. 
Subjects will be numbered according to the following scheme, which is a different number than 
the RNR: 
14001XXXX 
Whereas the “Xs” will be replaced with a four digit sequentially assigned number as each subject 
enters the study (e.g. first subject number will be 140011001). 
The unique subject identifier number will be assigned in numerical order stratified by baseline 2 
or 3 categorical pain level (moderate or severe) prior to dosing.  Subjects who designate their 
baseline pain as moderate will use the lowest RNR available with subsequent moderate 
randomizations using the next available lowest RNR.  Subjects who designate their baseline 
pain as severe will use the highest RNR available with subsequent severe randomizations using 
the next available highest RNR.  Subjects who characterize their pain severity as mild and <5 on 
the NRS will not receive treatment and be withdrawn from the study. 
Once a number has been assigned to a subject, it cannot be reassigned to another subject.   
Subjects completing the Screening Visit, if not scheduled for surgery the same day, will return to 
the trial site within 28 days, and if they continue to meet inclusion/exclusion criteria postsurgery 
will be randomized to one of three treatment groups: 
• Naproxen sodium tablets (220 mg x 2 tablets) 
• Ibuprofen tablets (200 mg x 2 tablets) 
• Placebo tablets (2 tablets) 
Subjects will be assigned to treatment groups in accordance with the randomization schedule.  
The Sponsor or designee will provide a randomization schedule to the study site.    
4.1.2 
Blinding 
Subjects enrolled in the trial, investigators and their staff involved in protocol procedures or who 
are involved in data collection, data entry and data analysis will be blinded to the identity of the 
treatments until the database is locked. The study monitor will conduct product accountability 
after database lock. To preserve blinding, subjects will be blindfolded. Study drug will be 
dispensed by an unblinded study team member based on the randomization schedule. That team 
member may have no other role in the study conduct and may not reveal the study drug’s identity 
to any members of the blinded study team. 
Sponsor will supply study medication in bulk containers. Selection of the proper dose for an 
individual subject will be performed by an unblinded study team member using the provided 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
randomization schedule. The unblinded study team member will withdraw the appropriate study 
medication from the bulk container and transfer it to a dispensing cup. The unblinded study team 
member will then bring the study medication to the treatment room where it will be dispensed to 
the subject by the unblinded study team member. The unblinded study team member should have 
no other responsibilities in the study. 
5. EFFICACY AND SAFETY ENDPOINTS 
5.1 
Efficacy Endpoints 
5.1.1 
Primary Efficacy Endpoint 
The primary efficacy analyses population will be based on the PP population. 
The primary efficacy endpoint is the time to first use of rescue medication. 
5.1.2 
Secondary Efficacy Endpoints 
The secondary endpoints are as follows: 
• SPID 0-24; 
• TOTPAR 0-24. 
5.1.3 
Other Efficacy Endpoints 
Other efficacy endpoints are as follows: 
• SPID 0-4, SPID 0-8, SPID 0-12, SPID 6-12; 
• TOTPAR 0-4, TOTPAR 0-8, TOTPAR 0-12, and TOTPAR 6-12; 
• Peak Pain Intensity Difference; 
• Peak Pain Relief; 
• Cumulative proportion taking rescue medication by timepoint; 
• Proportion of subjects with Pain Half Gone by 24 hours; 
• Proportion of subjects with pain at least half gone at each time point; 
• Duration of time that subjects reported their pain was at least half gone; 
• Total amount of time that subjects reported at least a 2-point PID; 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
• Global Pain Assessment. 
5.2 
Safety Endpoints 
Safety will be assessed by reports of adverse events (AEs) and absolute and change from 
baseline in vital signs. 
6. STATISTICAL AND ANALYTICAL PLANS 
6.1 
General Methodology 
All statistical processing will be performed using SAS® Version 9.3 or higher unless otherwise 
stated. No interim analyses are planned. Except where noted, all statistical tests will be two-sided 
and will be performed at the 0.05 level of significance. No adjustments for multiplicity will be 
made. 
Descriptive statistics will be used to provide an overview of the efficacy and safety results. For 
categorical parameters, the number and percentage of subjects in each category will be 
presented. For continuous parameters, descriptive statistics will include n (number of subjects), 
mean, standard deviation (SD), median, minimum (min), and maximum (max). Appropriate 
inferential statistics will be used for the primary and other efficacy variables. 
The efficacy analysis performed on the Per-Protocol (PP) population is considered the primary 
analysis. The efficacy analysis performed on the Intent-to-Treat population is considered a 
supportive analysis. 
Reported AEs, medical history terms, and prior and concomitant procedures and therapies will 
be classified on the basis of Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. Prior and concomitant medications as well as rescue medication will be classified 
on the basis of World Health Organization Drug Dictionary Enhanced (WHO-DDE) 
terminology. 
6.1.1 
Statistical Analysis 
All analyses will be performed by 
 using SAS® Version 9.3 or 
later. All summary tables and data listings will be prepared utilizing SAS® software. 
The standard operating procedures of 
 will be followed in the creation and quality control of 
all data displays and analyses. 
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Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
6.1.2 
Baseline Definition 
Baseline is from the last measurement prior to study treatment. 
6.1.3 
Visit Windowing 
Visits will not be windowed. Visits will be summarized and listed by their nominal value. 
6.1.4 
Adjustments for Covariates 
Baseline pain intensity will be used as a covariate for the efficacy analysis where appropriate. 
6.1.5 
Handling of Dropouts or Missing Data 
A LOCF method will be used to extrapolate efficacy data that are missing beyond the last 
observation. Missing scheduled pain and relief scores prior to the last observation will be 
imputed using the weighted average of adjacent evaluations as follows: 
 
Si = (Si+1 - Si-1)*(ti - ti-1)/(ti+1 - ti-1) + Si-1 
Where Si-1 and Si+1 are scheduled nonmissing adjacent evaluations at ti-1 and ti+1, respectively, 
where ti is the scheduled time postdose in hours, and ti-1 and ti+1 are actual hours postdose of 
scheduled evaluations. 
If a partial date is reported where the day is missing, then the day will be imputed as the first day 
of the month unless the month is the same month as the first dose then the day will be that of first 
dose with the month and year remaining the same. If a partial date is reported where the month is 
missing, then the month will be imputed to January unless the year is the same year as the first 
dose then the month will be that of first dose with the year remaining the same. If a partial date 
where both the day and month is missing, follow details as stated previously.  
Missing AE start dates will be imputed using partial date imputation rules as previously 
described in this Section. Missing data for other parameters will not be imputed for analysis 
unless otherwise defined. 
6.1.6 
Interim Analyses and Data Monitoring 
No interim analysis or data monitoring is planned for this study. 
6.1.7 
Multicenter Studies 
Not applicable; this is a single center study. 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
6.1.8 
Multiple Comparisons / Multiplicity 
No adjustments for multiple comparisons or multiplicity will be made. 
6.1.9 
Use of an Efficacy Subset of Subjects 
The PP population will be used for the primary analysis. 
6.1.10 
Active-Control Studies Intended to Show Equivalence 
Not applicable to this study. 
6.1.11 
Examination of Subgroups 
Not applicable to this study. 
6.2 
Disposition of Subjects 
The number of subjects enrolled, randomized, completed, and discontinued (including the 
reasons for discontinuation) will be summarized for each treatment group.  
6.3 
Protocol Deviations 
Protocol deviations will not be entered into the database. Deviations leading to exclusion from 
analysis populations will be identified and summarized. 
6.4 
Analysis Sets  
The number of subjects included in each analysis population will be summarized by treatment 
group. Subjects who are excluded from an analysis population will be summarized by the 
reasons for exclusion.  
6.4.1 
Safety Population  
All subjects who are randomized and take at least one dose of investigational product will be 
included in the safety population and analyzed according to the treatment they actually received. 
All safety analyses will be performed using the Safety population. 
6.4.2 
Intent-to-Treat (ITT) Population 
All subjects in the Safety population who provide at least one pain assessment after the first dose 
of the investigational product will be included in the ITT population and analyzed according to 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
the treatment they were randomized to. All efficacy analyses will be presented using the ITT 
population for supportive purposes.   
6.4.3 
Per-Protocol (PP) Population 
All subjects in the ITT population who do not have any major protocol violations will be 
included in the PP population and analyzed according to the treatment they actually received.   
Major protocol violations include: 
• Inclusion / Exclusion Criteria violations 
• Took prohibited medications 
• Were noncompliant with study medication 
• Use of rescue medication at or prior to 60 minutes after ingesting study medication 
• Vomiting at or prior to 60 minutes after ingesting study medication 
Evaluability for inclusion in the PP population will be reviewed and finalized prior to database 
lock. 
The primary efficacy analysis will be performed using the PP population. The ITT population 
will be used as supportive. 
6.5 
Demographic and Other Baseline Characteristics 
All baseline summaries will be done on the ITT, PP, and Safety populations. 
Sex, race, and ethnicity will be summarized by counts and percentages. Age, height (cm), weight 
(kg), and BMI will be summarized with descriptive statistics by treatment group and overall.   
Oral surgery site will be presented by frequency counts and percentages for each treatment group 
and overall. Number of teeth extracted, impaction scores, and duration of surgery (first incision 
to last suture) will be summarized with descriptive statistics by treatment group and overall. All 
dental surgery information and oral examination data will be presented in by-subject listings. 
Baseline pain score will be summarized with frequency counts and percentages as well as with 
descriptive statistics by treatment group and overall. 
Social history (drug, alcohol, tobacco, and caffeine use) will be summarized with frequency 
counts and percentages by treatment group and overall.  Social history will also be presented in 
a by-subject listing.  
Medical histories / surgeries will be coded using the MedDRA dictionary and presented in a 
by-subject listing. Inclusion / exclusion criteria will also be presented in by-subject listings. 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
6.6 
Prior and Concomitant Medications 
Concomitant medications will be coded to preferred name and Anatomical Therapeutic Chemical 
(ATC) classification of ingredients using the WHO-DDE.  
Medications which start prior to first dose will be considered prior medications. Ongoing 
medications and medications ending after the date of first dose will be considered concomitant 
medications. Incomplete start and end dates which could be either prior to first dose or after first 
dose will be considered prior to first dose. 
A by-subject listing of all prior and concomitant medications will be presented. Concomitant 
medications will be summarized by drug class and preferred name by treatment group and 
overall for each population. 
6.7 
Rescue Medications 
Rescue medications will be coded to preferred name and ATC classification of ingredients using 
the WHO-DDE.  
Rescue medications will be summarized by drug class and preferred name by treatment group 
and overall for each population. 
A by-subject listing of all rescue medications will be presented.  
6.8 
Analysis of Efficacy 
All statistical tests will be 2-sided at the significance level of 5% and no multiplicity adjustment 
will be made.  
In all analyses, for subjects who take rescue medication, all pain intensity scores after intake of 
rescue medication will be replaced by the worse of the baseline or the score assessed 
immediately before taking rescue medication. All pain relief after intake of rescue medication 
will be replaced by “no relief” (0). 
For the purposes of analysis, dates of the subject assessments for efficacy will be populated 
programmatically when the time indicates a date change, i.e., the collection time of the time 
point went past midnight. 
6.8.1 
Primary Efficacy Analysis 
Time to first use of rescue medication during the treatment period is the primary efficacy 
endpoint. If a subject did not take the rescue medication during the treatment period, the subject 
will be considered censored at the time of last assessment. Time to first use of rescue medication 
will be estimated and plotted using Kaplan-Meier method and analyzed using a log-rank test 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
stratified by baseline pain intensity. Time to first use of rescue medication will be measured and 
presented in hours. 
Time to first use of rescue medication will be summarized by count and percentage of subjects 
taking the rescue medication and count and percentage of subjects censored. Kaplan-Meier 25th, 
50th, and 75th percentiles, as well as minimum and maximum times observed, will be determined 
and summarized and Kaplan-Meier curves will be plotted. Elapsed times will be computed from 
the date and time of first dose of study medication. Subjects not taking any rescue medication by 
the time of study completion (24 hours post-surgery) will be right-censored. The date and time of 
the last recorded non-missing assessment will be used as the censoring date.  Log-rank tests will 
be used to compare naproxen sodium to ibuprofen and naproxen sodium to placebo. 
The primary efficacy analysis will be presented using the PP population. The ITT population will 
be presented as supportive. 
Time to first use of rescue medication will also be presented in a by-subject listing. 
6.8.2 
Secondary Efficacy Analysis 
For each postdose time point, PIDs will be derived by subtracting the pain intensity at the 
postdose time point from the baseline intensity score (baseline score – post-baseline score). A 
positive difference is indicative of improvement. Time-weighted sum of pain intensity 
differences (SPIDs) will be calculated for 4, 8, 12, 6-12, and 24 hours by multiplying the PID 
score at each postdose time point by the duration (in hours) since the preceding time point and 
then summing these values over 4, 8, 12, 6-12, and 24 hours, respectively. Similarly, total pain 
relief scores (TOTPARs) will be calculated by multiplying the pain relief score at each postdose 
time point by the duration (in hours) since the preceding time point and then summing these 
values. Nominal times as recorded by the site will be used for timepoints mentioned above. 
SPID 0-24 and TOTPAR 0-24 will be analyzed using an analysis of covariance model 
(ANCOVA) with treatment as fixed effect and baseline pain intensity score as the covariate. The 
least squares mean (LSMean), least squares standard deviation (LSSD), and 95% confidence 
intervals (CIs) for the treatment differences (naproxen-placebo; naproxen-ibuprofen; 
ibuprofen-placebo) will be calculated based on the above mentioned model.  
6.8.3 
Other Efficacy Analysis 
The SPID 0-4, 0-8, 0-12, and 6-12 will be analyzed using an ANCOVA model with treatment as 
fixed effect and baseline pain intensity score as the covariate. The LSMean, LSSD, and 95% CIs 
for the treatment differences will be calculated from the above mentioned model as well. 
The TOTPAR 0-4, 0-8, 0-12, and 6-12 will be analyzed using the same method as stated above. 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
Peak PID and peak pain relief will be summarized using descriptive statistics for each treatment 
group.  PIDs and pain relief scores at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 
and 24 hour postdose will be summarized using descriptive statistics for each treatment group.  
In addition line graphs showing the time effect curves will also be presented by treatment group 
for both PID and the pain relief scores. In addition, pain intensity scores will be summarized by 
timepoint including pre-dose. 
The cumulative proportion of subjects taking rescue medication by each time point will be 
summarized and Chi-square tests will be presented to compare treatments.  In addition, the 
cumulative proportion of subjects taking rescue medication will be plotted at every time point for 
each treatment group to show the time-effect.  The number of times a subject took a rescue 
medication over the 24 hour period will be summarized using frequency counts and percentages 
by treatment group. 
The percent of subjects with pain half gone by 24 hours will be summarized using frequency 
counts and percentages by treatment group.  Subjects reporting at least one time point as pain 
half gone, regardless of response at 24 hours will be considered to have pain half gone by 24 
hours. In addition, the proportion of subjects with pain at least half gone at each time point will 
be summarized using frequency counts and percentages by treatment group.  The proportion of 
subjects with pain at least half gone will be plotted at every time point for each treatment group. 
The duration of time (in hours) that subjects reported their pain was at least half gone will be 
summarized using descriptive statistics by treatment group. The start of any period of reporting 
pain half gone will be the reported time of the first “Yes” response and the end of the period will 
be the time of the first “No” response after the “Yes” response. For example, if a subject reported 
pain half gone at 1 hr, 2 hr, 3 hr, and 4 hr and reported pain not half gone at 5 hr time point then 
the duration of time pain was at least half gone would be (exact time of 5 hr assessment) – (exact 
time of 1 hr assessment). A subject may have more than 1 period of time in which they reported 
their pain half gone. All periods of time will be summed together per subject. Only assessments 
taken prior to rescue medications will be considered. 
The total amount of time (in hours) a subject reported at least a 2-point PID will be summarized 
using descriptive statistics by treatment group. The PID at each time point is calculated as the 
pain intensity numerical rating score (NRS) – baseline pain intensity NRS. A subject may have 
more than 1 period of time of reporting at least a 2-point PID.  Each period of time will be 
summed together. Only assessments taken prior to rescue medications will be considered. 
The global assessment score will be summarized using frequency counts and percentages as well 
as with descriptive statistics.  The treatments will be compared using CMH method with 
modified ridit score (SCORES=MODRIDIT option). An overall CMH test with modified ridit 
score will also be presented. 


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
6.9 
Safety Evaluation 
Only descriptive analyses will be presented for the Safety population. No imputation will be 
made for missing safety data. Quantitative data for safety variables will be described by 
summary statistics for the original data as well as for the differences to baseline when it is 
appropriate. Frequency tables will be provided for qualitative data.  
6.9.1 
Extent of Exposure 
Study treatment administration data will be presented with a by-subject listing. 
6.9.2 
Adverse Events 
All AEs that occur during the study will be recorded and classified on the basis of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. Treatment-emergent AEs 
(TEAEs) are defined as AEs with an onset on or after the date of the first study drug 
administration. AEs noted prior to the first study drug administration that worsen after baseline 
will also be reported as AEs and included in the summaries.  
TEAEs will be summarized by treatment group, the number of subjects reporting a TEAE, 
system organ class, preferred name, severity, relationship to study treatment (causality), and 
seriousness. When summarizing TEAEs by severity and relationship, each subject will be 
counted once within a system organ class or a preferred term by using the event with the highest 
severity and greatest relationship within each classification. 
Serious AEs (SAEs) will be summarized.  
The number and percent of subjects who experience any event, by System Organ Class (SOC), 
and by Preferred Term (PT) will be displayed by treatment group for the Safety population. 
All adverse events and all serious adverse events will be presented in individual listings. In 
addition, a list of subjects who prematurely discontinue from the study due to an AE will be 
provided. 
6.9.3 
Clinical Laboratory Evaluation 
Urine pregnancy tests will be presented in a by-subject listing. 
Urine drug screens and cotinine tests taken during screening and presurgery will be presented in 
a by-subject listing.  


Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
6.9.4 
Other Observations Related to Safety 
6.9.4.1 
Vital Signs 
Vital signs data for blood pressure, pulse rate, and respiratory rate will be summarized using 
descriptive statistics by treatment group for both the observed values and change from baseline 
values.  
A by-subject listing will be presented of all vital signs data. 
6.9.4.2 
Physical Examination 
Physical examination data will be presented in a by-subject listing.  
6.9.4.3 
ECG Measurements 
Not applicable to this study. 
7. DETERMINATION OF SAMPLE SIZE 
The objective of this study is to establish superiority of naproxen sodium 440 mg over 24 hours 
compared to ibuprofen 400 mg over 24 hours with respect to the time to rescue medication. 
 
 
 
 A total of 385 subjects will be randomized into 
the study if a drop-out rate of 5% is assumed. 
8. CHANGES IN THE PLANNED ANALYSES 
There are no changes in the planned analyses. 
9. REFERENCES 
1. Grosser T, Smyth E, FitzGerald GA. Anti-inflammatory, Antipyretic, and Analgesic 
Agents; Pharmacotherapy of Gout. In: Brunton LL, Chabner BA, Knollmann BC. eds. 
Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e New York, NY: 
McGraw-Hill; 2011. 
http://accesspharmacy.mhmedical.com/content.aspx?bookid=1613&sectionid=10216104
8. Accessed July 16, 2017. 
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Statistical Analysis Plan for Bayer HealthCare LLC 
Protocol Number: 19762 
2. Kiersch TA, Halladay SC, and Hormel PC. A Single-Dose, Double-Blind Comparison of 
Naproxen Sodium, Acetaminophen, and Placebo in Postoperative Dental Pain. Clin Ther 
1994;16(3):394-404. 
3. Kiersch TA, Halladay SC, and Koschik M. A Double-Blind, Randomized Study of 
Naproxen Sodium, Ibuprofen, and Placebo in Postoperative Dental Pain. Clin Ther 
1993;15(5):845-54. 
4. Fricke JR, Halladay SC, and Francisco CA. Efficacy and Safety of Naproxen Sodium and 
Ibuprofen for Pain Relief After Oral Surgery. Curr Ther Res 1993;54(6):619-27. 
5. U.S. Department of Health and Human Services Food and Drug Administration Center 
for Drug Evaluation and Research (CDER).  Guidance for Industry Analgesic 
Indications: Developing Drug and Biological Products. February 2014  
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm384691.pdf Accessed July 16, 2017. 
6. Cooper SA and Desjardins PJ. The value of the dental impaction pain model in drug 
development.  Methods Mol Biol, Szallasi A, Ed.  Humana Press  617: 175 – 190, 
2010. 
7. Cooper SA, Beaver WT. A model to evaluate mild analgesics in oral surgery outpatients. 
Clin Pharmacol Ther 1976;20:241-50.  
8. Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P.  Single dose analgesic 
efficacy of tapentadol in postsurgical dental pain: the results of a randomized, 
double-blind, placebo-controlled study.  Anesth Analg. 2008;107:2048-55.