Clinical trial NCT03785756
Conditions: Pain
Sponsor: Reckitt Benckiser Healthcare (UK) Limited
Start date: 2019-04-29; Completion date: 2020-02-28
Enrollment: 280 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a single centre, randomised, double-blind, double-dummy, parallel group, multiple-dose, active and placebo-controlled efficacy study to evaluate the efficacy and safety of 2×300mg ibuprofen Prolonged Release (PR) tablets in subjects with postoperative dental pain.

Detailed description:
This is a single centre, randomised, double-blind, double-dummy, parallel group, multiple-dose, active and placebo controlled efficacy study to evaluate the efficacy and safety of ibuprofen 2 × 300 mg ibuprofen PR tablets in subjects with postoperative dental pain.

Eligible subjects will complete all screening procedures within 28 days before the surgery and randomisation.

At Screening, subjects will provide written informed consent to participate in the study before any protocol specified procedures or assessments are completed. On Day 1, subjects who continue to be eligible for study participation after completing screening procedures and assessments will undergo extraction of 2 or more third molars. At least 1 of the third molars must be a fully or partially bone impacted mandibular molar. If only 2 molars are removed, then they must be ipsilateral.

All subjects will receive local anaesthesia (2% lidocaine with 1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion of the investigator. Subjects who experience moderate to severe pain intensity (a score of ≥5 on a numeric rating scale \[NRS\] from 0-10 where 0 = no pain, 10 = worst pain ever) within 6 hours after surgery and who continue to meet all study entry criteria will be randomised in a 3:3:1 ratio to receive 2 × 300 mg ibuprofen PR tablets every 12 hours (Q12h), 2 × 200 mg ibuprofen immediate release (IR) tablets every 8 hours (Q8h), or placebo. The randomisation will be stratified by baseline pain category (moderate or severe) using a categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and severe (8-10).

Subjects will re-assess their baseline pain intensity using the NRS immediately before receiving study drug (pre-dose, Time 0) and their pain intensity (NRS) and pain relief (5-point categorical scale) at the following time points (pre-dose, if at one of the dosing time points of 0, 8, 12 and/or 16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours after Time 0; and immediately before each dose of rescue medication, if any. For assessments less than 1 hour apart a window of +/-2 min is allowable whilst for assessments at least 1 hour apart a +/-5 min window is allowable.

The double stopwatch method will be used to record the time to perceptible pain relief and time to meaningful pain relief during the 8 hours following the first dose or until subject takes rescue medication. Subjects will complete a global evaluation of study drug 24 hours (+/- 5 minutes) after Time 0 or immediately before the first dose of rescue medication (whichever occurs first). Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at the following times: before surgery, within 30 minutes before Time 0, 12 and 24 hours after Time 0, and/or immediately before the first dose of rescue medication. Adverse events (AEs) will be monitored and recorded from the time of signing of the informed consent form (ICF) until the Follow-up Visit (or Early Termination Visit). During the 24 hours following Time 0, subjects will complete efficacy and safety assessments. Subjects will remain at the study site overnight and will be discharged on Day 2.

Paracetamol / acetaminophen (1000 mg) will be permitted as the initial rescue medication. Subjects will be encouraged to wait at least 60 minutes after receiving study drug before taking rescue medication. If acetaminophen rescue medication is not effective in relieving the subject's pain, 5 mg oxycodone rescue medication may be administered at the discretion of the investigator.

Subjects are not permitted to take any concomitant medications that might confound assessments of pain relief, such as psychotropic drugs, antidepressants, sedative-hypnotics (other than those permitted for conscious sedation), or other analgesics taken within five times of their elimination half-lives (other than those used at the surgery). Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject has been on a stable dose for at least four weeks prior to Visit 1 (screening).

Other restrictions include the following: alcohol use is prohibited from 24 hours before surgery until discharge on Day 2; nothing by mouth from midnight before surgery until 1 hour after surgery; clear liquids only are allowed starting 1 hour after surgery until 1 hour after dosing; 1 hour after dosing, the subject's diet may be advanced according to standard practice.

Upon discharge from the study site, subjects may be prescribed pain medication for use at home according to the standard practice of the study site. On Day 8 (± 2 days), subjects will return to the study site for an abbreviated confirmatory physical assessment and AE assessments.

Arms: arm 1: 2 × 300 mg ibuprofen PR tablets at Hours 0 and 12

2 × placebo of PR tablets at Hours 8 and 16

2 × placebo of IR tablets at Hours 0, 8, 12, and 16 arm 2: 2 × 200 mg ibuprofen IR tablets at Hours 0, 8, and 16

2 × placebo of IR tablets at Hour 12

2 × placebo of PR tablets at Hours 0, 8, 12, and 16 arm 3: 2 × placebo of PR tablets at Hours 0, 8, 12, and 16

2 × placebo of IR tablets at Hours 0, 8, 12, and 16
Interventions: intervention 1: Ibuprofen 300 mg Oral Tablet intervention 2: Ibuprofen 200 mg Oral Tablet intervention 3: Placebo of PR tablet intervention 4: Placebo of IR tablet
Intervention descriptions: intervention 1: 2 × 300 mg tablets at Hours 0 and 12 intervention 2: 2 × 200 mg tablets at Hours 0, 8, and 16 intervention 3: 2 tablets up to four times in 24 hours intervention 4: 2 tablets up to four times in 24 hours

Protocol documents:
Prot_000.pdf: 
Reckitt Benckiser 
Clinical Study Report 5003601 
AD-MW-36.04 18-Jun-2019 
CONFIDENTIAL 
Protocol and Protocol Amendments 
Non-substantial Protocol Amendment 2, Version 4.0, dated 12-May-2020 
Summary of Changes, Version 3.0 to Version 4.0, dated 12-May-2020 
Substantial Protocol Amendment 1, Version 3.0, dated 19-Nov-2019 
Summary of Changes, Version 2.0 to Version 3.0, dated 19-Nov-2019 
Non-substantial Protocol Amendment 1, Version 2.0, dated 19-Jul-2019 
Summary of Changes, Version 1.0 to Version 2.0, dated 19-Jul-2019 
File Note, dated 18-Dec-2018
Final Protocol, Version 1.0, dated 20-Nov-2018 
Page 1 of 276
Study title: A Randomised, Double-Blind, Double-Dummy, 
Parallel-Group, Multiple-Dose, Active and Placebo Controlled 
Efficacy Study of Ibuprofen Prolonged-Release Tablets for the 
Treatment of Pain after Surgical Removal of Impacted Third 
Molars
ClinicalTrials.gov ID: NCT03785756


Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 12-May-2020, FINAL Version 4.0 
Page 1 of 63 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
RECKITT BENCKISER 
STUDY TITLE 
A Randomised, Double-Blind, Double-Dummy, Parallel-Group, Multiple-Dose, Active and 
Placebo Controlled Efficacy Study of Ibuprofen Prolonged-Release Tablets for the Treatment of 
Pain after Surgical Removal of Impacted Third Molars 
Short Study Title 
Efficacy Study of 300mg Ibuprofen Prolonged-Release Tablets for the Treatment of Pain After 
Surgical Removal of Impacted Third Molars 
IND (Investigational New 
Drug) Number: 
141948 
RB Study Number: 
5003601 
CRO Study Number: 
RECK.177369 
Protocol Version and Date: 
FINAL V4.0 / 12-May-2020 
Previous Versions / Date(s): FINAL V3.0 / 19-Nov-2019 
Confidentiality Statement: 
The information contained in this document is privileged and 
confidential. Do not copy, circulate or otherwise distribute 
without written authority from Reckitt Benckiser 
DocuSign Envelope ID: E5C8FB9A-6542-4088-90A8-75E3998F3A16
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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 12-May-2020, FINAL Version 4.0 
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KEY CONTACTS 
Name and title 
Address 
Phone 
e-mail
Sponsor:  
RB Healthcare UK 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom 
+44 (0)1482
326151 
5003601@rb.com 
Sponsor’s Medical 
Expert:  
Neil Fawkes 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom 
+44 (0)1482
5833242 
neil.fawkes@rb.com 
Principal / Chief / 
Coordinating 
Investigator(s): 
Dr Todd Bertoch 
JBR Clinical 
Research 
650 East 4500 South 
Suite 100 
Salt Lake City 
Utah, 84107 
USA 
+ 1 928
8307354 
tbertoch@jbrutah.com 
Sponsors 
Statistician: 
Darren Targett 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom 
N/A 
darren.targett@primoriscs.co.uk 
Contract Research 
Organisation: 
Premier Research 
One Park Drive, 
Suite 150 
Durham, NC 27709 
USA 
+ 1 919 627
9100 
N/A 
CRO Project 
Manager:  
Paul Brittain 
One Park Drive, 
Suite 150 
Durham, NC 27709 
USA 
+ 1 617 934
2233 
paul.brittain@premier-
research.com 
Clinical 
Laboratory: 
Quest Diagnostics, 
Inc. 
3489 W 2100 S, 
Suite 200,  
West Valley City, 
Utah 84119 
USA 
N/A 
N/A 
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Study No: 5003601 
Protocol Version: 12-May-2020, FINAL Version 4.0 
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SIGNATURE PAGE 
Protocol Final Author 
Protocol Statistician 
(Statistics and DM sections reviewed and approved): 
 
 
 
_______________________  ___________ 
 
 
 
_______________________  ___________ 
Mr Stephen Fincham  
Date 
BSc, MSc 
Associate Clinical Study Manager 
RB 
Darren Targett 
Date 
Consultant Statistician 
RB Representative 
Sponsor’s Medical Expert 
(Reviewed and approved): 
Sponsor’s Medical Director 
(Approved to Proceed): 
 
 
 
_______________________  ___________ 
_______________________  ___________ 
Dr. Neil Fawkes, MBChB 
Date 
Clinical Research Physician  
RB  
Bruce Charlesworth, MBChB    Date     
Chief Medical Officer – Health Relief, Hygiene 
and Wellness 
RB 
DocuSign Envelope ID: E5C8FB9A-6542-4088-90A8-75E3998F3A16
1
□ocuS i gned by· 
I Slw,., f'i~ 
l(J 
Signer Name: Steve Fincham 
L 
Signing Reason: I am the author of this document 
Signing Time: 12-05-2020 I 08:06 BST 
BE76143718734BEE968873959AA3DE4C 
1
oocuSigned by: 
j 
Neil Fawkes 
l(J 
Signer Name: Neil Fawkes 
L 
Signing Reason: I approve this document 
Signing Time: 12-05-20201 10:55 BST 
FB E2F9E6498A4252927 4F2F A907 3AD21 
1
oocuSigned by: 
j 
Darren Targett 
l(J 
Signer Name: Darren Targett 
L
S!gn!ng R_eason: I approve this document 
Signing Time: 12-05-2020 I 09:16 BST 
AFBA8AD99F4542D DA 7D 194 D987 EF 1679 
I 
DocuSigned by: 
j 
Bruce Charlesworth 
(J 
Signer Name: Bruce Charlesworth 
L
S!gn!ng R_eason: I have reviewed this document 
Signing Time: 13-05-2020 114:26 BST 
8D51 A4AE69 E E449887C482A 182264320 
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DocuSign Envelope ID: E5C8FB9A-6542-4088-90A8-75E3998F3A 16 
~~ 
lnvestigational Study Protocol 
Study No: 5003601 
I Protocol Version: 12-May-2020, FINAL Version 4.0 I Page 4 of 63 
HlAUH • HYG!lH( • HOM( 
INVESTIGATOR STATEMENT 
I have read and understood this Clinical Study Protocol and agree: 
• 
to conduct this clinical study in accordance with the protocol and to abide by all provisions 
of this protocol (including other manuals and documents referenced from this protocol). 
Amendments to the protocol are acceptable only upon mutual agreement with the 
exception of urgent safety measures that need to be taken to protect study subjects from 
any immediate hazard to their health and safety. 
• 
to conduct this clinical study in accordance with the principles as set out in the Declaration 
of Helsinki and with International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
• 
to conduct this study only after a favourable opinion is obtained from the Independent 
Review Board and Regulatory Authority 
• 
to report all information or data in accordance with the protocol. 
• 
to report any serious adverse events as defined in the "Safety Reporting" section of this 
protocol. 
• 
to handle all clinical supplies provided by the Sponsor and collect and handle all clinical 
specimens in accordance with the protocol. 
I understand: 
• 
that information that identifies me will be used and disclosed as described in the protocol 
and that such information may be transferred to countries that do not have laws protecting 
such information. 
• 
that since the information in the protocol and the references in the Investigator's brochure 
(if applicable) are confidential, its disclosure to any third parties, other than those involved 
in approval, supervision or conduct of the study is prohibited. I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent 
disclosure or access by third parties. 
Principal Investigator 
(Reviewed and Accepted): 
v;:z;;-Q>i 
Todd Bertoch, MD 
Chief Scientific Officer 
JBR Clinical Research 
/ 3 j/U4-f co 2 0 
Date 
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Investigational Study Protocol 
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TABLE OF CONTENTS 
KEY CONTACTS .................................................................................................................. 2 
SIGNATURE PAGE .............................................................................................................. 3 
INVESTIGATOR STATEMENT ............................................................................................. 4 
TABLE OF CONTENTS ........................................................................................................ 5 
LIST OF ABBREVIATIONS ..................................................................................................10 
STUDY SYNOPSIS ..............................................................................................................12 
1 
BACKGROUND AND RATIONALE ....................................................................22 
1.1 
Background for the Study and Rationale ........................................................22 
1.2 
Investigational Product ...................................................................................22 
1.3 
Treatment Rationale ......................................................................................23 
1.4 
Study Population and Indication .....................................................................23 
1.5 
Non-Clinical Evidence ....................................................................................23 
1.6 
Clinical Evidence to Date ...............................................................................24 
1.7 
Risks / Benefits ..............................................................................................24 
1.8 
Ethical Conduct of the Study ..........................................................................25 
2 
STUDY OBJECTIVES .......................................................................................26 
3 
STUDY DESIGN AND RATIONALE FOR DESIGN ............................................26 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................30 
4.1 
Study Population ............................................................................................30 
4.2 
Inclusion Criteria ............................................................................................30 
4.3 
Exclusion Criteria ...........................................................................................30 
4.4 
Subjects of Reproductive Potential ................................................................31 
4.5 
Discontinuation / Withdrawal and Replacement of Subjects ...........................32 
5 
STUDY TREATMENT ........................................................................................33 
5.1 
Investigational Products .................................................................................33 
5.2 
Non-Investigational Products .........................................................................36 
5.3 
Permitted Therapies .......................................................................................36 
5.4 
Treatment Compliance ...................................................................................37 
5.5 
Packaging and Labelling and Supply / Resupply ............................................37 
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5.6 
Storage Conditions ........................................................................................37 
5.7 
Blinding ..........................................................................................................38 
5.8 
Emergency Unblinding Procedures ................................................................38 
5.9 
Drug Accountability ........................................................................................38 
5.10 
Return and Destruction ..................................................................................39 
6 
STUDY PROCEDURES BY VARIABLE .............................................................39 
6.1 
Informed Consent ..........................................................................................39 
6.2 
Randomisation ...............................................................................................39 
6.3 
Drug Administration .......................................................................................39 
6.4 
Demographics ................................................................................................39 
6.5 
Medical History and Concomitant Medication .................................................40 
6.6 
Physical Examination .....................................................................................40 
6.7 
Laboratory Tests ............................................................................................40 
6.8 
Electrocardiograms ........................................................................................41 
6.9 
Vital Signs ......................................................................................................41 
6.10 
Blood Sampling ..............................................................................................41 
6.11 
Oral Radiography ...........................................................................................41 
6.12 
Pain Intensity .................................................................................................41 
6.13 
Stopwatch Assessment ..................................................................................41 
6.14 
Pain Relief Scale ...........................................................................................41 
6.15 
Subject’s Global Evaluation of Study Drug .....................................................42 
6.16 
Adverse Events ..............................................................................................42 
7 
STUDY PROCEDURES BY VISIT .....................................................................42 
7.1 
Study Flow Chart / Table of Study Procedures and Assessments ..................42 
7.2 
Screening Visit (Day -28 to Day -1) ................................................................46 
7.3 
Day of Surgery (Day 1) ..................................................................................46 
 
Pre-Surgery................................................................................................46 
 
Surgery ......................................................................................................47 
 
Post-surgery Eligibility Assessments and Randomisation ...........................47 
 
Dosing and Post-dose Assessments (Hour 0 through Hour 24) .................47 
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7.3.2 
7.3.3 
7.3.4 
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7.4 
Follow-up Visit (Day 8 ± 2 days) or Early Termination ....................................48 
7.5 
Unscheduled Visits ........................................................................................48 
7.6 
Study Restrictions ..........................................................................................48 
 
Prohibited Therapies ..................................................................................48 
 
General and Dietary Restrictions ................................................................48 
8 
SAFETY REPORTING .......................................................................................49 
8.1 
Adverse Event Definitions ..............................................................................49 
8.2 
Assessment of Adverse Events ......................................................................49 
8.3 
Reporting of Adverse Events .........................................................................51 
8.4 
Follow-up of Adverse Events .........................................................................52 
8.5 
Overdose, Abuse, Misuse and Medication Errors ..........................................52 
8.6 
Pregnancy .....................................................................................................53 
9 
STATISTICAL CONSIDERATIONS ...................................................................53 
9.1 
Determination of Sample Size ........................................................................53 
9.2 
Interim Analysis .............................................................................................53 
9.3 
Analysis Datasets ..........................................................................................53 
9.4 
Subject Disposition and Characteristics .........................................................54 
9.5 
Efficacy Analyses ...........................................................................................54 
 
Primary Endpoint(s) ...................................................................................54 
9.5.1.1 
Primary Analysis .....................................................................................54 
9.5.1.2 
Secondary Analysis ................................................................................55 
 
Secondary Endpoints .................................................................................55 
9.5.2.1 
Secondary Endpoint Analyses ................................................................55 
9.6 
Safety Analyses .............................................................................................56 
 
Safety Endpoint(s)......................................................................................56 
9.6.1.1 
Safety Endpoint Analyses .......................................................................56 
9.7 
Handling of Missing Data and Drop-outs ........................................................57 
9.8 
Changes to the Original Statistical Plan .........................................................57 
10 
DATA HANDLING AND RECORD KEEPING ....................................................57 
10.1 
Case Report Forms (CRFs) ...........................................................................57 
10.2 
Specification of Source Documents ...............................................................58 
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7.6.2 
9.5.1 
9.5.2 
9.6.1 
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10.3 
Data Management .........................................................................................58 
10.4 
Reporting of Protocol Deviations ....................................................................58 
10.5 
Retention of Essential Documentation ...........................................................58 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ..........................................59 
11.1 
Monitoring ......................................................................................................59 
11.2 
Audits and Inspections ...................................................................................60 
11.3 
Sponsor Policy on Fraud in Clinical Studies ...................................................60 
12 
ETHICAL AND REGULATORY ASPECTS ........................................................60 
12.1 
Ethics Review and Regulatory Authority Approval..........................................60 
12.2 
Subject Information and Consent ...................................................................61 
12.3 
Early / Premature Termination of the Study ...................................................61 
13 
COMPENSATION, INDEMNITY AND INSURANCE ..........................................62 
13.1 
Clinical Study Agreement ...............................................................................62 
13.2 
Compensation ................................................................................................62 
13.3 
Indemnity .......................................................................................................62 
13.4 
Insurance .......................................................................................................62 
14 
REPORTING, PUBLICATION AND PRESENTATION .......................................62 
15 
REFERENCES ..................................................................................................62 
 
List of Tables Contained in the Body of the Protocol 
Table 3-1 Study Objectives and Endpoints ...........................................................................27 
Table 3-2 Treatment Regimens ............................................................................................29 
Table 5-1 Active Test Product ..............................................................................................33 
Table 5-2 Placebo for Test Product ......................................................................................34 
Table 5-3 Comparator Product .............................................................................................35 
Table 5-4 Placebo for Comparator Product ..........................................................................35 
Table 7-1 Schedule of Assessments ....................................................................................43 
Table 8-1 AE Relationship Descriptions ...............................................................................50 
Table 8-2 AE Severity Descriptions ......................................................................................51 
 
List of Figures Contained in the Body of the Protocol 
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Figure 3.1 Study Design Schematic ......................................................................................27 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Abbreviation in Full 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Plasma Concentration Curve 
BID 
Twice Daily 
BMI 
Body Mass Index 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
eCRF 
Electronic Case Report Form 
FDA 
(US) Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GVG 
Global Vigilance Group 
HDL 
High Density Lipoprotein 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric Rating Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OTC 
Over the Counter 
PID 
Pain Intensity Difference 
PP 
Per Protocol 
PR 
Prolonged Release 
RB 
Reckitt Benckiser 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SNRI 
Serotonin and Noradrenaline Reuptake Inhibitor 
SPID 
Summed Pain Intensity Difference 
SPRID 
Summed Pain Relief and Intensity Difference 
SSRI 
Selective Serotonin Reuptake Inhibitor 
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Abbreviation 
Abbreviation in Full 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent Adverse Event 
TID 
Three Times a Day 
Tmax 
Time to Maximum Plasma Concentration 
TOTPAR 
Sum of Total Pain Relief 
WOCF 
Worst Observation Carried Forward 
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STUDY SYNOPSIS 
Study Title: 
A randomised, double-blind, double-dummy, parallel-group, multiple-
dose, active and placebo-controlled efficacy study of ibuprofen 
prolonged-release tablets for the treatment of pain after surgical 
removal of impacted third molars 
RB Study 
Number: 
5003601 
Background and 
Rationale: 
Reckitt Benckiser (RB) is co-developing a new 300 mg ibuprofen 
prolonged release (PR) tablet with Strides Shasun Ltd. The product 
has been developed to meet consumer and patient needs to have 
access to longer acting over-the-counter analgesics. This PR 
formulation will reduce fluctuations in drug plasma concentrations and 
allow for a lower frequency of administration which is desirable in 
situations where pain duration is expected to be prolonged and require 
multiple doses of immediate release formulations. As a result, the 
product would be more consumer friendly, require less dosing and 
improve compliance with treatment. 
The proposed therapeutic indications of the PR product are for the 
short-term symptomatic treatment of mild to moderate pain such as 
dysmenorrhea, rheumatic pain, muscular pain, pain of non-serious 
arthritic conditions and backache. 
The proposed posology in adults over the age of 18 is: 
Ibuprofen 300 mg PR tablets.  Two tablets to be taken every 12 hours 
when required for pain relief. No more than 2 doses in 24 hours. The 
maximum daily dose is 1200 mg and there is no proposed indication in 
the paediatric population. 
 
Therefore, the purpose of the proposed study is to provide supporting 
pivotal efficacy evidence for registration applications in Europe, 
Australia and Russia. The decision to progress to an efficacy clinical 
trial was determined on the basis of successful outcomes of the 2 
phase 1 clinical trials (BE/17/279 and BE/17/281) in terms of 
bioavailability (BA) versus a reference ibuprofen immediate release 
(IR) product and bioequivalence (BE) versus comparator 600 mg 
ibuprofen PR. 
Objectives:  
Primary Objective:  
 
To evaluate the superiority of 2×300 mg ibuprofen PR tablets 
compared with placebo in subjects experiencing acute 
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moderate to severe pain after third molar extraction over 
12 hours post initial dose. 
Key Secondary Objectives: 
 
To evaluate the analgesic performance of a total daily dose of 
1200 mg of ibuprofen PR formulation compared to ibuprofen 
immediate release (IR) formulation over 24 hours post initial 
dose. 
 
To evaluate the safety and tolerability of 2×300 mg ibuprofen 
PR tablets. 
Additional Secondary Objectives: 
 
To evaluate the total analgesic effect, peak analgesic effect, 
onset and duration of action and the subject’s overall 
assessment of the study medications. 
Design: 
This is a single centre, randomised, double-blind, double-dummy, 
parallel group, multiple-dose, active and placebo-controlled efficacy 
study to evaluate the efficacy and safety of 2×300 mg ibuprofen PR 
tablets in subjects with post-surgical dental pain. 
Primary 
Endpoint: 
The Summed Pain Intensity Difference (SPID) over 0 to 12 hours 
(SPID12) will be used to compare the test product (2×300 mg ibuprofen 
PR tablets) against the placebo product. 
Confirmatory 
Evaluation: 
Clinically relevant difference between placebo and PR ibuprofen over 
12 hours after initial dose (for the purposes of this study, a difference 
of 30 % in PID scores over 12 hours after initial dose will be considered 
clinically relevant).(1)  
Secondary 
Endpoints: 
Key secondary efficacy endpoint: 
 
The summed pain intensity difference (SPID) over 0 to 
24 hours (SPID24) will be used to compare the test product 
(2×300 mg ibuprofen PR tablets twice daily [BID]) and active 
comparator product (2×200 mg ibuprofen IR tablets three times 
a day [TID]). 
Efficacy endpoints: 
 
Summed pain intensity difference (SPID) over 0 to 4 hours 
(SPID4), over 0 to 8 hours (SPID8), and over 0 to 12 hours 
(SPID12) after Time 0 
 
Sum of total pain relief (TOTPAR) over 0 to 4 hours 
(TOTPAR4), over 0 to 8 hours (TOTPAR8), over 0 to 12 hours 
(TOTPAR12), and over 0 to 24 hours (TOTPAR24) after Time 0 
 
Summed pain relief and intensity difference (sum of TOTPAR 
and SPID [SPRID]) over 0 to 4 hours (SPRID4), over 0 to 
8 hours (SPRID8), over 0 to 12 hours (SPRID12), and over 0 to 
24 hours (SPRID24) after Time 0 
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 
Response to study drug (a responder will be defined as a 
subject with ≥30 % improvement in pain intensity without 
rescue medication during the first 8 hours) 
 
Numeric rating scale (NRS) pain intensity difference (PID) at 
each scheduled time point after Time 0 
 
Pain intensity score at each scheduled time point 
 
Pain relief score at each scheduled time point after Time 0 
 
Peak pain relief 
 
Time to onset of analgesia (measured as time to perceptible 
pain relief confirmed by time to meaningful pain relief) using 
double stopwatch 
 
Time to first perceptible pain relief 
 
Time to meaningful pain relief 
 
Time to peak pain relief 
 
Proportion of subjects using rescue medication 
 
Time to first use of rescue medication 
Exploratory endpoint: 
 
Patient’s global evaluation of study drug 
Safety 
Endpoints: 
 
Incidence of treatment-emergent adverse events (TEAEs) 
 
Incidence of clinically relevant changes in vital sign 
measurements 
Subjects: 
Inclusion Criteria 
A subject will be eligible for study entry if all the following inclusion 
criteria are met: 
1) Is male or female ≥ 18 and ≤ 50 years of age. 
2) Requires extraction of 2 or more third molars. At least 1 of the third 
molars must be a fully or partially bone impacted mandibular molar. 
If only 2 molars are removed, then they must be ipsilateral.   
3) Experiences moderate to severe pain intensity within 6 hours after 
surgery, as measured by a numeric rating scale (NRS) score of ≥ 5 
on a 0-10 scale. 
4) Has a body weight ≥ 45 kg and a body mass index (BMI) 
≤ 35 kg/m2. 
5) Female subjects of child-bearing potential must have been using 
an acceptable method of contraception for at least 30 days prior to 
randomization and be willing to continue use until at least 48 hours 
post discharge from the clinic (see Section 4.4). 
To be considered not of child-bearing potential, females must be 
surgically sterile (defined as bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy) or post-menopausal (defined as 
no menses for 12 months without an alternative medical cause). 
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6) Free of clinically significant abnormal findings as determined by 
medical history, physical examination, vital signs, laboratory tests 
and ECG. 
7) Is able to provide written informed consent. 
8) Is willing and able to comply with study requirements (including diet 
and smoking restrictions), complete the pain evaluations, remain 
at the study site overnight, and return for follow-up 7 (± 2) days 
after surgery, (Day 8 ± 2 days). 
Exclusion Criteria 
A subject will not be eligible for study entry if any of the following 
exclusion criteria are met: 
1) Known hypersensitivity reactions or allergy (e.g. asthma, rhinitis, 
angioedema or urticaria) in response to nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen), acetylsalicylic 
acid (aspirin), ingredients of the study drug, or any other drugs 
used in the study, including anaesthetics and antibiotics that may 
be required on the day of surgery. 
2) A history of active or previous peptic ulceration/ haemorrhage, 
gastrointestinal bleeding or perforation, heart failure, renal or 
hepatic failure, uncontrolled hypertension, asthma, nasal polyps, or 
chronic rhinitis. 
3) Has complications from the tooth extraction or any other clinically 
significant medical history that, in the opinion of the investigator, 
would affect the subject’s ability to comply or otherwise 
contraindicate study participation, including but not limited to the 
following: cardiac, respiratory, gastroenterological, neurological, 
psychological, immunological, haematological, oncological, or 
renal disease. 
4) Has undergone another dental surgery within 60 days prior to the 
day of surgery. 
5) A positive urine drugs of abuse screen or alcohol breathalyser test 
at screening and during the study (with the exception of a positive 
drugs of abuse screen that is a consequence of permitted 
prescription medicines). 
6) If female, has a positive pregnancy test at screening (serum) or on 
the day of surgery prior to surgery (urine), or is lactating. 
7) Has known or suspected, (in the opinion of the investigator), history 
of alcoholism or drug abuse within 2 years of screening or evidence 
of tolerance or physical dependence before dosing with study drug. 
8) Taking any concomitant medications that might confound 
assessments of pain relief, such as psychotropic drugs, 
antidepressants, sedative-hypnotics (other than those permitted for 
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conscious sedation), or other analgesics taken within five times of 
their elimination half-lives. Selective serotonin reuptake inhibitors 
(SSRIs) and serotonin and noradrenaline reuptake inhibitors 
(SNRIs) are permitted if the subject has been on a stable dose for 
at least four weeks prior to Visit 1 (screening). 
9) Is considered by the investigator, for any reason (including, but not 
limited to the risks described as precautions, warnings and 
contraindications in the current version of the investigator’s 
brochure for 300 mg ibuprofen PR tablets), to be an unsuitable 
candidate to receive the study drug. 
10) Has a history of chronic use (defined as daily use for > 2 weeks) of 
nonsteroidal 
anti-inflammatory 
(NSAIDs), 
opiates, 
or 
glucocorticoids (except inhaled nasal steroids and topical 
corticosteroids), for any condition within 6 months before dosing 
with study drug.  
11) Has significant difficulties swallowing capsules or tablets or is 
unable to tolerate oral medication. 
12) Subject has received an investigational product or participated in 
another trial involving a marketed or investigational drug in the 30 
days (or for investigational agents with a long half-life, a washout 
of 5 half-lives) prior to first drug administration (washout period 
between studies is defined as the period of time elapsed between 
the last dose of the previous study and first dose for this study). Or 
if the investigator believes that any previous participation in an 
investigational study would be to the detriment of the safety of the 
participant or the conduct of the study. 
13) Enrolment of the Investigator, his / her family members, employees 
and other dependent persons. 
14) Failure to satisfy the investigator of fitness to participate for any 
other reason. 
Products to be 
Evaluated and 
Treatment 
Regimen: 
Test product:  
 
300 mg ibuprofen PR tablets for oral administration 
Reference products:  
 
200 mg ibuprofen IR tablets for oral administration 
 
Placebo (for blinding purposes, two types of placebo tablets will 
be made; one to look like the test product and one to look like 
the reference product) 
Treatment regimens: 
Eligible subjects meeting all study entry criteria will be randomised to 
receive 1 of the following treatments: 
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 
Treatment A: test product; 2×300 mg ibuprofen PR tablets, BID 
(total daily dose 1200 mg) 
 
Treatment B: reference product; 2×200 mg ibuprofen IR 
tablets, TID (total daily dose 1200 mg) 
 
Treatment C: matching placebo tablets 
Methodology: 
This is a single centre, randomised, double blind, double-dummy, 
parallel group-, multiple-dose, active and placebo controlled efficacy 
study to evaluate the efficacy and safety of ibuprofen 2×300 mg 
ibuprofen PR tablets in subjects with post-surgical dental pain. 
Eligible subjects will complete all screening procedures within 28 days 
before the surgery and randomisation. 
At Screening, subjects will provide written informed consent to 
participate in the study before any protocol specified procedures or 
assessments are completed. On Day 1, subjects who continue to be 
eligible for study participation after completing screening procedures 
and assessments will undergo extraction of 2 or more third molars. At 
least 1 of the third molars must be a fully or partially bone impacted 
mandibular molar. If only 2 molars are removed, then they must be 
ipsilateral. 
All subjects will receive local anaesthesia (2% lidocaine with 
1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion 
of the investigator. Subjects who experience moderate to severe pain 
intensity (a score of ≥ 5 on a numeric rating scale [NRS] from 0-10 
where 0 = no pain, 10 = worst pain ever) within 6 hours after surgery 
and who continue to meet all study entry criteria will be randomised in 
a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets every 12 hours 
(Q12h), 2×200 mg ibuprofen IR tablets every 8 hours (Q8h), or 
placebo. The randomisation will be stratified by baseline pain category 
(moderate or severe) using a categorical scale that includes the 
categories of none (0), mild (1-4), moderate (5-7), and severe (8-10).  
Subjects will re-assess their baseline pain intensity using the NRS 
immediately before receiving study drug (pre-dose, Time 0) and their 
pain intensity (NRS) and pain relief (5-point categorical scale) at the 
following time points (pre-dose, if at one of the dosing timepoints of 0, 
8, 12 and/or 16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 
6, 7, 8, 10, 12, 16, and 24 hours after Time 0; and immediately before 
each dose of rescue medication, if any. For assessments less than 
1 hour apart a window of +/-2 min is allowable whilst for assessments 
at least 1 hour apart a +/-5 min window is allowable. 
The double stopwatch method will be used to record the time to 
perceptible pain relief and time to meaningful pain relief during the 
8 hours following the first dose or until subject takes rescue 
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medication. Subjects will complete a global evaluation of study drug 
24 hours (+/- 5 minutes) after Time 0 or immediately before the first 
dose of rescue medication (whichever occurs first). Vital signs will be 
recorded after the subject has been in a sitting position for 3 minutes 
at the following times: before surgery, within 30 minutes before Time 0, 
12 and 24 hours after Time 0, and/or immediately before the first dose 
of rescue medication. Adverse events (AEs) will be monitored and 
recorded from the time of signing of the informed consent form (ICF) 
until the Follow up- Visit (or Early Termination Visit). During the 
24 hours following Time 0, subjects will complete efficacy and safety 
assessments. Subjects will remain at the study site overnight and will 
be discharged on Day 2.  
Paracetamol / acetaminophen (1000 mg) will be permitted as the initial 
rescue medication. Subjects will be encouraged to wait at least 
60 minutes after receiving study drug before taking rescue medication. 
If acetaminophen rescue medication is not effective in relieving the 
subject’s pain, 5 mg oxycodone rescue medication may be 
administered at the discretion of the investigator. 
Subjects are not permitted to take any concomitant medications that 
might confound assessments of pain relief, such as psychotropic 
drugs, antidepressants, sedative-hypnotics (other than those permitted 
for conscious sedation), or other analgesics taken within five times of 
their elimination half-lives (other than those used at the surgery). 
Selective serotonin reuptake inhibitors (SSRIs) and serotonin and 
noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject 
has been on a stable dose for at least four weeks prior to Visit 1 
(screening).  
Other restrictions include the following: alcohol use is prohibited from 
24 hours before surgery until discharge on Day 2; nothing by mouth 
from midnight before surgery until 1 hour after surgery; clear liquids 
only are allowed starting 1 hour after surgery until 1 hour after dosing; 
1 hour after dosing, the subject’s diet may be advanced according to 
standard practice. 
Upon discharge from the study site, subjects may be prescribed pain 
medication for use at home according to the standard practice of the 
study site. On Day 8 (± 2 days), subjects will return to the study site for 
an 
abbreviated 
confirmatory 
physical 
assessment 
and 
AE 
assessments. 
Statistical 
Evaluation: 
Analysis Populations 
The analysis populations include the following: 
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 
The intent-to-treat (ITT) population will consist of all subjects 
who are treated with study drug and who have at least 1 pain 
relief assessment after Time 0. The ITT population is the 
primary population for the efficacy analysis. 
 
The per protocol- (PP) population will consist of all ITT subjects 
who do not incur a major protocol violation that would challenge 
the validity of their data. This population will be utilized to 
evaluate the sensitivity of the primary efficacy analysis. 
 
The safety population will include all subjects who are treated 
with study drug. The safety population is the population for all 
safety assessments. 
Subject Characteristics 
Demographic and baseline characteristics (including date of birth, sex, 
race, weight, height, BMI and medical history) will be summarized for 
each treatment group and for the overall population using descriptive 
statistics. No formal statistical analyses will be performed. 
Efficacy Analyses 
The primary efficacy null hypothesis is that SPID12 for placebo is equal 
to SPID12 for ibuprofen 2×300 mg PR tablets. The primary analysis 
will be an ANCOVA (Analysis of Covariance) model that includes the 
main effect of treatment and the baseline pain score as a covariate and 
will use windowed worst observation carried forward (WOCF) 
imputation for subjects who use rescue medication. The primary 
analysis will be based on a 2-sided test at the significance level of 0.05. 
All other comparisons between the treatment regimens, including 
ibuprofen 2×200 mg IR tablets versus placebo, will be considered 
secondary. No P value adjustment will be made for multiple endpoints 
or multiple comparisons. 
Each efficacy endpoint will be summarized descriptively by treatment 
group. 
For continuous secondary endpoints such as pain intensity score, 
SPID at each scheduled time point, peak pain intensity, TOTPAR4, 
TOTPAR8, TOTPAR12, TOTPAR24, SPID4, SPID8, SPID24, 
SPRID4, SPRID8, SPRID12, and SPRID24, descriptive statistics 
(such as mean, standard deviation, median, minimum, and maximum) 
will be provided for each treatment regimen. Nominal P values from 
ANCOVA models comparing the placebo group with other treatment 
groups, including terms for treatment and baseline pain will be 
provided for SPID, SPRID, and TOTPAR variables, but no formal 
statistical inferences will be drawn on the basis of these tests. 
For ordinal secondary endpoints, such as pain intensity difference at 
each scheduled time point, pain relief at each scheduled time point, 
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peak pain relief, response to study drug, and global evaluation of study 
drug, descriptive summaries will be provided and will include the 
number and percentage of subjects within each category for each 
treatment group. Nominal P values from Fisher’s exact tests (or 
chi-square- tests, as appropriate) comparing the placebo group with 
other treatment groups will be provided for peak pain relief and global 
evaluation of study drug, but no formal statistical inferences will be 
drawn on the basis of these tests. For each time to- event endpoint, 
Kaplan Meier methodology will be used to evaluate the treatment 
effect. Time to onset of analgesia (measured as time to perceptible 
pain relief confirmed by meaningful pain relief) will be based on data 
collected using the double stopwatch method. Time to onset of 
analgesia will be -right censored- at 8 hours for subjects who do not 
experience both perceptible pain relief and meaningful pain relief 
during the 8-hour interval after Time 0. For time to onset of analgesia, 
the comparison of interest will be the ibuprofen 2×300 mg PR group 
versus the ibuprofen 2×200 mg IR group. The summary tables will 
provide the number of subjects analysed, the number of subjects 
censored, estimates for the quartiles, and 95% confidence intervals 
(CIs) for the estimated median and the restricted mean estimate. 
P values from the Wilcoxon or log rank- tests (as appropriate) will also 
be used to compare placebo to the active treatments. 
For the responder analysis and the proportion of subjects using rescue 
medication, logistic regression models that adjust for baseline intensity 
and/or significant demographic variables, if appropriate, will be used to 
evaluate the treatment effect. 
Baseline values are defined as the last measurements taken before 
dosing with a study drug. 
Missing pain assessments for all efficacy analyses will be handled as 
follows: 
 
Missing pain assessments scheduled before the first observed 
assessment will be imputed with the subject’s worst observed 
pain assessment. 
 
Missing intermediate pain assessments will be replaced by 
linear interpolation. 
 
Missing pain assessments at the end of the observation period 
due to premature discontinuation of pain assessments will be 
imputed by carrying forward the last observation prior to that 
missing. 
The primary analysis will use windowed worst observation carried 
forward (WOCF) methodology for subjects who use rescue medication. 
Any pain measurements taken during a period of time in which rescue 
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medication (any intervention used by the participant intended to 
alleviate pain) is active (4 hours) will be replaced by the worst pain 
measurement from time 0 up until when the first dose of rescue 
medication was taken. If the pain score for the windowed observation 
is higher than the worst observed score, it will not be replaced. The 
same approach will be used for the pain relief scores. Any pain 
assessments impacted by the use of prohibited medications/therapies 
and thus needing to implement windowed WOCF will be identified 
during the blinded Data Review Meeting (DRM) prior to database lock 
and study unblinding.  A sensitivity analysis will also be performed, in 
which all pain assessments recorded after the first dose of rescue 
medication has been taken will be disregarded and the rules outlined 
above will be used for missing data. 
All data for assessments other than pain assessments will be analysed 
as collected; missing data due to premature termination or any other 
reason will be left as missing. Additional sensitivity analyses including 
use of rescue medication will be detailed in the Statistical Analysis 
Plan. 
Safety Analysis 
Data listings will be provided for protocol-specified safety data. The 
Medical Dictionary for Regulatory Activities (MedDRA) (Version 19.0 
or higher) will be used to classify all AEs with respect to system organ 
class and preferred term. Adverse event summaries will include only 
TEAEs, which will be summarized for each treatment group.  
For vital sign measurements, descriptive statistics will be provided at 
each scheduled time point for each treatment group. Changes from 
Baseline for vital signs will be calculated for each subject, and 
descriptive statistics will be provided on changes in vital signs from 
Baseline for each treatment group at each scheduled time point after 
Baseline. No formal statistical tests will be performed. 
 
 
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1 
BACKGROUND AND RATIONALE 
1.1 Background for the Study and Rationale 
Reckitt Benckiser (RB) is co-developing a new 300 mg ibuprofen prolonged release (PR) tablet 
with Strides Shasun Ltd. The product has been developed to meet consumer and patient needs 
to have access to longer acting over-the-counter analgesics. This PR formulation will reduce 
fluctuations in drug plasma concentrations and allow for a lower frequency of administration 
which is desirable in situations where pain duration is expected to be prolonged and require 
multiple doses of immediate release formulations. As a result, the product would be more 
consumer friendly, require less dosing and improve compliance with treatment. 
The proposed therapeutic indications of the PR product are for the short-term symptomatic 
treatment of mild to moderate pain such as dysmenorrhea, rheumatic pain, muscular pain, pain 
of non-serious arthritic conditions and backache. 
The proposed posology in adults over the age of 18 is: 
Ibuprofen 300 mg PR tablets.  Two tablets to be taken every 12 hours when required for pain 
relief. No more than 2 doses in 24 hours. The maximum daily dose is 1200 mg and there is 
no proposed indication in the paediatric population. 
 
Therefore, the purpose of the proposed study is to provide supporting pivotal efficacy evidence 
for European, Russian, and Australian applications and not to support any application in the 
USA. This efficacy study will provide further evidence on the safety and efficacy of the product 
in addition to the data obtained in two bioequivalence studies BE/17/279 and BE/17/281. 
1.2 Investigational Product 
Ibuprofen [2-(4-isobutylphenyl) propionic acid] is a non-steroidal anti-inflammatory drug 
(NSAID) with anti-inflammatory, analgesic and anti-pyretic properties (2). It was initially available 
in 1969 as a prescription only medicine, indicated for rheumatoid arthritis, osteoarthritis and 
other chronic painful conditions such as ankylosing spondylitis. Following further research and 
the establishment of a reassuring safety profile, it was launched in 1983 as an over-the-counter 
(OTC) medication, marketed as Nurofen®. 
Absorption of ibuprofen after oral administration is fairly rapid with peak serum concentrations 
occurring within 1 to 2 hours after administration. Ibuprofen is extensively bound to plasma 
proteins (99%) when administered at therapeutic levels and has a plasma half-life of about 
2 hours. Excretion by the kidney is both rapid and complete, but only a small proportion of drug 
is excreted unchanged in urine, the majority being extensively metabolised in the liver to 
2 major inactive metabolites. The pharmacokinetics of ibuprofen has been extensively 
reviewed by Davies (3). 
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1.3 Treatment Rationale 
The treatment of the test product is in line with the proposed posology of the final product and 
the treatment of the active comparator is in line with the posology provided in the label of the 
product. The treatments will be administered orally, as this is the standard route of 
administration for these products. 
 
The following are the treatment regimens of each product in the study: 
 
Treatment A: test product, 2x300 mg PR ibuprofen tablet, twice daily [total daily dose 
1200 mg] 
 
Treatment B: reference product, 2x200 mg IR ibuprofen tablet, three times a day [total 
daily dose 1200 mg] 
 
Treatment C: matching placebo tablets for both the test and reference regimens 
 
The active comparator (Treatment B) currently marketed in a number of geographies including 
a number of different European countries.  It has therefore been chosen to fulfil requirements 
that when it is included in a marketing authorisation dossier as a comparator that it is licenced 
within the EU.     
 
1.4 Study Population and Indication 
The following study population will be invited to participate in this clinical trial: 
Adult participants aged 18 to 50 requiring extraction of 2 or more third molars, at least 1 of 
which must be a fully or partially bone-impacted mandibular molar, (if only 2 molars are 
removed, then they must be ipsilateral), and who experience moderate to severe pain following 
surgery. 
Such population is expected to present pain levels that will allow for assessing the magnitude 
of treatment effect in a low variability setting. 
 
1.5 Non-Clinical Evidence 
No non-clinical evidence is available for the PR tablet.   
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1.6 Clinical Evidence to Date 
A total of 5 single and multiple-dose pharmacokinetic studies (139-15, BE-16-081, BE-16-295, 
BE-17-279, BE-17-281) have been performed with the test product.  These studies 
demonstrated the oral bioavailability (BA) of the ibuprofen PR tablets (dosed at 2x300 mg) is 
comparable to Brufen® (Ibuprofen) IR Tablets (dosed at 3x200 mg) after a single dose and at 
steady state conditions.  In terms of the release profile and absorption, Cmax tends to be slightly 
higher in the IR formulation when compared with the PR formulation [21.96 ±3.87 µg/mL vs 
14.51 ±3.1 µg/mL].  However the Cmax, (Maximum Observed Plasma Concentration), Tmax, 
(Time to Maximum Plasma Concentration) and AUC0-Tmax (Area Under the Plasma 
Concentration Curve) of the PR formulation suggest that’s the onset of action should not be 
any slower than the IR reference when considering the minimum effective concentration of 
ibuprofen (4).  In terms of total exposure (AUC0-∞) the concentration profile is bioequivalent 
between the PR test product and the IR reference product [163.41 ±43.0 µg.h/mL vs 168.59 
±37.7 µg.h/mL].  A food effect is demonstrated when the test product is taken in the fed state, 
with an expected increase in the absorption rate. 
In the 5 PK studies performed (over 200 subjects) only a limited number of mild, transient 
adverse events were reported.   
Summary Outcomes: 
 
The Clinical data available for this reformulation (Ibuprofen 300 mg PR) suggests an 
adequate pharmacokinetic profile to achieve a sufficient therapeutic effect in the 
proposed study 
 
There are no safety concerns with the test product 
 
Ibuprofen 300 mg PR had an increased rate of absorption when administered with food. 
 
Ibuprofen 300 mg PR tablets had a comparable concentration profile to the comparator 
IR product and was bioequivalent based on AUC0-∞ 
 
1.7 Risks / Benefits 
This study has been designed to confirm the therapeutic efficacy of ibuprofen 300 mg PR.  
Participants in this study are subjects aged 18-50 who require the extraction of 2 or more third 
molars, at least 1 of which must be a fully or partially bone impacted mandibular molar.  
Subjects will undergo dental surgery that is equivalent to that of the standard-of-care that would 
be expected for the above condition. They should be otherwise healthy and each subject 
will undergo a full health check as part of the enrolment into the study to confirm that they 
are healthy as defined in this protocol (see Section 4). 
Participants randomised into the placebo arm would not be expected to derive any therapeutic 
benefit from the administration of the placebo tablets. The placebo arm is essential to the study 
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design as it ensures that any conclusion of non-inferiority from the trial is a reflection of the 
true properties of the treatments; that is, it demonstrates the assay sensitivity of the study.  
However, this obviously leaves the participants without adequate analgesia in the post-surgery 
procedure and from an ethical perspective this is mitigated in the study design by the use of 
rescue medication that would be in line with standards of treatment. Although it is hypothesised 
that the investigational medicinal product (IMP) will provide adequate analgesia in the study, 
this cannot be guaranteed, and therefore the use of rescue medication also addresses the 
potential of reduced or lack of efficacy. 
Ibuprofen is an established pharmaceutical ingredient and the adverse reactions associated 
with administration of 1200 mg/24 hour (OTC doses) are well known and documented (2)(5).  
The adverse reactions most frequently occurring with a single dose being nausea, 
gastrointestinal upset, vomiting, diarrhoea, light headedness, dizziness and headache. Rarely, 
more serious reactions have been reported including GI bleeding, ulceration and perforations, 
hypertension and renal failure. When OTC doses of ibuprofen (200-400 mg/dose; 1200 
mg/day) are taken for acute episodes of pain there is an extremely low risk of causing serious 
gastrointestinal events (5).  
The specific 200mg Ibuprofen tablet to be used in this study as the active comparator 
(Treatment B) is marketed in the EU under the Nurofen brand and has an excellent safety 
profile.   
It is not anticipated that the safety profile of ibuprofen will be altered after administration of 
multiple single doses of ibuprofen 300 mg PR in the context of this study.  There are not 
expected to be any drug-drug interactions with the non-investigational medicinal products 
included within the study design. A washout period of at least 6 days is deemed to be sufficient 
prior to the Follow-up/Early Termination Visit to ensure adequate safety monitoring of the IMP. 
The investigation site will have adequate set up, experience and safety measures that would 
be expected of a centre able to perform regular molar extractions. They will also have adequate 
experience in the safety monitoring of participants post dose that would be expected in a 
clinical trial setting.  Therefore, it is considered that the risk related to study procedures are low 
and limited to common adverse events (AEs) related to the dental procedure, administration 
of routine anaesthetics, and discomfort from vital sign measurements.  Any subject that 
experiences immediate complications during the surgery will be excluded from the study. 
Therefore, the overall benefit-risk profile for the use of the investigational product as 
defined in this protocol is considered favourable. 
1.8 Ethical Conduct of the Study 
This study will be conducted in accordance with this protocol and the principles set out in the 
Declaration of Helsinki. It will comply with International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
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2 
STUDY OBJECTIVES 
Primary Objective:  
 
To evaluate the superiority of 2×300 mg ibuprofen PR tablets compared with placebo in 
subjects experiencing acute moderate to severe pain after third molar extraction over 
12 hours post initial dose.  
Key Secondary Objectives: 
 
To evaluate the analgesic performance of a total daily dose of 1200 mg of ibuprofen PR 
formulation compared to ibuprofen IR formulation over 24 hours post initial dose. 
 
To evaluate the safety and tolerability of 2×300 mg ibuprofen PR tablets. 
Additional Secondary Objectives: 
 
To evaluate the total analgesic effect, peak analgesic effect, onset and duration of action 
and the subject’s overall assessment of the study medications. 
3 
STUDY DESIGN AND RATIONALE FOR DESIGN 
This is a single centre randomised, double-blind, double dummy, parallel group, multiple-dose, 
active and placebo-controlled efficacy study to evaluate the efficacy and safety of 2×300 mg 
ibuprofen PR tablets in subjects with post-surgical dental pain. 
The dental pain model used in this study is a robust and well established post-surgical pain 
model that produces pain that is predictable in its character, duration, and intensity(6). The 
model is widely accepted and has a proven record of assay sensitivity (i.e. separating active 
drugs from each other, as well as from placebo). The model is frequently used to evaluate 
NSAID type analgesics. Results from dental pain studies are accepted by the US Food and 
Drug Administration (FDA) and European authorities and have been widely extrapolated to 
other general pain conditions. 
The decision to conduct the study in the United States was taken as suitably qualified and 
experienced test sites could not be found in Europe.  The specific test site has been chosen 
to conduct the study as they have a proven history of quality and safety when conducting 
studies of this type. 
The placebo products have two purposes:  
1. To mask the treatment identify for PR and IR arms  
2. Act as a control arm 
The dose of the test product is the proposed posology of the final product and the dose of the 
active comparator is the posology provided in the label of the product. 
Eligible subjects will be randomised in a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets 
Q12h, 2×200 mg ibuprofen IR tablets Q8h, or placebo. The randomisation will be stratified by 
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baseline pain category (moderate or severe) using a categorical scale that includes the 
categories of none (0), mild (1-4), moderate (5-7), and severe (8-10). The randomisation 
schedule will be prepared by a statistician not otherwise involved in the study. Randomisation 
will be performed using an interactive web response system (IWRS). Access to the unblinding 
codes will be restricted to personnel not otherwise involved in the study and will be available 
to the investigator only in the case of a subject requiring unblinding prior to database lock. 
Figure 3.1 Study Design Schematic 
Screening 
Visit 
Day 
-28 to -1 
 
In-patient Surgical Stay 
 
Follow-up 
Visit 
Day 8± 2 d 
or Early 
Termination 
 
 
 
 
 
Day of Surgery (Day 1) 
Day 2 
 
→ Pre-
surgery 
Surgery 
Post-
surgery 
eligibility 
Randomisation 
& pre-dose 
(Baseline) 
assessments 
Dosing & 
post-dose 
assessments 
24 h 
post-dose 
assessments 
→
 
 
Note: Un-scheduled visits may occur at any point throughout the study 
 
Table 3-1 Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective: 
To evaluate the superiority of 2×300 mg 
ibuprofen PR tablets compared with placebo 
in subjects experiencing acute dental pain 
after third molar extraction over 12 hours 
post initial dose. 
Primary Endpoint:  
The primary efficacy endpoint is the summed 
pain intensity difference (SPID) over the 0 to 
12 hours (SPID12) after Time 0 and will be 
used to compare the test product (2x300 mg 
PR ibuprofen) and the placebo product.  
The clinical relevance of the difference 
between placebo and PR ibuprofen over 
12 hours after initial dose will be evaluated 
as confirmatory evidence (for the purposes 
of this study, a difference of 30% in PID 
scores over 12 hours after initial dose will be 
considered clinically relevant). 
Secondary Efficacy Objectives: 
 To evaluate the analgesic performance 
of a total daily dose of 1200 mg of 
ibuprofen PR formulation compared to 
ibuprofen IR formulation over 24 hours 
post initial dose.  
 To evaluate the total analgesic effect, 
peak analgesic effect, onset and duration 
Key Secondary Efficacy Endpoints: 
 The summed pain intensity difference 
(SPID) over 0 to 24 hours (SPID24) will 
be used to compare the test product 
(2×300 mg ibuprofen PR tablets twice 
daily [BID]) and comparator product 
(2×200 mg ibuprofen IR tablets three 
times a day [TID]). 
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of action and the subject’s overall 
assessment of the study medications. 
Efficacy Endpoints: 
 Summed pain intensity difference (SPID) 
over 0 to 4 hours (SPID4), over 0 to 
8 hours (SPID8), over 0 to 12 hours 
(SPID12), and over 0 to 24 hours 
(SPID24) after Time 0 
 Sum of total pain relief (TOTPAR) over 
0 to 4 hours (TOTPAR4), over 0 to 
8 hours (TOTPAR8), over 0 to 12 hours 
(TOTPAR12), and over 0 to 24 hours 
(TOTPAR24) after Time 0 
 Summed pain relief and intensity 
difference (sum of TOTPAR and SPID 
[SPRID]) over 0 to 4 hours (SPRID4), 
over 0 to 8 hours (SPRID8), over 0 to 
12 hours (SPRID12), and over 0 to 
24 hours (SPRID24) after Time 0 
 Response to study drug (a responder will 
be defined as a subject with ≥30% 
improvement in pain intensity without 
rescue medication during the first 
8 hours) 
 NRS pain intensity difference (PID) at 
each scheduled time point after Time 0 
 Pain intensity score at each scheduled 
time point 
 Pain relief score at each scheduled time 
point after Time 0 
 Peak pain relief 
 Time to onset of analgesia (measured as 
time to perceptible pain relief confirmed 
by time to meaningful pain relief) using 
double stopwatch 
 Time to first perceptible pain relief 
 Time to meaningful pain relief 
 Time to peak pain relief 
 Proportion of subjects using rescue 
medication 
 Time to first use of rescue medication  
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Exploratory Endpoint: 
 Patient’s global evaluation of study drug 
Safety Objective: 
To evaluate the safety and tolerability of 
2×300 mg ibuprofen PR tablets. 
Safety Endpoints: 
 Incidence of treatment-emergent 
adverse events (TEAEs) 
 Incidence of clinically relevant changes 
in vital sign measurements 
 
Subjects in the PR group will take 2×300 mg ibuprofen PR tablets at Hours 0 and 12. Subjects 
in the IR group will take 2×200 mg ibuprofen IR tablets at Hours 0, 8, and 16. To maintain 
double-blinding, at each dosing timepoint (Hours 0, 8, 12, and 16) all subjects will take a total 
of 4 tablets (placebo-only or active plus placebo, depending on randomised treatment group). 
Table 3-2 Treatment Regimens 
 
PR Group 
 
IR Group 
Placebo Group 
Hour 0 
2 PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 8 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 12 
2 PR, 
2 placebo for IR 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 placebo for IR 
Hour 16 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 24 
final assessments 
final assessments 
final assessments 
 
The study will enrol approximately 280 male and female subjects 18-50 years of age who 
experience moderate to severe pain intensity within 6 hours after dental surgery to remove 
2 or more third molars. At least 1 of the third molars must be a fully or partially bone impacted 
mandibular molar. If only 2 molars are removed, they must be ipsilateral. Subjects must satisfy 
all eligibility criteria including providing informed consent and willingness to remain at the clinic 
overnight. 
The study will be conducted in 1 study site in the United States.   
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 Study Population 
The study will enrol approximately 280 male and female subjects. 
 
4.2 Inclusion Criteria 
Only subjects to whom all of the following conditions apply will be included: 
1. Is male or female ≥ 18 and ≤ 50 years of age. 
2. Requires extraction of 2 or more third molars. At least 1 of the third molars must be a 
fully or partially bone-impacted mandibular molar. If only 2 molars are removed, then 
they must be ipsilateral. 
3. Experiences moderate to severe pain intensity within 6 hours after surgery, as 
measured by a numeric rating scale (NRS) score of ≥ 5 on a 0-10 scale. 
4. Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 35 kg/m2. 
5. Female subjects of child-bearing potential must have been using an acceptable 
method of contraception for at least 30 days prior to randomization and be willing to 
continue use until at least 48 hours post discharge from the clinic (see Section 4.4). 
To be considered not of child-bearing potential, females must be surgically sterile 
(defined as bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or post-
menopausal (defined as no menses for 12 months without an alternative medical 
cause). 
6. Free of clinically significant abnormal findings as determined by medical history, 
physical examination, vital signs, laboratory tests and ECG. 
7. Is able to provide written informed consent. 
8. Is willing and able to comply with study requirements (including diet and smoking 
restrictions), complete the pain evaluations, remain at the study site overnight, and 
return for follow-up 7 (± 2) days after surgery, (Day 8 ± 2 days).  
4.3 Exclusion Criteria 
A subject will not be eligible for study entry if any of the following exclusion criteria are met: 
1. Known hypersensitivity reactions or allergy (e.g., asthma, rhinitis, angioedema or 
urticaria) in response to nonsteroidal anti-inflammatory drugs (NSAIDs, including 
ibuprofen), acetylsalicylic acid (aspirin), ingredients of the study drug, or any other 
drugs used in the study, including anaesthetics and antibiotics that may be required 
on the day of surgery. 
2.  A history of active or previous peptic ulceration/ haemorrhage, gastrointestinal 
bleeding or perforation, heart failure, renal or hepatic failure, uncontrolled 
hypertension, asthma, nasal polyps, or chronic rhinitis. 
3. Has complications from the tooth extraction or any other clinically significant medical 
history that, in the opinion of the investigator, would affect the subject’s ability to 
comply or otherwise contraindicate study participation, including but not limited to the 
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following: cardiac, respiratory, gastroenterological, neurological, psychological, 
immunological, haematological, oncological, or renal disease. 
4. Has undergone another dental surgery within 60 days prior to the day of surgery. 
5. A positive urine drugs of abuse screen or alcohol breathalyser test at screening and 
during the study (with the exception of a positive drugs of abuse screen that is a 
consequence of permitted prescription medicines). 
6. If female, has a positive pregnancy test at screening (serum) or on the day of surgery 
prior to surgery (urine), or is lactating. 
7. Has known or suspected, (in the opinion of the investigator), history of alcoholism or 
drug abuse within 2 years of screening or evidence of tolerance or physical 
dependence before dosing with study drug. 
8. Taking any concomitant medications that might confound assessments of pain relief, 
such as psychotropic drugs, antidepressants, sedative-hypnotics (other than those 
permitted for conscious sedation), or other analgesics taken within five times of their 
elimination half-lives. Selective serotonin reuptake inhibitors (SSRIs) and serotonin 
and noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject has been 
on a stable dose for at least four weeks prior to Visit 1 (screening). 
9. Is considered by the investigator, for any reason (including, but not limited to the risks 
described as precautions, warnings and contraindications in the current version of the 
investigator’s brochure [IB] for 300 mg ibuprofen PR tablets), to be an unsuitable 
candidate to receive the study drug. 
10. Has a history of chronic use (defined as daily use for > 2 weeks) of nonsteroidal anti-
inflammatory (NSAIDs), opiates, or glucocorticoids (except inhaled nasal steroids and 
topical corticosteroids), for any condition within 6 months before dosing with study 
drug.  
11. Has significant difficulties swallowing capsules or tablets or is unable to tolerate oral 
medication. 
12. Subject has received an investigational product or participated in another trial 
involving a marketed or investigational drug in the 30 days (or for investigational 
agents with a long half-life, a washout of 5 half-lives) prior to first drug administration 
(washout period between studies is defined as the period of time elapsed between 
the last dose of the previous study and first dose for this study). Or if the investigator 
believes that any previous participation in an investigational study would be to the 
detriment of the safety of the participant or the conduct of the study. 
13. Enrolment of the Investigator, his / her family members, employees and other 
dependent persons. 
14. Failure to satisfy the investigator of fitness to participate for any other reason. 
4.4 Subjects of Reproductive Potential 
Female subjects of childbearing potential must have been using an acceptable method of 
contraception for at least 30 days prior to randomization and be willing to continue use until at 
least 48 hours post discharge from the clinic. An acceptable method of contraception includes:  
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a. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
b. Male or female condom with or without spermicide 
c. Cap, diaphragm or sponge with spermicide 
Alternatively, highly effective methods of contraception are also considered acceptable, such 
as: 
d. Surgical sterilisation 
e. Established use of oral, injected or implanted hormonal methods of contraception 
f. Some intrauterine devices (IUDs) or intrauterine systems (IUSs) 
g. Male sterilisation (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). [For female subjects on the study, the vasectomised male 
partner should be the sole partner for that subject] 
h. True abstinence which is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence such as calendar, ovulation, symptothermal, or post-ovulation 
methods; declaration of abstinence for the duration of the trial; and withdrawal are not 
acceptable methods of contraception. 
4.5 Discontinuation / Withdrawal and Replacement of Subjects  
The Investigator may withdraw the subject from the study at any time. Reasons for removing 
a subject from the study include, but are not limited to: 
 
AEs that in the judgement of the Investigator may cause severe or permanent harm 
(significant clinical deterioration is an AE) 
 
Violation of the study protocol 
 
In the Investigator’s judgement, it is in the subject’s best interest 
 
Subject declines further study participation 
 
If applicable, randomisation code is broken 
If subjects choose to prematurely stop the study prior to the scheduled discharge at Hour 24, 
safety and tolerability assessments must be performed prior to discharge, and, if possible, 
efficacy assessments should be performed. 
If subjects choose to prematurely stop the study after clinic discharge but prior to the follow-up 
visit, at least 2 documented attempts should be made to contact the subjects for follow-up 
assessments which will include the assessments described for the follow-up visit (Section 7.4). 
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5 
STUDY TREATMENT 
5.1 Investigational Products 
Active Test Product 
Ibuprofen PR tablets 300 mg, single oral dose of 600 mg.  A yellow to pale yellow coloured, 
film coated, caplet shaped tablet, debossed as ‘N12’ on one side and plain on the other side. 
Table 5-1 Active Test Product 
Name of Ingredient 
Quantity/Tablet(mg) 
Function 
Reference 
Ibuprofen  
300.00 
Active 
Ph.Eur. 
Silicon dioxide 
3.00 
Glidant/Anti-adherent 
Ph.Eur. 
Hypromellose K4M 
Premium 
62.50 
Rate Controlling Polymer 
Ph.Eur. 
Hypromellose K100 LV 
32.50 
Rate Controlling Polymer 
Ph.Eur. 
Silicified Microcrystalline 
cellulose 50  
100.00 
Filler/Binder 
NF 
Silicified Microcrystalline 
cellulose 90 
50.00 
Filler/Binder 
NF 
Croscarmellose sodium 
17.50 
Disintegrant 
Ph.Eur. 
Glycine 
25.00 
Release Modifier 
Ph.Eur 
Silicon dioxide 
3.00 
Glidant/Anti-adherent 
Ph.Eur. 
Stearic acid 
6.00 
Lubricant 
Ph.Eur. 
Total weight of core 
tablet 
599.50 mg 
Film coating and Polishing  
Opadry Yellow 
15B520019 
7.50 
Coating agent 
In House 
Purified water# 
q.s. 
Coating vehicle 
Ph.Eur. 
Carnauba Wax   
0.025 
Polishing Agent 
Ph.Eur 
Total weight  
607.025 mg 
#   Removed during the process.  
 
 
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Placebo for Test Product 
A yellow to pale yellow coloured, film coated, caplet shaped tablet, debossed as ‘N12’ on one 
side and plain on the other side. 
Table 5-2 Placebo for Test Product 
Ingredient 
mg/tablet Function 
Reference 
Standard 
Core  
Hypromellose K4M Premium 
125.10 
Rate Controlling 
Polymer 
Ph. Eur. 
Hypromellose K100 Premium LV  
65.05 
Rate Controlling 
Polymer 
Ph. Eur. 
Silicified Microcrystalline Cellulose 50 
200.17 
Filler/ Binder 
NF 
Silicified Microcrystalline Cellulose 90 
100.08 
Filler/ Binder 
NF 
Croscarmellose Sodium  
35.03 
Disintegrant 
Ph. Eur. 
Glycine 
50.04 
Release Modifier 
Ph. Eur. 
Silica, Colloidal Hydrated 
12.02 
Glidant/ Anti-adherent 
Ph. Eur. 
Stearic Acid  
12.01 
Lubricant 
Ph. Eur. 
Coating and Polishing  
Opadry Yellow 15B520019 
7.50 
Coating Agent 
In house 
Carnauba Wax  
0.025 
Polishing Agent 
Ph. Eur. 
Processing agent 
Purified Water 
q.s.* 
Coating Vehicle 
Ph. Eur. 
Total 
607.025 
 
 
* Does not remain in final product except traces. Removed during the coating process.  
 
 
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Comparator Product 
Nurofen Ibuprofen acid tablets 200 mg, single oral dose of 400 mg.  A white to off white, 
biconvex, round, sugar coated tablet. 
Table 5-3 Comparator Product 
Name of Ingredient 
Unit Formula 
(mg/tablet) 
Function 
Reference to 
Standards 
Active Ingredient 
 
 
 
Ibuprofen 
200.0 
Active ingredient 
Ph.Eur. 
Other Ingredients 
 
 
 
Croscarmellose Sodium 
30.0 
Disintegrating agent 
Ph.Eur. 
Sodium Lauryl Sulphate 
0.5 
Tablet lubricant 
Ph.Eur. 
Sodium Citrate 
43.5 
Bulk filler 
Ph.Eur. 
Stearic Acid 
2.0 
Tablet lubricant 
Ph.Eur. 
Colloidal Anhydrous Silica 
1.0 
Granule flow aid 
Ph.Eur. 
Tablet Core Weight 
277.0 
 
 
Sugar Coat Ingredients 
 
 
 
Carmellose Sodium 
0.7 
Sugar coat binder 
Ph.Eur. 
Talc 
33.0 
Sugar coat bulking agent 
Ph.Eur. 
Acacia Spray Dried 
0.6 
Sugar coat binder 
Ph.Eur. 
Sucrose 
116.1 
Sugar coat 
Ph.Eur. 
Titanium Dioxide  
1.4 
Colour 
Ph.Eur. 
Macrogol 6000 
0.2 
Tablet polish 
Ph.Eur. 
Purified Water 
ND 
Sugar syrup solvent 
Ph.Eur. 
Coated Tablet Weight 
429.0 
 
 
 
 
Placebo for Comparator Product 
A white to off white, biconvex, round, sugar coated tablet. 
Table 5-4 Placebo for Comparator Product 
Ingredient 
Quantity (%w/w) 
Function 
Reference 
Standard 
Core 
Mannitol 
46.81 
Filler 
Ph. Eur 
Microcrystalline 
Cellulose 
16.14 
Filler 
USP/NF 
Magnesium Stearate 
1.61 
Lubricant 
Ph. Eur. 
Sugar coating 
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Carmellose Sodium 
0.16 
Sugar coat binder 
Ph. Eur 
Talc 
7.69 
Sugar coat bulking 
agent 
Ph. Eur 
Acacia Spray Dried 
0.14 
Sugar coat binder 
Ph. Eur 
Sucrose 
27.06 
Sugar coat 
Ph. Eur 
Titanium Dioxide 
0.33 
Colour 
Ph. Eur 
Macrogol 6000 
0.05 
Tablet polish 
Ph. Eur 
Purified Water* 
ND 
Sugar syrup solvent 
Ph. Eur 
 
Test Product and Placebo for Test Product will be manufactured and packed (primary pack) to 
Good Manufacturing Practice (GMP) standards by Strides Shasun Limited, R.S No 32-34 
PIMS Road, Periyakalpet, Kalapet, Pondicherry, 605014, India and shipped to Investigational 
Materials Supplies Unit (IMSU), RB, Dansom Lane, Hull, HU8 7DS. 
Nurofen Ibuprofen acid (Comparator) and the Placebo for Comparator tablets will be 
manufactured to GMP standards by Reckitt Benckiser, Thane Road, Nottingham, NG90 2DB, 
UK. Both active and placebo tablets will be unprinted for blinding purpose. 
Both the products (Comparator and Placebo) will be primary packed at Sharp Clinical Services, 
Elvicta Business Park, Crichowell, NP8 1DF, UK and shipped to Investigational Materials 
Supplies Unit (IMSU), RB, Dansom Lane, Hull, HU8 7DS. 
The Test Product, Placebo for Test Product, Comparator Product and the Placebo for 
Comparator product will be assembled to GMP standards by the IMSU, RB, Dansom Lane, 
Hull HU8 7DS, and bulk certified by RB Research and Development Qualified Person. All the 
products will be shipped directly from IMSU to the study site.  
5.2 Non-Investigational Products 
In preparation for the surgery, subjects will receive local anaesthesia (2% lidocaine with 
1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion of the investigator.  
5.3 Permitted Therapies 
After randomisation and administration of study drug, paracetamol / acetaminophen (1000 mg) 
will be permitted as the initial rescue medication. Subjects will be encouraged to wait at least 
60 minutes after receiving study drug before taking rescue medication. If acetaminophen 
rescue medication is not effective in relieving the subject’s pain, 5 mg oxycodone rescue 
medication may be administered at the discretion of the investigator.  
At the investigators discretion repeat doses of rescue medication may also be administered as 
required. 
The Investigator or designees will record all medication taken by the subject at the screening 
visit in the subject’s electronic Case Report Form (eCRF). Any medication taken by the subject 
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from the time of giving informed consent through to the end of the subject’s participation in the 
study (last assessment) will be recorded on the concomitant medication page in the eCRF. 
Upon discharge from the study site, subjects may be prescribed pain medication for use at 
home according to the standard practice of the study site.  
5.4 Treatment Compliance 
For the duration of each assessment the subject will remain at the study site under the 
supervision of the Investigator or designees. The Investigator or designees will provide 
supervised drug administration along with clear instructions and support to the subject to 
facilitate the best possible compliance with study requirements. Any non-compliance during 
the study will be observed and recorded by study site staff as a protocol deviation. 
5.5 Packaging and Labelling and Supply / Resupply 
For each subject one pack will be provided containing all required tablets for each dosing 
timepoint.  Each tablet will be held in a blister within the pack.  The pack will clearly show which 
tablets are to be taken at which timepoint. 
All packs regardless of treatment regimen will be the same except for a kit number and will 
therefore not identify the treatment. 
The IMP will be labelled in accordance with EudraLex Volume 4 Good Manufacturing Practice 
(GMP) Guidelines, Annex 13 - Manufacture of Investigational Medicinal Products, parts 26 to 
33 (Labelling) and in accordance with directive 2003/94/EC as amended and including any 
other applicable national/state legislation. The IMP will be labelled in English 
All IMP will be packed and labelled to GMP by the Investigational Material Supplies Unit 
(IMSU), Reckitt Benckiser Healthcare (UK) Ltd, Dansom Lane, Hull, HU8 7DS, UK. IMP will 
be shipped from the IMSU to the study site. 
5.6 Storage Conditions 
The Investigator or designated individual will keep all IMP(s) in a pharmacy or a secure storage 
facility, accessible only to those individuals authorised by the Investigator to dispense the 
medication. 
The Investigator or designated individual will maintain an inventory. This will include the 
description and quantity of IMP(s) received during the course of this study, as well as a record 
of the materials that are dispensed and returned (how much, to whom and when). This 
inventory (“Drug Dispensing Log”) will be subject to review by the study monitor during 
monitoring visits. 
The Investigator agrees not to supply IMP(s) to any person except study personnel and 
patients enrolled in this study. 
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The IMP should be stored between 8-25 °C and is not to be refrigerated or frozen. 
Temperatures must be constantly monitored and readings logged in a temperature log on 
working days.  
The temperature in the secure storage facility will be recorded using a minimum/maximum 
thermometer. If the temperature falls outside the specified range of 8-25 °C, the Sponsor 
should be notified immediately and appropriate action should be agreed and documented. The 
temperature log will be reviewed by the study monitor at each monitoring visit.  
5.7 Blinding 
This study is a double-blind, double dummy study.  There will be two placebo tablets designed 
to be comparable to each of the active products (PR and IR) in both shape, size, colour and 
weight. 
All subjects will receive 4 tablets at each dosing timepoint.  At each timepoint each subject will 
receive 2 tablets that may be either PR or the placebo made to look like PR and 2 tablets that 
may be IR or the placebo made to look like IR. See Table 3-2 Treatment Regimens.  This 
includes those in the placebo arm who will receive 2 placebo tablets designed to look like PR 
and 2 placebo tablets designed to look like IR at all dose timepoints. 
All subject packs will be designed and labelled to ensure blinding is maintained. 
Subjects, investigators and site staff will all be blind to the treatments. 
Unblinding will only occur after database lock or in the case of emergency unblinding, see 
Section 5.8. 
5.8 Emergency Unblinding Procedures 
Treatment unblinding is discouraged if knowledge of the treatment assignment will not 
materially change the planned management of a medical emergency. Unblinding will be 
permitted in a medical emergency that requires immediate knowledge of the subject’s 
treatment assignment. 
For emergency unblinding, study personnel will use the IWRS. If treatment assignment is 
unblinded for an individual subject, study personnel will be notified of that subject’s treatment 
assignment without unblinding the treatment assignments for the remaining subjects in the 
study. Thus, the overall study blind will not be compromised. If a subject’s treatment 
assignment is unblinded, he/she may or may not be asked to withdraw from the study. The 
investigator should make this decision after consultation with the medical monitor. 
5.9 Drug Accountability 
The Investigator will keep all study medication (including rescue medication) in a pharmacy or 
a secure storage facility, accessible only to those individuals authorised by the Investigator to 
dispense the medication. 
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The Investigator or designated individual will maintain an inventory. This will include the 
description and quantity of study drug received during the course of the study, as well as a 
record of the materials that are dispensed and returned (how much, to whom and when). This 
inventory will be subject to review by the study monitor during monitoring visits.  
The Investigator agrees not to supply study drug to any person except study personnel and 
subjects in this study.  
5.10 
Return and Destruction  
The Investigator agrees to conduct a drug-supply inventory, to record the results of this 
inventory (“IMP Removal from Site” form) and to ensure all original IMP containers whether 
empty or containing IMP are sent to RB’s representative at the end of the study. 
RBs representative will then arrange for the appropriate and timely destruction of all containers 
and unused IMP upon confirmation from RB following provision of a full reconciliation by 
Premier (on finalisation of the study report).   
6 
STUDY PROCEDURES BY VARIABLE 
6.1 Informed Consent 
Prior to conducting any study-related activities, written informed consent must be obtained 
from the subject (Section 12.2). 
6.2 Randomisation 
Eligible subjects will be randomised in a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets 
Q12h, 2x200 mg ibuprofen IR tablets Q8h, or placebo using permuted blocks of fixed size. The 
randomisation will be stratified by baseline pain category (moderate or severe) using a 
categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and 
severe (8-10). The randomisation schedule will be prepared by a statistician not otherwise 
involved in the study. Randomisation will be performed using an interactive web response 
system. Access to the unblinding codes will be restricted to personnel not otherwise involved 
in the study and will be available to the investigator only in the case of a subject requiring 
unblinding prior to database lock. 
6.3 Drug Administration 
Subjects will be dosed under clinic supervision to ensure compliance. Prior to dosing, each 
subject will be instructed by the Investigator or clinic staff on how to take the medication. 
 
6.4 Demographics 
Demographic information will be recorded including gender, date of birth and race. 
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6.5 Medical History and Concomitant Medication 
Relevant medical history, including history of current disease and information regarding 
underlying diseases will be recorded. The duration of surgery and all concomitant medication 
taken will be recorded as well as permitted therapies (see Section 5.3). 
6.6 Physical Examination 
A complete physical examination (excluding the genitourinary examination) will be performed 
at Screening. An abbreviated confirmatory physical assessment, including an examination of 
the subject’s mouth and neck, will be performed at the Follow-up Visit (or Early Termination 
Visit). 
Height, weight, and BMI will be assessed at Screening. 
6.7 Laboratory Tests 
The following clinical laboratory tests will be performed at Screening.  
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea 
nitrogen, creatinine, glucose, sodium, potassium, chloride, bicarbonate, 
lactate dehydrogenase, uric acid, urea, inorganic phosphorous, 
cholesterol (total and High Density Lipoprotein (HDL)), triglycerides, 
gamma glutamyl transferase 
Coagulation: 
prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones, leucocyte 
esterase, nitrites (in the event that the dipstick test is positive, red blood 
cells, white blood cells, epithelial cells, crystals, bacteria and casts will 
be examined microscopically) 
Virology: 
hepatitis B, hepatitis C, HIV 
The following laboratory tests will also be performed: 
 
Alcohol breathalyzer test will be performed before surgery on Day 1. 
 
Urine drug screen samples will be collected at Screening and before surgery on Day 1 to 
test for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine 
(PCP), and tetrahydrocannabinol (THC). 
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 
For female subjects of childbearing potential, a blood sample for the serum pregnancy 
test will be collected at Screening and a urine pregnancy test sample will be collected 
before surgery on Day 1. 
Blood and urine samples for hematology, serum chemistry, and urinalysis will be prepared 
using standard procedures and will be sent to a central laboratory for analyses. 
6.8 Electrocardiograms 
A 12-lead electrocardiogram will be performed at Screening. 
6.9 Vital Signs 
Vital signs will be recorded after the subject has been in a sitting position for 3 minutes. Vital 
sign assessments will include blood pressure, heart rate, respiratory rate, and body 
temperature. Clinically significant abnormalities in vital signs should be recorded as AEs. 
6.10 
Blood Sampling 
Blood sampling will be performed according to the site’s standard practices, as described in 
the study manual or other site documentation. 
6.11 
Oral Radiography 
Oral radiographs (X-rays) will be taken at Screening (radiographs taken within 1 year before 
Screening will be acceptable and do not need to be repeated). 
6.12 
Pain Intensity  
Subjects will rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no 
pain and 10 = worst pain ever at the timepoints mentioned on Table 7-1. 
6.13 
Stopwatch Assessment  
Two stopwatches will be started immediately after the subject has swallowed the study drug 
with 8 ounces of water. Each subject will be instructed, “Stop the first stopwatch when you first 
feel any pain relief whatsoever. This does not mean you feel completely better, although you 
might, but when you first feel any relief in the pain you have now” (perceptible pain relief). The 
subject will also be instructed, “Stop the second stopwatch when you feel the pain relief is 
meaningful to you” (meaningful pain relief). If the subject does not press the stopwatches within 
8 hours after Time 0 the subject will discontinue use of the stopwatches. 
6.14 
Pain Relief Scale  
Subjects will rate their pain relief relative to Time 0 using a 5-point categorical scale. Subjects 
will be asked “How much relief have you had since your starting pain?” with response choices 
of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. At each assessment time point, 
the pain intensity NRS assessment will be completed first and the pain relief assessment will 
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be completed second. Subjects will not be able to compare their responses with their previous 
responses. 
6.15 
Subject’s Global Evaluation of Study Drug 
For the global evaluation of study drug, the subject will be asked “How effective do you think 
the study drug is as a treatment for pain?” with response choices of 0 = poor, 1 = fair, 2 = good, 
3 = very good, or 4 = excellent. Subjects will complete the global evaluation of study drug 
24 hours after Time 0 or immediately before the first dose of rescue medication (whichever 
occurs first). 
6.16 
Adverse Events  
During the study the Investigator will ask the subject: “Are you experiencing any symptoms or 
complaints?” at the baseline visit, and “Have you had any symptoms or complaints since the 
last time you were asked?” during the study. In addition, spontaneously reported AEs are 
collected. 
The observation period for an individual subject will start after giving informed consent and will 
finish at the last visit (follow-up visit) for the given individual subject. All AEs that arise during 
the observation period will be recorded and an assessment of the AE will be performed as per 
Section 8.2 by a medically qualified Investigator. If a subject has an AE that is still ongoing at 
the last visit, an attempt will be made by the Investigator to follow this up as per Section 8.4.   
If an untoward medical occurrence happens after the subject has signed the consent form but 
before administration of the IMP, it should be reported as an adverse event, including those 
associated with study procedures. 
Note this does not include any pre-existing medical conditions or findings associated with 
medical history which are identified during the screening process. 
7 
STUDY PROCEDURES BY VISIT 
7.1 Study Flow Chart / Table of Study Procedures and Assessments 
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Table 7-1 Schedule of Assessments 
 
Screening 
(Day -28 to 
Day -1) 
Surgery (Day 1) 
Day 2 
Follow-up 
(Day 8 ±2 days) or 
ETk 
 
 
Pre-
Surgery 
 
Post-surgery 
 
 
 
 
Pre-
dose 
0 h 
15, 30, 
45 min 
1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 
10 h 
12 h 
16 
h 
24h 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Assign a screening number 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xb 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
 
 
 
X 
 
X 
X 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (hematology, 
chemistry, urinalysis) 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test for female subjects of 
childbearing potentiale 
X 
X 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
Alcohol breathalyzer test 
 
X 
 
 
 
 
 
 
 
 
Oral radiographyf 
X 
 
 
 
 
 
 
 
 
 
Review study restrictions with subject 
X 
 
 
 
 
 
 
 
 
 
Pain intensity (NRS)g 
 
 
X 
 
X 
X 
X 
X 
X 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
Dosing with study drug 
 
 
 
0 h 
 
8 h 
12 h 
16h 
 
 
Stopwatch assessmenth 
 
 
 
X 
 
 
 
 
 
 
Pain relief (5-point categorical scale)g 
 
 
 
 
X 
X 
X 
 
X 
 
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Screening 
(Day -28 to 
Day -1) 
Surgery (Day 1) 
Day 2 
Follow-up 
(Day 8 ±2 days) or 
ETk 
 
 
Pre-
Surgery 
 
Post-surgery 
 
 
 
 
Pre-
dose 
0 h 
15, 30, 
45 min 
1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 
10 h 
12 h 
16 
h 
24h 
 
Global evaluation of study drugi 
 
 
 
 
 
 
 
 
X 
 
Concomitant medications 
 
Xb 
X 
X 
X 
X 
X 
 
X 
X 
Adverse eventsj 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Provide prescription for pain medication.  
 
 
 
 
 
 
 
 
X 
 
Collect unused home pain medications, as 
needed 
 
 
 
 
 
 
 
 
 
X 
Discharge from study site 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: BMI=body mass index; ET=early termination; h=hour; min=minute; NRS=numeric rating scale;. 
a Times listed are relative to dosing with study drug. 
b Medical history and concomitant medication use since Screening will be updated on Day 1 before surgery. 
c A complete physical examination (excluding the genitourinary examination) will be performed at Screening. An abbreviated confirmatory physical assessment, 
including an examination of the subject’s mouth and neck, will be performed at the Follow-up Visit (or Early Termination Visit). 
d Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at the following times: at Screening, before surgery, within 30 minutes 
before Time 0, 12 hours after Time 0, 24 hours after Time 0, and/or immediately before the first dose of rescue medication, and at the Follow-up Visit (or Early 
Termination Visit). 
e Serum pregnancy test at Screening and urine pregnancy test before surgery on Day 1 (female subjects of childbearing potential only). Test results must be 
negative for the subject to continue in the study. 
f 
Oral radiographs taken within 1 year before Screening will be acceptable and do not need to be repeated. 
g Pain assessments will be conducted (pre-dose, if at one of the dosing timepoints of 0, 8, 12 or 16 hours) at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 
8, 10, 12, 16 and 24 hours after Time 0 and immediately before each dose of rescue medication. Pain intensity will also be assessed pre-dose. At each 
assessment time point, the pain intensity assessment will be completed first and the pain relief assessment will be completed second. Subjects will not be 
able to compare their responses with their previous responses.  Note for assessments less than 1 hour apart a window of +/-2 min is allowable whilst for 
assessments at least 1 hour apart a +/-5 min window is allowable. 
h Two stopwatches will be started immediately after the subject has swallowed the first dose of study drug with 8 ounces of water (Time 0). Subjects will record 
the time to perceptible and meaningful pain relief, respectively, by stopping the stopwatches. 
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i 
Subjects will complete a global evaluation of study drug 24 hours after Time 0 or immediately before the first dose of rescue medication (whichever occurs 
first). 
j 
Adverse events will be monitored and recorded from the time of signing of the informed consent form until the Follow-up Visit (or Early Termination Visit). 
k If an unscheduled visit occurs the Investigator should follow the activities detailed in Section 7.5. 
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7.2 Screening Visit (Day -28 to Day -1) 
 
Written informed consent 
 
Assign a screening number 
 
Inclusion/exclusion criteria 
 
Demographics 
 
Medical history 
 
Complete physical examination (excluding the genitourinary examination) 
 
Vital signs 
 
Electrocardiogram 
 
Height, weight, and BMI 
 
Clinical laboratory tests (haematology, chemistry, urinalysis) 
 
Serum pregnancy test for female subjects of childbearing potential 
 
Urine drug screen 
 
Oral radiography (oral radiographs taken within 1 year before Screening will be 
acceptable and do not need to be repeated)  
 
Review study restrictions with subject 
 
Schedule surgery 
7.3 Day of Surgery (Day 1) 
 
Pre-Surgery 
 
Inclusion/exclusion criteria review 
 
Medical history review 
 
Vital signs 
 
Urine pregnancy test for female subjects of childbearing potential 
 
Urine drug screen 
 
Alcohol breathalyzer test 
 
Concomitant medications 
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 
Adverse events 
 
Surgery 
 
Subjects who continue to be eligible for study participation after completing screening 
procedures and assessments will undergo extraction of 2 or more third molars. At least 
1 of the third molars must be a fully or partially bone impacted mandibular molar. If only 
2 molars are removed, then they must be ipsilateral.  
 
All subjects will receive local anesthesia (2% lidocaine with 1:100,000 epinephrine).  
 
Nitrous oxide will be allowed at the discretion of the investigator. 
 
Post-surgery Eligibility Assessments and Randomisation 
 
Vital signs 
 
Concomitant medications 
 
Adverse events  
 
Pain intensity NRS  
 
Subjects who experience moderate to severe pain intensity (NRS score of ≥ 5) within 
6 hours after surgery and who continue to meet all study entry criteria will be randomised 
 
Dosing and Post-dose Assessments (Hour 0 through Hour 24) 
 
Subjects will re-assess their baseline pain intensity using the NRS immediately before 
receiving IMP (pre-dose, Time 0) 
 
Administer IMP at the timepoints in Table 3-2 
 
Subjects will assess their pain intensity (NRS) and pain relief (5 point categorical scale) 
at the following time points (pre-dose, if at one of the dosing timepoints of 0, 8, 12 or 
16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours 
after Time 0; and immediately before each dose of rescue medication, if any. For 
assessments less than 1 hour apart a window of +/-2 min is allowable whilst for 
assessments at least 1 hour apart a +/-5 min window is allowable. 
 
Subjects will use the double stopwatch method to record the time to perceptible pain 
relief and time to meaningful pain relief during the 8 hours following the first dose or until 
subject takes rescue medication 
 
Subjects will complete a global evaluation of study drug 24 hours after Time 0 or 
immediately before the first dose of rescue medication (whichever occurs first) 
 
Vital signs will be recorded after the subject has been in a sitting position for 3 minutes 
at the following times: before surgery, within 30 minutes before Time 0, 12 and 24 hours 
after Time 0, and/or immediately before the first dose of rescue medication 
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 
Concomitant medications 
 
Adverse events  
 
Subjects will remain at the study site overnight and will be discharged on Day 2.  
 
Upon discharge from the study site, provide prescription for pain medication.  
 
Schedule follow-up visit 
7.4 Follow-up Visit (Day 8 ± 2 days) or Early Termination 
 
Abbreviated confirmatory physical assessment, including an examination of the 
subject’s mouth and neck 
 
Vital signs 
 
Concomitant medications 
 
Record any post discharge adverse events 
7.5 Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the reason for unscheduled visit, 
including any AEs, concomitant therapy changes, withdrawal (if deemed appropriate) and any 
clinical assessments deemed appropriate for the clinical care of the subject. Unscheduled 
visits should not alter the timing of the routine study schedule. 
7.6 Study Restrictions 
 
Prohibited Therapies 
Subjects are not permitted to take any concomitant medications that might confound 
assessments of pain relief, such as psychotropic drugs, antidepressants, sedative-hypnotics 
(other than those permitted for conscious sedation), or other analgesics taken within five times 
of their elimination half-lives (other than those used at the surgery). Selective serotonin 
reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are 
permitted if the subject has been on a stable dose for at least four weeks prior to Visit 1 
(screening).  
 
General and Dietary Restrictions 
Other restrictions include the following: alcohol use is prohibited from 24 hours before surgery 
until discharge on Day 2; nothing by mouth from midnight before surgery until 1 hour after 
surgery; clear liquids only are allowed starting 1 hour after surgery until 1 hour after dosing; 
1 hour after dosing, the subject’s diet may be advanced according to standard practice. 
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8 
SAFETY REPORTING 
8.1 Adverse Event Definitions 
An Adverse Event (AE)  
An adverse event (AE) is any untoward medical occurrence in a patient or a clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have a causal relationship with  this treatment. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. [ICH E6 1.2].  
Serious Adverse Event (SAE)  
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that:  
 
results in death  
 
is life-threatening 
 
requires in-patient hospitalization or prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity or  
 
is a congenital anomaly/birth defect 
In addition, important medical events that may not be immediately life-threatening or result in 
death, or require hospitalisation, but may jeopardise the patient or may require intervention to 
prevent one of the other outcomes listed above should also usually be considered serious.  
[ICH E2A] Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, 
or development of drug dependency or drug abuse.  
Note: If the event is related to the investigational product and is both serious and unexpected, 
it is classified as a suspected unexpected serious adverse reaction (SUSAR). In case of 
double-blinded studies, unblinding is needed in order to determine a SUSAR. 
8.2 Assessment of Adverse Events 
Any untoward medical occurrences that arise after the subject has given informed consent will 
be recorded in the subject’s source documents and electronic case report forms (eCRFs). 
Untoward medical occurrences can be reported spontaneously by the subject or in response 
to non-leading questioning or observation by the Investigator or be a significant laboratory 
abnormality. 
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Untoward medical occurrences, including all adverse events (AE) and all serious adverse 
events (SAEs) are collected, fully investigated and documented.  
As the study will be conducted on subjects who have been through removal of impacted third 
molars, it is expected that they will present post-surgical symptoms, for example: swelling and 
bruising. For the purposes of this study, when at normal/expected magnitude, such 
occurrences will not be reported as AEs as they are expected and, therefore, are not 
“untoward” as in the AE standard definition. 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at 
study termination will be further followed up until recovery or until stabilisation of the disease 
after termination. 
For each AE a causality assessment of the event to the study drug must be performed. The 
relationship to IMP must be determined by the Investigator (if medically qualified) or by a 
medically qualified Co-Investigator. 
Table 8-1 AE Relationship Descriptions 
Relationship 
Description 
Unassessable/ 
Unclassifiable 
Insufficient information to be able to make an assessment 
Conditional/ 
Unclassified 
Insufficient information to make an assessment at present (causality 
is conditional on additional information) 
Unrelated 
No possibility that the AE was caused by the IMP 
Unlikely 
Slight, but remote, chance that the AE was caused by the IMP, but 
the balance of judgement is that it was most likely not due to the IMP 
Possible 
Reasonable suspicion that the AE was caused by the IMP 
Probable 
Most likely that the AE was caused by the IMP 
Certain 
The AE was definitely caused by the IMP 
 
For each AE a severity description should be given. 
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Table 8-2 AE Severity Descriptions 
Severity 
Description 
Mild 
The AE does not limit usual activities; the subject may experience 
slight discomfort 
Moderate 
The AE results in some limitation of usual activities; the subject may 
experience significant discomfort 
Severe 
The AE results in an inability to carry out usual activities; the subject 
may experience intolerable discomfort or pain 
 
Expectedness for each AE will be determined based on the information in Section 6.9 of the 
Investigator’s Brochure. 
All AEs will be coded by the Sponsor using the most up-to-date version of MedDRA. 
8.3 Reporting of Adverse Events 
In the event of a Serious Adverse Event (SAE), the Investigator must report the event using 
the SAE form to the Sponsor Global Vigilance Group (GVG), by contacting GVG by email: 
gvg@rb.com while copying in the contract research organisation (CRO) and Sponsor 
Project/Study Managers within 24 hours of knowledge of the event. 
The out of hours emergency phone number is +44 (0)1482 326151. An alternative number 
may additionally be provided by Premier Research to give access to the study Medical Monitor 
our of hours. 
This emergency phone number will be confirmed to the Investigator at the Study Initiation Visit.  
All SAE Forms must be provided via email. Any inconsistencies in the information received 
from the Investigator will be clarified using the Adverse Event Data Clarification Form. The 
Investigator must retain a copy of all the SAE forms in the Investigator Site File. 
The Investigator must inform their Institutional Review Board (IRB) of all SAEs occurring in the 
study within 7 days for fatal or life-threatening SAEs and 15 days for all other SAEs as per 
Sponsor instructions and as described in the Safety Management Plan.  
The Investigator should not break the randomisation code except when it is necessary to do 
so in order to ensure the subject receives appropriate medical care. 
SAEs and non-serious AEs will be reported to the appropriate regulatory authorities by the 
Sponsor in accordance with the authorities’ requirements. The Sponsor is responsible for 
expedited reporting of all SUSARs/ SAEs to relevant authorities and IECs/IRBs as required by 
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regulations. If the event requires expedited reporting, a CIOMS (Council for International 
Organizations of Medical Sciences) form will be produced and GVG will take actions as per 
the study specific Safety Management Plan.  
8.4 Follow-up of Adverse Events 
All SAEs and all AEs that have not resolved by the end of the study will be followed up by the 
Investigator until resolution or until the Investigator believes there will be no further change, 
whichever is the earlier. This may involve the subject making additional visits to the site.  
If a subject has unresolved AEs requiring follow-up, investigators must attempt to contact 
subjects by telephone or other means.  
8.5 Overdose, Abuse, Misuse and Medication Errors 
The Sponsor defines “overdose” as the administration of a quantity of an investigational IMP 
given per administration or cumulatively, which is above the maximum recommended dose 
according to the authorised product information. 
The Sponsor defines “abuse” as the persistent or sporadic, intentional excessive use of an 
IMP, which is intended to produce harmful physical or psychological effects e.g. intentional 
overdose to experience psychological effects. 
The Sponsor defines “misuse” as situations where the IMP is intentionally and inappropriately 
used not in accordance with the authorised product information. 
Overdoses, abuse, misuse are reportable to the Sponsor irrespective of the presence of an 
associated AE / SAE. The overdose, abuse, misuse and any associated AE / SAE will be 
captured on an AE CRF (Case Report Form) page / SAE form. 
Due to the full inpatient nature of this study, in which medication doses will be supervised by 
site staff, cases of overdose, abuse or misuse are not expected to occur.  
Medication errors are any unintentional errors in dispensing or administration of the IMP which 
relates to: 
 
Taking / being administered an incorrect IMP 
 
Taking / being administered a drug by the wrong route of administration e.g. swallowing 
a suppository 
 
The accidental administration of the IMP to a person who is not a subject within the 
study 
Medication errors are reportable to the Sponsor irrespective of the presence of an associated 
AE / SAE. Medication errors with or without an associated AE / SAE will be captured on the 
AE CRF page / SAE form. 
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8.6 Pregnancy 
Pregnancy both in a female subject or the female partner of a male subject is considered a 
collectable event and will be recorded as an AE in all cases. It will be qualified as an SAE only 
if it fulfils SAE criteria. 
Due to the full inpatient nature of this study, pregnancy cases are not expected to occur during 
the study.  
 
9 
STATISTICAL CONSIDERATIONS 
This section presents a summary of the planned statistical analyses. A statistical analysis plan 
(SAP) that describes the details of the analyses to be conducted will be written prior to 
database lock. 
Summary statistics for continuous variables will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, summary 
statistics will typically include the number and percentage of subjects in each category. All data 
will be presented in listings. 
Baseline values are defined as the last measurements taken before dosing with study drug. 
9.1 Determination of Sample Size 
The sample size determination is based on the primary efficacy variable, SPID12. According 
to Farrar 2001(1), a clinically important improvement in pain is represented by a 2 point 
reduction on an 11-point NRS. Based on a baseline pain score of 7 this corresponds to an 
approximate 30% reduction in pain. An average 2 point difference in pain scores between 
Ibuprofen PR and placebo across all 14 assessments up to 12 hours will correspond to a 
difference in SPID12 of 24 points. In a previous study (7), the pooled standard deviation (SD) 
for SPID12 was 31.65. Assuming the same variability in this study, a sample size of 40 subjects 
per group will have >90% power to detect a difference of 24 points in SPID12, between 
ibuprofen 2×300-mg PR tablets and placebo using a 2-sided test with an alpha level of 0.05. 
In order to provide a robust estimate of treatment effect differences between PR and IR, and 
to obtain a more precise estimate for this comparison, a 3:3:1 allocation ratio will be used, so 
that 120 subjects are randomised into each of the PR and IR groups. Thus 280 subjects will 
be enrolled into the study. 
9.2 Interim Analysis 
No interim analysis is planned.  
9.3 Analysis Datasets 
The analysis populations include the following: 
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 
The intent-to-treat (ITT) population will consist of all subjects who are treated with 
study drug and who have at least 1 pain relief assessment after Time 0. The ITT 
population is the primary population for the efficacy analysis. 
 
The per-protocol (PP) population will consist of all ITT subjects who do not incur a 
major protocol violation that would challenge the validity of their data. This population 
will be utilized to evaluate the sensitivity of the primary efficacy analysis. 
 
The safety population will include all subjects who are treated with study drug. The 
safety population is the population for all safety assessments. 
 
9.4 Subject Disposition and Characteristics 
The numbers of subjects randomised, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. Demographic and baseline characteristics (including date 
of birth, sex, race, weight, height, BMI, medical history, and surgery duration) will be 
summarized for each treatment group and for the overall population using descriptive statistics. 
No formal statistical analyses will be performed. 
9.5 Efficacy Analyses 
The comparison of primary interest is between PR ibuprofen and placebo. In addition, the 
comparison between IR ibuprofen and placebo will be presented with p-values to demonstrate 
study sensitivity. Point estimates and 95% confidence intervals will be used to evaluate the 
clinical relevance of any differences between the PR and IR formulations. All treatment 
differences will be presented with 95% confidence intervals. No P value adjustment will be 
made for multiple endpoints or multiple comparisons. In the event of model assumptions for 
normality being violated, non-parametric methods will be used. 
Each efficacy endpoint will be summarized descriptively by treatment group. 
 
Primary Endpoint(s) 
The primary endpoint, summed pain intensity difference (SPID) over 0 to 12 hours (SPID12), 
will be used to compare the test product (2×300 mg ibuprofen PR tablets) against the placebo 
product. 
9.5.1.1 
Primary Analysis 
The primary efficacy null hypothesis is that SPID12 for placebo is equal to SPID12 for ibuprofen 
2×300 mg PR tablets. The primary analysis will be an ANCOVA model that includes the main 
effect of treatment and a covariate of the baseline NRS pain score and will use windowed worst 
observation carried forward (WOCF) imputation for subjects who use rescue medication. The 
primary analysis will be based on a 2-sided test at the significance level of 0.05. 
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9.5.1.2 
Secondary Analysis 
The clinical relevance of the difference between placebo and PR ibuprofen over 12 hours after 
initial dose will be evaluated. 
 
Secondary Endpoints 
 
The summed pain intensity difference (SPID) over 0 to 24 hours (SPID24) will be 
used to compare the test product (2×300 mg ibuprofen PR tablets twice daily [BID]) 
and comparator product (2×200 mg ibuprofen IR tablets three times a day [TID]). 
 
Summed pain intensity difference (SPID) over 0 to 4 hours (SPID4), over 0 to 8 hours 
(SPID8), and over 0 to 12 hours (SPID12) after Time 0 
 
Sum of total pain relief (TOTPAR) over 0 to 4 hours (TOTPAR4), over 0 to 8 hours 
(TOTPAR8), over 0 to 12 hours (TOTPAR12), and over 0 to 24 hours (TOTPAR24) 
after Time 0 
 
Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) 
over 0 to 4 hours (SPRID4), over 0 to 8 hours (SPRID8), over 0 to 12 hours 
(SPRID12), and over 0 to 24 hours (SPRID24) after Time 0 
 
Response to study drug (a responder will be defined as a subject with ≥30% 
improvement in pain intensity without rescue medication during the first 8 hours) 
 
Numeric rating scale (NRS) pain intensity difference (PID) at each scheduled time 
point after Time 0 
 
Pain intensity score at each scheduled time point 
 
Pain relief score at each scheduled time point after Time 0 
 
Peak pain relief 
 
Time to onset of analgesia (measured as time to perceptible pain relief confirmed by 
time to meaningful pain relief) using double stopwatch 
 
Time to first perceptible pain relief 
 
Time to meaningful pain relief 
 
Time to peak pain relief 
 
Proportion of subjects using rescue medication 
 
Time to first use of rescue medication  
 
9.5.2.1 
Secondary Endpoint Analyses 
For continuous secondary endpoints such as pain intensity score, SPID at each scheduled 
time point, peak pain intensity, TOTPAR4, TOTPAR8, TOTPAR12, TOTPAR24, SPID4, 
SPID8, SPID24, SPRID4, SPRID8, SPRID12, and SPRID24, descriptive statistics (such as 
mean, standard deviation, median, minimum, and maximum) will be provided for each 
treatment regimen. P values from ANCOVA models comparing the placebo group with other 
treatment groups, including terms for treatment and a covariate for baseline pain will be 
provided for SPID, SPRID, and TOTPAR variables, but no formal statistical inferences will be 
drawn on the basis of these tests. In the event that normality assumptions are violated for a 
parameter, non-parametric analysis methods will be used.  
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For ordinal secondary endpoints, such as pain intensity difference at each scheduled time 
point, pain relief at each scheduled time point, peak pain relief, and global evaluation of study 
drug, descriptive summaries will be provided and will include the number and percentage of 
subjects within each category for each treatment group. Nominal P values from Fisher’s exact 
tests (or chi-square tests, as appropriate) comparing the placebo group with other treatment 
groups will be provided for peak pain relief and global evaluation of study drug, but no formal 
statistical inferences will be drawn on the basis of these tests. 
For each time-to-event endpoint, Kaplan-Meier methodology will be used to evaluate the 
treatment effect. Time to onset of analgesia (measured as time to perceptible pain relief 
confirmed by meaningful pain relief) will be based on data collected using the double stopwatch 
method. Time to onset of analgesia will be right-censored at 8 hours for subjects who do not 
experience both perceptible pain relief and meaningful pain relief during the 8-hour interval 
after Time 0. The summary tables will provide the number of subjects analysed, the number of 
subjects censored, estimates for the quartiles, and 95% confidence intervals (CIs) for the 
estimated median and the restricted mean estimate. P values comparing placebo to active 
treatment from Wilcoxon or log-rank tests (as appropriate) will also be used to examine 
treatment effect. 
For time to onset of analgesia, the comparison of interest will be the ibuprofen 2×300 mg PR 
group versus the ibuprofen 2×200 mg IR group. The summary table for this comparison will 
provide the number of subjects analysed, the number of subjects censored, estimates for the 
quartiles, and 95% confidence intervals (CIs) for the estimated median and the restricted mean 
estimate.  
For the proportion of subjects who are responders and the proportion of subjects using rescue 
medication, logistic regression models that adjust for baseline intensity and/or significant 
demographic variables, if appropriate, will be used to evaluate the treatment effect.   
For the responder analysis, subjects will be censored at 8 hours and for the use of rescue 
medication/time to first rescue subjects will be censored at 24 hours.  
9.6 Safety Analyses 
 
Safety Endpoint(s) 
 
Incidence of treatment-emergent adverse events (TEAEs) 
 
Incidence of changes in vital sign measurements 
9.6.1.1 
Safety Endpoint Analyses 
Data listings will be provided for protocol-specified safety data. The Medical Dictionary for 
Regulatory Activities (MedDRA) (Version 19.0 or higher) will be used to classify all AEs with 
respect to system organ class and preferred term. Adverse event summaries will include only 
TEAEs, which will be summarized for each treatment group.  
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For vital sign measurements, descriptive statistics will be provided at each scheduled time 
point for each treatment group. Changes from Baseline for vital signs will be calculated for 
each subject, and descriptive statistics will be provided on changes in vital signs from Baseline 
for each treatment group at each scheduled time point after Baseline. No formal statistical tests 
will be performed. 
9.7 Handling of Missing Data and Drop-outs 
Missing pain assessments for all efficacy analyses will be handled as follows: 
 
Missing pain assessments scheduled before the first observed assessment will be 
imputed with the subject’s worst observed pain assessment. 
 
Missing intermediate pain assessments will be replaced by linear interpolation. 
 
Missing pain assessments at the end of the observation period due to premature 
discontinuation of pain assessments will be imputed by carrying forward the last 
observation prior to that missing. 
 
The primary analysis will use windowed worst observation carried forward (WOCF) 
methodology for subjects who use rescue medication. Any pain measurements taken during a 
period of time in which rescue medication (any intervention used by the participant intended to 
alleviate pain) is active (4 hours) will be replaced by the worst pain measurement from Time 0 
up until when the first dose of rescue medication was taken. If the pain score for the windowed 
observation is higher than the worst observed score, it will not be replaced. The same approach 
will be used for the pain relief scores. Any other pain assessments impacted by the use of 
prohibited medications/therapies and thus needing to implement windowed WOCF will be 
identified prior to database lock and study unblinding. A sensitivity analysis will also be 
performed, in which all pain assessments recorded after the first dose of rescue medication 
has been taken will be disregarded and the rules outlined above will be used for missing data. 
All data for assessments other than pain assessments will be analysed as collected; missing 
data due to premature termination or any other reason will be left as missing. Additional 
sensitivity analyses including use of rescue medication will be detailed in the Statistical 
Analysis Plan. 
 
9.8 Changes to the Original Statistical Plan 
If there are any deviations to the proposed statistical analysis as described in this protocol 
these will either be documented in the final SAP or in a protocol amendment prior to database 
lock with the rationale and impact of the changes addressed. 
10 
DATA HANDLING AND RECORD KEEPING 
10.1 
Case Report Forms (CRFs) 
Data will be recorded in an electronic Case Report Form (eCRF). For each enrolled study 
subject an eCRF is maintained. The Investigator or designees is responsible for the quality of 
the data record in the eCRF. eCRFs must be kept current to reflect subject status at each 
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phase during the course of study. Subjects must not be identified in the eCRF by name or 
initials.  
In the eCRF subjects will be identified by a subject number in combination with date of birth 
only, i.e., not by their name or initials. eCRF entries must be completed by appropriately trained 
site staff only. A log of trained and authorised staff able to complete the eCRF will be kept. 
10.2 
Specification of Source Documents 
Source data must be available at the site to document the existence of the study subjects. 
Source data must include the original documents relating to the study, as well as the medical 
treatment and medical history of the subject. The investigator and study monitor will identify 
the data that will be recorded directly on the eCRF and for this data the eCRF will be considered 
the source document (i.e., no prior written or electronic record of the data). The study monitor 
will document this at the screening and it will also be documented in the Data Management 
Plan.  
Source documents will include notes taken at the site and will include data such as 
demographic data, participation in study and ICF, medical history, SAEs, AEs and concomitant 
medication, results of examinations and assessments.  
Where source data are in the form of a computer printout (e.g. medical records, laboratory 
data) they will be signed and dated by the investigator or designated person, confirming that 
the print out is a true and faithful record of the data for that subject. These print-outs will be 
filed in the study files. 
The Investigator agrees to provide direct access to source data for study-related monitoring, 
audits, IRB review, and regulatory inspection(s). Direct access to source data requires that the 
subject gives written, documented consent to this. 
10.3 
Data Management 
The data management group at Premier Research will be responsible for data management 
and eCRF activities.  
Full details regarding data management will be described within the Data Management Plan.  
10.4 
Reporting of Protocol Deviations 
Site staff should make the study monitor aware of any deviation from the protocol as soon as 
possible after occurrence. Waivers for inclusion / exclusion criteria are not allowed. 
10.5 
Retention of Essential Documentation 
The Investigator should retain all essential documents (as defined in ICH E6 or according to 
other national and international regulations) until at least 5 years after the completion of the 
study (defined as last subject last visit in the study). These documents should be retained for 
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a longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the Investigator 
when these documents no longer need to be retained. 
Subject files and other source data must be kept for the maximum period of time permitted by 
the Clinical Unit. The Investigator must notify the Sponsor of the retention period if this is 
shorter than described above. 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Monitoring 
The Sponsor will organise regular monitoring visits to be performed at intervals agreed with 
the Investigator. The anticipated monitoring frequency will be stated in the Monitoring Plan. 
Monitoring will also involve, as appropriate, correspondence and telephone contacts. 
On-site monitoring includes source data verification (SDV) which is the procedure whereby the 
data contained in the eCRFs are compared with the primary source data and thereby verified 
as accurate. It will be performed in such a way as to preserve subject confidentiality, taking 
into account all ethical and legislative requirements. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during the monitoring visit to review the data and resolve any queries and to allow direct 
access to the subject’s records for SDV).  
SDV will include as a minimum verification for all subjects, subject identity (date of birth, sex, 
initials and subject number), record of entry into the study and signature of the informed 
consent. In addition, details of SAEs in the subject’s notes will be verified. Details included in 
the subject’s notes as a minimum: 
 
Study number, brief description or title of study 
 
Date that the subject gave written consent 
 
All visit dates 
 
All SAEs 
 
All concomitant medications 
At a site visit the eCRFs should be complete and available in order that the accuracy of their 
completion may be checked. Each completed eCRF for each subject must be signed 
electronically by the Investigator, to verify the data and statements submitted. Similarly, all 
alterations on paper records must be initialled and dated by the Investigator or a designated 
person, explained as necessary, with the original mistake left legible. 
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11.2 
Audits and Inspections 
For the purpose of ensuring compliance with the protocol, ICH GCP and applicable regulatory 
requirements, clinical studies sponsored by RB may be subject to an independent audit at the 
study site which will be conducted by personnel from an appropriate Quality Assurance Unit. 
Full consultation with the Investigator will be made prior to and during such audit, which will be 
conducted according to Quality Assurance Unit Standard Operating Procedures. 
As soon as the Investigator is notified of a planned inspection by a Regulatory Authority, he / 
she must inform the Sponsor promptly and allow the Sponsor to participate in the inspection 
as permitted by applicable regulations and local laws. 
11.3 
Sponsor Policy on Fraud in Clinical Studies 
In accordance with GCP, it is the Sponsor’s policy to always follow-up suspected cases of 
fraud. 
12 
ETHICAL AND REGULATORY ASPECTS 
12.1 
Ethics Review and Regulatory Authority Approval 
Written approval to conduct the study by an independent and appropriately constituted IRB 
must be obtained and a copy provided to the Sponsor before any protocol-related procedures 
that do not form part of the subject’s normal clinical treatment are performed. The approval 
letter must contain: 
 
Name and address of the IRB. 
 
Date of meeting. 
 
Sufficient information to identify the version of the Protocol and subject 
information/informed consent. 
 
Sufficient information to identify the version of other documents reviewed. 
The investigator must also provide the Sponsor with a list of IRB members that includes each 
member’s name and profession. 
Any amendments to the Protocol must be submitted to the IRB for approval unless where 
necessary to eliminate apparent immediate hazards to study subjects, and any administrative 
changes must be notified.  
This study will be submitted to the applicable Regulatory Authorities. The study will only be 
undertaken when regulatory authorisation has been obtained by the Sponsor. 
The Sponsor will notify the Regulatory Authority within 90 days of the end of the study (within 
15 days if the study is terminated prematurely). 
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Premier Research will notify the IRB within 90 days of the end of the study (within 15 days if 
the study is terminated prematurely). 
12.2 
Subject Information and Consent 
Informed consent should be obtained by means of a patient information sheet and ICF, 
prepared in accordance with ICH E6 (R2) section 4.8.10 and the applicable local regulations, 
written in a non-technical language.  All subjects will be provided with oral and written 
information describing the nature and duration of the study and the procedures to be 
performed.  The subject will be asked to sign and date an ICF prior to any study-specific 
procedures being performed.  No subject can enter the study before his/her informed consent 
has been obtained.  A sample subject ICF used in the study will be included in the clinical study 
report for this protocol.  
As part of administering the informed consent document, the Investigator must explain to each 
subject the nature of the study, its purpose, the procedures involved, the expected duration, 
the potential risks and benefits involved, and any potential discomfort.  Each subject must be 
informed that participation in the study is voluntary and that he/she may withdraw from the 
study at any time and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician.  The subject should understand the study, 
patient information sheet, and ICF before signing and dating the ICF.  The Investigator or 
person obtaining consent must also sign and date the form.  Each subject will be given a copy 
of the signed informed consent and written information. 
12.3 
Early / Premature Termination of the Study 
In the unlikely event that this study generates an excessive frequency of adverse events, 
subjects’ termination or suspension may be requested by the sponsor or the IRB or the 
Regulatory Authority. 
The sponsor retains the right to terminate the study for non-safety reasons by giving an 
appropriate period of notice to all involved parties as per contractual agreements. 
Any decisions to terminate or suspend the study will be notified in writing to the Investigator or 
designees, the IRB, Regulatory Authority and the clinicaltrials.gov database. 
If the study is terminated early, study subjects who have attended screening will be informed 
that they are no longer required and if they have any questions, they should consult the study 
site staff. For subjects who have completed the study they will not be informed that the clinical 
study has been terminated. All data collected up to the point of study termination will be used 
in an abbreviated Clinical Investigation Report.  
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CLINICAL STUDY PROTOCOL 
Study No: 5003601 
Protocol Version: 12-May- 2020, FINAL Version 4.0 
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D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
13 
COMPENSATION, INDEMNITY AND INSURANCE 
13.1 
Clinical Study Agreement 
Before the study commences, a contract between the Sponsor and Premier Research, who 
contracts with the Investigator, will be signed in which financial aspects of the study (including 
financial disclosure) as well as responsibilities and obligations are described. 
13.2 
Compensation 
The Sponsor and the CRO carry insurance to pay compensation for injury, accident, ill health 
and death caused by participation in this study without regard to proof of negligence in 
accordance with the current local regulations and requirements. Details on finance and 
insurance will be provided in a separate agreement between the investigator and the sponsor.  
13.3 
Indemnity 
The Sponsor will provide appropriate indemnity for the Investigator and staff who conduct part 
or all of this study, upon request. The request must be received before the first subject is 
recruited. 
13.4 
Insurance 
If required and in accordance with applicable regulatory and legal requirements, the Sponsor 
will take out appropriate insurance policies on behalf of the Investigator and staff who conduct 
part or all of this study and/or on behalf of the subjects participating in the study. 
14 
REPORTING, PUBLICATION AND PRESENTATION 
A clinical study report will be prepared according to ICH E3 (Structure and Content of Clinical 
Study Reports) as part of the Sponsor’s commitment to Good Clinical Practice. The report will 
be a record of the total study conduct and findings and will be subject to approval by the 
Investigator who will sign the final report. 
The study data will be owned by the Sponsor. The Sponsor retains the right to publish the data 
independently of the Investigator. The Sponsor agrees that before it publishes the results, it 
will provide the Investigator with at least 30 days for full review prior to submission of the 
manuscript to the publisher. The Investigator must submit any proposed manuscript to the 
Sponsor for approval prior to submission for publication. 
15 
REFERENCES 
(1) Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of 
changes in chronic pain intensity measured on an 11-point numerical pain rating scale. 
Pain. 2001 Nov; 94(2):149-58. 
(2) Summary of Product Characteristics for Nurofen 200 mg tablets Reckitt Benckiser 
Healthcare Ltd. (PL 00063/0385). 09 November 2015. 
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(3) Davies, NM Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin. 
Pharmacokinetic. 1998, 34 (2), 101-154. 
(4) Lisa Miles, Jessica Hall, Bartosz Jenner, Richard Addis & Simon Hutchings (2018) 
Predicting rapid analgesic onset of ibuprofen salts compared with ibuprofen acid: Tlag, 
Tlow, Tmed, and a novel parameter, TCmax Ref, Current Medical Research and 
Opinion, DOI: 10.1080/03007995.2018.1466697. 
(5) Cooper SA, Desjardins PJ, Turk DC, et al. Research design considerations for single-
dose analgesic clinical trials in acute pain: IMMPACT recommendations. Pain. 2016 
Feb; 157(2):288-301. doi: 10.1097/j.pain.0000000000000375. 
(6) Wyeth Consumer Healthcare. (2002). NDAC Meeting on Risks of NSAIDs. Available: 
https://www.fda.gov/ohrms/dockets/ac/02/briefing/3882b2_04_wyeth-ibuprophen.htm. 
Last accessed 13th March 2018 
(7) Singla, Neil Kumar et al. “A comparison of the clinical and experimental characteristics 
of four acute surgical pain models: Dental extraction, bunionectomy, joint replacement, 
and soft tissue surgery.” PAIN® 155 (2014): 441-456. 
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Investigational Study Protocol Amendment 
Page 1 of 6 
D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
Document Name: 
Non-Substantial Protocol Amendment Number 2 
Version Number & Date: 
Version 1.0 12 May 2020 
Study Number: 
5003601 
Study Title: 
A Randomised, Double-Blind, Double-Dummy, Parallel-Group, 
Multiple-Dose, Active and Placebo Controlled Efficacy Study of 
Ibuprofen Prolonged-Release Tablets for the Treatment of Pain 
after Surgical Removal of Impacted Third Molars 
EudraCT / IND / Other 
Number: 
IND 141948 
Study Type: 
Efficacy 
Protocol Version 
Number: 
From: 
3.0 
To: 
4.0 
Principal Investigator 
Name: 
Todd Bertoch, M.D.
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Investigational Study Protocol Amendment 
Page 2 of 6 
 
 
D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
 
Details of 
Amendment: 
Amendments are required to the Study Synopsis: Statistical Evaluation 
section and section 9.7 Handling of Missing Data and Drop Outs. 
1. Correction of the description of the windowed worst observation 
carried forward (WOCF) method and additional details of sensitivity 
analyses that will be documented in the statistical analysis plan 
2. An update to the time window for pain measurements during 
rescue medication / therapies.  
Section(s) to be Changed:  
Study Synopsis: 
Statistical 
Evaluation 
From: 
The primary analysis will use windowed worst observation carried 
forward (WOCF) methodology for subjects who use rescue 
medication. Any pain measurements taken during a period of 
time in which rescue medication is active (4 hours) will be 
replaced by the last pain measurement before the rescue 
medication was taken. A sensitivity analysis will also be 
performed, in which all pain assessments recorded after the first 
dose of rescue medication has been taken will be disregarded 
and the rules outlined above will be used for missing data. 
All data for assessments other than pain assessments will be 
analysed as collected; missing data due to premature termination 
or any other reason will be left as missing. 
To: 
The primary analysis will use windowed worst observation carried 
forward (WOCF) methodology for subjects who use rescue 
medication. Any pain measurements taken during a period of 
time in which rescue medication (any intervention used by the 
participant intended to alleviate pain) is active (4 hours) will be 
replaced by the worst pain measurement from time 0 up until 
when the first dose of rescue medication was taken. If the pain 
score for the windowed observation is higher than the worst 
observed score, it will not be replaced. The same approach will 
be used for the pain relief scores. Any pain assessments 
impacted by the use of prohibited medications/therapies and thus 
needing to implement windowed WOCF will be identified during 
the blinded Data Review Meeting (DRM) prior to database lock 
and study unblinding. A sensitivity analysis will also be 
performed, in which all pain assessments recorded after the first 
dose of rescue medication has been taken will be disregarded 
and the rules outlined above will be used for missing data. 
All data for assessments other than pain assessments will be 
analysed as collected; missing data due to premature termination 
or any other reason will be left as missing. Additional sensitivity 
analyses including use of rescue medication will be detailed in 
the Statistical Analysis Plan. 
Section 9.7 
Handling of 
From: 
The primary analysis will use windowed worst observation carried 
forward (WOCF) methodology for subjects who use rescue 
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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
Missing Data 
and Dropouts 
medication. Any pain measurements taken during a period of 
time in which rescue medication is active (4 hours) will be 
replaced by the last pain measurement before the rescue 
medication was taken. A sensitivity analysis will also be 
performed, in which all pain assessments recorded after the first 
dose of rescue medication has been taken will be disregarded 
and the rules outlined above will be used for missing data. 
All data for assessments other than pain assessments will be 
analysed as collected; missing data due to premature termination 
or any other reason will be left as missing. In the event of a 
notable difference between treatment groups in the number of 
subjects using rescue medication, other sensitivity analyses may 
be performed. These will be detailed in the Statistical Analysis 
Plan (SAP). 
To: 
The primary analysis will use windowed worst observation carried 
forward (WOCF) methodology for subjects who use rescue 
medication. Any pain measurements taken during a period of 
time in which rescue medication (any intervention used by the 
participant intended to alleviate pain)  is active (4 hours) will be 
replaced by the worst pain measurement from Time 0 up until 
when the first dose of rescue medication was taken. If the pain 
score for the windowed observation is higher than the worst 
observed score, it will not be replaced. The same approach will 
be used for the pain relief scores. Any other pain assessments 
impacted by the use of prohibited medications/therapies and thus 
needing to implement windowed WOCF will be identified prior to 
database lock and study unblinding. A sensitivity analysis will 
also be performed, in which all pain assessments recorded after 
the first dose of rescue medication has been taken will be 
disregarded and the rules outlined above will be used for missing 
data. 
All data for assessments other than pain assessments will be 
analysed as collected; missing data due to premature termination 
or any other reason will be left as missing. Additional sensitivity 
analyses including use of rescue medication will be detailed in 
the Statistical Analysis Plan. 
Reason for  
Changes (in 
green text): 
These changes are not intended to change or replace the analysis 
planned for this study. The method for imputing data for participants who 
had taken rescue medication was correctly detailed in the Statistical 
Analysis Plan (V1.0 07 Oct 2019 Section 6.1.5 Analysis Windows) and the 
Evidence Brief (Feb 2018 Statistical Methods, Efficacy Analysis Section), 
both of which state “The primary analysis will use windowed worst 
observation carried forward (WOCF) methodology for subjects who use 
rescue medication.”  
However, in the protocol the description of the method for imputing data 
for participants who took rescue medication was incorrectly detailed in 
these sections. Therefore, these amendments have been made to correct 
these typographical errors aligning with the SAP, whilst also providing 
DocuSign Envelope ID: E5C8FB9A-6542-4088-90A8-75E3998F3A16
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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
clarity to the description and application of the statistical methodology 
(windowed Worst Observation Carried Forward) to be used. 
Reason for 
Change (in blue 
text): 
The amendment details the intention to conduct multiple sensitivity 
analyses which will be conducted to assess the impact of rescue 
medication. 
Reason for 
Change (in 
purple text): 
This change acknowledges the fact that rescue medication and / or 
therapies other than those specified in the protocol at the discretion of the 
investigator may have been used. 
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Investigational Study Protocol Amendment 
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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
SIGNATURE PAGE 
 
Protocol Author  
Protocol Statistician  
(Statistics and DM sections reviewed and approved):  
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Mr Stephen Fincham  
Date 
BSc, MSc 
Associate Clinical Study Manager 
RB 
Darren Targett 
Date 
Consultant Statistician 
RB Representative 
 
 
 Sponsor’s Medical Expert  
(Reviewed and approved): 
Senior Representative – Medical Science 
(Approved to Proceed):  
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Dr. Neil Fawkes, MBChB 
Date 
Clinical Research Physician  
RB 
Bruce Charlesworth, MBChB    Date             
Chief Medical Officer – Health Relief, Hygiene 
and Wellness 
RB 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: E5C8FB9A-6542-4088-90A8-75E3998F3A16
HEALTH • HYGIENE • HOME 
1 oocuSigned by: 
I S/-w,.,fi~ 
CJ 
Signer Name: Steve Fincham 
L
Signing Reason: I am the author of this document 
Signing Time: 12-05-2020 I 08:06 BST 
BE7614371 B734BEE96BB73959AA3DE4C 
1
oocuSigned by: 
j 
Neil Fawkes 
ll(J 
Signer Name: Neil Fawkes 
L
Signing Reason: I approve this document 
Signing Time: 12-05-2020110:55 BST 
FB E2 F9 E6498A4252927 4 F2F A9073AD21 
1
oocuSigned by: 
j 
Darren Targett 
l(J 
Signer Name: Darren Targett 
L
Signing Reason: I approve this document 
Signing Time: 12-05-2020 I 09:16 BST 
AFBA8AD99F4542DDA 7D194D987EF1679 
1
oocuSigned by: 
j 
Bruce Charlesworth 
ll(J 
Signer Name: Bruce Charlesworth 
L
Signing Reason: I have reviewed this document 
Signing Time: 13-05-2020 I 14:24 BST 
B D51 A4AE69 EE4498B7C482A 182264320 
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DocuSign Envelope ID: E5C8FB9A-6542-4088-90A8-75E3998F3A16 
lnvestigational Study Protocol Amendment 
HEALTH• HYGIENE• HOME 
Page 6 of6 
INVESTIGATOR APPROVAL 
I have read and understood this Clinical Study Protocol Amendment 
Principal Investigator 
(Reviewed and Accepted): 
v~ 
Todd Bertoch, MD 
Chief Scientific Officer 
JBR Clinical Research 
Date 
I 3 MA-/ Zo ? o 
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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 19-Nov-2019, FINAL Version 3.0 
Page 1 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
RECKITT BENCKISER 
 
 
STUDY TITLE 
A Randomised, Double-Blind, Double-Dummy, Parallel-Group, Multiple-Dose, Active and 
Placebo Controlled Efficacy Study of Ibuprofen Prolonged-Release Tablets for the Treatment of 
Pain after Surgical Removal of Impacted Third Molars 
Short Study Title 
Efficacy Study of 300mg Ibuprofen Prolonged-Release Tablets for the Treatment of Pain After 
Surgical Removal of Impacted Third Molars 
IND (Investigational New 
Drug) Number: 
141948 
RB Study Number: 
5003601 
CRO Study Number: 
RECK.177369 
Protocol Version and Date: 
FINAL V3.0 / 19-Nov-2019 
Previous Versions / Date(s): None 
Confidentiality Statement: 
The information contained in this document is privileged and 
confidential. Do not copy, circulate or otherwise distribute 
without written authority from Reckitt Benckiser 
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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 19-Nov-2019, FINAL Version 3.0 
Page 2 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
KEY CONTACTS 
  
Name and title 
Address 
Phone  
e-mail 
Sponsor:  
RB Healthcare UK 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom  
+44 (0)1482 
326151 
5003601@rb.com 
Sponsor’s Medical 
Expert:  
Neil Fawkes 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom 
+44 (0)1482 
5833242 
neil.fawkes@rb.com 
Principal / Chief / 
Coordinating 
Investigator(s): 
Dr Todd Bertoch 
JBR Clinical 
Research 
650 East 4500 South 
Suite 100 
Salt Lake City 
Utah, 84107 
USA 
+ 1 928 
8307354 
tbertoch@jbrutah.com 
Sponsors 
Statistician: 
Darren Targett 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom 
N/A 
darren.targett@primoriscs.co.uk 
Contract Research 
Organisation: 
Premier Research 
One Park Drive, 
Suite 150 
Durham, NC 27709 
USA 
+ 1 919 627 
9100 
N/A 
CRO Project 
Manager:  
Paul Brittain 
One Park Drive, 
Suite 150 
Durham, NC 27709 
USA 
+ 1 617 934 
2233 
paul.brittain@premier-
research.com 
Clinical 
Laboratory: 
Quest Diagnostics, 
Inc. 
3489 W 2100 S, 
Suite 200,  
West Valley City, 
Utah 84119 
USA 
N/A 
N/A 
DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2D4E7D2BD92D
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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 19-Nov-2019, FINAL Version 3.0 
Page 3 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
SIGNATURE PAGE 
 
 
Protocol Final Author  
Protocol Statistician  
(Statistics and DM sections reviewed and approved):  
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Mrs S. Jane Thomas  
Date 
BSc (Hons) 
Senior Clinical Study Manager 
RB 
Darren Targett 
Date 
Consultant Statistician 
RB Representative 
 
 
 
Sponsor’s Medical Expert  
(Reviewed and approved):  
Sponsor’s Medical Director  
(Approved to Proceed):  
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Dr. Neil Fawkes, MBChB 
Date 
Clinical Research Physician  
RB  
Bruce Charlesworth, MBChB    Date             
Chief Medical Officer – Health Relief, Hygiene 
and Wellness 
RB 
 
 
 
 
 
 
 
DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2D4E7D2BD92D
I _1.~. li---------------,-----~------l 
(
DocuSigned by: 
I 
'3.-.M. '"1\,.o~-.. 
l(J 
Signer Name: Jane Thomas 
L
Signing Reason: I am the author of this document 
Signing Time: 19-Nov-2019I18:29:34 PM GMT 
F09BC76EBAC349BDBA7BAD8C6988DDD3 
( 
DocuSigned by: 
I 
Neil Fawkes 
(J 
Signer Name: Neil Fawkes 
L
Signing Reason: I approve this document 
Signing Time: 20-Nov-2019 110:37:34 AM GMT 
FB E2F9 E6498A42 52927 4F2F A9073AD21 
( 
DocuSigned by: 
I 
Darren Targett 
l(J 
Signer Name: Darren Targett 
L
Signing Reason: I approve this document 
Signing Time: 20-Nov-2019 I 08:02:57 AM GMT 
AFBA8AD99F4542DDA 7D 194D987EF1679 
1
oocuSigned by: 
I 
Bruce Charlesworth 
V 
Signer Name: Bruce Charlesworth 
L
Signing Reason: I approve this document 
Signing Time: 25-Nov-2019I14:47:04 PM GMT 
8D51 A4AE69EE449887C482A 182264320 
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DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2O4E702BO92O 
~~ 
lnvestigational Study Protocol 
Study No: 5003601 
I Protocol Version: 19-Nov-2019, FINAL Version 3.0 I Page 4 of 63 
HlAUlf•W'l'Gltfill • HON.I 
INVESTIGATOR STATEMENT 
I have read and understood this Clinical Study Protocol and agree: 
• 
to conduct this clinical study in accordance with the protocol and to abide by all provisions 
of this protocol (including other manuals and documents referenced from this protocol). 
Amendments to the protocol are acceptable only upon mutual agreement with the 
exception of urgent safety measures that need to be taken to protect study subjects from 
any immediate hazard to their health and safety. 
• 
to conduct this clinical study in accordance with the principles as set out in the Declaration 
of Helsinki and with International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
• 
to conduct this study only after a favourable opinion is obtained from the Independent 
Review Board and Regulatory Authority 
• 
to report all information or data in accordance with the protocol. 
• 
to report any serious adverse events as defined in the "Safety Reporting" section of this 
protocol. 
• 
to handle all clinical supplies provided by the Sponsor and collect and handle all clinical 
specimens in accordance with the protocol. 
I understand: 
• 
that information that identifies me will be used and disclosed as described in the protocol 
and that such information may be transferred to countries that do not have laws protecting 
such information. 
• 
that since the information in the protocol and the references in the Investigator's brochure 
(if applicable) are confidential, its disclosure to any third parties, other than those involved 
in approval, supervision or conduct of the study is prohibited. I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent 
disclosure or access by third parties. 
Principal Investigator 
(Reviewed and Accepted): 
1:a:fb,,---
Chief Scientific Officer 
JBR Clinical Research 
r!)Z. D e,,c ?..v/7 
Date 
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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 19-Nov-2019, FINAL Version 3.0 
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D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
TABLE OF CONTENTS 
KEY CONTACTS .................................................................................................................. 2 
SIGNATURE PAGE .............................................................................................................. 3 
INVESTIGATOR STATEMENT ............................................................................................. 4 
TABLE OF CONTENTS ........................................................................................................ 5 
LIST OF ABBREVIATIONS ..................................................................................................10 
STUDY SYNOPSIS ..............................................................................................................12 
1 
BACKGROUND AND RATIONALE ....................................................................22 
1.1 
Background for the Study and Rationale ........................................................22 
1.2 
Investigational Product ...................................................................................22 
1.3 
Treatment Rationale ......................................................................................23 
1.4 
Study Population and Indication .....................................................................23 
1.5 
Non-Clinical Evidence ....................................................................................23 
1.6 
Clinical Evidence to Date ...............................................................................24 
1.7 
Risks / Benefits ..............................................................................................24 
1.8 
Ethical Conduct of the Study ..........................................................................25 
2 
STUDY OBJECTIVES .......................................................................................26 
3 
STUDY DESIGN AND RATIONALE FOR DESIGN ............................................26 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................30 
4.1 
Study Population ............................................................................................30 
4.2 
Inclusion Criteria ............................................................................................30 
4.3 
Exclusion Criteria ...........................................................................................30 
4.4 
Subjects of Reproductive Potential ................................................................31 
4.5 
Discontinuation / Withdrawal and Replacement of Subjects ...........................32 
5 
STUDY TREATMENT ........................................................................................33 
5.1 
Investigational Products .................................................................................33 
5.2 
Non-Investigational Products .........................................................................36 
5.3 
Permitted Therapies .......................................................................................36 
5.4 
Treatment Compliance ...................................................................................37 
5.5 
Packaging and Labelling and Supply / Resupply ............................................37 
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5.6 
Storage Conditions ........................................................................................37 
5.7 
Blinding ..........................................................................................................38 
5.8 
Emergency Unblinding Procedures ................................................................38 
5.9 
Drug Accountability ........................................................................................38 
5.10 
Return and Destruction ..................................................................................39 
6 
STUDY PROCEDURES BY VARIABLE .............................................................39 
6.1 
Informed Consent ..........................................................................................39 
6.2 
Randomisation ...............................................................................................39 
6.3 
Drug Administration .......................................................................................39 
6.4 
Demographics ................................................................................................39 
6.5 
Medical History and Concomitant Medication .................................................40 
6.6 
Physical Examination .....................................................................................40 
6.7 
Laboratory Tests ............................................................................................40 
6.8 
Electrocardiograms ........................................................................................41 
6.9 
Vital Signs ......................................................................................................41 
6.10 
Blood Sampling ..............................................................................................41 
6.11 
Oral Radiography ...........................................................................................41 
6.12 
Pain Intensity .................................................................................................41 
6.13 
Stopwatch Assessment ..................................................................................41 
6.14 
Pain Relief Scale ...........................................................................................41 
6.15 
Subject’s Global Evaluation of Study Drug .....................................................42 
6.16 
Adverse Events ..............................................................................................42 
7 
STUDY PROCEDURES BY VISIT .....................................................................42 
7.1 
Study Flow Chart / Table of Study Procedures and Assessments ..................42 
7.2 
Screening Visit (Day -28 to Day -1) ................................................................46 
7.3 
Day of Surgery (Day 1) ..................................................................................46 
 
Pre-Surgery................................................................................................46 
 
Surgery ......................................................................................................47 
 
Post-surgery Eligibility Assessments and Randomisation ...........................47 
 
Dosing and Post-dose Assessments (Hour 0 through Hour 24) .................47 
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7.3.1 
7.3.2 
7.3.3 
7.3.4 
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7.4 
Follow-up Visit (Day 8 ± 2 days) or Early Termination ....................................48 
7.5 
Unscheduled Visits ........................................................................................48 
7.6 
Study Restrictions ..........................................................................................48 
 
Prohibited Therapies ..................................................................................48 
 
General and Dietary Restrictions ................................................................48 
8 
SAFETY REPORTING .......................................................................................49 
8.1 
Adverse Event Definitions ..............................................................................49 
8.2 
Assessment of Adverse Events ......................................................................49 
8.3 
Reporting of Adverse Events .........................................................................51 
8.4 
Follow-up of Adverse Events .........................................................................52 
8.5 
Overdose, Abuse, Misuse and Medication Errors ..........................................52 
8.6 
Pregnancy .....................................................................................................53 
9 
STATISTICAL CONSIDERATIONS ...................................................................53 
9.1 
Determination of Sample Size ........................................................................53 
9.2 
Interim Analysis .............................................................................................53 
9.3 
Analysis Datasets ..........................................................................................53 
9.4 
Subject Disposition and Characteristics .........................................................54 
9.5 
Efficacy Analyses ...........................................................................................54 
 
Primary Endpoint(s) ...................................................................................54 
9.5.1.1 
Primary Analysis .....................................................................................54 
9.5.1.2 
Secondary Analysis ................................................................................55 
 
Secondary Endpoints .................................................................................55 
9.5.2.1 
Secondary Endpoint Analyses ................................................................55 
9.6 
Safety Analyses .............................................................................................56 
 
Safety Endpoint(s)......................................................................................56 
9.6.1.1 
Safety Endpoint Analyses .......................................................................56 
9.7 
Handling of Missing Data and Drop-outs ........................................................57 
9.8 
Changes to the Original Statistical Plan .........................................................57 
10 
DATA HANDLING AND RECORD KEEPING ....................................................57 
10.1 
Case Report Forms (CRFs) ...........................................................................57 
10.2 
Specification of Source Documents ...............................................................58 
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7.6.1 
7.6.2 
9.5.1 
9.5.2 
9.6.1 
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10.3 
Data Management .........................................................................................58 
10.4 
Reporting of Protocol Deviations ....................................................................58 
10.5 
Retention of Essential Documentation ...........................................................58 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ..........................................59 
11.1 
Monitoring ......................................................................................................59 
11.2 
Audits and Inspections ...................................................................................59 
11.3 
Sponsor Policy on Fraud in Clinical Studies ...................................................60 
12 
ETHICAL AND REGULATORY ASPECTS ........................................................60 
12.1 
Ethics Review and Regulatory Authority Approval..........................................60 
12.2 
Subject Information and Consent ...................................................................61 
12.3 
Early / Premature Termination of the Study ...................................................61 
13 
COMPENSATION, INDEMNITY AND INSURANCE ..........................................61 
13.1 
Clinical Study Agreement ...............................................................................61 
13.2 
Compensation ................................................................................................62 
13.3 
Indemnity .......................................................................................................62 
13.4 
Insurance .......................................................................................................62 
14 
REPORTING, PUBLICATION AND PRESENTATION .......................................62 
15 
REFERENCES ..................................................................................................62 
 
List of Tables Contained in the Body of the Protocol 
Table 3-1 Study Objectives and Endpoints ...........................................................................27 
Table 3-2 Treatment Regimens ............................................................................................29 
Table 5-1 Active Test Product ..............................................................................................33 
Table 5-2 Placebo for Test Product ......................................................................................34 
Table 5-3 Comparator Product .............................................................................................35 
Table 5-4 Placebo for Comparator Product ..........................................................................35 
Table 7-1 Schedule of Assessments ....................................................................................43 
Table 8-1 AE Relationship Descriptions ...............................................................................50 
Table 8-2 AE Severity Descriptions ......................................................................................51 
 
List of Figures Contained in the Body of the Protocol 
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Figure 3.1 Study Design Schematic ......................................................................................27 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Abbreviation in Full 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Plasma Concentration Curve 
BID 
Twice Daily 
BMI 
Body Mass Index 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
eCRF 
Electronic Case Report Form 
FDA 
(US) Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GVG 
Global Vigilance Group 
HDL 
High Density Lipoprotein 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric Rating Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OTC 
Over the Counter 
PID 
Pain Intensity Difference 
PP 
Per Protocol 
PR 
Prolonged Release 
RB 
Reckitt Benckiser 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SNRI 
Serotonin and Noradrenaline Reuptake Inhibitor 
SPID 
Summed Pain Intensity Difference 
SPRID 
Summed Pain Relief and Intensity Difference 
SSRI 
Selective Serotonin Reuptake Inhibitor 
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Abbreviation 
Abbreviation in Full 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent Adverse Event 
TID 
Three Times a Day 
Tmax 
Time to Maximum Plasma Concentration 
TOTPAR 
Sum of Total Pain Relief 
WOCF 
Worst Observation Carried Forward 
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STUDY SYNOPSIS 
Study Title: 
A randomised, double-blind, double-dummy, parallel-group, multiple-
dose, active and placebo-controlled efficacy study of ibuprofen 
prolonged-release tablets for the treatment of pain after surgical 
removal of impacted third molars 
RB Study 
Number: 
5003601 
Background and 
Rationale: 
Reckitt Benckiser (RB) is co-developing a new 300 mg ibuprofen 
prolonged release (PR) tablet with Strides Shasun Ltd. The product 
has been developed to meet consumer and patient needs to have 
access to longer acting over-the-counter analgesics. This PR 
formulation will reduce fluctuations in drug plasma concentrations and 
allow for a lower frequency of administration which is desirable in 
situations where pain duration is expected to be prolonged and require 
multiple doses of immediate release formulations. As a result, the 
product would be more consumer friendly, require less dosing and 
improve compliance with treatment. 
The proposed therapeutic indications of the PR product are for the 
short-term symptomatic treatment of mild to moderate pain such as 
dysmenorrhea, rheumatic pain, muscular pain, pain of non-serious 
arthritic conditions and backache. 
The proposed posology in adults over the age of 18 is: 
Ibuprofen 300 mg PR tablets.  Two tablets to be taken every 12 hours 
when required for pain relief. No more than 2 doses in 24 hours. The 
maximum daily dose is 1200 mg and there is no proposed indication in 
the paediatric population. 
 
Therefore, the purpose of the proposed study is to provide supporting 
pivotal efficacy evidence for registration applications in Europe, 
Australia and Russia. The decision to progress to an efficacy clinical 
trial was determined on the basis of successful outcomes of the 2 
phase 1 clinical trials (BE/17/279 and BE/17/281) in terms of 
bioavailability (BA) versus a reference ibuprofen immediate release 
(IR) product and bioequivalence (BE) versus comparator 600 mg 
ibuprofen PR. 
Objectives:  
Primary Objective:  
 
To evaluate the superiority of 2×300 mg ibuprofen PR tablets 
compared with placebo in subjects experiencing acute 
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moderate to severe pain after third molar extraction over 
12 hours post initial dose. 
Key Secondary Objectives: 
 
To evaluate the analgesic performance of a total daily dose of 
1200 mg of ibuprofen PR formulation compared to ibuprofen 
immediate release (IR) formulation over 24 hours post initial 
dose. 
 
To evaluate the safety and tolerability of 2×300 mg ibuprofen 
PR tablets. 
Additional Secondary Objectives: 
 
To evaluate the total analgesic effect, peak analgesic effect, 
onset and duration of action and the subject’s overall 
assessment of the study medications. 
Design: 
This is a single centre, randomised, double-blind, double-dummy, 
parallel group, multiple-dose, active and placebo-controlled efficacy 
study to evaluate the efficacy and safety of 2×300 mg ibuprofen PR 
tablets in subjects with post-surgical dental pain. 
Primary 
Endpoint: 
The Summed Pain Intensity Difference (SPID) over 0 to 12 hours 
(SPID12) will be used to compare the test product (2×300 mg ibuprofen 
PR tablets) against the placebo product. 
Confirmatory 
Evaluation: 
Clinically relevant difference between placebo and PR ibuprofen over 
12 hours after initial dose (for the purposes of this study, a difference 
of 30 % in PID scores over 12 hours after initial dose will be considered 
clinically relevant).(1)  
Secondary 
Endpoints: 
Key secondary efficacy endpoint: 
 
The summed pain intensity difference (SPID) over 0 to 
24 hours (SPID24) will be used to compare the test product 
(2×300 mg ibuprofen PR tablets twice daily [BID]) and active 
comparator product (2×200 mg ibuprofen IR tablets three times 
a day [TID]). 
Efficacy endpoints: 
 
Summed pain intensity difference (SPID) over 0 to 4 hours 
(SPID4), over 0 to 8 hours (SPID8), and over 0 to 12 hours 
(SPID12) after Time 0 
 
Sum of total pain relief (TOTPAR) over 0 to 4 hours 
(TOTPAR4), over 0 to 8 hours (TOTPAR8), over 0 to 12 hours 
(TOTPAR12), and over 0 to 24 hours (TOTPAR24) after Time 0 
 
Summed pain relief and intensity difference (sum of TOTPAR 
and SPID [SPRID]) over 0 to 4 hours (SPRID4), over 0 to 
8 hours (SPRID8), over 0 to 12 hours (SPRID12), and over 0 to 
24 hours (SPRID24) after Time 0 
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 
Response to study drug (a responder will be defined as a 
subject with ≥30 % improvement in pain intensity without 
rescue medication during the first 8 hours) 
 
Numeric rating scale (NRS) pain intensity difference (PID) at 
each scheduled time point after Time 0 
 
Pain intensity score at each scheduled time point 
 
Pain relief score at each scheduled time point after Time 0 
 
Peak pain relief 
 
Time to onset of analgesia (measured as time to perceptible 
pain relief confirmed by time to meaningful pain relief) using 
double stopwatch 
 
Time to first perceptible pain relief 
 
Time to meaningful pain relief 
 
Time to peak pain relief 
 
Proportion of subjects using rescue medication 
 
Time to first use of rescue medication 
Exploratory endpoint: 
 
Patient’s global evaluation of study drug 
Safety 
Endpoints: 
 
Incidence of treatment-emergent adverse events (TEAEs) 
 
Incidence of clinically relevant changes in vital sign 
measurements 
Subjects: 
Inclusion Criteria 
A subject will be eligible for study entry if all the following inclusion 
criteria are met: 
1) Is male or female ≥ 18 and ≤ 50 years of age. 
2) Requires extraction of 2 or more third molars. At least 1 of the third 
molars must be a fully or partially bone impacted mandibular molar. 
If only 2 molars are removed, then they must be ipsilateral.   
3) Experiences moderate to severe pain intensity within 6 hours after 
surgery, as measured by a numeric rating scale (NRS) score of ≥ 5 
on a 0-10 scale. 
4) Has a body weight ≥ 45 kg and a body mass index (BMI) 
≤ 35 kg/m2. 
5) Female subjects of child-bearing potential must have been using 
an acceptable method of contraception for at least 30 days prior to 
randomization and be willing to continue use until at least 48 hours 
post discharge from the clinic (see Section 4.4). 
To be considered not of child-bearing potential, females must be 
surgically sterile (defined as bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy) or post-menopausal (defined as 
no menses for 12 months without an alternative medical cause). 
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6) Free of clinically significant abnormal findings as determined by 
medical history, physical examination, vital signs, laboratory tests 
and ECG. 
7) Is able to provide written informed consent. 
8) Is willing and able to comply with study requirements (including diet 
and smoking restrictions), complete the pain evaluations, remain 
at the study site overnight, and return for follow-up 7 (± 2) days 
after surgery, (Day 8 ± 2 days). 
Exclusion Criteria 
A subject will not be eligible for study entry if any of the following 
exclusion criteria are met: 
1) Known hypersensitivity reactions or allergy (e.g. asthma, rhinitis, 
angioedema or urticaria) in response to nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen), acetylsalicylic 
acid (aspirin), ingredients of the study drug, or any other drugs 
used in the study, including anaesthetics and antibiotics that may 
be required on the day of surgery. 
2) A history of active or previous peptic ulceration/ haemorrhage, 
gastrointestinal bleeding or perforation, heart failure, renal or 
hepatic failure, uncontrolled hypertension, asthma, nasal polyps, or 
chronic rhinitis. 
3) Has complications from the tooth extraction or any other clinically 
significant medical history that, in the opinion of the investigator, 
would affect the subject’s ability to comply or otherwise 
contraindicate study participation, including but not limited to the 
following: cardiac, respiratory, gastroenterological, neurological, 
psychological, immunological, haematological, oncological, or 
renal disease. 
4) Has undergone another dental surgery within 60 days prior to the 
day of surgery. 
5) A positive urine drugs of abuse screen or alcohol breathalyser test 
at screening and during the study (with the exception of a positive 
drugs of abuse screen that is a consequence of permitted 
prescription medicines). 
6) If female, has a positive pregnancy test at screening (serum) or on 
the day of surgery prior to surgery (urine), or is lactating. 
7) Has known or suspected, (in the opinion of the investigator), history 
of alcoholism or drug abuse within 2 years of screening or evidence 
of tolerance or physical dependence before dosing with study drug. 
8) Taking any concomitant medications that might confound 
assessments of pain relief, such as psychotropic drugs, 
antidepressants, sedative-hypnotics (other than those permitted for 
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conscious sedation), or other analgesics taken within five times of 
their elimination half-lives. Selective serotonin reuptake inhibitors 
(SSRIs) and serotonin and noradrenaline reuptake inhibitors 
(SNRIs) are permitted if the subject has been on a stable dose for 
at least four weeks prior to Visit 1 (screening). 
9) Is considered by the investigator, for any reason (including, but not 
limited to the risks described as precautions, warnings and 
contraindications in the current version of the investigator’s 
brochure for 300 mg ibuprofen PR tablets), to be an unsuitable 
candidate to receive the study drug. 
10) Has a history of chronic use (defined as daily use for > 2 weeks) of 
nonsteroidal 
anti-inflammatory 
(NSAIDs), 
opiates, 
or 
glucocorticoids (except inhaled nasal steroids and topical 
corticosteroids), for any condition within 6 months before dosing 
with study drug.  
11) Has significant difficulties swallowing capsules or tablets or is 
unable to tolerate oral medication. 
12) Subject has received an investigational product or participated in 
another trial involving a marketed or investigational drug in the 30 
days (or for investigational agents with a long half-life, a washout 
of 5 half-lives) prior to first drug administration (washout period 
between studies is defined as the period of time elapsed between 
the last dose of the previous study and first dose for this study). Or 
if the investigator believes that any previous participation in an 
investigational study would be to the detriment of the safety of the 
participant or the conduct of the study. 
13) Enrolment of the Investigator, his / her family members, employees 
and other dependent persons. 
14) Failure to satisfy the investigator of fitness to participate for any 
other reason. 
Products to be 
Evaluated and 
Treatment 
Regimen: 
Test product:  
 
300 mg ibuprofen PR tablets for oral administration 
Reference products:  
 
200 mg ibuprofen IR tablets for oral administration 
 
Placebo (for blinding purposes, two types of placebo tablets will 
be made; one to look like the test product and one to look like 
the reference product) 
Treatment regimens: 
Eligible subjects meeting all study entry criteria will be randomised to 
receive 1 of the following treatments: 
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 
Treatment A: test product; 2×300 mg ibuprofen PR tablets, BID 
(total daily dose 1200 mg) 
 
Treatment B: reference product; 2×200 mg ibuprofen IR 
tablets, TID (total daily dose 1200 mg) 
 
Treatment C: matching placebo tablets 
Methodology: 
This is a single centre, randomised, double blind, double-dummy, 
parallel group-, multiple-dose, active and placebo controlled efficacy 
study to evaluate the efficacy and safety of ibuprofen 2×300 mg 
ibuprofen PR tablets in subjects with post-surgical dental pain. 
Eligible subjects will complete all screening procedures within 28 days 
before the surgery and randomisation. 
At Screening, subjects will provide written informed consent to 
participate in the study before any protocol specified procedures or 
assessments are completed. On Day 1, subjects who continue to be 
eligible for study participation after completing screening procedures 
and assessments will undergo extraction of 2 or more third molars. At 
least 1 of the third molars must be a fully or partially bone impacted 
mandibular molar. If only 2 molars are removed, then they must be 
ipsilateral. 
All subjects will receive local anaesthesia (2% lidocaine with 
1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion 
of the investigator. Subjects who experience moderate to severe pain 
intensity (a score of ≥ 5 on a numeric rating scale [NRS] from 0-10 
where 0 = no pain, 10 = worst pain ever) within 6 hours after surgery 
and who continue to meet all study entry criteria will be randomised in 
a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets every 12 hours 
(Q12h), 2×200 mg ibuprofen IR tablets every 8 hours (Q8h), or 
placebo. The randomisation will be stratified by baseline pain category 
(moderate or severe) using a categorical scale that includes the 
categories of none (0), mild (1-4), moderate (5-7), and severe (8-10).  
Subjects will re-assess their baseline pain intensity using the NRS 
immediately before receiving study drug (pre-dose, Time 0) and their 
pain intensity (NRS) and pain relief (5-point categorical scale) at the 
following time points (pre-dose, if at one of the dosing timepoints of 0, 
8, 12 and/or 16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 
6, 7, 8, 10, 12, 16, and 24 hours after Time 0; and immediately before 
each dose of rescue medication, if any. For assessments less than 
1 hour apart a window of +/-2 min is allowable whilst for assessments 
at least 1 hour apart a +/-5 min window is allowable. 
The double stopwatch method will be used to record the time to 
perceptible pain relief and time to meaningful pain relief during the 
8 hours following the first dose or until subject takes rescue 
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medication. Subjects will complete a global evaluation of study drug 
24 hours (+/- 5 minutes) after Time 0 or immediately before the first 
dose of rescue medication (whichever occurs first). Vital signs will be 
recorded after the subject has been in a sitting position for 3 minutes 
at the following times: before surgery, within 30 minutes before Time 0, 
12 and 24 hours after Time 0, and/or immediately before the first dose 
of rescue medication. Adverse events (AEs) will be monitored and 
recorded from the time of signing of the informed consent form (ICF) 
until the Follow up- Visit (or Early Termination Visit). During the 
24 hours following Time 0, subjects will complete efficacy and safety 
assessments. Subjects will remain at the study site overnight and will 
be discharged on Day 2.  
Paracetamol / acetaminophen (1000 mg) will be permitted as the initial 
rescue medication. Subjects will be encouraged to wait at least 
60 minutes after receiving study drug before taking rescue medication. 
If acetaminophen rescue medication is not effective in relieving the 
subject’s pain, 5 mg oxycodone rescue medication may be 
administered at the discretion of the investigator. 
Subjects are not permitted to take any concomitant medications that 
might confound assessments of pain relief, such as psychotropic 
drugs, antidepressants, sedative-hypnotics (other than those permitted 
for conscious sedation), or other analgesics taken within five times of 
their elimination half-lives (other than those used at the surgery). 
Selective serotonin reuptake inhibitors (SSRIs) and serotonin and 
noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject 
has been on a stable dose for at least four weeks prior to Visit 1 
(screening).  
Other restrictions include the following: alcohol use is prohibited from 
24 hours before surgery until discharge on Day 2; nothing by mouth 
from midnight before surgery until 1 hour after surgery; clear liquids 
only are allowed starting 1 hour after surgery until 1 hour after dosing; 
1 hour after dosing, the subject’s diet may be advanced according to 
standard practice. 
Upon discharge from the study site, subjects may be prescribed pain 
medication for use at home according to the standard practice of the 
study site. On Day 8 (± 2 days), subjects will return to the study site for 
an 
abbreviated 
confirmatory 
physical 
assessment 
and 
AE 
assessments. 
Statistical 
Evaluation: 
Analysis Populations 
The analysis populations include the following: 
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 
The intent-to-treat (ITT) population will consist of all subjects 
who are treated with study drug and who have at least 1 pain 
relief assessment after Time 0. The ITT population is the 
primary population for the efficacy analysis. 
 
The per protocol- (PP) population will consist of all ITT subjects 
who do not incur a major protocol violation that would challenge 
the validity of their data. This population will be utilized to 
evaluate the sensitivity of the primary efficacy analysis. 
 
The safety population will include all subjects who are treated 
with study drug. The safety population is the population for all 
safety assessments. 
Subject Characteristics 
Demographic and baseline characteristics (including date of birth, sex, 
race, weight, height, BMI and medical history) will be summarized for 
each treatment group and for the overall population using descriptive 
statistics. No formal statistical analyses will be performed. 
Efficacy Analyses 
The primary efficacy null hypothesis is that SPID12 for placebo is equal 
to SPID12 for ibuprofen 2×300 mg PR tablets. The primary analysis 
will be an ANCOVA (Analysis of Covariance) model that includes the 
main effect of treatment and the baseline pain score as a covariate and 
will use windowed worst observation carried forward (WOCF) 
imputation for subjects who use rescue medication. The primary 
analysis will be based on a 2-sided test at the significance level of 0.05. 
All other comparisons between the treatment regimens, including 
ibuprofen 2×200 mg IR tablets versus placebo, will be considered 
secondary. No P value adjustment will be made for multiple endpoints 
or multiple comparisons. 
Each efficacy endpoint will be summarized descriptively by treatment 
group. 
For continuous secondary endpoints such as pain intensity score, 
SPID at each scheduled time point, peak pain intensity, TOTPAR4, 
TOTPAR8, TOTPAR12, TOTPAR24, SPID4, SPID8, SPID24, 
SPRID4, SPRID8, SPRID12, and SPRID24, descriptive statistics 
(such as mean, standard deviation, median, minimum, and maximum) 
will be provided for each treatment regimen. Nominal P values from 
ANCOVA models comparing the placebo group with other treatment 
groups, including terms for treatment and baseline pain will be 
provided for SPID, SPRID, and TOTPAR variables, but no formal 
statistical inferences will be drawn on the basis of these tests. 
For ordinal secondary endpoints, such as pain intensity difference at 
each scheduled time point, pain relief at each scheduled time point, 
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peak pain relief, response to study drug, and global evaluation of study 
drug, descriptive summaries will be provided and will include the 
number and percentage of subjects within each category for each 
treatment group. Nominal P values from Fisher’s exact tests (or 
chi-square- tests, as appropriate) comparing the placebo group with 
other treatment groups will be provided for peak pain relief and global 
evaluation of study drug, but no formal statistical inferences will be 
drawn on the basis of these tests. For each time to- event endpoint, 
Kaplan Meier methodology will be used to evaluate the treatment 
effect. Time to onset of analgesia (measured as time to perceptible 
pain relief confirmed by meaningful pain relief) will be based on data 
collected using the double stopwatch method. Time to onset of 
analgesia will be -right censored- at 8 hours for subjects who do not 
experience both perceptible pain relief and meaningful pain relief 
during the 8-hour interval after Time 0. For time to onset of analgesia, 
the comparison of interest will be the ibuprofen 2×300 mg PR group 
versus the ibuprofen 2×200 mg IR group. The summary tables will 
provide the number of subjects analysed, the number of subjects 
censored, estimates for the quartiles, and 95% confidence intervals 
(CIs) for the estimated median and the restricted mean estimate. 
P values from the Wilcoxon or log rank- tests (as appropriate) will also 
be used to compare placebo to the active treatments. 
For the responder analysis and the proportion of subjects using rescue 
medication, logistic regression models that adjust for baseline intensity 
and/or significant demographic variables, if appropriate, will be used to 
evaluate the treatment effect. 
Baseline values are defined as the last measurements taken before 
dosing with a study drug. 
Missing pain assessments for all efficacy analyses will be handled as 
follows: 
 
Missing pain assessments scheduled before the first observed 
assessment will be imputed with the subject’s worst observed 
pain assessment. 
 
Missing intermediate pain assessments will be replaced by 
linear interpolation. 
 
Missing pain assessments at the end of the observation period 
due to premature discontinuation of pain assessments will be 
imputed by carrying forward the last observation prior to that 
missing. 
The primary analysis will use windowed worst observation carried 
forward (WOCF) methodology for subjects who use rescue medication. 
Any pain measurements taken during a period of time in which rescue 
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medication is active (4 hours) will be replaced by the last pain 
measurement before the rescue medication was taken. A sensitivity 
analysis will also be performed, in which all pain assessments 
recorded after the first dose of rescue medication has been taken will 
be disregarded and the rules outlined above will be used for missing 
data. 
All data for assessments other than pain assessments will be analysed 
as collected; missing data due to premature termination or any other 
reason will be left as missing. 
Safety Analysis 
Data listings will be provided for protocol-specified safety data. The 
Medical Dictionary for Regulatory Activities (MedDRA) (Version 19.0 
or higher) will be used to classify all AEs with respect to system organ 
class and preferred term. Adverse event summaries will include only 
TEAEs, which will be summarized for each treatment group.  
For vital sign measurements, descriptive statistics will be provided at 
each scheduled time point for each treatment group. Changes from 
Baseline for vital signs will be calculated for each subject, and 
descriptive statistics will be provided on changes in vital signs from 
Baseline for each treatment group at each scheduled time point after 
Baseline. No formal statistical tests will be performed. 
 
 
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1 
BACKGROUND AND RATIONALE 
1.1 Background for the Study and Rationale 
Reckitt Benckiser (RB) is co-developing a new 300 mg ibuprofen prolonged release (PR) tablet 
with Strides Shasun Ltd. The product has been developed to meet consumer and patient needs 
to have access to longer acting over-the-counter analgesics. This PR formulation will reduce 
fluctuations in drug plasma concentrations and allow for a lower frequency of administration 
which is desirable in situations where pain duration is expected to be prolonged and require 
multiple doses of immediate release formulations. As a result, the product would be more 
consumer friendly, require less dosing and improve compliance with treatment. 
The proposed therapeutic indications of the PR product are for the short-term symptomatic 
treatment of mild to moderate pain such as dysmenorrhea, rheumatic pain, muscular pain, pain 
of non-serious arthritic conditions and backache. 
The proposed posology in adults over the age of 18 is: 
Ibuprofen 300 mg PR tablets.  Two tablets to be taken every 12 hours when required for pain 
relief. No more than 2 doses in 24 hours. The maximum daily dose is 1200 mg and there is 
no proposed indication in the paediatric population. 
 
Therefore, the purpose of the proposed study is to provide supporting pivotal efficacy evidence 
for European, Russian, and Australian applications and not to support any application in the 
USA. This efficacy study will provide further evidence on the safety and efficacy of the product 
in addition to the data obtained in two bioequivalence studies BE/17/279 and BE/17/281. 
1.2 Investigational Product 
Ibuprofen [2-(4-isobutylphenyl) propionic acid] is a non-steroidal anti-inflammatory drug 
(NSAID) with anti-inflammatory, analgesic and anti-pyretic properties (2). It was initially available 
in 1969 as a prescription only medicine, indicated for rheumatoid arthritis, osteoarthritis and 
other chronic painful conditions such as ankylosing spondylitis. Following further research and 
the establishment of a reassuring safety profile, it was launched in 1983 as an over-the-counter 
(OTC) medication, marketed as Nurofen®. 
Absorption of ibuprofen after oral administration is fairly rapid with peak serum concentrations 
occurring within 1 to 2 hours after administration. Ibuprofen is extensively bound to plasma 
proteins (99%) when administered at therapeutic levels and has a plasma half-life of about 
2 hours. Excretion by the kidney is both rapid and complete, but only a small proportion of drug 
is excreted unchanged in urine, the majority being extensively metabolised in the liver to 
2 major inactive metabolites. The pharmacokinetics of ibuprofen has been extensively 
reviewed by Davies (3). 
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1.3 Treatment Rationale 
The treatment of the test product is in line with the proposed posology of the final product and 
the treatment of the active comparator is in line with the posology provided in the label of the 
product. The treatments will be administered orally, as this is the standard route of 
administration for these products. 
 
The following are the treatment regimens of each product in the study: 
 
Treatment A: test product, 2x300 mg PR ibuprofen tablet, twice daily [total daily dose 
1200 mg] 
 
Treatment B: reference product, 2x200 mg IR ibuprofen tablet, three times a day [total 
daily dose 1200 mg] 
 
Treatment C: matching placebo tablets for both the test and reference regimens 
 
The active comparator (Treatment B) currently marketed in a number of geographies including 
a number of different European countries.  It has therefore been chosen to fulfil requirements 
that when it is included in a marketing authorisation dossier as a comparator that it is licenced 
within the EU.     
 
1.4 Study Population and Indication 
The following study population will be invited to participate in this clinical trial: 
Adult participants aged 18 to 50 requiring extraction of 2 or more third molars, at least 1 of 
which must be a fully or partially bone-impacted mandibular molar, (if only 2 molars are 
removed, then they must be ipsilateral), and who experience moderate to severe pain following 
surgery. 
Such population is expected to present pain levels that will allow for assessing the magnitude 
of treatment effect in a low variability setting. 
 
1.5 Non-Clinical Evidence 
No non-clinical evidence is available for the PR tablet.   
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1.6 Clinical Evidence to Date 
A total of 5 single and multiple-dose pharmacokinetic studies (139-15, BE-16-081, BE-16-295, 
BE-17-279, BE-17-281) have been performed with the test product.  These studies 
demonstrated the oral bioavailability (BA) of the ibuprofen PR tablets (dosed at 2x300 mg) is 
comparable to Brufen® (Ibuprofen) IR Tablets (dosed at 3x200 mg) after a single dose and at 
steady state conditions.  In terms of the release profile and absorption, Cmax tends to be slightly 
higher in the IR formulation when compared with the PR formulation [21.96 ±3.87 µg/mL vs 
14.51 ±3.1 µg/mL].  However the Cmax, (Maximum Observed Plasma Concentration), Tmax, 
(Time to Maximum Plasma Concentration) and AUC0-Tmax (Area Under the Plasma 
Concentration Curve) of the PR formulation suggest that’s the onset of action should not be 
any slower than the IR reference when considering the minimum effective concentration of 
ibuprofen (4).  In terms of total exposure (AUC0-∞) the concentration profile is bioequivalent 
between the PR test product and the IR reference product [163.41 ±43.0 µg.h/mL vs 168.59 
±37.7 µg.h/mL].  A food effect is demonstrated when the test product is taken in the fed state, 
with an expected increase in the absorption rate. 
In the 5 PK studies performed (over 200 subjects) only a limited number of mild, transient 
adverse events were reported.   
Summary Outcomes: 
 
The Clinical data available for this reformulation (Ibuprofen 300 mg PR) suggests an 
adequate pharmacokinetic profile to achieve a sufficient therapeutic effect in the 
proposed study 
 
There are no safety concerns with the test product 
 
Ibuprofen 300 mg PR had an increased rate of absorption when administered with food. 
 
Ibuprofen 300 mg PR tablets had a comparable concentration profile to the comparator 
IR product and was bioequivalent based on AUC0-∞ 
 
1.7 Risks / Benefits 
This study has been designed to confirm the therapeutic efficacy of ibuprofen 300 mg PR.  
Participants in this study are subjects aged 18-50 who require the extraction of 2 or more third 
molars, at least 1 of which must be a fully or partially bone impacted mandibular molar.  
Subjects will undergo dental surgery that is equivalent to that of the standard-of-care that would 
be expected for the above condition. They should be otherwise healthy and each subject 
will undergo a full health check as part of the enrolment into the study to confirm that they 
are healthy as defined in this protocol (see Section 4). 
Participants randomised into the placebo arm would not be expected to derive any therapeutic 
benefit from the administration of the placebo tablets. The placebo arm is essential to the study 
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design as it ensures that any conclusion of non-inferiority from the trial is a reflection of the 
true properties of the treatments; that is, it demonstrates the assay sensitivity of the study.  
However, this obviously leaves the participants without adequate analgesia in the post-surgery 
procedure and from an ethical perspective this is mitigated in the study design by the use of 
rescue medication that would be in line with standards of treatment. Although it is hypothesised 
that the investigational medicinal product (IMP) will provide adequate analgesia in the study, 
this cannot be guaranteed, and therefore the use of rescue medication also addresses the 
potential of reduced or lack of efficacy. 
Ibuprofen is an established pharmaceutical ingredient and the adverse reactions associated 
with administration of 1200 mg/24 hour (OTC doses) are well known and documented (2)(5).  
The adverse reactions most frequently occurring with a single dose being nausea, 
gastrointestinal upset, vomiting, diarrhoea, light headedness, dizziness and headache. Rarely, 
more serious reactions have been reported including GI bleeding, ulceration and perforations, 
hypertension and renal failure. When OTC doses of ibuprofen (200-400 mg/dose; 1200 
mg/day) are taken for acute episodes of pain there is an extremely low risk of causing serious 
gastrointestinal events (5).  
The specific 200mg Ibuprofen tablet to be used in this study as the active comparator 
(Treatment B) is marketed in the EU under the Nurofen brand and has an excellent safety 
profile.   
It is not anticipated that the safety profile of ibuprofen will be altered after administration of 
multiple single doses of ibuprofen 300 mg PR in the context of this study.  There are not 
expected to be any drug-drug interactions with the non-investigational medicinal products 
included within the study design. A washout period of at least 6 days is deemed to be sufficient 
prior to the Follow-up/Early Termination Visit to ensure adequate safety monitoring of the IMP. 
The investigation site will have adequate set up, experience and safety measures that would 
be expected of a centre able to perform regular molar extractions. They will also have adequate 
experience in the safety monitoring of participants post dose that would be expected in a 
clinical trial setting.  Therefore, it is considered that the risk related to study procedures are low 
and limited to common adverse events (AEs) related to the dental procedure, administration 
of routine anaesthetics, and discomfort from vital sign measurements.  Any subject that 
experiences immediate complications during the surgery will be excluded from the study. 
Therefore, the overall benefit-risk profile for the use of the investigational product as 
defined in this protocol is considered favourable. 
1.8 Ethical Conduct of the Study 
This study will be conducted in accordance with this protocol and the principles set out in the 
Declaration of Helsinki. It will comply with International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
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2 
STUDY OBJECTIVES 
Primary Objective:  
 
To evaluate the superiority of 2×300 mg ibuprofen PR tablets compared with placebo in 
subjects experiencing acute moderate to severe pain after third molar extraction over 
12 hours post initial dose.  
Key Secondary Objectives: 
 
To evaluate the analgesic performance of a total daily dose of 1200 mg of ibuprofen PR 
formulation compared to ibuprofen IR formulation over 24 hours post initial dose. 
 
To evaluate the safety and tolerability of 2×300 mg ibuprofen PR tablets. 
Additional Secondary Objectives: 
 
To evaluate the total analgesic effect, peak analgesic effect, onset and duration of action 
and the subject’s overall assessment of the study medications. 
3 
STUDY DESIGN AND RATIONALE FOR DESIGN 
This is a single centre randomised, double-blind, double dummy, parallel group, multiple-dose, 
active and placebo-controlled efficacy study to evaluate the efficacy and safety of 2×300 mg 
ibuprofen PR tablets in subjects with post-surgical dental pain. 
The dental pain model used in this study is a robust and well established post-surgical pain 
model that produces pain that is predictable in its character, duration, and intensity(6). The 
model is widely accepted and has a proven record of assay sensitivity (i.e. separating active 
drugs from each other, as well as from placebo). The model is frequently used to evaluate 
NSAID type analgesics. Results from dental pain studies are accepted by the US Food and 
Drug Administration (FDA) and European authorities and have been widely extrapolated to 
other general pain conditions. 
The decision to conduct the study in the United States was taken as suitably qualified and 
experienced test sites could not be found in Europe.  The specific test site has been chosen 
to conduct the study as they have a proven history of quality and safety when conducting 
studies of this type. 
The placebo products have two purposes:  
1. To mask the treatment identify for PR and IR arms  
2. Act as a control arm 
The dose of the test product is the proposed posology of the final product and the dose of the 
active comparator is the posology provided in the label of the product. 
Eligible subjects will be randomised in a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets 
Q12h, 2×200 mg ibuprofen IR tablets Q8h, or placebo. The randomisation will be stratified by 
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baseline pain category (moderate or severe) using a categorical scale that includes the 
categories of none (0), mild (1-4), moderate (5-7), and severe (8-10). The randomisation 
schedule will be prepared by a statistician not otherwise involved in the study. Randomisation 
will be performed using an interactive web response system (IWRS). Access to the unblinding 
codes will be restricted to personnel not otherwise involved in the study and will be available 
to the investigator only in the case of a subject requiring unblinding prior to database lock. 
Figure 3.1 Study Design Schematic 
Screening 
Visit 
Day 
-28 to -1 
 
In-patient Surgical Stay 
 
Follow-up 
Visit 
Day 8± 2 d 
or Early 
Termination 
 
 
 
 
 
Day of Surgery (Day 1) 
Day 2 
 
→ Pre-
surgery 
Surgery 
Post-
surgery 
eligibility 
Randomisation 
& pre-dose 
(Baseline) 
assessments 
Dosing & 
post-dose 
assessments 
24 h 
post-dose 
assessments 
→
 
 
Note: Un-scheduled visits may occur at any point throughout the study 
 
Table 3-1 Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective: 
To evaluate the superiority of 2×300 mg 
ibuprofen PR tablets compared with placebo 
in subjects experiencing acute dental pain 
after third molar extraction over 12 hours 
post initial dose. 
Primary Endpoint:  
The primary efficacy endpoint is the summed 
pain intensity difference (SPID) over the 0 to 
12 hours (SPID12) after Time 0 and will be 
used to compare the test product (2x300 mg 
PR ibuprofen) and the placebo product.  
The clinical relevance of the difference 
between placebo and PR ibuprofen over 
12 hours after initial dose will be evaluated 
as confirmatory evidence (for the purposes 
of this study, a difference of 30% in PID 
scores over 12 hours after initial dose will be 
considered clinically relevant). 
Secondary Efficacy Objectives: 
 To evaluate the analgesic performance 
of a total daily dose of 1200 mg of 
ibuprofen PR formulation compared to 
ibuprofen IR formulation over 24 hours 
post initial dose.  
 To evaluate the total analgesic effect, 
peak analgesic effect, onset and duration 
Key Secondary Efficacy Endpoints: 
 The summed pain intensity difference 
(SPID) over 0 to 24 hours (SPID24) will 
be used to compare the test product 
(2×300 mg ibuprofen PR tablets twice 
daily [BID]) and comparator product 
(2×200 mg ibuprofen IR tablets three 
times a day [TID]). 
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of action and the subject’s overall 
assessment of the study medications. 
Efficacy Endpoints: 
 Summed pain intensity difference (SPID) 
over 0 to 4 hours (SPID4), over 0 to 
8 hours (SPID8), over 0 to 12 hours 
(SPID12), and over 0 to 24 hours 
(SPID24) after Time 0 
 Sum of total pain relief (TOTPAR) over 
0 to 4 hours (TOTPAR4), over 0 to 
8 hours (TOTPAR8), over 0 to 12 hours 
(TOTPAR12), and over 0 to 24 hours 
(TOTPAR24) after Time 0 
 Summed pain relief and intensity 
difference (sum of TOTPAR and SPID 
[SPRID]) over 0 to 4 hours (SPRID4), 
over 0 to 8 hours (SPRID8), over 0 to 
12 hours (SPRID12), and over 0 to 
24 hours (SPRID24) after Time 0 
 Response to study drug (a responder will 
be defined as a subject with ≥30% 
improvement in pain intensity without 
rescue medication during the first 
8 hours) 
 NRS pain intensity difference (PID) at 
each scheduled time point after Time 0 
 Pain intensity score at each scheduled 
time point 
 Pain relief score at each scheduled time 
point after Time 0 
 Peak pain relief 
 Time to onset of analgesia (measured as 
time to perceptible pain relief confirmed 
by time to meaningful pain relief) using 
double stopwatch 
 Time to first perceptible pain relief 
 Time to meaningful pain relief 
 Time to peak pain relief 
 Proportion of subjects using rescue 
medication 
 Time to first use of rescue medication  
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Exploratory Endpoint: 
 Patient’s global evaluation of study drug 
Safety Objective: 
To evaluate the safety and tolerability of 
2×300 mg ibuprofen PR tablets. 
Safety Endpoints: 
 Incidence of treatment-emergent 
adverse events (TEAEs) 
 Incidence of clinically relevant changes 
in vital sign measurements 
 
Subjects in the PR group will take 2×300 mg ibuprofen PR tablets at Hours 0 and 12. Subjects 
in the IR group will take 2×200 mg ibuprofen IR tablets at Hours 0, 8, and 16. To maintain 
double-blinding, at each dosing timepoint (Hours 0, 8, 12, and 16) all subjects will take a total 
of 4 tablets (placebo-only or active plus placebo, depending on randomised treatment group). 
Table 3-2 Treatment Regimens 
 
PR Group 
 
IR Group 
Placebo Group 
Hour 0 
2 PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 8 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 12 
2 PR, 
2 placebo for IR 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 placebo for IR 
Hour 16 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 24 
final assessments 
final assessments 
final assessments 
 
The study will enrol approximately 280 male and female subjects 18-50 years of age who 
experience moderate to severe pain intensity within 6 hours after dental surgery to remove 
2 or more third molars. At least 1 of the third molars must be a fully or partially bone impacted 
mandibular molar. If only 2 molars are removed, they must be ipsilateral. Subjects must satisfy 
all eligibility criteria including providing informed consent and willingness to remain at the clinic 
overnight. 
The study will be conducted in 1 study site in the United States.   
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 Study Population 
The study will enrol approximately 280 male and female subjects. 
 
4.2 Inclusion Criteria 
Only subjects to whom all of the following conditions apply will be included: 
1. Is male or female ≥ 18 and ≤ 50 years of age. 
2. Requires extraction of 2 or more third molars. At least 1 of the third molars must be a 
fully or partially bone-impacted mandibular molar. If only 2 molars are removed, then 
they must be ipsilateral. 
3. Experiences moderate to severe pain intensity within 6 hours after surgery, as 
measured by a numeric rating scale (NRS) score of ≥ 5 on a 0-10 scale. 
4. Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 35 kg/m2. 
5. Female subjects of child-bearing potential must have been using an acceptable 
method of contraception for at least 30 days prior to randomization and be willing to 
continue use until at least 48 hours post discharge from the clinic (see Section 4.4). 
To be considered not of child-bearing potential, females must be surgically sterile 
(defined as bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or post-
menopausal (defined as no menses for 12 months without an alternative medical 
cause). 
6. Free of clinically significant abnormal findings as determined by medical history, 
physical examination, vital signs, laboratory tests and ECG. 
7. Is able to provide written informed consent. 
8. Is willing and able to comply with study requirements (including diet and smoking 
restrictions), complete the pain evaluations, remain at the study site overnight, and 
return for follow-up 7 (± 2) days after surgery, (Day 8 ± 2 days).  
4.3 Exclusion Criteria 
A subject will not be eligible for study entry if any of the following exclusion criteria are met: 
1. Known hypersensitivity reactions or allergy (e.g., asthma, rhinitis, angioedema or 
urticaria) in response to nonsteroidal anti-inflammatory drugs (NSAIDs, including 
ibuprofen), acetylsalicylic acid (aspirin), ingredients of the study drug, or any other 
drugs used in the study, including anaesthetics and antibiotics that may be required 
on the day of surgery. 
2.  A history of active or previous peptic ulceration/ haemorrhage, gastrointestinal 
bleeding or perforation, heart failure, renal or hepatic failure, uncontrolled 
hypertension, asthma, nasal polyps, or chronic rhinitis. 
3. Has complications from the tooth extraction or any other clinically significant medical 
history that, in the opinion of the investigator, would affect the subject’s ability to 
comply or otherwise contraindicate study participation, including but not limited to the 
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following: cardiac, respiratory, gastroenterological, neurological, psychological, 
immunological, haematological, oncological, or renal disease. 
4. Has undergone another dental surgery within 60 days prior to the day of surgery. 
5. A positive urine drugs of abuse screen or alcohol breathalyser test at screening and 
during the study (with the exception of a positive drugs of abuse screen that is a 
consequence of permitted prescription medicines). 
6. If female, has a positive pregnancy test at screening (serum) or on the day of surgery 
prior to surgery (urine), or is lactating. 
7. Has known or suspected, (in the opinion of the investigator), history of alcoholism or 
drug abuse within 2 years of screening or evidence of tolerance or physical 
dependence before dosing with study drug. 
8. Taking any concomitant medications that might confound assessments of pain relief, 
such as psychotropic drugs, antidepressants, sedative-hypnotics (other than those 
permitted for conscious sedation), or other analgesics taken within five times of their 
elimination half-lives. Selective serotonin reuptake inhibitors (SSRIs) and serotonin 
and noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject has been 
on a stable dose for at least four weeks prior to Visit 1 (screening). 
9. Is considered by the investigator, for any reason (including, but not limited to the risks 
described as precautions, warnings and contraindications in the current version of the 
investigator’s brochure [IB] for 300 mg ibuprofen PR tablets), to be an unsuitable 
candidate to receive the study drug. 
10. Has a history of chronic use (defined as daily use for > 2 weeks) of nonsteroidal anti-
inflammatory (NSAIDs), opiates, or glucocorticoids (except inhaled nasal steroids and 
topical corticosteroids), for any condition within 6 months before dosing with study 
drug.  
11. Has significant difficulties swallowing capsules or tablets or is unable to tolerate oral 
medication. 
12. Subject has received an investigational product or participated in another trial 
involving a marketed or investigational drug in the 30 days (or for investigational 
agents with a long half-life, a washout of 5 half-lives) prior to first drug administration 
(washout period between studies is defined as the period of time elapsed between 
the last dose of the previous study and first dose for this study). Or if the investigator 
believes that any previous participation in an investigational study would be to the 
detriment of the safety of the participant or the conduct of the study. 
13. Enrolment of the Investigator, his / her family members, employees and other 
dependent persons. 
14. Failure to satisfy the investigator of fitness to participate for any other reason. 
4.4 Subjects of Reproductive Potential 
Female subjects of childbearing potential must have been using an acceptable method of 
contraception for at least 30 days prior to randomization and be willing to continue use until at 
least 48 hours post discharge from the clinic. An acceptable method of contraception includes:  
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a. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
b. Male or female condom with or without spermicide 
c. Cap, diaphragm or sponge with spermicide 
Alternatively, highly effective methods of contraception are also considered acceptable, such 
as: 
d. Surgical sterilisation 
e. Established use of oral, injected or implanted hormonal methods of contraception 
f. Some intrauterine devices (IUDs) or intrauterine systems (IUSs) 
g. Male sterilisation (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). [For female subjects on the study, the vasectomised male 
partner should be the sole partner for that subject] 
h. True abstinence which is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence such as calendar, ovulation, symptothermal, or post-ovulation 
methods; declaration of abstinence for the duration of the trial; and withdrawal are not 
acceptable methods of contraception. 
4.5 Discontinuation / Withdrawal and Replacement of Subjects  
The Investigator may withdraw the subject from the study at any time. Reasons for removing 
a subject from the study include, but are not limited to: 
 
AEs that in the judgement of the Investigator may cause severe or permanent harm 
(significant clinical deterioration is an AE) 
 
Violation of the study protocol 
 
In the Investigator’s judgement, it is in the subject’s best interest 
 
Subject declines further study participation 
 
If applicable, randomisation code is broken 
If subjects choose to prematurely stop the study prior to the scheduled discharge at Hour 24, 
safety and tolerability assessments must be performed prior to discharge, and, if possible, 
efficacy assessments should be performed. 
If subjects choose to prematurely stop the study after clinic discharge but prior to the follow-up 
visit, at least 2 documented attempts should be made to contact the subjects for follow-up 
assessments which will include the assessments described for the follow-up visit (Section 7.4). 
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5 
STUDY TREATMENT 
5.1 Investigational Products 
Active Test Product 
Ibuprofen PR tablets 300 mg, single oral dose of 600 mg.  A yellow to pale yellow coloured, 
film coated, caplet shaped tablet, debossed as ‘N12’ on one side and plain on the other side. 
Table 5-1 Active Test Product 
Name of Ingredient 
Quantity/Tablet(mg) 
Function 
Reference 
Ibuprofen  
300.00 
Active 
Ph.Eur. 
Silicon dioxide 
3.00 
Glidant/Anti-adherent 
Ph.Eur. 
Hypromellose K4M 
Premium 
62.50 
Rate Controlling Polymer 
Ph.Eur. 
Hypromellose K100 LV 
32.50 
Rate Controlling Polymer 
Ph.Eur. 
Silicified Microcrystalline 
cellulose 50  
100.00 
Filler/Binder 
NF 
Silicified Microcrystalline 
cellulose 90 
50.00 
Filler/Binder 
NF 
Croscarmellose sodium 
17.50 
Disintegrant 
Ph.Eur. 
Glycine 
25.00 
Release Modifier 
Ph.Eur 
Silicon dioxide 
3.00 
Glidant/Anti-adherent 
Ph.Eur. 
Stearic acid 
6.00 
Lubricant 
Ph.Eur. 
Total weight of core 
tablet 
599.50 mg 
Film coating and Polishing  
Opadry Yellow 
15B520019 
7.50 
Coating agent 
In House 
Purified water# 
q.s. 
Coating vehicle 
Ph.Eur. 
Carnauba Wax   
0.025 
Polishing Agent 
Ph.Eur 
Total weight  
607.025 mg 
#   Removed during the process.  
 
 
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Placebo for Test Product 
A yellow to pale yellow coloured, film coated, caplet shaped tablet, debossed as ‘N12’ on one 
side and plain on the other side. 
Table 5-2 Placebo for Test Product 
Ingredient 
mg/tablet Function 
Reference 
Standard 
Core  
Hypromellose K4M Premium 
125.10 
Rate Controlling 
Polymer 
Ph. Eur. 
Hypromellose K100 Premium LV  
65.05 
Rate Controlling 
Polymer 
Ph. Eur. 
Silicified Microcrystalline Cellulose 50 
200.17 
Filler/ Binder 
NF 
Silicified Microcrystalline Cellulose 90 
100.08 
Filler/ Binder 
NF 
Croscarmellose Sodium  
35.03 
Disintegrant 
Ph. Eur. 
Glycine 
50.04 
Release Modifier 
Ph. Eur. 
Silica, Colloidal Hydrated 
12.02 
Glidant/ Anti-adherent 
Ph. Eur. 
Stearic Acid  
12.01 
Lubricant 
Ph. Eur. 
Coating and Polishing  
Opadry Yellow 15B520019 
7.50 
Coating Agent 
In house 
Carnauba Wax  
0.025 
Polishing Agent 
Ph. Eur. 
Processing agent 
Purified Water 
q.s.* 
Coating Vehicle 
Ph. Eur. 
Total 
607.025 
 
 
* Does not remain in final product except traces. Removed during the coating process.  
 
 
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Comparator Product 
Nurofen Ibuprofen acid tablets 200 mg, single oral dose of 400 mg.  A white to off white, 
biconvex, round, sugar coated tablet. 
Table 5-3 Comparator Product 
Name of Ingredient 
Unit Formula 
(mg/tablet) 
Function 
Reference to 
Standards 
Active Ingredient 
 
 
 
Ibuprofen 
200.0 
Active ingredient 
Ph.Eur. 
Other Ingredients 
 
 
 
Croscarmellose Sodium 
30.0 
Disintegrating agent 
Ph.Eur. 
Sodium Lauryl Sulphate 
0.5 
Tablet lubricant 
Ph.Eur. 
Sodium Citrate 
43.5 
Bulk filler 
Ph.Eur. 
Stearic Acid 
2.0 
Tablet lubricant 
Ph.Eur. 
Colloidal Anhydrous Silica 
1.0 
Granule flow aid 
Ph.Eur. 
Tablet Core Weight 
277.0 
 
 
Sugar Coat Ingredients 
 
 
 
Carmellose Sodium 
0.7 
Sugar coat binder 
Ph.Eur. 
Talc 
33.0 
Sugar coat bulking agent 
Ph.Eur. 
Acacia Spray Dried 
0.6 
Sugar coat binder 
Ph.Eur. 
Sucrose 
116.1 
Sugar coat 
Ph.Eur. 
Titanium Dioxide  
1.4 
Colour 
Ph.Eur. 
Macrogol 6000 
0.2 
Tablet polish 
Ph.Eur. 
Purified Water 
ND 
Sugar syrup solvent 
Ph.Eur. 
Coated Tablet Weight 
429.0 
 
 
 
 
Placebo for Comparator Product 
A white to off white, biconvex, round, sugar coated tablet. 
Table 5-4 Placebo for Comparator Product 
Ingredient 
Quantity (%w/w) 
Function 
Reference 
Standard 
Core 
Mannitol 
46.81 
Filler 
Ph. Eur 
Microcrystalline 
Cellulose 
16.14 
Filler 
USP/NF 
Magnesium Stearate 
1.61 
Lubricant 
Ph. Eur. 
Sugar coating 
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Carmellose Sodium 
0.16 
Sugar coat binder 
Ph. Eur 
Talc 
7.69 
Sugar coat bulking 
agent 
Ph. Eur 
Acacia Spray Dried 
0.14 
Sugar coat binder 
Ph. Eur 
Sucrose 
27.06 
Sugar coat 
Ph. Eur 
Titanium Dioxide 
0.33 
Colour 
Ph. Eur 
Macrogol 6000 
0.05 
Tablet polish 
Ph. Eur 
Purified Water* 
ND 
Sugar syrup solvent 
Ph. Eur 
 
Test Product and Placebo for Test Product will be manufactured and packed (primary pack) to 
Good Manufacturing Practice (GMP) standards by Strides Shasun Limited, R.S No 32-34 
PIMS Road, Periyakalpet, Kalapet, Pondicherry, 605014, India and shipped to Investigational 
Materials Supplies Unit (IMSU), RB, Dansom Lane, Hull, HU8 7DS. 
Nurofen Ibuprofen acid (Comparator) and the Placebo for Comparator tablets will be 
manufactured to GMP standards by Reckitt Benckiser, Thane Road, Nottingham, NG90 2DB, 
UK. Both active and placebo tablets will be unprinted for blinding purpose. 
Both the products (Comparator and Placebo) will be primary packed at Sharp Clinical Services, 
Elvicta Business Park, Crichowell, NP8 1DF, UK and shipped to Investigational Materials 
Supplies Unit (IMSU), RB, Dansom Lane, Hull, HU8 7DS. 
The Test Product, Placebo for Test Product, Comparator Product and the Placebo for 
Comparator product will be assembled to GMP standards by the IMSU, RB, Dansom Lane, 
Hull HU8 7DS, and bulk certified by RB Research and Development Qualified Person. All the 
products will be shipped directly from IMSU to the study site.  
5.2 Non-Investigational Products 
In preparation for the surgery, subjects will receive local anaesthesia (2% lidocaine with 
1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion of the investigator.  
5.3 Permitted Therapies 
After randomisation and administration of study drug, paracetamol / acetaminophen (1000 mg) 
will be permitted as the initial rescue medication. Subjects will be encouraged to wait at least 
60 minutes after receiving study drug before taking rescue medication. If acetaminophen 
rescue medication is not effective in relieving the subject’s pain, 5 mg oxycodone rescue 
medication may be administered at the discretion of the investigator.  
At the investigators discretion repeat doses of rescue medication may also be administered as 
required. 
The Investigator or designees will record all medication taken by the subject at the screening 
visit in the subject’s electronic Case Report Form (eCRF). Any medication taken by the subject 
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from the time of giving informed consent through to the end of the subject’s participation in the 
study (last assessment) will be recorded on the concomitant medication page in the eCRF. 
Upon discharge from the study site, subjects may be prescribed pain medication for use at 
home according to the standard practice of the study site.  
5.4 Treatment Compliance 
For the duration of each assessment the subject will remain at the study site under the 
supervision of the Investigator or designees. The Investigator or designees will provide 
supervised drug administration along with clear instructions and support to the subject to 
facilitate the best possible compliance with study requirements. Any non-compliance during 
the study will be observed and recorded by study site staff as a protocol deviation. 
5.5 Packaging and Labelling and Supply / Resupply 
For each subject one pack will be provided containing all required tablets for each dosing 
timepoint.  Each tablet will be held in a blister within the pack.  The pack will clearly show which 
tablets are to be taken at which timepoint. 
All packs regardless of treatment regimen will be the same except for a kit number and will 
therefore not identify the treatment. 
The IMP will be labelled in accordance with EudraLex Volume 4 Good Manufacturing Practice 
(GMP) Guidelines, Annex 13 - Manufacture of Investigational Medicinal Products, parts 26 to 
33 (Labelling) and in accordance with directive 2003/94/EC as amended and including any 
other applicable national/state legislation. The IMP will be labelled in English 
All IMP will be packed and labelled to GMP by the Investigational Material Supplies Unit 
(IMSU), Reckitt Benckiser Healthcare (UK) Ltd, Dansom Lane, Hull, HU8 7DS, UK. IMP will 
be shipped from the IMSU to the study site. 
5.6 Storage Conditions 
The Investigator or designated individual will keep all IMP(s) in a pharmacy or a secure storage 
facility, accessible only to those individuals authorised by the Investigator to dispense the 
medication. 
The Investigator or designated individual will maintain an inventory. This will include the 
description and quantity of IMP(s) received during the course of this study, as well as a record 
of the materials that are dispensed and returned (how much, to whom and when). This 
inventory (“Drug Dispensing Log”) will be subject to review by the study monitor during 
monitoring visits. 
The Investigator agrees not to supply IMP(s) to any person except study personnel and 
patients enrolled in this study. 
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The IMP should be stored between 8-25 °C and is not to be refrigerated or frozen. 
Temperatures must be constantly monitored and readings logged in a temperature log on 
working days.  
The temperature in the secure storage facility will be recorded using a minimum/maximum 
thermometer. If the temperature falls outside the specified range of 8-25 °C, the Sponsor 
should be notified immediately and appropriate action should be agreed and documented. The 
temperature log will be reviewed by the study monitor at each monitoring visit.  
5.7 Blinding 
This study is a double-blind, double dummy study.  There will be two placebo tablets designed 
to be comparable to each of the active products (PR and IR) in both shape, size, colour and 
weight. 
All subjects will receive 4 tablets at each dosing timepoint.  At each timepoint each subject will 
receive 2 tablets that may be either PR or the placebo made to look like PR and 2 tablets that 
may be IR or the placebo made to look like IR. See Table 3-2 Treatment Regimens.  This 
includes those in the placebo arm who will receive 2 placebo tablets designed to look like PR 
and 2 placebo tablets designed to look like IR at all dose timepoints. 
All subject packs will be designed and labelled to ensure blinding is maintained. 
Subjects, investigators and site staff will all be blind to the treatments. 
Unblinding will only occur after database lock or in the case of emergency unblinding, see 
Section 5.8. 
5.8 Emergency Unblinding Procedures 
Treatment unblinding is discouraged if knowledge of the treatment assignment will not 
materially change the planned management of a medical emergency. Unblinding will be 
permitted in a medical emergency that requires immediate knowledge of the subject’s 
treatment assignment. 
For emergency unblinding, study personnel will use the IWRS. If treatment assignment is 
unblinded for an individual subject, study personnel will be notified of that subject’s treatment 
assignment without unblinding the treatment assignments for the remaining subjects in the 
study. Thus, the overall study blind will not be compromised. If a subject’s treatment 
assignment is unblinded, he/she may or may not be asked to withdraw from the study. The 
investigator should make this decision after consultation with the medical monitor. 
5.9 Drug Accountability 
The Investigator will keep all study medication (including rescue medication) in a pharmacy or 
a secure storage facility, accessible only to those individuals authorised by the Investigator to 
dispense the medication. 
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The Investigator or designated individual will maintain an inventory. This will include the 
description and quantity of study drug received during the course of the study, as well as a 
record of the materials that are dispensed and returned (how much, to whom and when). This 
inventory will be subject to review by the study monitor during monitoring visits.  
The Investigator agrees not to supply study drug to any person except study personnel and 
subjects in this study.  
5.10 
Return and Destruction  
The Investigator agrees to conduct a drug-supply inventory, to record the results of this 
inventory (“IMP Removal from Site” form) and to ensure all original IMP containers whether 
empty or containing IMP are sent to RB’s representative at the end of the study. 
RBs representative will then arrange for the appropriate and timely destruction of all containers 
and unused IMP upon confirmation from RB following provision of a full reconciliation by 
Premier (on finalisation of the study report).   
6 
STUDY PROCEDURES BY VARIABLE 
6.1 Informed Consent 
Prior to conducting any study-related activities, written informed consent must be obtained 
from the subject (Section 12.2). 
6.2 Randomisation 
Eligible subjects will be randomised in a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets 
Q12h, 2x200 mg ibuprofen IR tablets Q8h, or placebo using permuted blocks of fixed size. The 
randomisation will be stratified by baseline pain category (moderate or severe) using a 
categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and 
severe (8-10). The randomisation schedule will be prepared by a statistician not otherwise 
involved in the study. Randomisation will be performed using an interactive web response 
system. Access to the unblinding codes will be restricted to personnel not otherwise involved 
in the study and will be available to the investigator only in the case of a subject requiring 
unblinding prior to database lock. 
6.3 Drug Administration 
Subjects will be dosed under clinic supervision to ensure compliance. Prior to dosing, each 
subject will be instructed by the Investigator or clinic staff on how to take the medication. 
 
6.4 Demographics 
Demographic information will be recorded including gender, date of birth and race. 
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6.5 Medical History and Concomitant Medication 
Relevant medical history, including history of current disease and information regarding 
underlying diseases will be recorded. The duration of surgery and all concomitant medication 
taken will be recorded as well as permitted therapies (see Section 5.3). 
6.6 Physical Examination 
A complete physical examination (excluding the genitourinary examination) will be performed 
at Screening. An abbreviated confirmatory physical assessment, including an examination of 
the subject’s mouth and neck, will be performed at the Follow-up Visit (or Early Termination 
Visit). 
Height, weight, and BMI will be assessed at Screening. 
6.7 Laboratory Tests 
The following clinical laboratory tests will be performed at Screening.  
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea 
nitrogen, creatinine, glucose, sodium, potassium, chloride, bicarbonate, 
lactate dehydrogenase, uric acid, urea, inorganic phosphorous, 
cholesterol (total and High Density Lipoprotein (HDL)), triglycerides, 
gamma glutamyl transferase 
Coagulation: 
prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones, leucocyte 
esterase, nitrites (in the event that the dipstick test is positive, red blood 
cells, white blood cells, epithelial cells, crystals, bacteria and casts will 
be examined microscopically) 
Virology: 
hepatitis B, hepatitis C, HIV 
The following laboratory tests will also be performed: 
 
Alcohol breathalyzer test will be performed before surgery on Day 1. 
 
Urine drug screen samples will be collected at Screening and before surgery on Day 1 to 
test for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine 
(PCP), and tetrahydrocannabinol (THC). 
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 
For female subjects of childbearing potential, a blood sample for the serum pregnancy 
test will be collected at Screening and a urine pregnancy test sample will be collected 
before surgery on Day 1. 
Blood and urine samples for hematology, serum chemistry, and urinalysis will be prepared 
using standard procedures and will be sent to a central laboratory for analyses. 
6.8 Electrocardiograms 
A 12-lead electrocardiogram will be performed at Screening. 
6.9 Vital Signs 
Vital signs will be recorded after the subject has been in a sitting position for 3 minutes. Vital 
sign assessments will include blood pressure, heart rate, respiratory rate, and body 
temperature. Clinically significant abnormalities in vital signs should be recorded as AEs. 
6.10 
Blood Sampling 
Blood sampling will be performed according to the site’s standard practices, as described in 
the study manual or other site documentation. 
6.11 
Oral Radiography 
Oral radiographs (X-rays) will be taken at Screening (radiographs taken within 1 year before 
Screening will be acceptable and do not need to be repeated). 
6.12 
Pain Intensity  
Subjects will rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no 
pain and 10 = worst pain ever at the timepoints mentioned on Table 7-1. 
6.13 
Stopwatch Assessment  
Two stopwatches will be started immediately after the subject has swallowed the study drug 
with 8 ounces of water. Each subject will be instructed, “Stop the first stopwatch when you first 
feel any pain relief whatsoever. This does not mean you feel completely better, although you 
might, but when you first feel any relief in the pain you have now” (perceptible pain relief). The 
subject will also be instructed, “Stop the second stopwatch when you feel the pain relief is 
meaningful to you” (meaningful pain relief). If the subject does not press the stopwatches within 
8 hours after Time 0 the subject will discontinue use of the stopwatches. 
6.14 
Pain Relief Scale  
Subjects will rate their pain relief relative to Time 0 using a 5-point categorical scale. Subjects 
will be asked “How much relief have you had since your starting pain?” with response choices 
of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. At each assessment time point, 
the pain intensity NRS assessment will be completed first and the pain relief assessment will 
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be completed second. Subjects will not be able to compare their responses with their previous 
responses. 
6.15 
Subject’s Global Evaluation of Study Drug 
For the global evaluation of study drug, the subject will be asked “How effective do you think 
the study drug is as a treatment for pain?” with response choices of 0 = poor, 1 = fair, 2 = good, 
3 = very good, or 4 = excellent. Subjects will complete the global evaluation of study drug 
24 hours after Time 0 or immediately before the first dose of rescue medication (whichever 
occurs first). 
6.16 
Adverse Events  
During the study the Investigator will ask the subject: “Are you experiencing any symptoms or 
complaints?” at the baseline visit, and “Have you had any symptoms or complaints since the 
last time you were asked?” during the study. In addition, spontaneously reported AEs are 
collected. 
The observation period for an individual subject will start after giving informed consent and will 
finish at the last visit (follow-up visit) for the given individual subject. All AEs that arise during 
the observation period will be recorded and an assessment of the AE will be performed as per 
Section 8.2 by a medically qualified Investigator. If a subject has an AE that is still ongoing at 
the last visit, an attempt will be made by the Investigator to follow this up as per Section 8.4.   
If an untoward medical occurrence happens after the subject has signed the consent form but 
before administration of the IMP, it should be reported as an adverse event, including those 
associated with study procedures. 
Note this does not include any pre-existing medical conditions or findings associated with 
medical history which are identified during the screening process. 
7 
STUDY PROCEDURES BY VISIT 
7.1 Study Flow Chart / Table of Study Procedures and Assessments 
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Table 7-1 Schedule of Assessments 
 
Screening 
(Day -28 to 
Day -1) 
Surgery (Day 1) 
Day 2 
Follow-up 
(Day 8 ±2 days) or 
ETk 
 
 
Pre-
Surgery 
 
Post-surgery 
 
 
 
 
Pre-
dose 
0 h 
15, 30, 
45 min 
1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 
10 h 
12 h 
16 
h 
24h 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Assign a screening number 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xb 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
 
 
 
X 
 
X 
X 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (hematology, 
chemistry, urinalysis) 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test for female subjects of 
childbearing potentiale 
X 
X 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
Alcohol breathalyzer test 
 
X 
 
 
 
 
 
 
 
 
Oral radiographyf 
X 
 
 
 
 
 
 
 
 
 
Review study restrictions with subject 
X 
 
 
 
 
 
 
 
 
 
Pain intensity (NRS)g 
 
 
X 
 
X 
X 
X 
X 
X 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
Dosing with study drug 
 
 
 
0 h 
 
8 h 
12 h 
16h 
 
 
Stopwatch assessmenth 
 
 
 
X 
 
 
 
 
 
 
Pain relief (5-point categorical scale)g 
 
 
 
 
X 
X 
X 
 
X 
 
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Screening 
(Day -28 to 
Day -1) 
Surgery (Day 1) 
Day 2 
Follow-up 
(Day 8 ±2 days) or 
ETk 
 
 
Pre-
Surgery 
 
Post-surgery 
 
 
 
 
Pre-
dose 
0 h 
15, 30, 
45 min 
1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 
10 h 
12 h 
16 
h 
24h 
 
Global evaluation of study drugi 
 
 
 
 
 
 
 
 
X 
 
Concomitant medications 
 
Xb 
X 
X 
X 
X 
X 
 
X 
X 
Adverse eventsj 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Provide prescription for pain medication.  
 
 
 
 
 
 
 
 
X 
 
Collect unused home pain medications, as 
needed 
 
 
 
 
 
 
 
 
 
X 
Discharge from study site 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: BMI=body mass index; ET=early termination; h=hour; min=minute; NRS=numeric rating scale;. 
a Times listed are relative to dosing with study drug. 
b Medical history and concomitant medication use since Screening will be updated on Day 1 before surgery. 
c A complete physical examination (excluding the genitourinary examination) will be performed at Screening. An abbreviated confirmatory physical assessment, 
including an examination of the subject’s mouth and neck, will be performed at the Follow-up Visit (or Early Termination Visit). 
d Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at the following times: at Screening, before surgery, within 30 minutes 
before Time 0, 12 hours after Time 0, 24 hours after Time 0, and/or immediately before the first dose of rescue medication, and at the Follow-up Visit (or Early 
Termination Visit). 
e Serum pregnancy test at Screening and urine pregnancy test before surgery on Day 1 (female subjects of childbearing potential only). Test results must be 
negative for the subject to continue in the study. 
f 
Oral radiographs taken within 1 year before Screening will be acceptable and do not need to be repeated. 
g Pain assessments will be conducted (pre-dose, if at one of the dosing timepoints of 0, 8, 12 or 16 hours) at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 
8, 10, 12, 16 and 24 hours after Time 0 and immediately before each dose of rescue medication. Pain intensity will also be assessed pre-dose. At each 
assessment time point, the pain intensity assessment will be completed first and the pain relief assessment will be completed second. Subjects will not be 
able to compare their responses with their previous responses.  Note for assessments less than 1 hour apart a window of +/-2 min is allowable whilst for 
assessments at least 1 hour apart a +/-5 min window is allowable. 
h Two stopwatches will be started immediately after the subject has swallowed the first dose of study drug with 8 ounces of water (Time 0). Subjects will record 
the time to perceptible and meaningful pain relief, respectively, by stopping the stopwatches. 
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i 
Subjects will complete a global evaluation of study drug 24 hours after Time 0 or immediately before the first dose of rescue medication (whichever occurs 
first). 
j 
Adverse events will be monitored and recorded from the time of signing of the informed consent form until the Follow-up Visit (or Early Termination Visit). 
k If an unscheduled visit occurs the Investigator should follow the activities detailed in Section 7.5. 
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7.2 Screening Visit (Day -28 to Day -1) 
 
Written informed consent 
 
Assign a screening number 
 
Inclusion/exclusion criteria 
 
Demographics 
 
Medical history 
 
Complete physical examination (excluding the genitourinary examination) 
 
Vital signs 
 
Electrocardiogram 
 
Height, weight, and BMI 
 
Clinical laboratory tests (haematology, chemistry, urinalysis) 
 
Serum pregnancy test for female subjects of childbearing potential 
 
Urine drug screen 
 
Oral radiography (oral radiographs taken within 1 year before Screening will be 
acceptable and do not need to be repeated)  
 
Review study restrictions with subject 
 
Schedule surgery 
7.3 Day of Surgery (Day 1) 
 
Pre-Surgery 
 
Inclusion/exclusion criteria review 
 
Medical history review 
 
Vital signs 
 
Urine pregnancy test for female subjects of childbearing potential 
 
Urine drug screen 
 
Alcohol breathalyzer test 
 
Concomitant medications 
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 
Adverse events 
 
Surgery 
 
Subjects who continue to be eligible for study participation after completing screening 
procedures and assessments will undergo extraction of 2 or more third molars. At least 
1 of the third molars must be a fully or partially bone impacted mandibular molar. If only 
2 molars are removed, then they must be ipsilateral.  
 
All subjects will receive local anesthesia (2% lidocaine with 1:100,000 epinephrine).  
 
Nitrous oxide will be allowed at the discretion of the investigator. 
 
Post-surgery Eligibility Assessments and Randomisation 
 
Vital signs 
 
Concomitant medications 
 
Adverse events  
 
Pain intensity NRS  
 
Subjects who experience moderate to severe pain intensity (NRS score of ≥ 5) within 
6 hours after surgery and who continue to meet all study entry criteria will be randomised 
 
Dosing and Post-dose Assessments (Hour 0 through Hour 24) 
 
Subjects will re-assess their baseline pain intensity using the NRS immediately before 
receiving IMP (pre-dose, Time 0) 
 
Administer IMP at the timepoints in Table 3-2 
 
Subjects will assess their pain intensity (NRS) and pain relief (5 point categorical scale) 
at the following time points (pre-dose, if at one of the dosing timepoints of 0, 8, 12 or 
16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours 
after Time 0; and immediately before each dose of rescue medication, if any. For 
assessments less than 1 hour apart a window of +/-2 min is allowable whilst for 
assessments at least 1 hour apart a +/-5 min window is allowable. 
 
Subjects will use the double stopwatch method to record the time to perceptible pain 
relief and time to meaningful pain relief during the 8 hours following the first dose or until 
subject takes rescue medication 
 
Subjects will complete a global evaluation of study drug 24 hours after Time 0 or 
immediately before the first dose of rescue medication (whichever occurs first) 
 
Vital signs will be recorded after the subject has been in a sitting position for 3 minutes 
at the following times: before surgery, within 30 minutes before Time 0, 12 and 24 hours 
after Time 0, and/or immediately before the first dose of rescue medication 
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7.3.3 
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 
Concomitant medications 
 
Adverse events  
 
Subjects will remain at the study site overnight and will be discharged on Day 2.  
 
Upon discharge from the study site, provide prescription for pain medication.  
 
Schedule follow-up visit 
7.4 Follow-up Visit (Day 8 ± 2 days) or Early Termination 
 
Abbreviated confirmatory physical assessment, including an examination of the 
subject’s mouth and neck 
 
Vital signs 
 
Concomitant medications 
 
Record any post discharge adverse events 
7.5 Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the reason for unscheduled visit, 
including any AEs, concomitant therapy changes, withdrawal (if deemed appropriate) and any 
clinical assessments deemed appropriate for the clinical care of the subject. Unscheduled 
visits should not alter the timing of the routine study schedule. 
7.6 Study Restrictions 
 
Prohibited Therapies 
Subjects are not permitted to take any concomitant medications that might confound 
assessments of pain relief, such as psychotropic drugs, antidepressants, sedative-hypnotics 
(other than those permitted for conscious sedation), or other analgesics taken within five times 
of their elimination half-lives (other than those used at the surgery). Selective serotonin 
reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are 
permitted if the subject has been on a stable dose for at least four weeks prior to Visit 1 
(screening).  
 
General and Dietary Restrictions 
Other restrictions include the following: alcohol use is prohibited from 24 hours before surgery 
until discharge on Day 2; nothing by mouth from midnight before surgery until 1 hour after 
surgery; clear liquids only are allowed starting 1 hour after surgery until 1 hour after dosing; 
1 hour after dosing, the subject’s diet may be advanced according to standard practice. 
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8 
SAFETY REPORTING 
8.1 Adverse Event Definitions 
An Adverse Event (AE)  
An adverse event (AE) is any untoward medical occurrence in a patient or a clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have a causal relationship with  this treatment. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. [ICH E6 1.2].  
Serious Adverse Event (SAE)  
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that:  
 
results in death  
 
is life-threatening 
 
requires in-patient hospitalization or prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity or  
 
is a congenital anomaly/birth defect 
In addition, important medical events that may not be immediately life-threatening or result in 
death, or require hospitalisation, but may jeopardise the patient or may require intervention to 
prevent one of the other outcomes listed above should also usually be considered serious.  
[ICH E2A] Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, 
or development of drug dependency or drug abuse.  
Note: If the event is related to the investigational product and is both serious and unexpected, 
it is classified as a suspected unexpected serious adverse reaction (SUSAR). In case of 
double-blinded studies, unblinding is needed in order to determine a SUSAR. 
8.2 Assessment of Adverse Events 
Any untoward medical occurrences that arise after the subject has given informed consent will 
be recorded in the subject’s source documents and electronic case report forms (eCRFs). 
Untoward medical occurrences can be reported spontaneously by the subject or in response 
to non-leading questioning or observation by the Investigator or be a significant laboratory 
abnormality. 
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Untoward medical occurrences, including all adverse events (AE) and all serious adverse 
events (SAEs) are collected, fully investigated and documented.  
As the study will be conducted on subjects who have been through removal of impacted third 
molars, it is expected that they will present post-surgical symptoms, for example: swelling and 
bruising. For the purposes of this study, when at normal/expected magnitude, such 
occurrences will not be reported as AEs as they are expected and, therefore, are not 
“untoward” as in the AE standard definition. 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at 
study termination will be further followed up until recovery or until stabilisation of the disease 
after termination. 
For each AE a causality assessment of the event to the study drug must be performed. The 
relationship to IMP must be determined by the Investigator (if medically qualified) or by a 
medically qualified Co-Investigator. 
Table 8-1 AE Relationship Descriptions 
Relationship 
Description 
Unassessable/ 
Unclassifiable 
Insufficient information to be able to make an assessment 
Conditional/ 
Unclassified 
Insufficient information to make an assessment at present (causality 
is conditional on additional information) 
Unrelated 
No possibility that the AE was caused by the IMP 
Unlikely 
Slight, but remote, chance that the AE was caused by the IMP, but 
the balance of judgement is that it was most likely not due to the IMP 
Possible 
Reasonable suspicion that the AE was caused by the IMP 
Probable 
Most likely that the AE was caused by the IMP 
Certain 
The AE was definitely caused by the IMP 
 
For each AE a severity description should be given. 
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Table 8-2 AE Severity Descriptions 
Severity 
Description 
Mild 
The AE does not limit usual activities; the subject may experience 
slight discomfort 
Moderate 
The AE results in some limitation of usual activities; the subject may 
experience significant discomfort 
Severe 
The AE results in an inability to carry out usual activities; the subject 
may experience intolerable discomfort or pain 
 
Expectedness for each AE will be determined based on the information in Section 6.9 of the 
Investigator’s Brochure. 
All AEs will be coded by the Sponsor using the most up-to-date version of MedDRA. 
8.3 Reporting of Adverse Events 
In the event of a Serious Adverse Event (SAE), the Investigator must report the event using 
the SAE form to the Sponsor Global Vigilance Group (GVG), by contacting GVG by email: 
gvg@rb.com while copying in the contract research organisation (CRO) and Sponsor 
Project/Study Managers within 24 hours of knowledge of the event. 
The out of hours emergency phone number is +44 (0)1482 326151. An alternative number 
may additionally be provided by Premier Research to give access to the study Medical Monitor 
our of hours. 
This emergency phone number will be confirmed to the Investigator at the Study Initiation Visit.  
All SAE Forms must be provided via email. Any inconsistencies in the information received 
from the Investigator will be clarified using the Adverse Event Data Clarification Form. The 
Investigator must retain a copy of all the SAE forms in the Investigator Site File. 
The Investigator must inform their Institutional Review Board (IRB) of all SAEs occurring in the 
study within 7 days for fatal or life-threatening SAEs and 15 days for all other SAEs as per 
Sponsor instructions and as described in the Safety Management Plan.  
The Investigator should not break the randomisation code except when it is necessary to do 
so in order to ensure the subject receives appropriate medical care. 
SAEs and non-serious AEs will be reported to the appropriate regulatory authorities by the 
Sponsor in accordance with the authorities’ requirements. The Sponsor is responsible for 
expedited reporting of all SUSARs/ SAEs to relevant authorities and IECs/IRBs as required by 
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regulations. If the event requires expedited reporting, a CIOMS (Council for International 
Organizations of Medical Sciences) form will be produced and GVG will take actions as per 
the study specific Safety Management Plan.  
8.4 Follow-up of Adverse Events 
All SAEs and all AEs that have not resolved by the end of the study will be followed up by the 
Investigator until resolution or until the Investigator believes there will be no further change, 
whichever is the earlier. This may involve the subject making additional visits to the site.  
If a subject has unresolved AEs requiring follow-up, investigators must attempt to contact 
subjects by telephone or other means.  
8.5 Overdose, Abuse, Misuse and Medication Errors 
The Sponsor defines “overdose” as the administration of a quantity of an investigational IMP 
given per administration or cumulatively, which is above the maximum recommended dose 
according to the authorised product information. 
The Sponsor defines “abuse” as the persistent or sporadic, intentional excessive use of an 
IMP, which is intended to produce harmful physical or psychological effects e.g. intentional 
overdose to experience psychological effects. 
The Sponsor defines “misuse” as situations where the IMP is intentionally and inappropriately 
used not in accordance with the authorised product information. 
Overdoses, abuse, misuse are reportable to the Sponsor irrespective of the presence of an 
associated AE / SAE. The overdose, abuse, misuse and any associated AE / SAE will be 
captured on an AE CRF (Case Report Form) page / SAE form. 
Due to the full inpatient nature of this study, in which medication doses will be supervised by 
site staff, cases of overdose, abuse or misuse are not expected to occur.  
Medication errors are any unintentional errors in dispensing or administration of the IMP which 
relates to: 
 
Taking / being administered an incorrect IMP 
 
Taking / being administered a drug by the wrong route of administration e.g. swallowing 
a suppository 
 
The accidental administration of the IMP to a person who is not a subject within the 
study 
Medication errors are reportable to the Sponsor irrespective of the presence of an associated 
AE / SAE. Medication errors with or without an associated AE / SAE will be captured on the 
AE CRF page / SAE form. 
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8.6 Pregnancy 
Pregnancy both in a female subject or the female partner of a male subject is considered a 
collectable event and will be recorded as an AE in all cases. It will be qualified as an SAE only 
if it fulfils SAE criteria. 
Due to the full inpatient nature of this study, pregnancy cases are not expected to occur during 
the study.  
 
9 
STATISTICAL CONSIDERATIONS 
This section presents a summary of the planned statistical analyses. A statistical analysis plan 
(SAP) that describes the details of the analyses to be conducted will be written prior to 
database lock. 
Summary statistics for continuous variables will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, summary 
statistics will typically include the number and percentage of subjects in each category. All data 
will be presented in listings. 
Baseline values are defined as the last measurements taken before dosing with study drug. 
9.1 Determination of Sample Size 
The sample size determination is based on the primary efficacy variable, SPID12. According 
to Farrar 2001(1), a clinically important improvement in pain is represented by a 2 point 
reduction on an 11-point NRS. Based on a baseline pain score of 7 this corresponds to an 
approximate 30% reduction in pain. An average 2 point difference in pain scores between 
Ibuprofen PR and placebo across all 14 assessments up to 12 hours will correspond to a 
difference in SPID12 of 24 points. In a previous study (7), the pooled standard deviation (SD) 
for SPID12 was 31.65. Assuming the same variability in this study, a sample size of 40 subjects 
per group will have >90% power to detect a difference of 24 points in SPID12, between 
ibuprofen 2×300-mg PR tablets and placebo using a 2-sided test with an alpha level of 0.05. 
In order to provide a robust estimate of treatment effect differences between PR and IR, and 
to obtain a more precise estimate for this comparison, a 3:3:1 allocation ratio will be used, so 
that 120 subjects are randomised into each of the PR and IR groups. Thus 280 subjects will 
be enrolled into the study. 
9.2 Interim Analysis 
No interim analysis is planned.  
9.3 Analysis Datasets 
The analysis populations include the following: 
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 
The intent-to-treat (ITT) population will consist of all subjects who are treated with 
study drug and who have at least 1 pain relief assessment after Time 0. The ITT 
population is the primary population for the efficacy analysis. 
 
The per-protocol (PP) population will consist of all ITT subjects who do not incur a 
major protocol violation that would challenge the validity of their data. This population 
will be utilized to evaluate the sensitivity of the primary efficacy analysis. 
 
The safety population will include all subjects who are treated with study drug. The 
safety population is the population for all safety assessments. 
 
9.4 Subject Disposition and Characteristics 
The numbers of subjects randomised, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. Demographic and baseline characteristics (including date 
of birth, sex, race, weight, height, BMI, medical history, and surgery duration) will be 
summarized for each treatment group and for the overall population using descriptive statistics. 
No formal statistical analyses will be performed. 
9.5 Efficacy Analyses 
The comparison of primary interest is between PR ibuprofen and placebo. In addition, the 
comparison between IR ibuprofen and placebo will be presented with p-values to demonstrate 
study sensitivity. Point estimates and 95% confidence intervals will be used to evaluate the 
clinical relevance of any differences between the PR and IR formulations. All treatment 
differences will be presented with 95% confidence intervals. No P value adjustment will be 
made for multiple endpoints or multiple comparisons. In the event of model assumptions for 
normality being violated, non-parametric methods will be used. 
Each efficacy endpoint will be summarized descriptively by treatment group. 
 
Primary Endpoint(s) 
The primary endpoint, summed pain intensity difference (SPID) over 0 to 12 hours (SPID12), 
will be used to compare the test product (2×300 mg ibuprofen PR tablets) against the placebo 
product. 
9.5.1.1 
Primary Analysis 
The primary efficacy null hypothesis is that SPID12 for placebo is equal to SPID12 for ibuprofen 
2×300 mg PR tablets. The primary analysis will be an ANCOVA model that includes the main 
effect of treatment and a covariate of the baseline NRS pain score and will use windowed worst 
observation carried forward (WOCF) imputation for subjects who use rescue medication. The 
primary analysis will be based on a 2-sided test at the significance level of 0.05. 
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9.5.1.2 
Secondary Analysis 
The clinical relevance of the difference between placebo and PR ibuprofen over 12 hours after 
initial dose will be evaluated. 
 
Secondary Endpoints 
 
The summed pain intensity difference (SPID) over 0 to 24 hours (SPID24) will be 
used to compare the test product (2×300 mg ibuprofen PR tablets twice daily [BID]) 
and comparator product (2×200 mg ibuprofen IR tablets three times a day [TID]). 
 
Summed pain intensity difference (SPID) over 0 to 4 hours (SPID4), over 0 to 8 hours 
(SPID8), and over 0 to 12 hours (SPID12) after Time 0 
 
Sum of total pain relief (TOTPAR) over 0 to 4 hours (TOTPAR4), over 0 to 8 hours 
(TOTPAR8), over 0 to 12 hours (TOTPAR12), and over 0 to 24 hours (TOTPAR24) 
after Time 0 
 
Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) 
over 0 to 4 hours (SPRID4), over 0 to 8 hours (SPRID8), over 0 to 12 hours 
(SPRID12), and over 0 to 24 hours (SPRID24) after Time 0 
 
Response to study drug (a responder will be defined as a subject with ≥30% 
improvement in pain intensity without rescue medication during the first 8 hours) 
 
Numeric rating scale (NRS) pain intensity difference (PID) at each scheduled time 
point after Time 0 
 
Pain intensity score at each scheduled time point 
 
Pain relief score at each scheduled time point after Time 0 
 
Peak pain relief 
 
Time to onset of analgesia (measured as time to perceptible pain relief confirmed by 
time to meaningful pain relief) using double stopwatch 
 
Time to first perceptible pain relief 
 
Time to meaningful pain relief 
 
Time to peak pain relief 
 
Proportion of subjects using rescue medication 
 
Time to first use of rescue medication  
 
9.5.2.1 
Secondary Endpoint Analyses 
For continuous secondary endpoints such as pain intensity score, SPID at each scheduled 
time point, peak pain intensity, TOTPAR4, TOTPAR8, TOTPAR12, TOTPAR24, SPID4, 
SPID8, SPID24, SPRID4, SPRID8, SPRID12, and SPRID24, descriptive statistics (such as 
mean, standard deviation, median, minimum, and maximum) will be provided for each 
treatment regimen. P values from ANCOVA models comparing the placebo group with other 
treatment groups, including terms for treatment and a covariate for baseline pain will be 
provided for SPID, SPRID, and TOTPAR variables, but no formal statistical inferences will be 
drawn on the basis of these tests. In the event that normality assumptions are violated for a 
parameter, non-parametric analysis methods will be used.  
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For ordinal secondary endpoints, such as pain intensity difference at each scheduled time 
point, pain relief at each scheduled time point, peak pain relief, and global evaluation of study 
drug, descriptive summaries will be provided and will include the number and percentage of 
subjects within each category for each treatment group. Nominal P values from Fisher’s exact 
tests (or chi-square tests, as appropriate) comparing the placebo group with other treatment 
groups will be provided for peak pain relief and global evaluation of study drug, but no formal 
statistical inferences will be drawn on the basis of these tests. 
For each time-to-event endpoint, Kaplan-Meier methodology will be used to evaluate the 
treatment effect. Time to onset of analgesia (measured as time to perceptible pain relief 
confirmed by meaningful pain relief) will be based on data collected using the double stopwatch 
method. Time to onset of analgesia will be right-censored at 8 hours for subjects who do not 
experience both perceptible pain relief and meaningful pain relief during the 8-hour interval 
after Time 0. The summary tables will provide the number of subjects analysed, the number of 
subjects censored, estimates for the quartiles, and 95% confidence intervals (CIs) for the 
estimated median and the restricted mean estimate. P values comparing placebo to active 
treatment from Wilcoxon or log-rank tests (as appropriate) will also be used to examine 
treatment effect. 
For time to onset of analgesia, the comparison of interest will be the ibuprofen 2×300 mg PR 
group versus the ibuprofen 2×200 mg IR group. The summary table for this comparison will 
provide the number of subjects analysed, the number of subjects censored, estimates for the 
quartiles, and 95% confidence intervals (CIs) for the estimated median and the restricted mean 
estimate.  
For the proportion of subjects who are responders and the proportion of subjects using rescue 
medication, logistic regression models that adjust for baseline intensity and/or significant 
demographic variables, if appropriate, will be used to evaluate the treatment effect.   
For the responder analysis, subjects will be censored at 8 hours and for the use of rescue 
medication/time to first rescue subjects will be censored at 24 hours.  
9.6 Safety Analyses 
 
Safety Endpoint(s) 
 
Incidence of treatment-emergent adverse events (TEAEs) 
 
Incidence of changes in vital sign measurements 
9.6.1.1 
Safety Endpoint Analyses 
Data listings will be provided for protocol-specified safety data. The Medical Dictionary for 
Regulatory Activities (MedDRA) (Version 19.0 or higher) will be used to classify all AEs with 
respect to system organ class and preferred term. Adverse event summaries will include only 
TEAEs, which will be summarized for each treatment group.  
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For vital sign measurements, descriptive statistics will be provided at each scheduled time 
point for each treatment group. Changes from Baseline for vital signs will be calculated for 
each subject, and descriptive statistics will be provided on changes in vital signs from Baseline 
for each treatment group at each scheduled time point after Baseline. No formal statistical tests 
will be performed. 
9.7 Handling of Missing Data and Drop-outs 
Missing pain assessments for all efficacy analyses will be handled as follows: 
 
Missing pain assessments scheduled before the first observed assessment will be 
imputed with the subject’s worst observed pain assessment. 
 
Missing intermediate pain assessments will be replaced by linear interpolation. 
 
Missing pain assessments at the end of the observation period due to premature 
discontinuation of pain assessments will be imputed by carrying forward the last 
observation prior to that missing. 
 
The primary analysis will use windowed worst observation carried forward (WOCF) 
methodology for subjects who use rescue medication. Any pain measurements taken during a 
period of time in which rescue medication is active (4 hours) will be replaced by the last pain 
measurement before the rescue medication was taken. A sensitivity analysis will also be 
performed, in which all pain assessments recorded after the first dose of rescue medication 
has been taken will be disregarded and the rules outlined above will be used for missing data. 
 
All data for assessments other than pain assessments will be analysed as collected; missing 
data due to premature termination or any other reason will be left as missing. In the event of a 
notable difference between treatment groups in the number of subjects using rescue 
medication, other sensitivity analyses may be performed. These will be detailed in the 
Statistical Analysis Plan (SAP). 
 
9.8 Changes to the Original Statistical Plan 
If there are any deviations to the proposed statistical analysis as described in this protocol 
these will either be documented in the final SAP or in a protocol amendment prior to database 
lock with the rationale and impact of the changes addressed. 
10 
DATA HANDLING AND RECORD KEEPING 
10.1 
Case Report Forms (CRFs) 
Data will be recorded in an electronic Case Report Form (eCRF). For each enrolled study 
subject an eCRF is maintained. The Investigator or designees is responsible for the quality of 
the data record in the eCRF. eCRFs must be kept current to reflect subject status at each 
phase during the course of study. Subjects must not be identified in the eCRF by name or 
initials.  
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In the eCRF subjects will be identified by a subject number in combination with date of birth 
only, i.e., not by their name or initials. eCRF entries must be completed by appropriately trained 
site staff only. A log of trained and authorised staff able to complete the eCRF will be kept. 
10.2 
Specification of Source Documents 
Source data must be available at the site to document the existence of the study subjects. 
Source data must include the original documents relating to the study, as well as the medical 
treatment and medical history of the subject. The investigator and study monitor will identify 
the data that will be recorded directly on the eCRF and for this data the eCRF will be considered 
the source document (i.e., no prior written or electronic record of the data). The study monitor 
will document this at the screening and it will also be documented in the Data Management 
Plan.  
Source documents will include notes taken at the site and will include data such as 
demographic data, participation in study and ICF, medical history, SAEs, AEs and concomitant 
medication, results of examinations and assessments.  
Where source data are in the form of a computer printout (e.g. medical records, laboratory 
data) they will be signed and dated by the investigator or designated person, confirming that 
the print out is a true and faithful record of the data for that subject. These print-outs will be 
filed in the study files. 
The Investigator agrees to provide direct access to source data for study-related monitoring, 
audits, IRB review, and regulatory inspection(s). Direct access to source data requires that the 
subject gives written, documented consent to this. 
10.3 
Data Management 
The data management group at Premier Research will be responsible for data management 
and eCRF activities.  
Full details regarding data management will be described within the Data Management Plan.  
10.4 
Reporting of Protocol Deviations 
Site staff should make the study monitor aware of any deviation from the protocol as soon as 
possible after occurrence. Waivers for inclusion / exclusion criteria are not allowed. 
10.5 
Retention of Essential Documentation 
The Investigator should retain all essential documents (as defined in ICH E6 or according to 
other national and international regulations) until at least 5 years after the completion of the 
study (defined as last subject last visit in the study). These documents should be retained for 
a longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the Investigator 
when these documents no longer need to be retained. 
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Subject files and other source data must be kept for the maximum period of time permitted by 
the Clinical Unit. The Investigator must notify the Sponsor of the retention period if this is 
shorter than described above. 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Monitoring 
The Sponsor will organise regular monitoring visits to be performed at intervals agreed with 
the Investigator. The anticipated monitoring frequency will be stated in the Monitoring Plan. 
Monitoring will also involve, as appropriate, correspondence and telephone contacts. 
On-site monitoring includes source data verification (SDV) which is the procedure whereby the 
data contained in the eCRFs are compared with the primary source data and thereby verified 
as accurate. It will be performed in such a way as to preserve subject confidentiality, taking 
into account all ethical and legislative requirements. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during the monitoring visit to review the data and resolve any queries and to allow direct 
access to the subject’s records for SDV).  
SDV will include as a minimum verification for all subjects, subject identity (date of birth, sex, 
initials and subject number), record of entry into the study and signature of the informed 
consent. In addition, details of SAEs in the subject’s notes will be verified. Details included in 
the subject’s notes as a minimum: 
 
Study number, brief description or title of study 
 
Date that the subject gave written consent 
 
All visit dates 
 
All SAEs 
 
All concomitant medications 
At a site visit the eCRFs should be complete and available in order that the accuracy of their 
completion may be checked. Each completed eCRF for each subject must be signed 
electronically by the Investigator, to verify the data and statements submitted. Similarly, all 
alterations on paper records must be initialled and dated by the Investigator or a designated 
person, explained as necessary, with the original mistake left legible. 
11.2 
Audits and Inspections 
For the purpose of ensuring compliance with the protocol, ICH GCP and applicable regulatory 
requirements, clinical studies sponsored by RB may be subject to an independent audit at the 
study site which will be conducted by personnel from an appropriate Quality Assurance Unit. 
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Full consultation with the Investigator will be made prior to and during such audit, which will be 
conducted according to Quality Assurance Unit Standard Operating Procedures. 
As soon as the Investigator is notified of a planned inspection by a Regulatory Authority, he / 
she must inform the Sponsor promptly and allow the Sponsor to participate in the inspection 
as permitted by applicable regulations and local laws. 
11.3 
Sponsor Policy on Fraud in Clinical Studies 
In accordance with GCP, it is the Sponsor’s policy to always follow-up suspected cases of 
fraud. 
12 
ETHICAL AND REGULATORY ASPECTS 
12.1 
Ethics Review and Regulatory Authority Approval 
Written approval to conduct the study by an independent and appropriately constituted IRB 
must be obtained and a copy provided to the Sponsor before any protocol-related procedures 
that do not form part of the subject’s normal clinical treatment are performed. The approval 
letter must contain: 
 
Name and address of the IRB. 
 
Date of meeting. 
 
Sufficient information to identify the version of the Protocol and subject 
information/informed consent. 
 
Sufficient information to identify the version of other documents reviewed. 
The investigator must also provide the Sponsor with a list of IRB members that includes each 
member’s name and profession. 
Any amendments to the Protocol must be submitted to the IRB for approval unless where 
necessary to eliminate apparent immediate hazards to study subjects, and any administrative 
changes must be notified.  
This study will be submitted to the applicable Regulatory Authorities. The study will only be 
undertaken when regulatory authorisation has been obtained by the Sponsor. 
The Sponsor will notify the Regulatory Authority within 90 days of the end of the study (within 
15 days if the study is terminated prematurely). 
Premier Research will notify the IRB within 90 days of the end of the study (within 15 days if 
the study is terminated prematurely). 
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12.2 
Subject Information and Consent 
Informed consent should be obtained by means of a patient information sheet and ICF, 
prepared in accordance with ICH E6 (R2) section 4.8.10 and the applicable local regulations, 
written in a non-technical language.  All subjects will be provided with oral and written 
information describing the nature and duration of the study and the procedures to be 
performed.  The subject will be asked to sign and date an ICF prior to any study-specific 
procedures being performed.  No subject can enter the study before his/her informed consent 
has been obtained.  A sample subject ICF used in the study will be included in the clinical study 
report for this protocol.  
As part of administering the informed consent document, the Investigator must explain to each 
subject the nature of the study, its purpose, the procedures involved, the expected duration, 
the potential risks and benefits involved, and any potential discomfort.  Each subject must be 
informed that participation in the study is voluntary and that he/she may withdraw from the 
study at any time and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician.  The subject should understand the study, 
patient information sheet, and ICF before signing and dating the ICF.  The Investigator or 
person obtaining consent must also sign and date the form.  Each subject will be given a copy 
of the signed informed consent and written information. 
12.3 
Early / Premature Termination of the Study 
In the unlikely event that this study generates an excessive frequency of adverse events, 
subjects’ termination or suspension may be requested by the sponsor or the IRB or the 
Regulatory Authority. 
The sponsor retains the right to terminate the study for non-safety reasons by giving an 
appropriate period of notice to all involved parties as per contractual agreements. 
Any decisions to terminate or suspend the study will be notified in writing to the Investigator or 
designees, the IRB, Regulatory Authority and the clinicaltrials.gov database. 
If the study is terminated early, study subjects who have attended screening will be informed 
that they are no longer required and if they have any questions, they should consult the study 
site staff. For subjects who have completed the study they will not be informed that the clinical 
study has been terminated. All data collected up to the point of study termination will be used 
in an abbreviated Clinical Investigation Report.  
13 
COMPENSATION, INDEMNITY AND INSURANCE 
13.1 
Clinical Study Agreement 
Before the study commences, a contract between the Sponsor and Premier Research, who 
contracts with the Investigator, will be signed in which financial aspects of the study (including 
financial disclosure) as well as responsibilities and obligations are described. 
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13.2 
Compensation 
The Sponsor and the CRO carry insurance to pay compensation for injury, accident, ill health 
and death caused by participation in this study without regard to proof of negligence in 
accordance with the current local regulations and requirements. Details on finance and 
insurance will be provided in a separate agreement between the investigator and the sponsor.  
13.3 
Indemnity 
The Sponsor will provide appropriate indemnity for the Investigator and staff who conduct part 
or all of this study, upon request. The request must be received before the first subject is 
recruited. 
13.4 
Insurance 
If required and in accordance with applicable regulatory and legal requirements, the Sponsor 
will take out appropriate insurance policies on behalf of the Investigator and staff who conduct 
part or all of this study and/or on behalf of the subjects participating in the study. 
14 
REPORTING, PUBLICATION AND PRESENTATION 
A clinical study report will be prepared according to ICH E3 (Structure and Content of Clinical 
Study Reports) as part of the Sponsor’s commitment to Good Clinical Practice. The report will 
be a record of the total study conduct and findings and will be subject to approval by the 
Investigator who will sign the final report. 
The study data will be owned by the Sponsor. The Sponsor retains the right to publish the data 
independently of the Investigator. The Sponsor agrees that before it publishes the results, it 
will provide the Investigator with at least 30 days for full review prior to submission of the 
manuscript to the publisher. The Investigator must submit any proposed manuscript to the 
Sponsor for approval prior to submission for publication. 
15 
REFERENCES 
(1) Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of 
changes in chronic pain intensity measured on an 11-point numerical pain rating scale. 
Pain. 2001 Nov; 94(2):149-58. 
(2) Summary of Product Characteristics for Nurofen 200 mg tablets Reckitt Benckiser 
Healthcare Ltd. (PL 00063/0385). 09 November 2015. 
(3) Davies, NM Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin. 
Pharmacokinetic. 1998, 34 (2), 101-154. 
(4) Lisa Miles, Jessica Hall, Bartosz Jenner, Richard Addis & Simon Hutchings (2018) 
Predicting rapid analgesic onset of ibuprofen salts compared with ibuprofen acid: Tlag, 
Tlow, Tmed, and a novel parameter, TCmax Ref, Current Medical Research and 
Opinion, DOI: 10.1080/03007995.2018.1466697. 
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(5) Cooper SA, Desjardins PJ, Turk DC, et al. Research design considerations for single-
dose analgesic clinical trials in acute pain: IMMPACT recommendations. Pain. 2016 
Feb; 157(2):288-301. doi: 10.1097/j.pain.0000000000000375. 
(6) Wyeth Consumer Healthcare. (2002). NDAC Meeting on Risks of NSAIDs. Available: 
https://www.fda.gov/ohrms/dockets/ac/02/briefing/3882b2_04_wyeth-ibuprophen.htm. 
Last accessed 13th March 2018 
(7) Singla, Neil Kumar et al. “A comparison of the clinical and experimental characteristics 
of four acute surgical pain models: Dental extraction, bunionectomy, joint replacement, 
and soft tissue surgery.” PAIN® 155 (2014): 441-456. 
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DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2D4E7D28D92D 
lnvestigational Study Protocol Amendment 
HEALTH • HYGIENE • HOME 
Page 1 of 7 
Document Name: 
Substantial Amendment Number 1 
Version Number & Date: 
Version 1.0 19-Nov-2019. 
Study Number: 
5003601 
A Randomised, Double-Blind, Double-Dummy, Parallel-Group, 
Study Title: 
Multiple-Dose, Active and Placebo Controlled Efficacy Study of 
Ibuprofen Prolonged-Release Tablets for the Treatment of Pain 
after Surgical Removal of Impacted Third Molars 
EudraCT /IND/ Other 
IND 141948 
Number: 
Protocol Version 
From: 
2.0 
Number: 
To: 
3.0 
Principal Investigator 
Todd Bertoch, M.D. 
Name: 
D8199934 V6.0, Appendix 7 - lnvestigational Study Protocol Amendment 
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OocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2O4E7O2BO92O 
lnvestigational Study Protocol Amendment 
HEALTH • HYGIENE • HOME 
Page 2 of 7 
Details of Amendment: 
Updates to 1 inclusion criteria and 1 exclusion criteria and to align 
section 4.4 with the update to the inclusion criteria. 
Section(s) to be Changed: 
5) 
Female subjects of child-bearing potential 
must be willing to use a highly effective method of 
contraception throughout the study. A highly 
effective method of birth control is defined as one 
which results in a low failure rate (i.e. less than 1 % 
per year) when used consistently and correctly, such 
as the following: 
a. 
Surgical sterilisation 
b. 
established use of oral, injected or implanted 
hormonal methods of contraception 
C. 
some intrauterine devices (IUDs) or 
intrauterine systems (IUSs) 
d. 
true sexual abstinence, when this is in line 
From: 
with the preferred and usual lifestyle of the subject 
(periodic abstinence such as calendar, ovulation, 
symptothermal, or post-ovulation methods; 
declaration of abstinence for the duration of the trial; 
or withdrawal are not acceptable methods of 
contraception) 
Study Synopsis and 
e. 
vasectomised partner. 
Section 4.2. Inclusion 
To be considered not of child-bearing potential, 
Criteria number 5. 
females must be surgically sterile ( defined as 
Pages 14 and 30. 
bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy) or post-menopausal ( defined as no 
menses for 12 months in women not using hormonal 
contraception or hormone replacement therapy, 
confirmed by a follicle stimulating hormone (FSH] 
level in the postmenopausal range at Screening). 
5) Female subjects of child-bearing potential must 
have been using_ an acce12.table method of 
contrace12.tion for at least 30 day_s 12.rior to 
randomization and be willing_ to continue use 
until at least 48 hours 12.ost discharge from the 
To: 
clinic (see Section 4.4). 
To be considered not of child-bearing potential, 
females must be surgically sterile ( defined as 
bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy) or post-menopausal (defined as no 
menses for 12 months without an alternative 
medical cause). 
D8199934 V6.0, Appendix 7 - lnvestigational Study Protocol Amendment 
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DocuSign Envelope 10: 086FD250-448 3-4A68-A96E-2O4E7028 O92D 
lnvestigational Study Protocol Amendment 
HEALTH • HYGIENE• HOME 
Page 3 of 7 
Due to delays in the study recruitment resulting from 
two temporary halts the lnvestigational Product (IP) 
is nearing its expiry date. It is felt that this change 
Reason for 
does not pose any risk to subjects or the study data 
Change: 
whilst aiming to make recruitment easier and 
therefore faster subsequently allowing the study to 
reach Last Subject Last Visit (LSL V) prior to the 
expiry of the IP. 
Woman of childbearing potential must use a highly 
effective contraceptive method for the entire 
duration of study participation. 
A highly effective method of birth control is defined 
as one which results in a low failure rate (i.e. less 
than 1 % per year) when used consistently and 
correctly, such as the following: 
. 
Surgical sterilisation 
. 
Established use of oral, injected or implanted 
hormonal methods of contraception 
. 
Some intrauterine devices (IUDs) or 
From: 
intrauterine systems (IUSs) 
. 
Male sterilisation (with the appropriate post-
vasectomy documentation of the absence of sperm 
in the ejaculate). [For female subjects on the study, 
the vasectomised male partner should be the sole 
partner for that subject) 
. 
True abstinence which is in line with the 
Section 4.4, original 
preferred and usual lifestyle of the subject. Periodic 
location page 32, new 
abstinence such as calendar, ovulation, 
location page 31. 
symptothermal, or post-ovulation methods; 
declaration of abstinence for the duration of the trial; 
and withdrawal are not acceptable methods of 
contraception. 
Female subiects of childbearing potential must have 
been using_ an acceQ.table method of contraceQ.tion 
for at least 30 da'f.S Q.rior to randomization and be 
willing_ to continue use until at least 48 hours Q.Ost 
discharg_e from the clinic. 
To: 
An acceQ.table method of contraceQ.tion includes: 
a. Prog_estog_en-onl'i. oral hormonal 
contraceQ.tion, where inhibition of 
ovulation is not the Q.rimar'i. mode of 
action 
b. Male or female condom with or 
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DocuSign Envelope ID: 086FD250-4483-4A68-A96E-2D4E7D28 D92D 
lnvestigational Study Protocol Amendment 
HEALTH • HYGIENE • HOME 
Page 4 of 7 
without spermicide 
C. 
Cap, diaphragm or sponge with 
spermicide 
Alternatively_, 
highly_ 
effective 
methods 
of 
contraception are also considered acceptable, such 
as: 
d. Surgical sterilisation 
e. Established use of oral, injected or implanted 
hormonal methods of contraception 
t. 
Some intrauterine devices (IUDs) or intrauterine 
systems (IUSs) 
9..:. Male sterilisation (with the appropriate post-
vasectomy documentation of the absence of 
sperm in the ejaculate). [For female subjects on 
the study, the vasectomised male partner should 
be the sole partner for that subject] 
fl True abstinence which is in line with the 
preferred and usual lifestyle of the subject. 
Periodic abstinence such as calendar, ovulation, 
symptothermal, or post-ovulation methods; 
declaration of abstinence for the duration of the 
trial; and withdrawal are not acceptable methods 
of contraception. 
Reason for 
To align with the changes to inclusion 5 above. 
Change: 
12) 
Previously participated (randomised) in 
From: 
another clinical study of 300 mg ibuprofen PR 
tablets, or received any investigational drug, device, 
or therapy within 90 days before screening. 
Study Synopsis and 
12) Subiect has received an investig_ational product 
Section 4.3. Exclusion 
or participated in another trial involving_ a 
Criteria number 12. 
Original Locations: 
marketed or investig_ational drug_ in the 30 da'i_s 
Pages 17 and 32, New 
(or for investig_ational agents with a long_ half-life, 
Locations: Pages 16 
To: 
a washout of 5 half-lives) prior to first drug_ 
and 31. 
administration (washout period between studies 
is defined as the period of time elapsed between 
the last dose of the previous study_ and first dose 
for this stud'i_). Or if the investigator believes that 
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lnvestigational Study Protocol Amendment 
HEALTH • HVGIENE • HOME 
Page 5 of 7 
an~ Q.revious Q.articiQ.ation in an investig_ational 
stud~ would be to the detriment of the safet~ of 
the Q.articiQ.ant or the conduct of the studt 
Due to delays in the study recruitment resulting from 
two temporary halts the lnvestigational Product (IP) 
is nearing its expiry date. This change does not 
Reason for 
pose any risk to subjects or the study data whilst 
Change: 
aiming to make recruitment easier and therefore 
faster subsequently allowing the study to reach Last 
Subject Last Visit (LSL V) prior to the expiry of the 
IP. 
From: 
Protocol Author 
To: 
Protocol Final Author 
Signature page, page 3 
The changes in the protocol from v2.0 to v3.0 due to 
Reason for this Substantial Amendment have not been made by 
Change: 
the original author. Therefore the title of the 
signatory has been updated. This is aligned with the 
signature page of this amendment. 
D8199934 V6.0, Appendix 7 - lnvestigational Study Protocol Amendment 
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DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2D4E7O2BD92D 
HEALTH• HYGIENE • HOME 
SIGNATURE PAGE 
Protocol Final Author 
( 
oocuSigned by: 
I 
~ ....... Tl.., ........ 
0 
Signer Name: Jane Thomas 
L
Sigmng Reason: I am the author ofth1s document 
Signing Time: I9-Nov-2019I18:29:03 PM GMT 
F098C76EBAC349BDBA7BAD8C6988DDD3 
Mrs S. Jane Thomas 
BSc (Hons) 
Date 
Senior Clinical Study Manager 
RB 
Sponsor's Medical Expert 
(Reviewed and approved): 
( 
OocuSigned by: 
j 
Neil Fawkes 
0 
Signer Name· Neil FaWkes 
L 
Signing Reason: I approve this document 
Signing nme· 20-Nov-2019 I 10·36:59 AM GMT 
FBE2F9E6498A42529274F2FA9073AD21 
Dr Neil Fawkes, MBChB 
Clinical Research Physician 
RB 
Date 
lnvestigational Study Protocol Amendment 
Page 6 of 7 
Protocol Statistician 
(Statistics and OM sections reviewed and approved): 
{OocuSigned by: 
I 
Darren Targett 
0 
Signer Name Darren Targeit 
L 
Signing Reason: I app,ove this document 
Signing Time: 20-No,-2019 I 08:02:29 AM GMT 
AFBA8AD99F4542DDA 701 94D987EF 16 79 
Darren Targett 
Consultant Statistician 
RB Representative 
Date 
Senior Representative - Medical Science 
(Approved to Proceed): 
{ 
DocuSigned by: 
I 
Bruce Charlesworth 
0 
Signer Name· Bruce Charlesworth 
L 
Signing Reason: I approve this document 
Signing nme: 25-Nov-2019I14:46:48 PM GMT 
8D5 1A4AE69EE449887C482A 182264320 
Bruce Charlesworth, MBChB Date 
Chief Medical Officer - Health Relief, Hygiene 
and Wellness 
RB 
D8199934 V6.0, Appendix 7 - lnvestigational Study Protocol Amendment 
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DocuSign Envelope ID: 086FD250-4483-4A68-A96E-204E702BD920 
lnvestigational Study Protocol Amendment 
HEALTH • HYGIENE • HOME 
Page 7 of 7 
INVESTIGATOR APPROVAL 
I have read and understood this Clinical Study Protocol Amendment 
Principal Investigator 
(Reviewed and Accepted): 
q-~ 
t)Z- DC-c 20 l'j 
Todd Bertoch, MD 
Date 
Chief Scientific Officer 
JBR Clinical Research 
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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 19 July 2019, FINAL Version 2.0 
Page 1 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
RECKITT BENCKISER 
 
 
STUDY TITLE 
A Randomised, Double-Blind, Double-Dummy, Parallel-Group, Multiple-Dose, Active and 
Placebo Controlled Efficacy Study of Ibuprofen Prolonged-Release Tablets for the Treatment of 
Pain after Surgical Removal of Impacted Third Molars 
Short Study Title 
Efficacy Study of 300mg Ibuprofen Prolonged-Release Tablets for the Treatment of Pain After 
Surgical Removal of Impacted Third Molars 
IND (Investigational New 
Drug) Number: 
141948 
RB Study Number: 
5003601 
CRO Study Number: 
RECK.177369 
Protocol Version and Date: 
FINAL V2.0 / 19-Jul-2019 
Previous Versions / Date(s): None 
Confidentiality Statement: 
The information contained in this document is privileged and 
confidential. Do not copy, circulate or otherwise distribute 
without written authority from Reckitt Benckiser 
DocuSign Envelope ID: 94223DB3-7863-400F-8A47-927CF624F1DA
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KEY CONTACTS 
  
Name and title 
Address 
Phone  
e-mail 
Sponsor:  
RB Healthcare UK 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom  
+44 (0)1482 
326151 
5003601@rb.com 
Sponsor’s Medical 
Expert:  
Neil Fawkes 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom 
+44 (0)1482 
5833242 
neil.fawkes@rb.com 
Principal / Chief / 
Coordinating 
Investigator(s): 
Dr Todd Bertoch 
JBR Clinical 
Research 
650 East 4500 South 
Suite 100 
Salt Lake City 
Utah, 84107 
USA 
+ 1 928 
8307354 
tbertoch@jbrutah.com 
Sponsors 
Statistician: 
Darren Targett 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom 
N/A 
darren.targett@primoriscs.co.uk 
Contract Research 
Organisation: 
Premier Research 
One Park Drive, 
Suite 150 
Durham, NC 27709 
USA 
+ 1 919 627 
9100 
N/A 
CRO Project 
Manager:  
Paul Brittain 
One Park Drive, 
Suite 150 
Durham, NC 27709 
USA 
+ 1 617 934 
2233 
paul.brittain@premier-
research.com 
Clinical 
Laboratory: 
Quest Diagnostics, 
Inc. 
3489 W 2100 S, 
Suite 200,  
West Valley City, 
Utah 84119 
USA 
N/A 
N/A 
DocuSign Envelope ID: 94223DB3-7863-400F-8A47-927CF624F1DA
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SIGNATURE PAGE 
 
 
Protocol Author  
Protocol Statistician  
(Statistics and DM sections reviewed and approved):  
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Donna Reed, MA 
Date 
Principal Medical Writer 
Premier Research 
Darren Targett 
Date 
Consultant Statistician 
RB Representative 
 
 
 
Sponsor’s Medical Expert  
(Reviewed and approved):  
Sponsor’s Medical Director  
(Approved to Proceed):  
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Dr. Neil Fawkes, MBChB 
Date 
Clinical Research Physician  
RB  
Robert Eichler, Phd                 Date 
Global Medical Affairs Head, Health 
RB 
 
 
 
 
 
 
 
DocuSign Envelope ID: 94223DB3-7863-400F-8A47-927CF624F1DA
22-Jul-2019 | 16:20:57 PM BST
25-Jul-2019 | 16:55:40 PM BST
22-Jul-2019 | 16:26:24 PM BST
DocuSign Envelope ID: E3E6664D-BF5F-4B8C-B3C9-631A328A0BEC
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INVESTIGATOR STATEMENT 
I have read and understood this Clinical Study Protocol and agree: 
 
to conduct this clinical study in accordance with the protocol and to abide by all provisions 
of this protocol (including other manuals and documents referenced from this protocol). 
Amendments to the protocol are acceptable only upon mutual agreement with the 
exception of urgent safety measures that need to be taken to protect study subjects from 
any immediate hazard to their health and safety. 
 
to conduct this clinical study in accordance with the principles as set out in the Declaration 
of Helsinki and with International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
 
to conduct this study only after a favourable opinion is obtained from the Independent 
Review Board and Regulatory Authority 
 
to report all information or data in accordance with the protocol. 
 
to report any serious adverse events as defined in the “Safety Reporting” section of this 
protocol.  
 
to handle all clinical supplies provided by the Sponsor and collect and handle all clinical 
specimens in accordance with the protocol.  
 
I understand: 
 
that information that identifies me will be used and disclosed as described in the protocol 
and that such information may be transferred to countries that do not have laws protecting 
such information.  
 
that since the information in the protocol and the references in the Investigator's brochure 
(if applicable) are confidential, its disclosure to any third parties, other than those involved 
in approval, supervision or conduct of the study is prohibited. I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent 
disclosure or access by third parties. 
 
Principal Investigator  
(Reviewed and Accepted):  
 
________________________   ____________________ 
Todd Bertoch, MD 
  Date 
Chief Scientific Officer 
JBR Clinical Research 
 
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TABLE OF CONTENTS 
KEY CONTACTS .................................................................................................................. 2 
SIGNATURE PAGE .............................................................................................................. 3 
INVESTIGATOR STATEMENT ............................................................................................. 4 
TABLE OF CONTENTS ........................................................................................................ 5 
LIST OF ABBREVIATIONS ..................................................................................................10 
STUDY SYNOPSIS ..............................................................................................................12 
1 
BACKGROUND AND RATIONALE ....................................................................22 
1.1 
Background for the Study and Rationale ........................................................22 
1.2 
Investigational Product ...................................................................................22 
1.3 
Treatment Rationale ......................................................................................23 
1.4 
Study Population and Indication .....................................................................23 
1.5 
Non-Clinical Evidence ....................................................................................23 
1.6 
Clinical Evidence to Date ...............................................................................24 
1.7 
Risks / Benefits ..............................................................................................24 
1.8 
Ethical Conduct of the Study ..........................................................................25 
2 
STUDY OBJECTIVES .......................................................................................26 
3 
STUDY DESIGN AND RATIONALE FOR DESIGN ............................................26 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................30 
4.1 
Study Population ............................................................................................30 
4.2 
Inclusion Criteria ............................................................................................30 
4.3 
Exclusion Criteria ...........................................................................................31 
4.4 
Subjects of Reproductive Potential ................................................................32 
4.5 
Discontinuation / Withdrawal and Replacement of Subjects ...........................32 
5 
STUDY TREATMENT ........................................................................................33 
5.1 
Investigational Products .................................................................................33 
5.2 
Non-Investigational Products .........................................................................36 
5.3 
Permitted Therapies .......................................................................................36 
5.4 
Treatment Compliance ...................................................................................37 
5.5 
Packaging and Labelling and Supply / Resupply ............................................37 
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5.6 
Storage Conditions ........................................................................................37 
5.7 
Blinding ..........................................................................................................38 
5.8 
Emergency Unblinding Procedures ................................................................38 
5.9 
Drug Accountability ........................................................................................38 
5.10 
Return and Destruction ..................................................................................39 
6 
STUDY PROCEDURES BY VARIABLE .............................................................39 
6.1 
Informed Consent ..........................................................................................39 
6.2 
Randomisation ...............................................................................................39 
6.3 
Drug Administration .......................................................................................39 
6.4 
Demographics ................................................................................................40 
6.5 
Medical History and Concomitant Medication .................................................40 
6.6 
Physical Examination .....................................................................................40 
6.7 
Laboratory Tests ............................................................................................40 
6.8 
Electrocardiograms ........................................................................................41 
6.9 
Vital Signs ......................................................................................................41 
6.10 
Blood Sampling ..............................................................................................41 
6.11 
Oral Radiography ...........................................................................................41 
6.12 
Pain Intensity .................................................................................................41 
6.13 
Stopwatch Assessment ..................................................................................41 
6.14 
Pain Relief Scale ...........................................................................................42 
6.15 
Subject’s Global Evaluation of Study Drug .....................................................42 
6.16 
Adverse Events ..............................................................................................42 
7 
STUDY PROCEDURES BY VISIT .....................................................................42 
7.1 
Study Flow Chart / Table of Study Procedures and Assessments ..................42 
7.2 
Screening Visit (Day -28 to Day -1) ................................................................46 
7.3 
Day of Surgery (Day 1) ..................................................................................46 
 
Pre-Surgery................................................................................................46 
 
Surgery ......................................................................................................47 
 
Post-surgery Eligibility Assessments and Randomisation ...........................47 
 
Dosing and Post-dose Assessments (Hour 0 through Hour 24) .................47 
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7.4 
Follow-up Visit (Day 8 ± 2 days) or Early Termination ....................................48 
7.5 
Unscheduled Visits ........................................................................................48 
7.6 
Study Restrictions ..........................................................................................48 
 
Prohibited Therapies ..................................................................................48 
 
General and Dietary Restrictions ................................................................48 
8 
SAFETY REPORTING .......................................................................................49 
8.1 
Adverse Event Definitions ..............................................................................49 
8.2 
Assessment of Adverse Events ......................................................................49 
8.3 
Reporting of Adverse Events .........................................................................51 
8.4 
Follow-up of Adverse Events .........................................................................52 
8.5 
Overdose, Abuse, Misuse and Medication Errors ..........................................52 
8.6 
Pregnancy .....................................................................................................53 
9 
STATISTICAL CONSIDERATIONS ...................................................................53 
9.1 
Determination of Sample Size ........................................................................53 
9.2 
Interim Analysis .............................................................................................53 
9.3 
Analysis Datasets ..........................................................................................53 
9.4 
Subject Disposition and Characteristics .........................................................54 
9.5 
Efficacy Analyses ...........................................................................................54 
 
Primary Endpoint(s) ...................................................................................54 
9.5.1.1 
Primary Analysis .....................................................................................54 
9.5.1.2 
Secondary Analysis ................................................................................54 
 
Secondary Endpoints .................................................................................55 
9.5.2.1 
Secondary Endpoint Analyses ................................................................55 
9.6 
Safety Analyses .............................................................................................56 
 
Safety Endpoint(s)......................................................................................56 
9.6.1.1 
Safety Endpoint Analyses .......................................................................56 
9.7 
Handling of Missing Data and Drop-outs ........................................................57 
9.8 
Changes to the Original Statistical Plan .........................................................57 
10 
DATA HANDLING AND RECORD KEEPING ....................................................57 
10.1 
Case Report Forms (CRFs) ...........................................................................57 
10.2 
Specification of Source Documents ...............................................................58 
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10.3 
Data Management .........................................................................................58 
10.4 
Reporting of Protocol Deviations ....................................................................58 
10.5 
Retention of Essential Documentation ...........................................................58 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ..........................................59 
11.1 
Monitoring ......................................................................................................59 
11.2 
Audits and Inspections ...................................................................................59 
11.3 
Sponsor Policy on Fraud in Clinical Studies ...................................................60 
12 
ETHICAL AND REGULATORY ASPECTS ........................................................60 
12.1 
Ethics Review and Regulatory Authority Approval..........................................60 
12.2 
Subject Information and Consent ...................................................................60 
12.3 
Early / Premature Termination of the Study ...................................................61 
13 
COMPENSATION, INDEMNITY AND INSURANCE ..........................................61 
13.1 
Clinical Study Agreement ...............................................................................61 
13.2 
Compensation ................................................................................................61 
13.3 
Indemnity .......................................................................................................62 
13.4 
Insurance .......................................................................................................62 
14 
REPORTING, PUBLICATION AND PRESENTATION .......................................62 
15 
REFERENCES ..................................................................................................62 
 
List of Tables Contained in the Body of the Protocol 
Table 3-1 Study Objectives and Endpoints ...........................................................................27 
Table 3-2 Treatment Regimens ............................................................................................29 
Table 5-1 Active Test Product ..............................................................................................33 
Table 5-2 Placebo for Test Product ......................................................................................34 
Table 5-3 Comparator Product .............................................................................................35 
Table 5-4 Placebo for Comparator Product ..........................................................................35 
Table 7-1 Schedule of Assessments ....................................................................................43 
Table 8-1 AE Relationship Descriptions ...............................................................................50 
Table 8-2 AE Severity Descriptions ......................................................................................51 
 
List of Figures Contained in the Body of the Protocol 
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Figure 3.1 Study Design Schematic ......................................................................................27 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Abbreviation in Full 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Plasma Concentration Curve 
BID 
Twice Daily 
BMI 
Body Mass Index 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
eCRF 
Electronic Case Report Form 
FDA 
(US) Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GVG 
Global Vigilance Group 
HDL 
High Density Lipoprotein 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric Rating Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OTC 
Over the Counter 
PID 
Pain Intensity Difference 
PP 
Per Protocol 
PR 
Prolonged Release 
RB 
Reckitt Benckiser 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SNRI 
Serotonin and Noradrenaline Reuptake Inhibitor 
SPID 
Summed Pain Intensity Difference 
SPRID 
Summed Pain Relief and Intensity Difference 
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Abbreviation 
Abbreviation in Full 
SSRI 
Selective Serotonin Reuptake Inhibitor 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent Adverse Event 
TID 
Three Times a Day 
Tmax 
Time to Maximum Plasma Concentration 
TOTPAR 
Sum of Total Pain Relief 
WOCF 
Worst Observation Carried Forward 
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STUDY SYNOPSIS 
Study Title: 
A randomised, double-blind, double-dummy, parallel-group, multiple-
dose, active and placebo-controlled efficacy study of ibuprofen 
prolonged-release tablets for the treatment of pain after surgical 
removal of impacted third molars 
RB Study 
Number: 
5003601 
Background and 
Rationale: 
Reckitt Benckiser (RB) is co-developing a new 300 mg ibuprofen 
prolonged release (PR) tablet with Strides Shasun Ltd. The product 
has been developed to meet consumer and patient needs to have 
access to longer acting over-the-counter analgesics. This PR 
formulation will reduce fluctuations in drug plasma concentrations and 
allow for a lower frequency of administration which is desirable in 
situations where pain duration is expected to be prolonged and require 
multiple doses of immediate release formulations. As a result, the 
product would be more consumer friendly, require less dosing and 
improve compliance with treatment. 
The proposed therapeutic indications of the PR product are for the 
short-term symptomatic treatment of mild to moderate pain such as 
dysmenorrhea, rheumatic pain, muscular pain, pain of non-serious 
arthritic conditions and backache. 
The proposed posology in adults over the age of 18 is: 
Ibuprofen 300 mg PR tablets.  Two tablets to be taken every 12 hours 
when required for pain relief. No more than 2 doses in 24 hours. The 
maximum daily dose is 1200 mg and there is no proposed indication in 
the paediatric population. 
 
Therefore, the purpose of the proposed study is to provide supporting 
pivotal efficacy evidence for registration applications in Europe, 
Australia and Russia. The decision to progress to an efficacy clinical 
trial was determined on the basis of successful outcomes of the 2 
phase 1 clinical trials (BE/17/279 and BE/17/281) in terms of 
bioavailability (BA) versus a reference ibuprofen immediate release 
(IR) product and bioequivalence (BE) versus comparator 600 mg 
ibuprofen PR. 
Objectives:  
Primary Objective:  
 
To evaluate the superiority of 2×300 mg ibuprofen PR tablets 
compared with placebo in subjects experiencing acute 
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moderate to severe pain after third molar extraction over 
12 hours post initial dose. 
Key Secondary Objectives: 
 
To evaluate the analgesic performance of a total daily dose of 
1200 mg of ibuprofen PR formulation compared to ibuprofen 
immediate release (IR) formulation over 24 hours post initial 
dose. 
 
To evaluate the safety and tolerability of 2×300 mg ibuprofen 
PR tablets. 
Additional Secondary Objectives: 
 
To evaluate the total analgesic effect, peak analgesic effect, 
onset and duration of action and the subject’s overall 
assessment of the study medications. 
Design: 
This is a single centre, randomised, double-blind, double-dummy, 
parallel group, multiple-dose, active and placebo-controlled efficacy 
study to evaluate the efficacy and safety of 2×300 mg ibuprofen PR 
tablets in subjects with post-surgical dental pain. 
Primary 
Endpoint: 
The Summed Pain Intensity Difference (SPID) over 0 to 12 hours 
(SPID12) will be used to compare the test product (2×300 mg ibuprofen 
PR tablets) against the placebo product. 
Confirmatory 
Evaluation: 
Clinically relevant difference between placebo and PR ibuprofen over 
12 hours after initial dose (for the purposes of this study, a difference 
of 30 % in PID scores over 12 hours after initial dose will be considered 
clinically relevant).(1)  
Secondary 
Endpoints: 
Key secondary efficacy endpoint: 
 
The summed pain intensity difference (SPID) over 0 to 
24 hours (SPID24) will be used to compare the test product 
(2×300 mg ibuprofen PR tablets twice daily [BID]) and active 
comparator product (2×200 mg ibuprofen IR tablets three times 
a day [TID]). 
Efficacy endpoints: 
 
Summed pain intensity difference (SPID) over 0 to 4 hours 
(SPID4), over 0 to 8 hours (SPID8), and over 0 to 12 hours 
(SPID12) after Time 0 
 
Sum of total pain relief (TOTPAR) over 0 to 4 hours 
(TOTPAR4), over 0 to 8 hours (TOTPAR8), over 0 to 12 hours 
(TOTPAR12), and over 0 to 24 hours (TOTPAR24) after Time 0 
 
Summed pain relief and intensity difference (sum of TOTPAR 
and SPID [SPRID]) over 0 to 4 hours (SPRID4), over 0 to 
8 hours (SPRID8), over 0 to 12 hours (SPRID12), and over 0 to 
24 hours (SPRID24) after Time 0 
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 
Response to study drug (a responder will be defined as a 
subject with ≥30 % improvement in pain intensity without 
rescue medication during the first 8 hours) 
 
Numeric rating scale (NRS) pain intensity difference (PID) at 
each scheduled time point after Time 0 
 
Pain intensity score at each scheduled time point 
 
Pain relief score at each scheduled time point after Time 0 
 
Peak pain relief 
 
Time to onset of analgesia (measured as time to perceptible 
pain relief confirmed by time to meaningful pain relief) using 
double stopwatch 
 
Time to first perceptible pain relief 
 
Time to meaningful pain relief 
 
Time to peak pain relief 
 
Proportion of subjects using rescue medication 
 
Time to first use of rescue medication 
Exploratory endpoint: 
 
Patient’s global evaluation of study drug 
Safety 
Endpoints: 
 
Incidence of treatment-emergent adverse events (TEAEs) 
 
Incidence of clinically relevant changes in vital sign 
measurements 
Subjects: 
Inclusion Criteria 
A subject will be eligible for study entry if all the following inclusion 
criteria are met: 
1) Is male or female ≥ 18 and ≤ 50 years of age. 
2) Requires extraction of 2 or more third molars. At least 1 of the third 
molars must be a fully or partially bone impacted mandibular molar. 
If only 2 molars are removed, then they must be ipsilateral.   
3) Experiences moderate to severe pain intensity within 6 hours after 
surgery, as measured by a numeric rating scale (NRS) score of ≥ 5 
on a 0-10 scale. 
4) Has a body weight ≥ 45 kg and a body mass index (BMI) 
≤ 35 kg/m2. 
5) Female subjects of child-bearing potential must be willing to use a 
highly effective method of contraception throughout the study. A 
highly effective method of birth control is defined as one which 
results in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly, such as the following: 
a. 
Surgical sterilisation 
b. 
established use of oral, injected or implanted hormonal 
methods of contraception 
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c. some intrauterine devices (IUDs) or intrauterine systems (IUSs) 
d. true sexual abstinence, when this is in line with the preferred 
and usual lifestyle of the subject (periodic abstinence such as 
calendar, ovulation, symptothermal, or post-ovulation methods; 
declaration of abstinence for the duration of the trial; or 
withdrawal are not acceptable methods of contraception)  
e. vasectomised partner. 
To be considered not of child-bearing potential, females must be 
surgically sterile (defined as bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy) or post-menopausal (defined as 
no menses for 12 months in women not using hormonal 
contraception or hormone replacement therapy, confirmed by a 
follicle stimulating hormone [FSH] level in the postmenopausal 
range at Screening). 
6) Free of clinically significant abnormal findings as determined by 
medical history, physical examination, vital signs, laboratory tests 
and ECG. 
7) Is able to provide written informed consent. 
8) Is willing and able to comply with study requirements (including diet 
and smoking restrictions), complete the pain evaluations, remain 
at the study site overnight, and return for follow-up 7 (± 2) days 
after surgery, (Day 8 ± 2 days). 
Exclusion Criteria 
A subject will not be eligible for study entry if any of the following 
exclusion criteria are met: 
1) Known hypersensitivity reactions or allergy (e.g. asthma, rhinitis, 
angioedema or urticaria) in response to nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen), acetylsalicylic 
acid (aspirin), ingredients of the study drug, or any other drugs 
used in the study, including anaesthetics and antibiotics that may 
be required on the day of surgery. 
2) A history of active or previous peptic ulceration/ haemorrhage, 
gastrointestinal bleeding or perforation, heart failure, renal or 
hepatic failure, uncontrolled hypertension, asthma, nasal polyps, or 
chronic rhinitis. 
3) Has complications from the tooth extraction or any other clinically 
significant medical history that, in the opinion of the investigator, 
would affect the subject’s ability to comply or otherwise 
contraindicate study participation, including but not limited to the 
following: cardiac, respiratory, gastroenterological, neurological, 
psychological, immunological, haematological, oncological, or 
renal disease. 
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4) Has undergone another dental surgery within 60 days prior to the 
day of surgery. 
5) A positive urine drugs of abuse screen or alcohol breathalyser test 
at screening and during the study (with the exception of a positive 
drugs of abuse screen that is a consequence of permitted 
prescription medicines). 
6) If female, has a positive pregnancy test at screening (serum) or on 
the day of surgery prior to surgery (urine), or is lactating. 
7) Has known or suspected, (in the opinion of the investigator), history 
of alcoholism or drug abuse within 2 years of screening or evidence 
of tolerance or physical dependence before dosing with study drug. 
8) Taking any concomitant medications that might confound 
assessments of pain relief, such as psychotropic drugs, 
antidepressants, sedative-hypnotics (other than those permitted for 
conscious sedation), or other analgesics taken within five times of 
their elimination half-lives. Selective serotonin reuptake inhibitors 
(SSRIs) and serotonin and noradrenaline reuptake inhibitors 
(SNRIs) are permitted if the subject has been on a stable dose for 
at least four weeks prior to Visit 1 (screening). 
9) Is considered by the investigator, for any reason (including, but not 
limited to the risks described as precautions, warnings and 
contraindications in the current version of the investigator’s 
brochure for 300 mg ibuprofen PR tablets), to be an unsuitable 
candidate to receive the study drug. 
10) Has a history of chronic use (defined as daily use for > 2 weeks) of 
nonsteroidal 
anti-inflammatory 
(NSAIDs), 
opiates, 
or 
glucocorticoids (except inhaled nasal steroids and topical 
corticosteroids), for any condition within 6 months before dosing 
with study drug.  
11) Has significant difficulties swallowing capsules or tablets or is 
unable to tolerate oral medication. 
12) Previously participated (randomised) in another clinical study of 
300 mg ibuprofen PR tablets, or received any investigational drug, 
device, or therapy within 90 days before screening. 
13) Enrolment of the Investigator, his / her family members, employees 
and other dependent persons. 
14) Failure to satisfy the investigator of fitness to participate for any 
other reason. 
Products to be 
Evaluated and 
Test product:  
 
300 mg ibuprofen PR tablets for oral administration 
Reference products:  
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Treatment 
Regimen: 
 
200 mg ibuprofen IR tablets for oral administration 
 
Placebo (for blinding purposes, two types of placebo tablets will 
be made; one to look like the test product and one to look like 
the reference product) 
Treatment regimens: 
Eligible subjects meeting all study entry criteria will be randomised to 
receive 1 of the following treatments: 
 
Treatment A: test product; 2×300 mg ibuprofen PR tablets, BID 
(total daily dose 1200 mg) 
 
Treatment B: reference product; 2×200 mg ibuprofen IR 
tablets, TID (total daily dose 1200 mg) 
 
Treatment C: matching placebo tablets 
Methodology: 
This is a single centre, randomised, double blind, double-dummy, 
parallel group-, multiple-dose, active and placebo controlled efficacy 
study to evaluate the efficacy and safety of ibuprofen 2×300 mg 
ibuprofen PR tablets in subjects with post-surgical dental pain. 
Eligible subjects will complete all screening procedures within 28 days 
before the surgery and randomisation. 
At Screening, subjects will provide written informed consent to 
participate in the study before any protocol specified procedures or 
assessments are completed. On Day 1, subjects who continue to be 
eligible for study participation after completing screening procedures 
and assessments will undergo extraction of 2 or more third molars. At 
least 1 of the third molars must be a fully or partially bone impacted 
mandibular molar. If only 2 molars are removed, then they must be 
ipsilateral. 
All subjects will receive local anaesthesia (2% lidocaine with 
1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion 
of the investigator. Subjects who experience moderate to severe pain 
intensity (a score of ≥ 5 on a numeric rating scale [NRS] from 0-10 
where 0 = no pain, 10 = worst pain ever) within 6 hours after surgery 
and who continue to meet all study entry criteria will be randomised in 
a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets every 12 hours 
(Q12h), 2×200 mg ibuprofen IR tablets every 8 hours (Q8h), or 
placebo. The randomisation will be stratified by baseline pain category 
(moderate or severe) using a categorical scale that includes the 
categories of none (0), mild (1-4), moderate (5-7), and severe (8-10).  
Subjects will re-assess their baseline pain intensity using the NRS 
immediately before receiving study drug (pre-dose, Time 0) and their 
pain intensity (NRS) and pain relief (5-point categorical scale) at the 
following time points (pre-dose, if at one of the dosing timepoints of 0, 
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8, 12 and/or 16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 
6, 7, 8, 10, 12, 16, and 24 hours after Time 0; and immediately before 
each dose of rescue medication, if any. For assessments less than 
1 hour apart a window of +/-2 min is allowable whilst for assessments 
at least 1 hour apart a +/-5 min window is allowable. 
The double stopwatch method will be used to record the time to 
perceptible pain relief and time to meaningful pain relief during the 
8 hours following the first dose or until subject takes rescue 
medication. Subjects will complete a global evaluation of study drug 
24 hours (+/- 5 minutes) after Time 0 or immediately before the first 
dose of rescue medication (whichever occurs first). Vital signs will be 
recorded after the subject has been in a sitting position for 3 minutes 
at the following times: before surgery, within 30 minutes before Time 0, 
12 and 24 hours after Time 0, and/or immediately before the first dose 
of rescue medication. Adverse events (AEs) will be monitored and 
recorded from the time of signing of the informed consent form (ICF) 
until the Follow up- Visit (or Early Termination Visit). During the 
24 hours following Time 0, subjects will complete efficacy and safety 
assessments. Subjects will remain at the study site overnight and will 
be discharged on Day 2.  
Paracetamol / acetaminophen (1000 mg) will be permitted as the initial 
rescue medication. Subjects will be encouraged to wait at least 
60 minutes after receiving study drug before taking rescue medication. 
If acetaminophen rescue medication is not effective in relieving the 
subject’s pain, 5 mg oxycodone rescue medication may be 
administered at the discretion of the investigator. 
Subjects are not permitted to take any concomitant medications that 
might confound assessments of pain relief, such as psychotropic 
drugs, antidepressants, sedative-hypnotics (other than those permitted 
for conscious sedation), or other analgesics taken within five times of 
their elimination half-lives (other than those used at the surgery). 
Selective serotonin reuptake inhibitors (SSRIs) and serotonin and 
noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject 
has been on a stable dose for at least four weeks prior to Visit 1 
(screening).  
Other restrictions include the following: alcohol use is prohibited from 
24 hours before surgery until discharge on Day 2; nothing by mouth 
from midnight before surgery until 1 hour after surgery; clear liquids 
only are allowed starting 1 hour after surgery until 1 hour after dosing; 
1 hour after dosing, the subject’s diet may be advanced according to 
standard practice. 
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Upon discharge from the study site, subjects may be prescribed pain 
medication for use at home according to the standard practice of the 
study site. On Day 8 (± 2 days), subjects will return to the study site for 
an 
abbreviated 
confirmatory 
physical 
assessment 
and 
AE 
assessments. 
Statistical 
Evaluation: 
Analysis Populations 
The analysis populations include the following: 
 
The intent-to-treat (ITT) population will consist of all subjects 
who are treated with study drug and who have at least 1 pain 
relief assessment after Time 0. The ITT population is the 
primary population for the efficacy analysis. 
 
The per protocol- (PP) population will consist of all ITT subjects 
who do not incur a major protocol violation that would challenge 
the validity of their data. This population will be utilized to 
evaluate the sensitivity of the primary efficacy analysis. 
 
The safety population will include all subjects who are treated 
with study drug. The safety population is the population for all 
safety assessments. 
Subject Characteristics 
Demographic and baseline characteristics (including date of birth, sex, 
race, weight, height, BMI and medical history) will be summarized for 
each treatment group and for the overall population using descriptive 
statistics. No formal statistical analyses will be performed. 
Efficacy Analyses 
The primary efficacy null hypothesis is that SPID12 for placebo is equal 
to SPID12 for ibuprofen 2×300 mg PR tablets. The primary analysis 
will be an ANCOVA (Analysis of Covariance) model that includes the 
main effect of treatment and the baseline pain score as a covariate and 
will use windowed worst observation carried forward (WOCF) 
imputation for subjects who use rescue medication. The primary 
analysis will be based on a 2-sided test at the significance level of 0.05. 
All other comparisons between the treatment regimens, including 
ibuprofen 2×200 mg IR tablets versus placebo, will be considered 
secondary. No P value adjustment will be made for multiple endpoints 
or multiple comparisons. 
Each efficacy endpoint will be summarized descriptively by treatment 
group. 
For continuous secondary endpoints such as pain intensity score, 
SPID at each scheduled time point, peak pain intensity, TOTPAR4, 
TOTPAR8, TOTPAR12, TOTPAR24, SPID4, SPID8, SPID24, 
SPRID4, SPRID8, SPRID12, and SPRID24, descriptive statistics 
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(such as mean, standard deviation, median, minimum, and maximum) 
will be provided for each treatment regimen. Nominal P values from 
ANCOVA models comparing the placebo group with other treatment 
groups, including terms for treatment and baseline pain will be 
provided for SPID, SPRID, and TOTPAR variables, but no formal 
statistical inferences will be drawn on the basis of these tests. 
For ordinal secondary endpoints, such as pain intensity difference at 
each scheduled time point, pain relief at each scheduled time point, 
peak pain relief, response to study drug, and global evaluation of study 
drug, descriptive summaries will be provided and will include the 
number and percentage of subjects within each category for each 
treatment group. Nominal P values from Fisher’s exact tests (or 
chi-square- tests, as appropriate) comparing the placebo group with 
other treatment groups will be provided for peak pain relief and global 
evaluation of study drug, but no formal statistical inferences will be 
drawn on the basis of these tests. For each time to- event endpoint, 
Kaplan Meier methodology will be used to evaluate the treatment 
effect. Time to onset of analgesia (measured as time to perceptible 
pain relief confirmed by meaningful pain relief) will be based on data 
collected using the double stopwatch method. Time to onset of 
analgesia will be -right censored- at 8 hours for subjects who do not 
experience both perceptible pain relief and meaningful pain relief 
during the 8-hour interval after Time 0. For time to onset of analgesia, 
the comparison of interest will be the ibuprofen 2×300 mg PR group 
versus the ibuprofen 2×200 mg IR group. The summary tables will 
provide the number of subjects analysed, the number of subjects 
censored, estimates for the quartiles, and 95% confidence intervals 
(CIs) for the estimated median and the restricted mean estimate. 
P values from the Wilcoxon or log rank- tests (as appropriate) will also 
be used to compare placebo to the active treatments. 
For the responder analysis and the proportion of subjects using rescue 
medication, logistic regression models that adjust for baseline intensity 
and/or significant demographic variables, if appropriate, will be used to 
evaluate the treatment effect. 
Baseline values are defined as the last measurements taken before 
dosing with a study drug. 
Missing pain assessments for all efficacy analyses will be handled as 
follows: 
 
Missing pain assessments scheduled before the first observed 
assessment will be imputed with the subject’s worst observed 
pain assessment. 
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 
Missing intermediate pain assessments will be replaced by 
linear interpolation. 
 
Missing pain assessments at the end of the observation period 
due to premature discontinuation of pain assessments will be 
imputed by carrying forward the last observation prior to that 
missing. 
The primary analysis will use windowed worst observation carried 
forward (WOCF) methodology for subjects who use rescue medication. 
Any pain measurements taken during a period of time in which rescue 
medication is active (4 hours) will be replaced by the last pain 
measurement before the rescue medication was taken. A sensitivity 
analysis will also be performed, in which all pain assessments 
recorded after the first dose of rescue medication has been taken will 
be disregarded and the rules outlined above will be used for missing 
data. 
All data for assessments other than pain assessments will be analysed 
as collected; missing data due to premature termination or any other 
reason will be left as missing. 
Safety Analysis 
Data listings will be provided for protocol-specified safety data. The 
Medical Dictionary for Regulatory Activities (MedDRA) (Version 19.0 
or higher) will be used to classify all AEs with respect to system organ 
class and preferred term. Adverse event summaries will include only 
TEAEs, which will be summarized for each treatment group.  
For vital sign measurements, descriptive statistics will be provided at 
each scheduled time point for each treatment group. Changes from 
Baseline for vital signs will be calculated for each subject, and 
descriptive statistics will be provided on changes in vital signs from 
Baseline for each treatment group at each scheduled time point after 
Baseline. No formal statistical tests will be performed. 
 
 
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1 
BACKGROUND AND RATIONALE 
1.1 Background for the Study and Rationale 
Reckitt Benckiser (RB) is co-developing a new 300 mg ibuprofen prolonged release (PR) tablet 
with Strides Shasun Ltd. The product has been developed to meet consumer and patient needs 
to have access to longer acting over-the-counter analgesics. This PR formulation will reduce 
fluctuations in drug plasma concentrations and allow for a lower frequency of administration 
which is desirable in situations where pain duration is expected to be prolonged and require 
multiple doses of immediate release formulations. As a result, the product would be more 
consumer friendly, require less dosing and improve compliance with treatment. 
The proposed therapeutic indications of the PR product are for the short-term symptomatic 
treatment of mild to moderate pain such as dysmenorrhea, rheumatic pain, muscular pain, pain 
of non-serious arthritic conditions and backache. 
The proposed posology in adults over the age of 18 is: 
Ibuprofen 300 mg PR tablets.  Two tablets to be taken every 12 hours when required for pain 
relief. No more than 2 doses in 24 hours. The maximum daily dose is 1200 mg and there is 
no proposed indication in the paediatric population. 
 
Therefore, the purpose of the proposed study is to provide supporting pivotal efficacy evidence 
for European, Russian, and Australian applications and not to support any application in the 
USA. This efficacy study will provide further evidence on the safety and efficacy of the product 
in addition to the data obtained in two bioequivalence studies BE/17/279 and BE/17/281. 
1.2 Investigational Product 
Ibuprofen [2-(4-isobutylphenyl) propionic acid] is a non-steroidal anti-inflammatory drug 
(NSAID) with anti-inflammatory, analgesic and anti-pyretic properties (2). It was initially available 
in 1969 as a prescription only medicine, indicated for rheumatoid arthritis, osteoarthritis and 
other chronic painful conditions such as ankylosing spondylitis. Following further research and 
the establishment of a reassuring safety profile, it was launched in 1983 as an over-the-counter 
(OTC) medication, marketed as Nurofen®. 
Absorption of ibuprofen after oral administration is fairly rapid with peak serum concentrations 
occurring within 1 to 2 hours after administration. Ibuprofen is extensively bound to plasma 
proteins (99%) when administered at therapeutic levels and has a plasma half-life of about 
2 hours. Excretion by the kidney is both rapid and complete, but only a small proportion of drug 
is excreted unchanged in urine, the majority being extensively metabolised in the liver to 
2 major inactive metabolites. The pharmacokinetics of ibuprofen has been extensively 
reviewed by Davies (3). 
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1.3 Treatment Rationale 
The treatment of the test product is in line with the proposed posology of the final product and 
the treatment of the active comparator is in line with the posology provided in the label of the 
product. The treatments will be administered orally, as this is the standard route of 
administration for these products. 
 
The following are the treatment regimens of each product in the study: 
 
Treatment A: test product, 2x300 mg PR ibuprofen tablet, twice daily [total daily dose 
1200 mg] 
 
Treatment B: reference product, 2x200 mg IR ibuprofen tablet, three times a day [total 
daily dose 1200 mg] 
 
Treatment C: matching placebo tablets for both the test and reference regimens 
 
The active comparator (Treatment B) currently marketed in a number of geographies including 
a number of different European countries.  It has therefore been chosen to fulfil requirements 
that when it is included in a marketing authorisation dossier as a comparator that it is licenced 
within the EU.     
 
1.4 Study Population and Indication 
The following study population will be invited to participate in this clinical trial: 
Adult participants aged 18 to 50 requiring extraction of 2 or more third molars, at least 1 of 
which must be a fully or partially bone-impacted mandibular molar, (if only 2 molars are 
removed, then they must be ipsilateral), and who experience moderate to severe pain following 
surgery. 
Such population is expected to present pain levels that will allow for assessing the magnitude 
of treatment effect in a low variability setting. 
 
1.5 Non-Clinical Evidence 
No non-clinical evidence is available for the PR tablet.   
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1.6 Clinical Evidence to Date 
A total of 5 single and multiple-dose pharmacokinetic studies (139-15, BE-16-081, BE-16-295, 
BE-17-279, BE-17-281) have been performed with the test product.  These studies 
demonstrated the oral bioavailability (BA) of the ibuprofen PR tablets (dosed at 2x300 mg) is 
comparable to Brufen® (Ibuprofen) IR Tablets (dosed at 3x200 mg) after a single dose and at 
steady state conditions.  In terms of the release profile and absorption, Cmax tends to be slightly 
higher in the IR formulation when compared with the PR formulation [21.96 ±3.87 µg/mL vs 
14.51 ±3.1 µg/mL].  However the Cmax, (Maximum Observed Plasma Concentration), Tmax, 
(Time to Maximum Plasma Concentration) and AUC0-Tmax (Area Under the Plasma 
Concentration Curve) of the PR formulation suggest that’s the onset of action should not be 
any slower than the IR reference when considering the minimum effective concentration of 
ibuprofen (4).  In terms of total exposure (AUC0-∞) the concentration profile is bioequivalent 
between the PR test product and the IR reference product [163.41 ±43.0 µg.h/mL vs 168.59 
±37.7 µg.h/mL].  A food effect is demonstrated when the test product is taken in the fed state, 
with an expected increase in the absorption rate. 
In the 5 PK studies performed (over 200 subjects) only a limited number of mild, transient 
adverse events were reported.   
Summary Outcomes: 
 
The Clinical data available for this reformulation (Ibuprofen 300 mg PR) suggests an 
adequate pharmacokinetic profile to achieve a sufficient therapeutic effect in the 
proposed study 
 
There are no safety concerns with the test product 
 
Ibuprofen 300 mg PR had an increased rate of absorption when administered with food. 
 
Ibuprofen 300 mg PR tablets had a comparable concentration profile to the comparator 
IR product and was bioequivalent based on AUC0-∞ 
 
1.7 Risks / Benefits 
This study has been designed to confirm the therapeutic efficacy of ibuprofen 300 mg PR.  
Participants in this study are subjects aged 18-50 who require the extraction of 2 or more third 
molars, at least 1 of which must be a fully or partially bone impacted mandibular molar.  
Subjects will undergo dental surgery that is equivalent to that of the standard-of-care that would 
be expected for the above condition. They should be otherwise healthy and each subject 
will undergo a full health check as part of the enrolment into the study to confirm that they 
are healthy as defined in this protocol (see Section 4). 
Participants randomised into the placebo arm would not be expected to derive any therapeutic 
benefit from the administration of the placebo tablets. The placebo arm is essential to the study 
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design as it ensures that any conclusion of non-inferiority from the trial is a reflection of the 
true properties of the treatments; that is, it demonstrates the assay sensitivity of the study.  
However, this obviously leaves the participants without adequate analgesia in the post-surgery 
procedure and from an ethical perspective this is mitigated in the study design by the use of 
rescue medication that would be in line with standards of treatment. Although it is hypothesised 
that the investigational medicinal product (IMP) will provide adequate analgesia in the study, 
this cannot be guaranteed, and therefore the use of rescue medication also addresses the 
potential of reduced or lack of efficacy. 
Ibuprofen is an established pharmaceutical ingredient and the adverse reactions associated 
with administration of 1200 mg/24 hour (OTC doses) are well known and documented (2)(5).  
The adverse reactions most frequently occurring with a single dose being nausea, 
gastrointestinal upset, vomiting, diarrhoea, light headedness, dizziness and headache. Rarely, 
more serious reactions have been reported including GI bleeding, ulceration and perforations, 
hypertension and renal failure. When OTC doses of ibuprofen (200-400 mg/dose; 1200 
mg/day) are taken for acute episodes of pain there is an extremely low risk of causing serious 
gastrointestinal events (5).  
The specific 200mg Ibuprofen tablet to be used in this study as the active comparator 
(Treatment B) is marketed in the EU under the Nurofen brand and has an excellent safety 
profile.   
It is not anticipated that the safety profile of ibuprofen will be altered after administration of 
multiple single doses of ibuprofen 300 mg PR in the context of this study.  There are not 
expected to be any drug-drug interactions with the non-investigational medicinal products 
included within the study design. A washout period of at least 6 days is deemed to be sufficient 
prior to the Follow-up/Early Termination Visit to ensure adequate safety monitoring of the IMP. 
The investigation site will have adequate set up, experience and safety measures that would 
be expected of a centre able to perform regular molar extractions. They will also have adequate 
experience in the safety monitoring of participants post dose that would be expected in a 
clinical trial setting.  Therefore, it is considered that the risk related to study procedures are low 
and limited to common adverse events (AEs) related to the dental procedure, administration 
of routine anaesthetics, and discomfort from vital sign measurements.  Any subject that 
experiences immediate complications during the surgery will be excluded from the study. 
Therefore, the overall benefit-risk profile for the use of the investigational product as 
defined in this protocol is considered favourable. 
1.8 Ethical Conduct of the Study 
This study will be conducted in accordance with this protocol and the principles set out in the 
Declaration of Helsinki. It will comply with International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
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2 
STUDY OBJECTIVES 
Primary Objective:  
 
To evaluate the superiority of 2×300 mg ibuprofen PR tablets compared with placebo in 
subjects experiencing acute moderate to severe pain after third molar extraction over 
12 hours post initial dose.  
Key Secondary Objectives: 
 
To evaluate the analgesic performance of a total daily dose of 1200 mg of ibuprofen PR 
formulation compared to ibuprofen IR formulation over 24 hours post initial dose. 
 
To evaluate the safety and tolerability of 2×300 mg ibuprofen PR tablets. 
Additional Secondary Objectives: 
 
To evaluate the total analgesic effect, peak analgesic effect, onset and duration of action 
and the subject’s overall assessment of the study medications. 
3 
STUDY DESIGN AND RATIONALE FOR DESIGN 
This is a single centre randomised, double-blind, double dummy, parallel group, multiple-dose, 
active and placebo-controlled efficacy study to evaluate the efficacy and safety of 2×300 mg 
ibuprofen PR tablets in subjects with post-surgical dental pain. 
The dental pain model used in this study is a robust and well established post-surgical pain 
model that produces pain that is predictable in its character, duration, and intensity(6). The 
model is widely accepted and has a proven record of assay sensitivity (i.e. separating active 
drugs from each other, as well as from placebo). The model is frequently used to evaluate 
NSAID type analgesics. Results from dental pain studies are accepted by the US Food and 
Drug Administration (FDA) and European authorities and have been widely extrapolated to 
other general pain conditions. 
The decision to conduct the study in the United States was taken as suitably qualified and 
experienced test sites could not be found in Europe.  The specific test site has been chosen 
to conduct the study as they have a proven history of quality and safety when conducting 
studies of this type. 
The placebo products have two purposes:  
1. To mask the treatment identify for PR and IR arms  
2. Act as a control arm 
The dose of the test product is the proposed posology of the final product and the dose of the 
active comparator is the posology provided in the label of the product. 
Eligible subjects will be randomised in a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets 
Q12h, 2×200 mg ibuprofen IR tablets Q8h, or placebo. The randomisation will be stratified by 
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baseline pain category (moderate or severe) using a categorical scale that includes the 
categories of none (0), mild (1-4), moderate (5-7), and severe (8-10). The randomisation 
schedule will be prepared by a statistician not otherwise involved in the study. Randomisation 
will be performed using an interactive web response system (IWRS). Access to the unblinding 
codes will be restricted to personnel not otherwise involved in the study and will be available 
to the investigator only in the case of a subject requiring unblinding prior to database lock. 
Figure 3.1 Study Design Schematic 
Screening 
Visit 
Day 
-28 to -1 
 
In-patient Surgical Stay 
 
Follow-up 
Visit 
Day 8± 2 d 
or Early 
Termination 
 
 
 
 
 
Day of Surgery (Day 1) 
Day 2 
 
→ Pre-
surgery 
Surgery 
Post-
surgery 
eligibility 
Randomisation 
& pre-dose 
(Baseline) 
assessments 
Dosing & 
post-dose 
assessments 
24 h 
post-dose 
assessments 
→
 
 
Note: Un-scheduled visits may occur at any point throughout the study 
 
Table 3-1 Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective: 
To evaluate the superiority of 2×300 mg 
ibuprofen PR tablets compared with placebo 
in subjects experiencing acute dental pain 
after third molar extraction over 12 hours 
post initial dose. 
Primary Endpoint:  
The primary efficacy endpoint is the summed 
pain intensity difference (SPID) over the 0 to 
12 hours (SPID12) after Time 0 and will be 
used to compare the test product (2x300 mg 
PR ibuprofen) and the placebo product.  
The clinical relevance of the difference 
between placebo and PR ibuprofen over 
12 hours after initial dose will be evaluated 
as confirmatory evidence (for the purposes 
of this study, a difference of 30% in PID 
scores over 12 hours after initial dose will be 
considered clinically relevant). 
Secondary Efficacy Objectives: 
 To evaluate the analgesic performance 
of a total daily dose of 1200 mg of 
ibuprofen PR formulation compared to 
ibuprofen IR formulation over 24 hours 
post initial dose.  
 To evaluate the total analgesic effect, 
peak analgesic effect, onset and duration 
Key Secondary Efficacy Endpoints: 
 The summed pain intensity difference 
(SPID) over 0 to 24 hours (SPID24) will 
be used to compare the test product 
(2×300 mg ibuprofen PR tablets twice 
daily [BID]) and comparator product 
(2×200 mg ibuprofen IR tablets three 
times a day [TID]). 
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of action and the subject’s overall 
assessment of the study medications. 
Efficacy Endpoints: 
 Summed pain intensity difference (SPID) 
over 0 to 4 hours (SPID4), over 0 to 
8 hours (SPID8), over 0 to 12 hours 
(SPID12), and over 0 to 24 hours 
(SPID24) after Time 0 
 Sum of total pain relief (TOTPAR) over 
0 to 4 hours (TOTPAR4), over 0 to 
8 hours (TOTPAR8), over 0 to 12 hours 
(TOTPAR12), and over 0 to 24 hours 
(TOTPAR24) after Time 0 
 Summed pain relief and intensity 
difference (sum of TOTPAR and SPID 
[SPRID]) over 0 to 4 hours (SPRID4), 
over 0 to 8 hours (SPRID8), over 0 to 
12 hours (SPRID12), and over 0 to 
24 hours (SPRID24) after Time 0 
 Response to study drug (a responder will 
be defined as a subject with ≥30% 
improvement in pain intensity without 
rescue medication during the first 
8 hours) 
 NRS pain intensity difference (PID) at 
each scheduled time point after Time 0 
 Pain intensity score at each scheduled 
time point 
 Pain relief score at each scheduled time 
point after Time 0 
 Peak pain relief 
 Time to onset of analgesia (measured as 
time to perceptible pain relief confirmed 
by time to meaningful pain relief) using 
double stopwatch 
 Time to first perceptible pain relief 
 Time to meaningful pain relief 
 Time to peak pain relief 
 Proportion of subjects using rescue 
medication 
 Time to first use of rescue medication  
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Exploratory Endpoint: 
 Patient’s global evaluation of study drug 
Safety Objective: 
To evaluate the safety and tolerability of 
2×300 mg ibuprofen PR tablets. 
Safety Endpoints: 
 Incidence of treatment-emergent 
adverse events (TEAEs) 
 Incidence of clinically relevant changes 
in vital sign measurements 
 
Subjects in the PR group will take 2×300 mg ibuprofen PR tablets at Hours 0 and 12. Subjects 
in the IR group will take 2×200 mg ibuprofen IR tablets at Hours 0, 8, and 16. To maintain 
double-blinding, at each dosing timepoint (Hours 0, 8, 12, and 16) all subjects will take a total 
of 4 tablets (placebo-only or active plus placebo, depending on randomised treatment group). 
Table 3-2 Treatment Regimens 
 
PR Group 
 
IR Group 
Placebo Group 
Hour 0 
2 PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 8 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 12 
2 PR, 
2 placebo for IR 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 placebo for IR 
Hour 16 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 24 
final assessments 
final assessments 
final assessments 
 
The study will enrol approximately 280 male and female subjects 18-50 years of age who 
experience moderate to severe pain intensity within 6 hours after dental surgery to remove 
2 or more third molars. At least 1 of the third molars must be a fully or partially bone impacted 
mandibular molar. If only 2 molars are removed, they must be ipsilateral. Subjects must satisfy 
all eligibility criteria including providing informed consent and willingness to remain at the clinic 
overnight. 
The study will be conducted in 1 study site in the United States.   
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 Study Population 
The study will enrol approximately 280 male and female subjects. 
 
4.2 Inclusion Criteria 
Only subjects to whom all of the following conditions apply will be included: 
1. Is male or female ≥ 18 and ≤ 50 years of age. 
2. Requires extraction of 2 or more third molars. At least 1 of the third molars must be a 
fully or partially bone-impacted mandibular molar. If only 2 molars are removed, then 
they must be ipsilateral. 
3. Experiences moderate to severe pain intensity within 6 hours after surgery, as 
measured by a numeric rating scale (NRS) score of ≥ 5 on a 0-10 scale. 
4. Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 35 kg/m2. 
5. Female subjects of child-bearing potential must be willing to use a highly effective 
method of contraception throughout the study. A highly effective method of birth 
control is defined as one which results in a low failure rate (i.e. less than 1% per year) 
when used consistently and correctly, such as the following: 
a. surgical sterilisation 
b. contraceptive implants or injectables 
c. combined oral contraceptives 
d. some IUDs (intrauterine devices) 
e. true sexual abstinence, when this is in line with the preferred and usual 
lifestyle of the subject (periodic abstinence such as calendar, ovulation, 
symptothermal, or post-ovulation methods; declaration of abstinence for the 
duration of the trial; or withdrawal are not acceptable methods of 
contraception), or  
f. vasectomised partner. 
To be considered not of child-bearing potential, females must be surgically sterile 
(defined as bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or post-
menopausal (defined as no menses for 12 months in women not using hormonal 
contraception or hormone replacement therapy, confirmed by a follicle stimulating 
hormone [FSH] level in the postmenopausal range at Screening). 
6. Free of clinically significant abnormal findings as determined by medical history, 
physical examination, vital signs, laboratory tests and ECG. 
7. Is able to provide written informed consent. 
8. Is willing and able to comply with study requirements (including diet and smoking 
restrictions), complete the pain evaluations, remain at the study site overnight, and 
return for follow-up 7 (± 2) days after surgery, (Day 8 ± 2 days).  
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4.3 Exclusion Criteria 
A subject will not be eligible for study entry if any of the following exclusion criteria are met: 
1. Known hypersensitivity reactions or allergy (e.g., asthma, rhinitis, angioedema or 
urticaria) in response to nonsteroidal anti-inflammatory drugs (NSAIDs, including 
ibuprofen), acetylsalicylic acid (aspirin), ingredients of the study drug, or any other 
drugs used in the study, including anaesthetics and antibiotics that may be required 
on the day of surgery. 
2.  A history of active or previous peptic ulceration/ haemorrhage, gastrointestinal 
bleeding or perforation, heart failure, renal or hepatic failure, uncontrolled 
hypertension, asthma, nasal polyps, or chronic rhinitis. 
3. Has complications from the tooth extraction or any other clinically significant medical 
history that, in the opinion of the investigator, would affect the subject’s ability to 
comply or otherwise contraindicate study participation, including but not limited to the 
following: cardiac, respiratory, gastroenterological, neurological, psychological, 
immunological, haematological, oncological, or renal disease. 
4. Has undergone another dental surgery within 60 days prior to the day of surgery. 
5. A positive urine drugs of abuse screen or alcohol breathalyser test at screening and 
during the study (with the exception of a positive drugs of abuse screen that is a 
consequence of permitted prescription medicines). 
6. If female, has a positive pregnancy test at screening (serum) or on the day of surgery 
prior to surgery (urine), or is lactating. 
7. Has known or suspected, (in the opinion of the investigator), history of alcoholism or 
drug abuse within 2 years of screening or evidence of tolerance or physical 
dependence before dosing with study drug. 
8. Taking any concomitant medications that might confound assessments of pain relief, 
such as psychotropic drugs, antidepressants, sedative-hypnotics (other than those 
permitted for conscious sedation), or other analgesics taken within five times of their 
elimination half-lives. Selective serotonin reuptake inhibitors (SSRIs) and serotonin 
and noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject has been 
on a stable dose for at least four weeks prior to Visit 1 (screening). 
9. Is considered by the investigator, for any reason (including, but not limited to the risks 
described as precautions, warnings and contraindications in the current version of the 
investigator’s brochure [IB] for 300 mg ibuprofen PR tablets), to be an unsuitable 
candidate to receive the study drug. 
10. Has a history of chronic use (defined as daily use for > 2 weeks) of nonsteroidal anti-
inflammatory (NSAIDs), opiates, or glucocorticoids (except inhaled nasal steroids and 
topical corticosteroids), for any condition within 6 months before dosing with study 
drug.  
11. Has significant difficulties swallowing capsules or tablets or is unable to tolerate oral 
medication. 
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12. Previously participated (randomised) in another clinical study of 300 mg ibuprofen PR 
tablets, or received any investigational drug, device, or therapy within 90 days before 
screening. 
13. Enrolment of the Investigator, his / her family members, employees and other 
dependent persons. 
14. Failure to satisfy the investigator of fitness to participate for any other reason. 
4.4 Subjects of Reproductive Potential 
Woman of childbearing potential must use a highly effective contraceptive method for the entire 
duration of study participation. 
A highly effective method of birth control is defined as one which results in a low failure rate 
(i.e. less than 1% per year) when used consistently and correctly, such as the following: 
 
Surgical sterilisation 
 
Established use of oral, injected or implanted hormonal methods of contraception 
 
Some intrauterine devices (IUDs) or intrauterine systems (IUSs) 
 
Male sterilisation (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). [For female subjects on the study, the vasectomised male 
partner should be the sole partner for that subject] 
 
True abstinence which is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence such as calendar, ovulation, symptothermal, or post-ovulation 
methods; declaration of abstinence for the duration of the trial; and withdrawal are not 
acceptable methods of contraception. 
4.5 Discontinuation / Withdrawal and Replacement of Subjects  
The Investigator may withdraw the subject from the study at any time. Reasons for removing 
a subject from the study include, but are not limited to: 
 
AEs that in the judgement of the Investigator may cause severe or permanent harm 
(significant clinical deterioration is an AE) 
 
Violation of the study protocol 
 
In the Investigator’s judgement, it is in the subject’s best interest 
 
Subject declines further study participation 
 
If applicable, randomisation code is broken 
If subjects choose to prematurely stop the study prior to the scheduled discharge at Hour 24, 
safety and tolerability assessments must be performed prior to discharge, and, if possible, 
efficacy assessments should be performed. 
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If subjects choose to prematurely stop the study after clinic discharge but prior to the follow-up 
visit, at least 2 documented attempts should be made to contact the subjects for follow-up 
assessments which will include the assessments described for the follow-up visit (Section 7.4). 
5 
STUDY TREATMENT 
5.1 Investigational Products 
Active Test Product 
Ibuprofen PR tablets 300 mg, single oral dose of 600 mg.  A yellow to pale yellow coloured, 
film coated, caplet shaped tablet, debossed as ‘N12’ on one side and plain on the other side. 
Table 5-1 Active Test Product 
Name of Ingredient 
Quantity/Tablet(mg) 
Function 
Reference 
Ibuprofen  
300.00 
Active 
Ph.Eur. 
Silicon dioxide 
3.00 
Glidant/Anti-adherent 
Ph.Eur. 
Hypromellose K4M 
Premium 
62.50 
Rate Controlling Polymer 
Ph.Eur. 
Hypromellose K100 LV 
32.50 
Rate Controlling Polymer 
Ph.Eur. 
Silicified Microcrystalline 
cellulose 50  
100.00 
Filler/Binder 
NF 
Silicified Microcrystalline 
cellulose 90 
50.00 
Filler/Binder 
NF 
Croscarmellose sodium 
17.50 
Disintegrant 
Ph.Eur. 
Glycine 
25.00 
Release Modifier 
Ph.Eur 
Silicon dioxide 
3.00 
Glidant/Anti-adherent 
Ph.Eur. 
Stearic acid 
6.00 
Lubricant 
Ph.Eur. 
Total weight of core 
tablet 
599.50 mg 
Film coating and Polishing  
Opadry Yellow 
15B520019 
7.50 
Coating agent 
In House 
Purified water# 
q.s. 
Coating vehicle 
Ph.Eur. 
Carnauba Wax   
0.025 
Polishing Agent 
Ph.Eur 
Total weight  
607.025 mg 
#   Removed during the process.  
 
 
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Placebo for Test Product 
A yellow to pale yellow coloured, film coated, caplet shaped tablet, debossed as ‘N12’ on one 
side and plain on the other side. 
Table 5-2 Placebo for Test Product 
Ingredient 
mg/tablet Function 
Reference 
Standard 
Core  
Hypromellose K4M Premium 
125.10 
Rate Controlling 
Polymer 
Ph. Eur. 
Hypromellose K100 Premium LV  
65.05 
Rate Controlling 
Polymer 
Ph. Eur. 
Silicified Microcrystalline Cellulose 50 
200.17 
Filler/ Binder 
NF 
Silicified Microcrystalline Cellulose 90 
100.08 
Filler/ Binder 
NF 
Croscarmellose Sodium  
35.03 
Disintegrant 
Ph. Eur. 
Glycine 
50.04 
Release Modifier 
Ph. Eur. 
Silica, Colloidal Hydrated 
12.02 
Glidant/ Anti-adherent 
Ph. Eur. 
Stearic Acid  
12.01 
Lubricant 
Ph. Eur. 
Coating and Polishing  
Opadry Yellow 15B520019 
7.50 
Coating Agent 
In house 
Carnauba Wax  
0.025 
Polishing Agent 
Ph. Eur. 
Processing agent 
Purified Water 
q.s.* 
Coating Vehicle 
Ph. Eur. 
Total 
607.025 
 
 
* Does not remain in final product except traces. Removed during the coating process.  
 
 
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Comparator Product 
Nurofen Ibuprofen acid tablets 200 mg, single oral dose of 400 mg.  A white to off white, 
biconvex, round, sugar coated tablet. 
Table 5-3 Comparator Product 
Name of Ingredient 
Unit Formula 
(mg/tablet) 
Function 
Reference to 
Standards 
Active Ingredient 
 
 
 
Ibuprofen 
200.0 
Active ingredient 
Ph.Eur. 
Other Ingredients 
 
 
 
Croscarmellose Sodium 
30.0 
Disintegrating agent 
Ph.Eur. 
Sodium Lauryl Sulphate 
0.5 
Tablet lubricant 
Ph.Eur. 
Sodium Citrate 
43.5 
Bulk filler 
Ph.Eur. 
Stearic Acid 
2.0 
Tablet lubricant 
Ph.Eur. 
Colloidal Anhydrous Silica 
1.0 
Granule flow aid 
Ph.Eur. 
Tablet Core Weight 
277.0 
 
 
Sugar Coat Ingredients 
 
 
 
Carmellose Sodium 
0.7 
Sugar coat binder 
Ph.Eur. 
Talc 
33.0 
Sugar coat bulking agent 
Ph.Eur. 
Acacia Spray Dried 
0.6 
Sugar coat binder 
Ph.Eur. 
Sucrose 
116.1 
Sugar coat 
Ph.Eur. 
Titanium Dioxide  
1.4 
Colour 
Ph.Eur. 
Macrogol 6000 
0.2 
Tablet polish 
Ph.Eur. 
Purified Water 
ND 
Sugar syrup solvent 
Ph.Eur. 
Coated Tablet Weight 
429.0 
 
 
 
 
Placebo for Comparator Product 
A white to off white, biconvex, round, sugar coated tablet. 
Table 5-4 Placebo for Comparator Product 
Ingredient 
Quantity (%w/w) 
Function 
Reference 
Standard 
Core 
Mannitol 
46.81 
Filler 
Ph. Eur 
Microcrystalline 
Cellulose 
16.14 
Filler 
USP/NF 
Magnesium Stearate 
1.61 
Lubricant 
Ph. Eur. 
Sugar coating 
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Carmellose Sodium 
0.16 
Sugar coat binder 
Ph. Eur 
Talc 
7.69 
Sugar coat bulking 
agent 
Ph. Eur 
Acacia Spray Dried 
0.14 
Sugar coat binder 
Ph. Eur 
Sucrose 
27.06 
Sugar coat 
Ph. Eur 
Titanium Dioxide 
0.33 
Colour 
Ph. Eur 
Macrogol 6000 
0.05 
Tablet polish 
Ph. Eur 
Purified Water* 
ND 
Sugar syrup solvent 
Ph. Eur 
 
Test Product and Placebo for Test Product will be manufactured and packed (primary pack) to 
Good Manufacturing Practice (GMP) standards by Strides Shasun Limited, R.S No 32-34 
PIMS Road, Periyakalpet, Kalapet, Pondicherry, 605014, India and shipped to Investigational 
Materials Supplies Unit (IMSU), RB, Dansom Lane, Hull, HU8 7DS. 
Nurofen Ibuprofen acid (Comparator) and the Placebo for Comparator tablets will be 
manufactured to GMP standards by Reckitt Benckiser, Thane Road, Nottingham, NG90 2DB, 
UK. Both active and placebo tablets will be unprinted for blinding purpose. 
Both the products (Comparator and Placebo) will be primary packed at Sharp Clinical Services, 
Elvicta Business Park, Crichowell, NP8 1DF, UK and shipped to Investigational Materials 
Supplies Unit (IMSU), RB, Dansom Lane, Hull, HU8 7DS. 
The Test Product, Placebo for Test Product, Comparator Product and the Placebo for 
Comparator product will be assembled to GMP standards by the IMSU, RB, Dansom Lane, 
Hull HU8 7DS, and bulk certified by RB Research and Development Qualified Person. All the 
products will be shipped directly from IMSU to the study site.  
5.2 Non-Investigational Products 
In preparation for the surgery, subjects will receive local anaesthesia (2% lidocaine with 
1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion of the investigator.  
5.3 Permitted Therapies 
After randomisation and administration of study drug, paracetamol / acetaminophen (1000 mg) 
will be permitted as the initial rescue medication. Subjects will be encouraged to wait at least 
60 minutes after receiving study drug before taking rescue medication. If acetaminophen 
rescue medication is not effective in relieving the subject’s pain, 5 mg oxycodone rescue 
medication may be administered at the discretion of the investigator.  
At the investigators discretion repeat doses of rescue medication may also be administered as 
required. 
The Investigator or designees will record all medication taken by the subject at the screening 
visit in the subject’s electronic Case Report Form (eCRF). Any medication taken by the subject 
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from the time of giving informed consent through to the end of the subject’s participation in the 
study (last assessment) will be recorded on the concomitant medication page in the eCRF. 
Upon discharge from the study site, subjects may be prescribed pain medication for use at 
home according to the standard practice of the study site.  
5.4 Treatment Compliance 
For the duration of each assessment the subject will remain at the study site under the 
supervision of the Investigator or designees. The Investigator or designees will provide 
supervised drug administration along with clear instructions and support to the subject to 
facilitate the best possible compliance with study requirements. Any non-compliance during 
the study will be observed and recorded by study site staff as a protocol deviation. 
5.5 Packaging and Labelling and Supply / Resupply 
For each subject one pack will be provided containing all required tablets for each dosing 
timepoint.  Each tablet will be held in a blister within the pack.  The pack will clearly show which 
tablets are to be taken at which timepoint. 
All packs regardless of treatment regimen will be the same except for a kit number and will 
therefore not identify the treatment. 
The IMP will be labelled in accordance with EudraLex Volume 4 Good Manufacturing Practice 
(GMP) Guidelines, Annex 13 - Manufacture of Investigational Medicinal Products, parts 26 to 
33 (Labelling) and in accordance with directive 2003/94/EC as amended and including any 
other applicable national/state legislation. The IMP will be labelled in English 
All IMP will be packed and labelled to GMP by the Investigational Material Supplies Unit 
(IMSU), Reckitt Benckiser Healthcare (UK) Ltd, Dansom Lane, Hull, HU8 7DS, UK. IMP will 
be shipped from the IMSU to the study site. 
5.6 Storage Conditions 
The Investigator or designated individual will keep all IMP(s) in a pharmacy or a secure storage 
facility, accessible only to those individuals authorised by the Investigator to dispense the 
medication. 
The Investigator or designated individual will maintain an inventory. This will include the 
description and quantity of IMP(s) received during the course of this study, as well as a record 
of the materials that are dispensed and returned (how much, to whom and when). This 
inventory (“Drug Dispensing Log”) will be subject to review by the study monitor during 
monitoring visits. 
The Investigator agrees not to supply IMP(s) to any person except study personnel and 
patients enrolled in this study. 
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The IMP should be stored between 8-25 °C and is not to be refrigerated or frozen. 
Temperatures must be constantly monitored and readings logged in a temperature log on 
working days.  
The temperature in the secure storage facility will be recorded using a minimum/maximum 
thermometer. If the temperature falls outside the specified range of 8-25 °C, the Sponsor 
should be notified immediately and appropriate action should be agreed and documented. The 
temperature log will be reviewed by the study monitor at each monitoring visit.  
5.7 Blinding 
This study is a double-blind, double dummy study.  There will be two placebo tablets designed 
to be comparable to each of the active products (PR and IR) in both shape, size, colour and 
weight. 
All subjects will receive 4 tablets at each dosing timepoint.  At each timepoint each subject will 
receive 2 tablets that may be either PR or the placebo made to look like PR and 2 tablets that 
may be IR or the placebo made to look like IR. See Table 3-2 Treatment Regimens.  This 
includes those in the placebo arm who will receive 2 placebo tablets designed to look like PR 
and 2 placebo tablets designed to look like IR at all dose timepoints. 
All subject packs will be designed and labelled to ensure blinding is maintained. 
Subjects, investigators and site staff will all be blind to the treatments. 
Unblinding will only occur after database lock or in the case of emergency unblinding, see 
Section 5.8. 
5.8 Emergency Unblinding Procedures 
Treatment unblinding is discouraged if knowledge of the treatment assignment will not 
materially change the planned management of a medical emergency. Unblinding will be 
permitted in a medical emergency that requires immediate knowledge of the subject’s 
treatment assignment. 
For emergency unblinding, study personnel will use the IWRS. If treatment assignment is 
unblinded for an individual subject, study personnel will be notified of that subject’s treatment 
assignment without unblinding the treatment assignments for the remaining subjects in the 
study. Thus, the overall study blind will not be compromised. If a subject’s treatment 
assignment is unblinded, he/she may or may not be asked to withdraw from the study. The 
investigator should make this decision after consultation with the medical monitor. 
5.9 Drug Accountability 
The Investigator will keep all study medication (including rescue medication) in a pharmacy or 
a secure storage facility, accessible only to those individuals authorised by the Investigator to 
dispense the medication. 
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The Investigator or designated individual will maintain an inventory. This will include the 
description and quantity of study drug received during the course of the study, as well as a 
record of the materials that are dispensed and returned (how much, to whom and when). This 
inventory will be subject to review by the study monitor during monitoring visits.  
The Investigator agrees not to supply study drug to any person except study personnel and 
subjects in this study.  
5.10 
Return and Destruction  
The Investigator agrees to conduct a drug-supply inventory, to record the results of this 
inventory (“IMP Removal from Site” form) and to ensure all original IMP containers whether 
empty or containing IMP are sent to RB’s representative at the end of the study. 
RBs representative will then arrange for the appropriate and timely destruction of all containers 
and unused IMP upon confirmation from RB following provision of a full reconciliation by 
Premier (on finalisation of the study report).   
6 
STUDY PROCEDURES BY VARIABLE 
6.1 Informed Consent 
Prior to conducting any study-related activities, written informed consent must be obtained 
from the subject (Section 12.2). 
6.2 Randomisation 
Eligible subjects will be randomised in a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets 
Q12h, 2x200 mg ibuprofen IR tablets Q8h, or placebo using permuted blocks of fixed size. The 
randomisation will be stratified by baseline pain category (moderate or severe) using a 
categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and 
severe (8-10). The randomisation schedule will be prepared by a statistician not otherwise 
involved in the study. Randomisation will be performed using an interactive web response 
system. Access to the unblinding codes will be restricted to personnel not otherwise involved 
in the study and will be available to the investigator only in the case of a subject requiring 
unblinding prior to database lock. 
6.3 Drug Administration 
Subjects will be dosed under clinic supervision to ensure compliance. Prior to dosing, each 
subject will be instructed by the Investigator or clinic staff on how to take the medication. 
 
6.4 Demographics 
Demographic information will be recorded including gender, date of birth and race. 
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6.5 Medical History and Concomitant Medication 
Relevant medical history, including history of current disease and information regarding 
underlying diseases will be recorded. The duration of surgery and all concomitant medication 
taken will be recorded as well as permitted therapies (see Section 5.3). 
6.6 Physical Examination 
A complete physical examination (excluding the genitourinary examination) will be performed 
at Screening. An abbreviated confirmatory physical assessment, including an examination of 
the subject’s mouth and neck, will be performed at the Follow-up Visit (or Early Termination 
Visit). 
Height, weight, and BMI will be assessed at Screening. 
6.7 Laboratory Tests 
The following clinical laboratory tests will be performed at Screening.  
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea 
nitrogen, creatinine, glucose, sodium, potassium, chloride, bicarbonate, 
lactate dehydrogenase, uric acid, urea, inorganic phosphorous, 
cholesterol (total and High Density Lipoprotein (HDL)), triglycerides, 
gamma glutamyl transferase 
Coagulation: 
prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones, leucocyte 
esterase, nitrites (in the event that the dipstick test is positive, red blood 
cells, white blood cells, epithelial cells, crystals, bacteria and casts will 
be examined microscopically) 
Virology: 
hepatitis B, hepatitis C, HIV 
The following laboratory tests will also be performed: 
 
Alcohol breathalyzer test will be performed before surgery on Day 1. 
 
Urine drug screen samples will be collected at Screening and before surgery on Day 1 to 
test for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine 
(PCP), and tetrahydrocannabinol (THC). 
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 
For female subjects of childbearing potential, a blood sample for the serum pregnancy 
test will be collected at Screening and a urine pregnancy test sample will be collected 
before surgery on Day 1. 
Blood and urine samples for hematology, serum chemistry, and urinalysis will be prepared 
using standard procedures and will be sent to a central laboratory for analyses. 
6.8 Electrocardiograms 
A 12-lead electrocardiogram will be performed at Screening. 
6.9 Vital Signs 
Vital signs will be recorded after the subject has been in a sitting position for 3 minutes. Vital 
sign assessments will include blood pressure, heart rate, respiratory rate, and body 
temperature. Clinically significant abnormalities in vital signs should be recorded as AEs. 
6.10 
Blood Sampling 
Blood sampling will be performed according to the site’s standard practices, as described in 
the study manual or other site documentation. 
6.11 
Oral Radiography 
Oral radiographs (X-rays) will be taken at Screening (radiographs taken within 1 year before 
Screening will be acceptable and do not need to be repeated). 
6.12 
Pain Intensity  
Subjects will rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no 
pain and 10 = worst pain ever at the timepoints mentioned on Table 7-1. 
6.13 
Stopwatch Assessment  
Two stopwatches will be started immediately after the subject has swallowed the study drug 
with 8 ounces of water. Each subject will be instructed, “Stop the first stopwatch when you first 
feel any pain relief whatsoever. This does not mean you feel completely better, although you 
might, but when you first feel any relief in the pain you have now” (perceptible pain relief). The 
subject will also be instructed, “Stop the second stopwatch when you feel the pain relief is 
meaningful to you” (meaningful pain relief). If the subject does not press the stopwatches within 
8 hours after Time 0 the subject will discontinue use of the stopwatches. 
6.14 
Pain Relief Scale  
Subjects will rate their pain relief relative to Time 0 using a 5-point categorical scale. Subjects 
will be asked “How much relief have you had since your starting pain?” with response choices 
of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. At each assessment time point, 
the pain intensity NRS assessment will be completed first and the pain relief assessment will 
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be completed second. Subjects will not be able to compare their responses with their previous 
responses. 
6.15 
Subject’s Global Evaluation of Study Drug 
For the global evaluation of study drug, the subject will be asked “How effective do you think 
the study drug is as a treatment for pain?” with response choices of 0 = poor, 1 = fair, 2 = good, 
3 = very good, or 4 = excellent. Subjects will complete the global evaluation of study drug 
24 hours after Time 0 or immediately before the first dose of rescue medication (whichever 
occurs first). 
6.16 
Adverse Events  
During the study the Investigator will ask the subject: “Are you experiencing any symptoms or 
complaints?” at the baseline visit, and “Have you had any symptoms or complaints since the 
last time you were asked?” during the study. In addition, spontaneously reported AEs are 
collected. 
The observation period for an individual subject will start after giving informed consent and will 
finish at the last visit (follow-up visit) for the given individual subject. All AEs that arise during 
the observation period will be recorded and an assessment of the AE will be performed as per 
Section 8.2 by a medically qualified Investigator. If a subject has an AE that is still ongoing at 
the last visit, an attempt will be made by the Investigator to follow this up as per Section 8.4.   
If an untoward medical occurrence happens after the subject has signed the consent form but 
before administration of the IMP, it should be reported as an adverse event, including those 
associated with study procedures. 
Note this does not include any pre-existing medical conditions or findings associated with 
medical history which are identified during the screening process. 
7 
STUDY PROCEDURES BY VISIT 
7.1 Study Flow Chart / Table of Study Procedures and Assessments 
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Table 7-1 Schedule of Assessments 
 
Screening 
(Day -28 to 
Day -1) 
Surgery (Day 1) 
Day 2 
Follow-up 
(Day 8 ±2 days) or 
ETk 
 
 
Pre-
Surgery 
 
Post-surgery 
 
 
 
 
Pre-
dose 
0 h 
15, 30, 
45 min 
1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 
10 h 
12 h 
16 
h 
24h 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Assign a screening number 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xb 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
 
 
 
X 
 
X 
X 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (hematology, 
chemistry, urinalysis) 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test for female subjects of 
childbearing potentiale 
X 
X 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
Alcohol breathalyzer test 
 
X 
 
 
 
 
 
 
 
 
Oral radiographyf 
X 
 
 
 
 
 
 
 
 
 
Review study restrictions with subject 
X 
 
 
 
 
 
 
 
 
 
Pain intensity (NRS)g 
 
 
X 
 
X 
X 
X 
X 
X 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
Dosing with study drug 
 
 
 
0 h 
 
8 h 
12 h 
16h 
 
 
Stopwatch assessmenth 
 
 
 
X 
 
 
 
 
 
 
Pain relief (5-point categorical scale)g 
 
 
 
 
X 
X 
X 
 
X 
 
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Screening 
(Day -28 to 
Day -1) 
Surgery (Day 1) 
Day 2 
Follow-up 
(Day 8 ±2 days) or 
ETk 
 
 
Pre-
Surgery 
 
Post-surgery 
 
 
 
 
Pre-
dose 
0 h 
15, 30, 
45 min 
1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 
10 h 
12 h 
16 
h 
24h 
 
Global evaluation of study drugi 
 
 
 
 
 
 
 
 
X 
 
Concomitant medications 
 
Xb 
X 
X 
X 
X 
X 
 
X 
X 
Adverse eventsj 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Provide prescription for pain medication.  
 
 
 
 
 
 
 
 
X 
 
Collect unused home pain medications, as 
needed 
 
 
 
 
 
 
 
 
 
X 
Discharge from study site 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: BMI=body mass index; ET=early termination; h=hour; min=minute; NRS=numeric rating scale;. 
a Times listed are relative to dosing with study drug. 
b Medical history and concomitant medication use since Screening will be updated on Day 1 before surgery. 
c A complete physical examination (excluding the genitourinary examination) will be performed at Screening. An abbreviated confirmatory physical assessment, 
including an examination of the subject’s mouth and neck, will be performed at the Follow-up Visit (or Early Termination Visit). 
d Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at the following times: at Screening, before surgery, within 30 minutes 
before Time 0, 12 hours after Time 0, 24 hours after Time 0, and/or immediately before the first dose of rescue medication, and at the Follow-up Visit (or Early 
Termination Visit). 
e Serum pregnancy test at Screening and urine pregnancy test before surgery on Day 1 (female subjects of childbearing potential only). Test results must be 
negative for the subject to continue in the study. 
f 
Oral radiographs taken within 1 year before Screening will be acceptable and do not need to be repeated. 
g Pain assessments will be conducted (pre-dose, if at one of the dosing timepoints of 0, 8, 12 or 16 hours) at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 
8, 10, 12, 16 and 24 hours after Time 0 and immediately before each dose of rescue medication. Pain intensity will also be assessed pre-dose. At each 
assessment time point, the pain intensity assessment will be completed first and the pain relief assessment will be completed second. Subjects will not be 
able to compare their responses with their previous responses.  Note for assessments less than 1 hour apart a window of +/-2 min is allowable whilst for 
assessments at least 1 hour apart a +/-5 min window is allowable. 
h Two stopwatches will be started immediately after the subject has swallowed the first dose of study drug with 8 ounces of water (Time 0). Subjects will record 
the time to perceptible and meaningful pain relief, respectively, by stopping the stopwatches. 
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i 
Subjects will complete a global evaluation of study drug 24 hours after Time 0 or immediately before the first dose of rescue medication (whichever occurs 
first). 
j 
Adverse events will be monitored and recorded from the time of signing of the informed consent form until the Follow-up Visit (or Early Termination Visit). 
k If an unscheduled visit occurs the Investigator should follow the activities detailed in Section 7.5. 
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7.2 Screening Visit (Day -28 to Day -1) 
 
Written informed consent 
 
Assign a screening number 
 
Inclusion/exclusion criteria 
 
Demographics 
 
Medical history 
 
Complete physical examination (excluding the genitourinary examination) 
 
Vital signs 
 
Electrocardiogram 
 
Height, weight, and BMI 
 
Clinical laboratory tests (haematology, chemistry, urinalysis) 
 
Serum pregnancy test for female subjects of childbearing potential 
 
Urine drug screen 
 
Oral radiography (oral radiographs taken within 1 year before Screening will be 
acceptable and do not need to be repeated)  
 
Review study restrictions with subject 
 
Schedule surgery 
7.3 Day of Surgery (Day 1) 
 
Pre-Surgery 
 
Inclusion/exclusion criteria review 
 
Medical history review 
 
Vital signs 
 
Urine pregnancy test for female subjects of childbearing potential 
 
Urine drug screen 
 
Alcohol breathalyzer test 
 
Concomitant medications 
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 
Adverse events 
 
Surgery 
 
Subjects who continue to be eligible for study participation after completing screening 
procedures and assessments will undergo extraction of 2 or more third molars. At least 
1 of the third molars must be a fully or partially bone impacted mandibular molar. If only 
2 molars are removed, then they must be ipsilateral.  
 
All subjects will receive local anesthesia (2% lidocaine with 1:100,000 epinephrine).  
 
Nitrous oxide will be allowed at the discretion of the investigator. 
 
Post-surgery Eligibility Assessments and Randomisation 
 
Vital signs 
 
Concomitant medications 
 
Adverse events  
 
Pain intensity NRS  
 
Subjects who experience moderate to severe pain intensity (NRS score of ≥ 5) within 
6 hours after surgery and who continue to meet all study entry criteria will be randomised 
 
Dosing and Post-dose Assessments (Hour 0 through Hour 24) 
 
Subjects will re-assess their baseline pain intensity using the NRS immediately before 
receiving IMP (pre-dose, Time 0) 
 
Administer IMP at the timepoints in Table 3-2 
 
Subjects will assess their pain intensity (NRS) and pain relief (5 point categorical scale) 
at the following time points (pre-dose, if at one of the dosing timepoints of 0, 8, 12 or 
16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours 
after Time 0; and immediately before each dose of rescue medication, if any. For 
assessments less than 1 hour apart a window of +/-2 min is allowable whilst for 
assessments at least 1 hour apart a +/-5 min window is allowable. 
 
Subjects will use the double stopwatch method to record the time to perceptible pain 
relief and time to meaningful pain relief during the 8 hours following the first dose or until 
subject takes rescue medication 
 
Subjects will complete a global evaluation of study drug 24 hours after Time 0 or 
immediately before the first dose of rescue medication (whichever occurs first) 
 
Vital signs will be recorded after the subject has been in a sitting position for 3 minutes 
at the following times: before surgery, within 30 minutes before Time 0, 12 and 24 hours 
after Time 0, and/or immediately before the first dose of rescue medication 
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 
Concomitant medications 
 
Adverse events  
 
Subjects will remain at the study site overnight and will be discharged on Day 2.  
 
Upon discharge from the study site, provide prescription for pain medication.  
 
Schedule follow-up visit 
7.4 Follow-up Visit (Day 8 ± 2 days) or Early Termination 
 
Abbreviated confirmatory physical assessment, including an examination of the 
subject’s mouth and neck 
 
Vital signs 
 
Concomitant medications 
 
Record any post discharge adverse events 
7.5 Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the reason for unscheduled visit, 
including any AEs, concomitant therapy changes, withdrawal (if deemed appropriate) and any 
clinical assessments deemed appropriate for the clinical care of the subject. Unscheduled 
visits should not alter the timing of the routine study schedule. 
7.6 Study Restrictions 
 
Prohibited Therapies 
Subjects are not permitted to take any concomitant medications that might confound 
assessments of pain relief, such as psychotropic drugs, antidepressants, sedative-hypnotics 
(other than those permitted for conscious sedation), or other analgesics taken within five times 
of their elimination half-lives (other than those used at the surgery). Selective serotonin 
reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are 
permitted if the subject has been on a stable dose for at least four weeks prior to Visit 1 
(screening).  
 
General and Dietary Restrictions 
Other restrictions include the following: alcohol use is prohibited from 24 hours before surgery 
until discharge on Day 2; nothing by mouth from midnight before surgery until 1 hour after 
surgery; clear liquids only are allowed starting 1 hour after surgery until 1 hour after dosing; 
1 hour after dosing, the subject’s diet may be advanced according to standard practice. 
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8 
SAFETY REPORTING 
8.1 Adverse Event Definitions 
An Adverse Event (AE)  
An adverse event (AE) is any untoward medical occurrence in a patient or a clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have a causal relationship with  this treatment. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. [ICH E6 1.2].  
Serious Adverse Event (SAE)  
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that:  
 
results in death  
 
is life-threatening 
 
requires in-patient hospitalization or prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity or  
 
is a congenital anomaly/birth defect 
In addition, important medical events that may not be immediately life-threatening or result in 
death, or require hospitalisation, but may jeopardise the patient or may require intervention to 
prevent one of the other outcomes listed above should also usually be considered serious.  
[ICH E2A] Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, 
or development of drug dependency or drug abuse.  
Note: If the event is related to the investigational product and is both serious and unexpected, 
it is classified as a suspected unexpected serious adverse reaction (SUSAR). In case of 
double-blinded studies, unblinding is needed in order to determine a SUSAR. 
8.2 Assessment of Adverse Events 
Any untoward medical occurrences that arise after the subject has given informed consent will 
be recorded in the subject’s source documents and electronic case report forms (eCRFs). 
Untoward medical occurrences can be reported spontaneously by the subject or in response 
to non-leading questioning or observation by the Investigator or be a significant laboratory 
abnormality. 
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Untoward medical occurrences, including all adverse events (AE) and all serious adverse 
events (SAEs) are collected, fully investigated and documented.  
As the study will be conducted on subjects who have been through removal of impacted third 
molars, it is expected that they will present post-surgical symptoms, for example: swelling and 
bruising. For the purposes of this study, when at normal/expected magnitude, such 
occurrences will not be reported as AEs as they are expected and, therefore, are not 
“untoward” as in the AE standard definition. 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at 
study termination will be further followed up until recovery or until stabilisation of the disease 
after termination. 
For each AE a causality assessment of the event to the study drug must be performed. The 
relationship to IMP must be determined by the Investigator (if medically qualified) or by a 
medically qualified Co-Investigator. 
Table 8-1 AE Relationship Descriptions 
Relationship 
Description 
Unassessable/ 
Unclassifiable 
Insufficient information to be able to make an assessment 
Conditional/ 
Unclassified 
Insufficient information to make an assessment at present (causality 
is conditional on additional information) 
Unrelated 
No possibility that the AE was caused by the IMP 
Unlikely 
Slight, but remote, chance that the AE was caused by the IMP, but 
the balance of judgement is that it was most likely not due to the IMP 
Possible 
Reasonable suspicion that the AE was caused by the IMP 
Probable 
Most likely that the AE was caused by the IMP 
Certain 
The AE was definitely caused by the IMP 
 
For each AE a severity description should be given. 
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Table 8-2 AE Severity Descriptions 
Severity 
Description 
Mild 
The AE does not limit usual activities; the subject may experience 
slight discomfort 
Moderate 
The AE results in some limitation of usual activities; the subject may 
experience significant discomfort 
Severe 
The AE results in an inability to carry out usual activities; the subject 
may experience intolerable discomfort or pain 
 
Expectedness for each AE will be determined based on the information in Section 6.9 of the 
Investigator’s Brochure. 
All AEs will be coded by the Sponsor using the most up-to-date version of MedDRA. 
8.3 Reporting of Adverse Events 
In the event of a Serious Adverse Event (SAE), the Investigator must report the event using 
the SAE form to the Sponsor Global Vigilance Group (GVG), by contacting GVG by email: 
gvg@rb.com while copying in the contract research organisation (CRO) and Sponsor 
Project/Study Managers within 24 hours of knowledge of the event. 
The out of hours emergency phone number is +44 (0)1482 326151. An alternative number 
may additionally be provided by Premier Research to give access to the study Medical Monitor 
our of hours. 
This emergency phone number will be confirmed to the Investigator at the Study Initiation Visit.  
All SAE Forms must be provided via email. Any inconsistencies in the information received 
from the Investigator will be clarified using the Adverse Event Data Clarification Form. The 
Investigator must retain a copy of all the SAE forms in the Investigator Site File. 
The Investigator must inform their Institutional Review Board (IRB) of all SAEs occurring in the 
study within 7 days for fatal or life-threatening SAEs and 15 days for all other SAEs as per 
Sponsor instructions and as described in the Safety Management Plan.  
The Investigator should not break the randomisation code except when it is necessary to do 
so in order to ensure the subject receives appropriate medical care. 
SAEs and non-serious AEs will be reported to the appropriate regulatory authorities by the 
Sponsor in accordance with the authorities’ requirements. The Sponsor is responsible for 
expedited reporting of all SUSARs/ SAEs to relevant authorities and IECs/IRBs as required by 
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regulations. If the event requires expedited reporting, a CIOMS (Council for International 
Organizations of Medical Sciences) form will be produced and GVG will take actions as per 
the study specific Safety Management Plan.  
8.4 Follow-up of Adverse Events 
All SAEs and all AEs that have not resolved by the end of the study will be followed up by the 
Investigator until resolution or until the Investigator believes there will be no further change, 
whichever is the earlier. This may involve the subject making additional visits to the site.  
If a subject has unresolved AEs requiring follow-up, investigators must attempt to contact 
subjects by telephone or other means.  
8.5 Overdose, Abuse, Misuse and Medication Errors 
The Sponsor defines “overdose” as the administration of a quantity of an investigational IMP 
given per administration or cumulatively, which is above the maximum recommended dose 
according to the authorised product information. 
The Sponsor defines “abuse” as the persistent or sporadic, intentional excessive use of an 
IMP, which is intended to produce harmful physical or psychological effects e.g. intentional 
overdose to experience psychological effects. 
The Sponsor defines “misuse” as situations where the IMP is intentionally and inappropriately 
used not in accordance with the authorised product information. 
Overdoses, abuse, misuse are reportable to the Sponsor irrespective of the presence of an 
associated AE / SAE. The overdose, abuse, misuse and any associated AE / SAE will be 
captured on an AE CRF (Case Report Form) page / SAE form. 
Due to the full inpatient nature of this study, in which medication doses will be supervised by 
site staff, cases of overdose, abuse or misuse are not expected to occur.  
Medication errors are any unintentional errors in dispensing or administration of the IMP which 
relates to: 
 
Taking / being administered an incorrect IMP 
 
Taking / being administered a drug by the wrong route of administration e.g. swallowing 
a suppository 
 
The accidental administration of the IMP to a person who is not a subject within the 
study 
Medication errors are reportable to the Sponsor irrespective of the presence of an associated 
AE / SAE. Medication errors with or without an associated AE / SAE will be captured on the 
AE CRF page / SAE form. 
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8.6 Pregnancy 
Pregnancy both in a female subject or the female partner of a male subject is considered a 
collectable event and will be recorded as an AE in all cases. It will be qualified as an SAE only 
if it fulfils SAE criteria. 
Due to the full inpatient nature of this study, pregnancy cases are not expected to occur during 
the study.  
 
9 
STATISTICAL CONSIDERATIONS 
This section presents a summary of the planned statistical analyses. A statistical analysis plan 
(SAP) that describes the details of the analyses to be conducted will be written prior to 
database lock. 
Summary statistics for continuous variables will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, summary 
statistics will typically include the number and percentage of subjects in each category. All data 
will be presented in listings. 
Baseline values are defined as the last measurements taken before dosing with study drug. 
9.1 Determination of Sample Size 
The sample size determination is based on the primary efficacy variable, SPID12. According 
to Farrar 2001(1), a clinically important improvement in pain is represented by a 2 point 
reduction on an 11-point NRS. Based on a baseline pain score of 7 this corresponds to an 
approximate 30% reduction in pain. An average 2 point difference in pain scores between 
Ibuprofen PR and placebo across all 14 assessments up to 12 hours will correspond to a 
difference in SPID12 of 24 points. In a previous study (7), the pooled standard deviation (SD) 
for SPID12 was 31.65. Assuming the same variability in this study, a sample size of 40 subjects 
per group will have >90% power to detect a difference of 24 points in SPID12, between 
ibuprofen 2×300-mg PR tablets and placebo using a 2-sided test with an alpha level of 0.05. 
In order to provide a robust estimate of treatment effect differences between PR and IR, and 
to obtain a more precise estimate for this comparison, a 3:3:1 allocation ratio will be used, so 
that 120 subjects are randomised into each of the PR and IR groups. Thus 280 subjects will 
be enrolled into the study. 
9.2 Interim Analysis 
No interim analysis is planned.  
9.3 Analysis Datasets 
The analysis populations include the following: 
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 
The intent-to-treat (ITT) population will consist of all subjects who are treated with 
study drug and who have at least 1 pain relief assessment after Time 0. The ITT 
population is the primary population for the efficacy analysis. 
 
The per-protocol (PP) population will consist of all ITT subjects who do not incur a 
major protocol violation that would challenge the validity of their data. This population 
will be utilized to evaluate the sensitivity of the primary efficacy analysis. 
 
The safety population will include all subjects who are treated with study drug. The 
safety population is the population for all safety assessments. 
 
9.4 Subject Disposition and Characteristics 
The numbers of subjects randomised, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. Demographic and baseline characteristics (including date 
of birth, sex, race, weight, height, BMI, medical history, and surgery duration) will be 
summarized for each treatment group and for the overall population using descriptive statistics. 
No formal statistical analyses will be performed. 
9.5 Efficacy Analyses 
The comparison of primary interest is between PR ibuprofen and placebo. In addition, the 
comparison between IR ibuprofen and placebo will be presented with p-values to demonstrate 
study sensitivity. Point estimates and 95% confidence intervals will be used to evaluate the 
clinical relevance of any differences between the PR and IR formulations. All treatment 
differences will be presented with 95% confidence intervals. No P value adjustment will be 
made for multiple endpoints or multiple comparisons. In the event of model assumptions for 
normality being violated, non-parametric methods will be used. 
Each efficacy endpoint will be summarized descriptively by treatment group. 
 
Primary Endpoint(s) 
The primary endpoint, summed pain intensity difference (SPID) over 0 to 12 hours (SPID12), 
will be used to compare the test product (2×300 mg ibuprofen PR tablets) against the placebo 
product. 
9.5.1.1 
Primary Analysis 
The primary efficacy null hypothesis is that SPID12 for placebo is equal to SPID12 for ibuprofen 
2×300 mg PR tablets. The primary analysis will be an ANCOVA model that includes the main 
effect of treatment and a covariate of the baseline NRS pain score and will use windowed worst 
observation carried forward (WOCF) imputation for subjects who use rescue medication. The 
primary analysis will be based on a 2-sided test at the significance level of 0.05. 
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9.5.1.2 
Secondary Analysis 
The clinical relevance of the difference between placebo and PR ibuprofen over 12 hours after 
initial dose will be evaluated. 
 
Secondary Endpoints 
 
The summed pain intensity difference (SPID) over 0 to 24 hours (SPID24) will be 
used to compare the test product (2×300 mg ibuprofen PR tablets twice daily [BID]) 
and comparator product (2×200 mg ibuprofen IR tablets three times a day [TID]). 
 
Summed pain intensity difference (SPID) over 0 to 4 hours (SPID4), over 0 to 8 hours 
(SPID8), and over 0 to 12 hours (SPID12) after Time 0 
 
Sum of total pain relief (TOTPAR) over 0 to 4 hours (TOTPAR4), over 0 to 8 hours 
(TOTPAR8), over 0 to 12 hours (TOTPAR12), and over 0 to 24 hours (TOTPAR24) 
after Time 0 
 
Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) 
over 0 to 4 hours (SPRID4), over 0 to 8 hours (SPRID8), over 0 to 12 hours 
(SPRID12), and over 0 to 24 hours (SPRID24) after Time 0 
 
Response to study drug (a responder will be defined as a subject with ≥30% 
improvement in pain intensity without rescue medication during the first 8 hours) 
 
Numeric rating scale (NRS) pain intensity difference (PID) at each scheduled time 
point after Time 0 
 
Pain intensity score at each scheduled time point 
 
Pain relief score at each scheduled time point after Time 0 
 
Peak pain relief 
 
Time to onset of analgesia (measured as time to perceptible pain relief confirmed by 
time to meaningful pain relief) using double stopwatch 
 
Time to first perceptible pain relief 
 
Time to meaningful pain relief 
 
Time to peak pain relief 
 
Proportion of subjects using rescue medication 
 
Time to first use of rescue medication  
 
9.5.2.1 
Secondary Endpoint Analyses 
For continuous secondary endpoints such as pain intensity score, SPID at each scheduled 
time point, peak pain intensity, TOTPAR4, TOTPAR8, TOTPAR12, TOTPAR24, SPID4, 
SPID8, SPID24, SPRID4, SPRID8, SPRID12, and SPRID24, descriptive statistics (such as 
mean, standard deviation, median, minimum, and maximum) will be provided for each 
treatment regimen. P values from ANCOVA models comparing the placebo group with other 
treatment groups, including terms for treatment and a covariate for baseline pain will be 
provided for SPID, SPRID, and TOTPAR variables, but no formal statistical inferences will be 
drawn on the basis of these tests. In the event that normality assumptions are violated for a 
parameter, non-parametric analysis methods will be used.  
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For ordinal secondary endpoints, such as pain intensity difference at each scheduled time 
point, pain relief at each scheduled time point, peak pain relief, and global evaluation of study 
drug, descriptive summaries will be provided and will include the number and percentage of 
subjects within each category for each treatment group. Nominal P values from Fisher’s exact 
tests (or chi-square tests, as appropriate) comparing the placebo group with other treatment 
groups will be provided for peak pain relief and global evaluation of study drug, but no formal 
statistical inferences will be drawn on the basis of these tests. 
For each time-to-event endpoint, Kaplan-Meier methodology will be used to evaluate the 
treatment effect. Time to onset of analgesia (measured as time to perceptible pain relief 
confirmed by meaningful pain relief) will be based on data collected using the double stopwatch 
method. Time to onset of analgesia will be right-censored at 8 hours for subjects who do not 
experience both perceptible pain relief and meaningful pain relief during the 8-hour interval 
after Time 0. The summary tables will provide the number of subjects analysed, the number of 
subjects censored, estimates for the quartiles, and 95% confidence intervals (CIs) for the 
estimated median and the restricted mean estimate. P values comparing placebo to active 
treatment from Wilcoxon or log-rank tests (as appropriate) will also be used to examine 
treatment effect. 
For time to onset of analgesia, the comparison of interest will be the ibuprofen 2×300 mg PR 
group versus the ibuprofen 2×200 mg IR group. The summary table for this comparison will 
provide the number of subjects analysed, the number of subjects censored, estimates for the 
quartiles, and 95% confidence intervals (CIs) for the estimated median and the restricted mean 
estimate.  
For the proportion of subjects who are responders and the proportion of subjects using rescue 
medication, logistic regression models that adjust for baseline intensity and/or significant 
demographic variables, if appropriate, will be used to evaluate the treatment effect.   
For the responder analysis, subjects will be censored at 8 hours and for the use of rescue 
medication/time to first rescue subjects will be censored at 24 hours.  
9.6 Safety Analyses 
 
Safety Endpoint(s) 
 
Incidence of treatment-emergent adverse events (TEAEs) 
 
Incidence of changes in vital sign measurements 
9.6.1.1 
Safety Endpoint Analyses 
Data listings will be provided for protocol-specified safety data. The Medical Dictionary for 
Regulatory Activities (MedDRA) (Version 19.0 or higher) will be used to classify all AEs with 
respect to system organ class and preferred term. Adverse event summaries will include only 
TEAEs, which will be summarized for each treatment group.  
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For vital sign measurements, descriptive statistics will be provided at each scheduled time 
point for each treatment group. Changes from Baseline for vital signs will be calculated for 
each subject, and descriptive statistics will be provided on changes in vital signs from Baseline 
for each treatment group at each scheduled time point after Baseline. No formal statistical tests 
will be performed. 
9.7 Handling of Missing Data and Drop-outs 
Missing pain assessments for all efficacy analyses will be handled as follows: 
 
Missing pain assessments scheduled before the first observed assessment will be 
imputed with the subject’s worst observed pain assessment. 
 
Missing intermediate pain assessments will be replaced by linear interpolation. 
 
Missing pain assessments at the end of the observation period due to premature 
discontinuation of pain assessments will be imputed by carrying forward the last 
observation prior to that missing. 
 
The primary analysis will use windowed worst observation carried forward (WOCF) 
methodology for subjects who use rescue medication. Any pain measurements taken during a 
period of time in which rescue medication is active (4 hours) will be replaced by the last pain 
measurement before the rescue medication was taken. A sensitivity analysis will also be 
performed, in which all pain assessments recorded after the first dose of rescue medication 
has been taken will be disregarded and the rules outlined above will be used for missing data. 
 
All data for assessments other than pain assessments will be analysed as collected; missing 
data due to premature termination or any other reason will be left as missing. In the event of a 
notable difference between treatment groups in the number of subjects using rescue 
medication, other sensitivity analyses may be performed. These will be detailed in the 
Statistical Analysis Plan (SAP). 
 
9.8 Changes to the Original Statistical Plan 
If there are any deviations to the proposed statistical analysis as described in this protocol 
these will either be documented in the final SAP or in a protocol amendment prior to database 
lock with the rationale and impact of the changes addressed. 
10 
DATA HANDLING AND RECORD KEEPING 
10.1 
Case Report Forms (CRFs) 
Data will be recorded in an electronic Case Report Form (eCRF). For each enrolled study 
subject an eCRF is maintained. The Investigator or designees is responsible for the quality of 
the data record in the eCRF. eCRFs must be kept current to reflect subject status at each 
phase during the course of study. Subjects must not be identified in the eCRF by name or 
initials.  
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In the eCRF subjects will be identified by a subject number in combination with date of birth 
only, i.e., not by their name or initials. eCRF entries must be completed by appropriately trained 
site staff only. A log of trained and authorised staff able to complete the eCRF will be kept. 
10.2 
Specification of Source Documents 
Source data must be available at the site to document the existence of the study subjects. 
Source data must include the original documents relating to the study, as well as the medical 
treatment and medical history of the subject. The investigator and study monitor will identify 
the data that will be recorded directly on the eCRF and for this data the eCRF will be considered 
the source document (i.e., no prior written or electronic record of the data). The study monitor 
will document this at the screening and it will also be documented in the Data Management 
Plan.  
Source documents will include notes taken at the site and will include data such as 
demographic data, participation in study and ICF, medical history, SAEs, AEs and concomitant 
medication, results of examinations and assessments.  
Where source data are in the form of a computer printout (e.g. medical records, laboratory 
data) they will be signed and dated by the investigator or designated person, confirming that 
the print out is a true and faithful record of the data for that subject. These print-outs will be 
filed in the study files. 
The Investigator agrees to provide direct access to source data for study-related monitoring, 
audits, IRB review, and regulatory inspection(s). Direct access to source data requires that the 
subject gives written, documented consent to this. 
10.3 
Data Management 
The data management group at Premier Research will be responsible for data management 
and eCRF activities.  
Full details regarding data management will be described within the Data Management Plan.  
10.4 
Reporting of Protocol Deviations 
Site staff should make the study monitor aware of any deviation from the protocol as soon as 
possible after occurrence. Waivers for inclusion / exclusion criteria are not allowed. 
10.5 
Retention of Essential Documentation 
The Investigator should retain all essential documents (as defined in ICH E6 or according to 
other national and international regulations) until at least 5 years after the completion of the 
study (defined as last subject last visit in the study). These documents should be retained for 
a longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the Investigator 
when these documents no longer need to be retained. 
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Subject files and other source data must be kept for the maximum period of time permitted by 
the Clinical Unit. The Investigator must notify the Sponsor of the retention period if this is 
shorter than described above. 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Monitoring 
The Sponsor will organise regular monitoring visits to be performed at intervals agreed with 
the Investigator. The anticipated monitoring frequency will be stated in the Monitoring Plan. 
Monitoring will also involve, as appropriate, correspondence and telephone contacts. 
On-site monitoring includes source data verification (SDV) which is the procedure whereby the 
data contained in the eCRFs are compared with the primary source data and thereby verified 
as accurate. It will be performed in such a way as to preserve subject confidentiality, taking 
into account all ethical and legislative requirements. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during the monitoring visit to review the data and resolve any queries and to allow direct 
access to the subject’s records for SDV).  
SDV will include as a minimum verification for all subjects, subject identity (date of birth, sex, 
initials and subject number), record of entry into the study and signature of the informed 
consent. In addition, details of SAEs in the subject’s notes will be verified. Details included in 
the subject’s notes as a minimum: 
 
Study number, brief description or title of study 
 
Date that the subject gave written consent 
 
All visit dates 
 
All SAEs 
 
All concomitant medications 
At a site visit the eCRFs should be complete and available in order that the accuracy of their 
completion may be checked. Each completed eCRF for each subject must be signed 
electronically by the Investigator, to verify the data and statements submitted. Similarly, all 
alterations on paper records must be initialled and dated by the Investigator or a designated 
person, explained as necessary, with the original mistake left legible. 
11.2 
Audits and Inspections 
For the purpose of ensuring compliance with the protocol, ICH GCP and applicable regulatory 
requirements, clinical studies sponsored by RB may be subject to an independent audit at the 
study site which will be conducted by personnel from an appropriate Quality Assurance Unit. 
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Full consultation with the Investigator will be made prior to and during such audit, which will be 
conducted according to Quality Assurance Unit Standard Operating Procedures. 
As soon as the Investigator is notified of a planned inspection by a Regulatory Authority, he / 
she must inform the Sponsor promptly and allow the Sponsor to participate in the inspection 
as permitted by applicable regulations and local laws. 
11.3 
Sponsor Policy on Fraud in Clinical Studies 
In accordance with GCP, it is the Sponsor’s policy to always follow-up suspected cases of 
fraud. 
12 
ETHICAL AND REGULATORY ASPECTS 
12.1 
Ethics Review and Regulatory Authority Approval 
Written approval to conduct the study by an independent and appropriately constituted IRB 
must be obtained and a copy provided to the Sponsor before any protocol-related procedures 
that do not form part of the subject’s normal clinical treatment are performed. The approval 
letter must contain: 
 
Name and address of the IRB. 
 
Date of meeting. 
 
Sufficient information to identify the version of the Protocol and subject 
information/informed consent. 
 
Sufficient information to identify the version of other documents reviewed. 
The investigator must also provide the Sponsor with a list of IRB members that includes each 
member’s name and profession. 
Any amendments to the Protocol must be submitted to the IRB for approval unless where 
necessary to eliminate apparent immediate hazards to study subjects, and any administrative 
changes must be notified.  
This study will be submitted to the applicable Regulatory Authorities. The study will only be 
undertaken when regulatory authorisation has been obtained by the Sponsor. 
The Sponsor will notify the Regulatory Authority within 90 days of the end of the study (within 
15 days if the study is terminated prematurely). 
Premier Research will notify the IRB within 90 days of the end of the study (within 15 days if 
the study is terminated prematurely). 
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12.2 
Subject Information and Consent 
Informed consent should be obtained by means of a patient information sheet and ICF, 
prepared in accordance with ICH E6 (R2) section 4.8.10 and the applicable local regulations, 
written in a non-technical language.  All subjects will be provided with oral and written 
information describing the nature and duration of the study and the procedures to be 
performed.  The subject will be asked to sign and date an ICF prior to any study-specific 
procedures being performed.  No subject can enter the study before his/her informed consent 
has been obtained.  A sample subject ICF used in the study will be included in the clinical study 
report for this protocol.  
As part of administering the informed consent document, the Investigator must explain to each 
subject the nature of the study, its purpose, the procedures involved, the expected duration, 
the potential risks and benefits involved, and any potential discomfort.  Each subject must be 
informed that participation in the study is voluntary and that he/she may withdraw from the 
study at any time and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician.  The subject should understand the study, 
patient information sheet, and ICF before signing and dating the ICF.  The Investigator or 
person obtaining consent must also sign and date the form.  Each subject will be given a copy 
of the signed informed consent and written information. 
12.3 
Early / Premature Termination of the Study 
In the unlikely event that this study generates an excessive frequency of adverse events, 
subjects’ termination or suspension may be requested by the sponsor or the IRB or the 
Regulatory Authority. 
The sponsor retains the right to terminate the study for non-safety reasons by giving an 
appropriate period of notice to all involved parties as per contractual agreements. 
Any decisions to terminate or suspend the study will be notified in writing to the Investigator or 
designees, the IRB, Regulatory Authority and the clinicaltrials.gov database. 
If the study is terminated early, study subjects who have attended screening will be informed 
that they are no longer required and if they have any questions, they should consult the study 
site staff. For subjects who have completed the study they will not be informed that the clinical 
study has been terminated. All data collected up to the point of study termination will be used 
in an abbreviated Clinical Investigation Report.  
13 
COMPENSATION, INDEMNITY AND INSURANCE 
13.1 
Clinical Study Agreement 
Before the study commences, a contract between the Sponsor and Premier Research, who 
contracts with the Investigator, will be signed in which financial aspects of the study (including 
financial disclosure) as well as responsibilities and obligations are described. 
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13.2 
Compensation 
The Sponsor and the CRO carry insurance to pay compensation for injury, accident, ill health 
and death caused by participation in this study without regard to proof of negligence in 
accordance with the current local regulations and requirements. Details on finance and 
insurance will be provided in a separate agreement between the investigator and the sponsor.  
13.3 
Indemnity 
The Sponsor will provide appropriate indemnity for the Investigator and staff who conduct part 
or all of this study, upon request. The request must be received before the first subject is 
recruited. 
13.4 
Insurance 
If required and in accordance with applicable regulatory and legal requirements, the Sponsor 
will take out appropriate insurance policies on behalf of the Investigator and staff who conduct 
part or all of this study and/or on behalf of the subjects participating in the study. 
14 
REPORTING, PUBLICATION AND PRESENTATION 
A clinical study report will be prepared according to ICH E3 (Structure and Content of Clinical 
Study Reports) as part of the Sponsor’s commitment to Good Clinical Practice. The report will 
be a record of the total study conduct and findings and will be subject to approval by the 
Investigator who will sign the final report. 
The study data will be owned by the Sponsor. The Sponsor retains the right to publish the data 
independently of the Investigator. The Sponsor agrees that before it publishes the results, it 
will provide the Investigator with at least 30 days for full review prior to submission of the 
manuscript to the publisher. The Investigator must submit any proposed manuscript to the 
Sponsor for approval prior to submission for publication. 
15 
REFERENCES 
(1) Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of 
changes in chronic pain intensity measured on an 11-point numerical pain rating scale. 
Pain. 2001 Nov; 94(2):149-58. 
(2) Summary of Product Characteristics for Nurofen 200 mg tablets Reckitt Benckiser 
Healthcare Ltd. (PL 00063/0385). 09 November 2015. 
(3) Davies, NM Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin. 
Pharmacokinetic. 1998, 34 (2), 101-154. 
(4) Lisa Miles, Jessica Hall, Bartosz Jenner, Richard Addis & Simon Hutchings (2018) 
Predicting rapid analgesic onset of ibuprofen salts compared with ibuprofen acid: Tlag, 
Tlow, Tmed, and a novel parameter, TCmax Ref, Current Medical Research and 
Opinion, DOI: 10.1080/03007995.2018.1466697. 
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(5) Cooper SA, Desjardins PJ, Turk DC, et al. Research design considerations for single-
dose analgesic clinical trials in acute pain: IMMPACT recommendations. Pain. 2016 
Feb; 157(2):288-301. doi: 10.1097/j.pain.0000000000000375. 
(6) Wyeth Consumer Healthcare. (2002). NDAC Meeting on Risks of NSAIDs. Available: 
https://www.fda.gov/ohrms/dockets/ac/02/briefing/3882b2_04_wyeth-ibuprophen.htm. 
Last accessed 13th March 2018 
(7) Singla, Neil Kumar et al. “A comparison of the clinical and experimental characteristics 
of four acute surgical pain models: Dental extraction, bunionectomy, joint replacement, 
and soft tissue surgery.” PAIN® 155 (2014): 441-456. 
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Investigational Study Protocol Amendment 
Page 1 of 9 
D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
Document Name: 
Non-Substantial Protocol Amendment Number 1 
Version Number & Date: 
Version 1.0, 19-Jul-2019. 
Study Number: 
5003601 
Study Title: 
A Randomised, Double-Blind, Double-Dummy, Parallel-Group, 
Multiple-Dose, Active and Placebo Controlled Efficacy Study of 
Ibuprofen Prolonged-Release Tablets for the Treatment of Pain 
after Surgical Removal of Impacted Third Molars 
EudraCT / IND / Other 
Number: 
IND 141948 
Protocol Version 
Number: 
From: 
1.0 
To: 
2.0 
Principal Investigator 
Name: 
Todd Bertoch, MD 
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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
 
Details of Amendment: 
Amendment to Adverse Event definition (section 8.1) not affecting 
the safety of subjects, with additional administrative updates. 
Section(s) to be Changed:  
Throughout protocol 
From: 
Post-operative or Post-op or postoperative 
Pre-operative or pre-op 
To: 
Post-surgery or post-surgical 
Pre-surgery or pre-surgical 
 
Note: Also, removal of the expansion of the term 
Post-op in the footnote to Table 7.1 Schedule of 
Assessments. 
Reason for 
Change: 
To ensure consistency of terminology throughout 
the protocol. 
Section 7.3.4 Dosing 
and Post-dose 
Assessments (Hour 0 
through Hour 24), page 
48. 
From: 
Dispense/prescribe 
To: 
provide prescription for pain medication 
Reason for 
Change: 
As the site will only provide a prescription for the 
pain medication, to be used at home, and not 
provide / dispense the medication the wording 
has been updated.   
This is consistent with other sections of the 
protocol (study synopsis page 19 & 5.3 page 37). 
Table 7.1 Schedule of 
Assessments, page 44 
From: 
Dispense/ prescribe pain medication for use at 
home, as needed 
To: 
Provide prescription for pain medication 
Reason for 
Change: 
As the site will only provide a prescription for the 
pain medication, to be used at home, and not 
provide / dispense the medication the wording 
has been updated.   
7.4 Follow up Visit 
(Day 8 ± 2 days) or 
Early Termination  
and  
Table 7.1 Schedule of 
Assessments 
From: 
Section 7.4 
 Abbreviated confirmatory physical assessment, 
including an examination of the subject’s 
mouth and neck 
 Vital signs 
 Concomitant medications 
 Collect unused pain medications 
 Record any post discharge adverse events 
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Table 7.1  
‘Collect unused home pain medications, as 
needed’ 
To: 
Section 7.4 
 Abbreviated confirmatory physical assessment, 
including an examination of the subject’s 
mouth and neck 
 Vital signs 
 Concomitant medications 
 Record any post discharge adverse events 
Table 7.1 Row deleted 
Reason for 
Change: 
As pain medications are not being dispensed 
from the site they will not be returned to the site. 
Section 6.7 Laboratory 
Tests, page 40. 
From: 
The following fasting clinical laboratory tests will 
be performed at Screening. 
To: 
The following clinical laboratory tests will be 
performed at Screening. 
Reason for 
Change: 
The laboratory tests being conducted are not 
impacted by food, therefore the requirement for 
fasting has been removed to ease the 
requirements placed on subjects at screening. 
Section 8.1 Adverse 
Event Definitions, page 
49 
From: 
An adverse event (AE) is any untoward medical 
occurrence in a patient or a clinical investigation 
participant administered a pharmaceutical 
product and which does not necessarily have a 
causal relationship with the study procedure. 
To: 
An adverse event (AE) is any untoward medical 
occurrence in a patient or a clinical investigation 
participant administered a pharmaceutical 
product and which does not necessarily have a 
causal relationship with this treatment. 
Reason for 
Change: 
To ensure full alignment with ICH E2A. 
Section 8.2 
Assessment of 
Adverse Events, page 
49 
From: 
All AEs that arise after the subject has given 
informed consent will be recorded in the 
subject’s source documents and electronic case 
report forms (eCRFs). AEs can be reported 
spontaneously by the subject or in response to 
non-leading questioning or observation by the 
Investigator or be a significant laboratory 
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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
abnormality.  
 
All adverse events (AE) and all serious adverse 
events (SAEs) are collected, fully investigated 
and documented. 
To: 
Any untoward medical occurrences that arise 
after the subject has given informed consent will 
be recorded in the subject’s source documents 
and electronic case report forms (eCRFs). 
Untoward medical occurrences can be reported 
spontaneously by the subject or in response to 
non-leading questioning or observation by the 
Investigator or be a significant laboratory 
abnormality. 
 
Untoward medical occurrences, including all 
adverse events (AE) and all serious adverse 
events (SAEs) are collected, fully investigated 
and documented. 
Reason for 
Change: 
To ensure full alignment with ICH E2A. 
Study Synopsis – 
Subjects, Pages 14 - 
15 
From: 
5) Female subjects of child-bearing potential 
must be willing to use a highly effective 
method of contraception throughout the 
study. A highly effective method of birth 
control is defined as one which results in a 
low failure rate (i.e. less than 1% per year) 
when used consistently and correctly, such 
as the following: 
a. established 
use 
of 
oral, 
injected 
or 
implanted 
hormonal 
methods 
of 
contraception 
b. some 
intrauterine 
devices 
(IUDs) 
or 
intrauterine systems (IUSs) 
c. true sexual abstinence, when this is in line 
with the preferred and usual lifestyle of the 
subject 
(periodic 
abstinence 
such 
as 
calendar, ovulation, symptothermal, or post-
ovulation 
methods; 
declaration 
of 
abstinence for the duration of the trial; or 
withdrawal are not acceptable methods of 
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contraception)  
d. vasectomised partner. 
To: 
5) Female subjects of child-bearing potential 
must be willing to use a highly effective 
method of contraception throughout the 
study. A highly effective method of birth 
control is defined as one which results in a 
low failure rate (i.e. less than 1% per year) 
when used consistently and correctly, such 
as the following: 
a. Surgical sterilisation 
b. established 
use 
of 
oral, 
injected 
or 
implanted 
hormonal 
methods 
of 
contraception 
c. some 
intrauterine 
devices 
(IUDs) 
or 
intrauterine systems (IUSs) 
d. true sexual abstinence, when this is in line 
with the preferred and usual lifestyle of the 
subject 
(periodic 
abstinence 
such 
as 
calendar, ovulation, symptothermal, or post-
ovulation 
methods; 
declaration 
of 
abstinence for the duration of the trial; or 
withdrawal are not acceptable methods of 
contraception)  
e. vasectomised partner. 
Reason for 
Change: 
Consistency with section 4.2 Inclusion Criteria in 
main body of protocol. 
Inclusion Criteria 
Number 8 (Study 
Synopsis – Subjects, 
Page 15 and Section 
4.2, Page 30) 
From: 
8. 
Is willing and able to comply with study 
requirements (including diet and smoking 
restrictions), complete the pain evaluations, 
remain at the study site overnight, and return for 
follow up 7 (± 2) days after surgery. 
To: 
8. 
Is willing and able to comply with study 
requirements (including diet and smoking 
restrictions), complete the pain evaluations, 
remain at the study site overnight, and return for 
follow up 7 (± 2) days after surgery, (Day 8 ± 2 
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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
days). 
Reason for 
Change: 
To clarify the timing of the follow-up visit and 
ensure consistency with other sections of the 
protocol. 
Section 8.3, Page 51 
From: 
The out of hours emergency phone number is 
+44 (0)1482 326151. 
To: 
The out of hours emergency phone number is 
+44 (0)1482 326151.  An alternative number 
may additionally be provided by Premier 
Research to give access to the study Medical 
Monitor our of hours. 
Reason for 
Change: 
Concern from CRO that many people in the US 
do not know how to make an international call.  
Hence alternative number may be provided to 
give immediate access to the Medical Monitor at 
the CRO. 
Header 
Pages 43-45 and 
Pages 46-63 
From: 
Pages 
43-45 
Protocol Version: 07 June 2018, draft Version 10 
Pages 
46-63 
 Protocol Version: 22 August 2018, draft Version 
0.17 
To: 
Pages 
43-45 
Protocol Version: 19-July-2019, FINAL Version 
2.0 
Pages 
46-63 
Protocol Version: 19-July-2019, FINAL Version 
2.0 
Reason for 
Change: 
Correction to both document date and version. 
Exclusion Criteria 
Pages 16 & 32 
From: 
12) Previously participated in another clinical 
study of 300 mg ibuprofen PR tablets, or 
received any investigational drug, device, or 
therapy within 90 days before screening. 
To: 
12) Previously participated (randomised) in 
another clinical study of 300 mg ibuprofen 
PR tablets, or received any investigational 
drug, device, or therapy within 90 days 
before screening. 
Reason for 
Change: 
To ensure full clarity that participated does not 
include screening process. 
Section 6.16 Adverse 
Event, page 42. 
From: 
If an untoward medical occurrence happens after 
the subject has signed the consent form but 
before administration of the IMP, it should be 
reported as an adverse event, including those 
associated with study procedures. 
To: 
If an untoward medical occurrence happens after 
the subject has signed the consent form but 
before administration of the IMP, it should be 
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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
reported as an adverse event, including those 
associated with study procedures. 
 
Note this does not include any pre-existing 
medical conditions or findings associated with 
medical history which are identified during the 
screening process. 
Reason for 
Change: 
To prevent any misunderstanding that because 
the consent form has been signed, any 
conditions identified following procedures during 
screening, that in the opinion of the investigator 
are deemed to be pre-existing should not be 
reported as AEs. 
 
 
 
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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
 
SIGNATURE PAGE 
 
 
Protocol Author  
Protocol Statistician  
(Statistics and DM sections reviewed and approved):  
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Donna Reed, MA 
Date 
Principal Medical Writer 
Premier Research 
Darren Targett 
Date 
Consultant Statistician 
RB Representative 
 
 
 
 
 
Sponsor’s Medical Expert  
(Reviewed and approved): 
Sponsor’s Medical Director  
(Approved to Proceed): 
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Dr. Neil Fawkes, MBChB 
Date 
Clinical Research Physician  
RB 
Robert Eichler, PhD  
Date 
Global Medical Affairs Head, Health  
RB 
 
 
  
 
  
 
 
 
 
 
 
 
 
INVESTIGATOR APPROVAL 
DocuSign Envelope ID: AF78319B-28BB-46B4-BFBC-F4517D9E7CB2
22-Jul-2019 | 13:50:32 PM BST
22-Jul-2019 | 14:05:32 PM BST
22-Jul-2019 | 16:03:56 PM BST
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26-Jul-2019 | 08:01:20 AM PDT
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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
I have read and understood this Clinical Study Protocol Amendment 
Principal Investigator  
(Reviewed and Accepted):  
 
 
 
________________________   ____________________ 
Todd Bertoch, MD 
 Date 
Chief Scientific Officer 
JBR Clinical Research 
650 East 4500 South 
Suite 100 
Salt Lake City 
Utah, 84107 
USA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: AF78319B-28BB-46B4-BFBC-F4517D9E7CB2
DocuSign Envelope ID: 7E6D0A13-1B6F-4966-990A-4C199934BFB7
07-Aug-2019 | 07:18:33 PDT
Page 212 of 276


HlAllH • HYOll"l • HOMl 
File Note Number: 
Study Number: 
Description: 
SIGNATURE: 
NAME: 
POSITION: 
DATE: 
FIie Note Template 
Page 1 of 1 
02 
5003601 
This File Note has been created to document the fact that the 
header in Protocol v1 .0, 20-Nov-2018 contains the incorrect 
information from page 43 onwards. 
The header incorrectly 
shows draft and incorrect version numbers and dates, (see 
below) 
Pages 43-45 
• 
Protocol Version: 07 June 2018, draft Version 10 
Pages 46-63 
• 
Protocol Version: 22 August 2018, draft Version 0.17 
The information contained within those pages however is 
consistent and correct for Protocol v1 .0 20-Nov.2018. 
The headers from pages 43-63 will be corrected if an 
amendment is made to the orotocol. 
/I 
~ 
Jane Thomas 
Senior Clinical Study Manager 
\'i;-'1)Gt:...- .2c:>\~ 
D8199956 Appendix 14 - File Note Template v4.0 29-Aug-2017 
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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 20 November 2018, FINAL 
Version 1.0 
Page 1 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
RECKITT BENCKISER 
STUDY TITLE 
A Randomised, Double-Blind, Double-Dummy, Parallel-Group, Multiple-Dose, Active and 
Placebo-Controlled Efficacy Study of Ibuprofen Prolonged-Release Tablets for the Treatment of 
Pain after Surgical Removal of Impacted Third Molars 
Short Study Title 
Efficacy Study of 300mg Ibuprofen Prolonged-Release Tablets for the Treatment of Pain After 
Surgical Removal of Impacted Third Molars 
IND (Investigational New 
Drug) Number: 
141948 
RB Study Number: 
5003601 
CRO Study Number: 
RECK.177369 
Protocol Version and Date: 
FINAL V1.0 / 20-November-2018 
Previous Versions / Date(s): None 
Confidentiality Statement: 
The information contained in this document is privileged and 
confidential. Do not copy, circulate or otherwise distribute 
without written authority from Reckitt Benckiser 
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Protocol Version: 20 November 2018, FINAL 
Version 1.0 
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D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
KEY CONTACTS 
  
Name and title 
Address 
Phone  
e-mail 
Sponsor:  
RB Healthcare UK 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom  
+44 (0)1482 
326151 
5003601@rb.com 
Sponsor’s Medical 
Expert:  
Neil Fawkes 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom 
+44 (0)1482 
5833242 
neil.fawkes@rb.com 
Principal / Chief / 
Coordinating 
Investigator(s): 
Dr Todd Bertoch 
JBR Clinical 
Research 
650 East 4500 South 
Suite 100 
Salt Lake City 
Utah, 84107 
USA 
+ 1 928 
8307354 
tbertoch@jbrutah.com 
Sponsors 
Statistician: 
Darren Targett 
Dansom Lane, 
Hull, HU8 7DS 
United Kingdom 
N/A 
darren.targett@primoriscs.co.uk 
Contract Research 
Organisation: 
Premier Research 
One Park Drive, 
Suite 150 
Durham, NC 27709 
USA 
+ 1 919 627 
9100 
N/A 
CRO Project 
Manager:  
Paul Brittain 
One Park Drive, 
Suite 150 
Durham, NC 27709 
USA 
+ 1 617 934 
2233 
paul.brittain@premier-
research.com 
Clinical 
Laboratory: 
Quest Diagnostics, 
Inc. 
3489 W 2100 S, 
Suite 200,  
West Valley City, 
Utah 84119 
USA 
N/A 
N/A 
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Version 1.0 
Page 3 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
SIGNATURE PAGE 
 
 
Protocol Author  
Protocol Statistician  
(Statistics and DM sections reviewed and approved):  
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Donna Reed, MA 
Date 
Principal Medical Writer 
Premier Research 
Darren Targett 
Date 
Consultant Statistician 
RB Representative 
 
 
 
Sponsor’s Medical Expert  
(Reviewed and approved):  
Sponsor’s Medical Director  
(Approved to Proceed):  
 
 
 
 
_______________________  ___________ 
 
 
 
 
_______________________  ___________ 
Dr. Neil Fawkes, MBChB 
Date 
Clinical Research Physician  
RB  
Dr. Dalma Sugar VetD                     Date 
R&D Director, Medical  
Affairs Analgesics & Respiratory 
RB 
 
 
 
 
 
 
 
DocuSign Envelope ID: DDB76DAA-2237-49F3-89CE-2998DA12432F
21-Nov-2018 | 13:40:08 EST
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Protocol Version: 20 November 2018, FINAL 
Version 1.0 
Page 4 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
INVESTIGATOR STATEMENT 
I have read and understood this Clinical Study Protocol and agree: 
 
to conduct this clinical study in accordance with the protocol and to abide by all provisions 
of this protocol (including other manuals and documents referenced from this protocol). 
Amendments to the protocol are acceptable only upon mutual agreement with the 
exception of urgent safety measures that need to be taken to protect study subjects from 
any immediate hazard to their health and safety. 
 
to conduct this clinical study in accordance with the principles as set out in the Declaration 
of Helsinki and with International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
 
to conduct this study only after a favourable opinion is obtained from the Independent 
Review Board and Regulatory Authority 
 
to report all information or data in accordance with the protocol. 
 
to report any serious adverse events as defined in the “Safety Reporting” section of this 
protocol.  
 
to handle all clinical supplies provided by the Sponsor and collect and handle all clinical 
specimens in accordance with the protocol.  
 
I understand: 
 
that information that identifies me will be used and disclosed as described in the protocol 
and that such information may be transferred to countries that do not have laws protecting 
such information.  
 
that since the information in the protocol and the references in the Investigator's brochure 
(if applicable) are confidential, its disclosure to any third parties, other than those involved 
in approval, supervision or conduct of the study is prohibited. I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent 
disclosure or access by third parties. 
 
Principal Investigator  
(Reviewed and Accepted):  
 
________________________   ____________________ 
Todd Bertoch, MD 
  Date 
Chief Scientific Officer 
JBR Clinical Research 
 
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D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
TABLE OF CONTENTS 
KEY CONTACTS .................................................................................................................. 2 
SIGNATURE PAGE .............................................................................................................. 3 
INVESTIGATOR STATEMENT ............................................................................................. 4 
TABLE OF CONTENTS ........................................................................................................ 5 
LIST OF ABBREVIATIONS ..................................................................................................10 
STUDY SYNOPSIS ..............................................................................................................12 
1 
BACKGROUND AND RATIONALE ....................................................................22 
1.1 
Background for the Study and Rationale ........................................................22 
1.2 
Investigational Product ...................................................................................22 
1.3 
Treatment Rationale ......................................................................................23 
1.4 
Study Population and Indication .....................................................................23 
1.5 
Non-Clinical Evidence ....................................................................................23 
1.6 
Clinical Evidence to Date ...............................................................................24 
1.7 
Risks / Benefits ..............................................................................................24 
1.8 
Ethical Conduct of the Study ..........................................................................25 
2 
STUDY OBJECTIVES .......................................................................................26 
3 
STUDY DESIGN AND RATIONALE FOR DESIGN ............................................26 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................30 
4.1 
Study Population ............................................................................................30 
4.2 
Inclusion Criteria ............................................................................................30 
4.3 
Exclusion Criteria ...........................................................................................31 
4.4 
Subjects of Reproductive Potential ................................................................32 
4.5 
Discontinuation / Withdrawal and Replacement of Subjects ...........................32 
5 
STUDY TREATMENT ........................................................................................33 
5.1 
Investigational Products .................................................................................33 
5.2 
Non-Investigational Products .........................................................................36 
5.3 
Permitted Therapies .......................................................................................36 
5.4 
Treatment Compliance ...................................................................................37 
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5.5 
Packaging and Labelling and Supply / Resupply ............................................37 
5.6 
Storage Conditions ........................................................................................37 
5.7 
Blinding ..........................................................................................................38 
5.8 
Emergency Unblinding Procedures ................................................................38 
5.9 
Drug Accountability ........................................................................................39 
5.10 
Return and Destruction ..................................................................................39 
6 
STUDY PROCEDURES BY VARIABLE .............................................................39 
6.1 
Informed Consent ..........................................................................................39 
6.2 
Randomisation ...............................................................................................39 
6.3 
Drug Administration .......................................................................................39 
6.4 
Demographics ................................................................................................40 
6.5 
Medical History and Concomitant Medication .................................................40 
6.6 
Physical Examination .....................................................................................40 
6.7 
Laboratory Tests ............................................................................................40 
6.8 
Electrocardiograms ........................................................................................41 
6.9 
Vital Signs ......................................................................................................41 
6.10 
Blood Sampling ..............................................................................................41 
6.11 
Oral Radiography ...........................................................................................41 
6.12 
Pain Intensity .................................................................................................41 
6.13 
Stopwatch Assessment ..................................................................................41 
6.14 
Pain Relief Scale ...........................................................................................42 
6.15 
Subject’s Global Evaluation of Study Drug .....................................................42 
6.16 
Adverse Events ..............................................................................................42 
7 
STUDY PROCEDURES BY VISIT .....................................................................42 
7.1 
Study Flow Chart / Table of Study Procedures and Assessments ..................42 
7.2 
Screening Visit (Day -28 to Day -1) ................................................................46 
7.3 
Day of Surgery (Day 1) ..................................................................................46 
 
Pre-Surgery................................................................................................46 
 
Surgery ......................................................................................................47 
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Post-surgery Eligibility Assessments and Randomisation ...........................47 
 
Dosing and Post-dose Assessments (Hour 0 through Hour 24) .................47 
7.4 
Follow-up Visit (Day 8 ± 2 days) or Early Termination ....................................48 
7.5 
Unscheduled Visits ........................................................................................48 
7.6 
Study Restrictions ..........................................................................................48 
 
Prohibited Therapies ..................................................................................48 
 
General and Dietary Restrictions ................................................................48 
8 
SAFETY REPORTING .......................................................................................49 
8.1 
Adverse Event Definitions ..............................................................................49 
8.2 
Assessment of Adverse Events ......................................................................49 
8.3 
Reporting of Adverse Events .........................................................................51 
8.4 
Follow-up of Adverse Events .........................................................................52 
8.5 
Overdose, Abuse, Misuse and Medication Errors ..........................................52 
8.6 
Pregnancy .....................................................................................................53 
9 
STATISTICAL CONSIDERATIONS ...................................................................53 
9.1 
Determination of Sample Size ........................................................................53 
9.2 
Interim Analysis .............................................................................................53 
9.3 
Analysis Datasets ..........................................................................................53 
9.4 
Subject Disposition and Characteristics .........................................................54 
9.5 
Efficacy Analyses ...........................................................................................54 
 
Primary Endpoint(s) ...................................................................................54 
9.5.1.1 
Primary Analysis .....................................................................................54 
9.5.1.2 
Secondary Analysis ................................................................................54 
 
Secondary Endpoints .................................................................................55 
9.5.2.1 
Secondary Endpoint Analyses ................................................................55 
9.6 
Safety Analyses .............................................................................................56 
 
Safety Endpoint(s)......................................................................................56 
9.6.1.1 
Safety Endpoint Analyses .......................................................................56 
9.7 
Handling of Missing Data and Drop-outs ........................................................57 
9.8 
Changes to the Original Statistical Plan .........................................................57 
10 
DATA HANDLING AND RECORD KEEPING ....................................................57 
10.1 
Case Report Forms (CRFs) ...........................................................................57 
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10.2 
Specification of Source Documents ...............................................................58 
10.3 
Data Management .........................................................................................58 
10.4 
Reporting of Protocol Deviations ....................................................................58 
10.5 
Retention of Essential Documentation ...........................................................58 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ..........................................59 
11.1 
Monitoring ......................................................................................................59 
11.2 
Audits and Inspections ...................................................................................59 
11.3 
Sponsor Policy on Fraud in Clinical Studies ...................................................60 
12 
ETHICAL AND REGULATORY ASPECTS ........................................................60 
12.1 
Ethics Review and Regulatory Authority Approval..........................................60 
12.2 
Subject Information and Consent ...................................................................60 
12.3 
Early / Premature Termination of the Study ...................................................61 
13 
COMPENSATION, INDEMNITY AND INSURANCE ..........................................61 
13.1 
Clinical Study Agreement ...............................................................................61 
13.2 
Compensation ................................................................................................61 
13.3 
Indemnity .......................................................................................................62 
13.4 
Insurance .......................................................................................................62 
14 
REPORTING, PUBLICATION AND PRESENTATION .......................................62 
15 
REFERENCES ..................................................................................................62 
 
List of Tables Contained in the Body of the Protocol 
Table 3-1 Study Objectives and Endpoints ...........................................................................27 
Table 3-2 Treatment Regimens ............................................................................................29 
Table 5-1 Active Test Product ..............................................................................................33 
Table 5-2 Placebo for Test Product ......................................................................................34 
Table 5-3 Comparator Product .............................................................................................35 
Table 5-4 Placebo for Comparator Product ..........................................................................35 
Table 7-1 Schedule of Assessments ....................................................................................43 
Table 8-1 AE Relationship Descriptions ...............................................................................50 
Table 8-2 AE Severity Descriptions ......................................................................................50 
 
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List of Figures Contained in the Body of the Protocol 
Figure 3.1 Study Design Schematic ......................................................................................27 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Abbreviation in Full 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Plasma Concentration Curve 
BID 
Twice Daily 
BMI 
Body Mass Index 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
eCRF 
Electronic Case Report Form 
FDA 
(US) Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GVG 
Global Vigilance Group 
HDL 
High Density Lipoprotein 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric Rating Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OTC 
Over the Counter 
PID 
Pain Intensity Difference 
PP 
Per Protocol 
PR 
Prolonged Release 
RB 
Reckitt Benckiser 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SNRI 
Serotonin and Noradrenaline Reuptake Inhibitor 
SPID 
Summed Pain Intensity Difference 
SPRID 
Summed Pain Relief and Intensity Difference 
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Abbreviation 
Abbreviation in Full 
SSRI 
Selective Serotonin Reuptake Inhibitor 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent Adverse Event 
TID 
Three Times a Day 
Tmax 
Time to Maximum Plasma Concentration 
TOTPAR 
Sum of Total Pain Relief 
WOCF 
Worst Observation Carried Forward 
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STUDY SYNOPSIS 
Study Title: 
A randomised, double-blind, double-dummy, parallel-group, multiple-
dose, active and placebo-controlled efficacy study of ibuprofen 
prolonged-release tablets for the treatment of pain after surgical 
removal of impacted third molars 
RB Study 
Number: 
5003601 
Background and 
Rationale: 
Reckitt Benckiser (RB) is co-developing a new 300 mg ibuprofen 
prolonged release (PR) tablet with Strides Shasun Ltd. The product 
has been developed to meet consumer and patient needs to have 
access to longer acting over-the-counter analgesics. This PR 
formulation will reduce fluctuations in drug plasma concentrations and 
allow for a lower frequency of administration which is desirable in 
situations where pain duration is expected to be prolonged and require 
multiple doses of immediate release formulations. As a result, the 
product would be more consumer friendly, require less dosing and 
improve compliance with treatment. 
The proposed therapeutic indications of the PR product are for the 
short-term symptomatic treatment of mild to moderate pain such as 
dysmenorrhea, rheumatic pain, muscular pain, pain of non-serious 
arthritic conditions and backache. 
The proposed posology in adults over the age of 18 is: 
Ibuprofen 300 mg PR tablets.  Two tablets to be taken every 12 hours 
when required for pain relief. No more than 2 doses in 24 hours. The 
maximum daily dose is 1200 mg and there is no proposed indication in 
the paediatric population. 
 
Therefore, the purpose of the proposed study is to provide supporting 
pivotal efficacy evidence for registration applications in Europe, 
Australia and Russia. The decision to progress to an efficacy clinical 
trial was determined on the basis of successful outcomes of the 2 
phase 1 clinical trials (BE/17/279 and BE/17/281) in terms of 
bioavailability (BA) versus a reference ibuprofen immediate release 
(IR) product and bioequivalence (BE) versus comparator 600 mg 
ibuprofen PR. 
Objectives:  
Primary Objective:  
 
To evaluate the superiority of 2×300 mg ibuprofen PR tablets 
compared with placebo in subjects experiencing acute 
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moderate to severe pain after third molar extraction over 
12 hours post initial dose. 
Key Secondary Objectives: 
 
To evaluate the analgesic performance of a total daily dose of 
1200 mg of ibuprofen PR formulation compared to ibuprofen 
immediate release (IR) formulation over 24 hours post initial 
dose. 
 
To evaluate the safety and tolerability of 2×300 mg ibuprofen 
PR tablets. 
Additional Secondary Objectives: 
 
To evaluate the total analgesic effect, peak analgesic effect, 
onset and duration of action and the subject’s overall 
assessment of the study medications. 
Design: 
This is a single centre, randomised, double-blind, double-dummy, 
parallel group, multiple-dose, active and placebo-controlled efficacy 
study to evaluate the efficacy and safety of 2×300 mg ibuprofen PR 
tablets in subjects with postoperative dental pain. 
Primary 
Endpoint: 
The Summed Pain Intensity Difference (SPID) over 0 to 12 hours 
(SPID12) will be used to compare the test product (2×300 mg ibuprofen 
PR tablets) against the placebo product. 
Confirmatory 
Evaluation: 
Clinically relevant difference between placebo and PR ibuprofen over 
12 hours after initial dose (for the purposes of this study, a difference 
of 30 % in PID scores over 12 hours after initial dose will be considered 
clinically relevant).(1)  
Secondary 
Endpoints: 
Key secondary efficacy endpoint: 
 
The summed pain intensity difference (SPID) over 0 to 
24 hours (SPID24) will be used to compare the test product 
(2×300 mg ibuprofen PR tablets twice daily [BID]) and active 
comparator product (2×200 mg ibuprofen IR tablets three times 
a day [TID]). 
Efficacy endpoints: 
 
Summed pain intensity difference (SPID) over 0 to 4 hours 
(SPID4), over 0 to 8 hours (SPID8), and over 0 to 12 hours 
(SPID12) after Time 0 
 
Sum of total pain relief (TOTPAR) over 0 to 4 hours 
(TOTPAR4), over 0 to 8 hours (TOTPAR8), over 0 to 12 hours 
(TOTPAR12), and over 0 to 24 hours (TOTPAR24) after Time 0 
 
Summed pain relief and intensity difference (sum of TOTPAR 
and SPID [SPRID]) over 0 to 4 hours (SPRID4), over 0 to 
8 hours (SPRID8), over 0 to 12 hours (SPRID12), and over 0 to 
24 hours (SPRID24) after Time 0 
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 
Response to study drug (a responder will be defined as a 
subject with ≥30 % improvement in pain intensity without 
rescue medication during the first 8 hours) 
 
Numeric rating scale (NRS) pain intensity difference (PID) at 
each scheduled time point after Time 0 
 
Pain intensity score at each scheduled time point 
 
Pain relief score at each scheduled time point after Time 0 
 
Peak pain relief 
 
Time to onset of analgesia (measured as time to perceptible 
pain relief confirmed by time to meaningful pain relief) using 
double stopwatch 
 
Time to first perceptible pain relief 
 
Time to meaningful pain relief 
 
Time to peak pain relief 
 
Proportion of subjects using rescue medication 
 
Time to first use of rescue medication 
Exploratory endpoint: 
 
Patient’s global evaluation of study drug 
Safety 
Endpoints: 
 
Incidence of treatment-emergent adverse events (TEAEs) 
 
Incidence of clinically relevant changes in vital sign 
measurements 
Subjects: 
Inclusion Criteria 
A subject will be eligible for study entry if all the following inclusion 
criteria are met: 
1) Is male or female ≥ 18 and ≤ 50 years of age. 
2) Requires extraction of 2 or more third molars. At least 1 of the third 
molars must be a fully or partially bone impacted mandibular molar. 
If only 2 molars are removed, then they must be ipsilateral. 
3) Experiences moderate to severe pain intensity within 6 hours after 
surgery, as measured by a numeric rating scale (NRS) score of ≥ 5 
on a 0-10 scale. 
4) Has a body weight ≥ 45 kg and a body mass index (BMI) 
≤ 35 kg/m2. 
5) Female subjects of child-bearing potential must be willing to use a 
highly effective method of contraception throughout the study. A 
highly effective method of birth control is defined as one which 
results in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly, such as the following: 
a. established use of oral, injected or implanted hormonal 
methods of contraception 
b. some intrauterine devices (IUDs) or intrauterine systems (IUSs) 
c. true sexual abstinence, when this is in line with the preferred 
and usual lifestyle of the subject (periodic abstinence such as 
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calendar, ovulation, symptothermal, or post-ovulation methods; 
declaration of abstinence for the duration of the trial; or 
withdrawal are not acceptable methods of contraception)  
d. vasectomised partner. 
To be considered not of child-bearing potential, females must be 
surgically sterile (defined as bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy) or post-menopausal (defined as 
no menses for 12 months in women not using hormonal 
contraception or hormone replacement therapy, confirmed by a 
follicle stimulating hormone [FSH] level in the postmenopausal 
range at Screening). 
6) Free of clinically significant abnormal findings as determined by 
medical history, physical examination, vital signs, laboratory tests 
and ECG. 
7) Is able to provide written informed consent. 
8) Is willing and able to comply with study requirements (including diet 
and smoking restrictions), complete the pain evaluations, remain 
at the study site overnight, and return for follow-up 7 (± 2) days 
after surgery. 
Exclusion Criteria 
A subject will not be eligible for study entry if any of the following 
exclusion criteria are met: 
1) Known hypersensitivity reactions or allergy (e.g. asthma, rhinitis, 
angioedema or urticaria) in response to nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen), acetylsalicylic 
acid (aspirin), ingredients of the study drug, or any other drugs 
used in the study, including anaesthetics and antibiotics that may 
be required on the day of surgery. 
2) A history of active or previous peptic ulceration/ haemorrhage, 
gastrointestinal bleeding or perforation, heart failure, renal or 
hepatic failure, uncontrolled hypertension, asthma, nasal polyps, or 
chronic rhinitis. 
3) Has complications from the tooth extraction or any other clinically 
significant medical history that, in the opinion of the investigator, 
would affect the subject’s ability to comply or otherwise 
contraindicate study participation, including but not limited to the 
following: cardiac, respiratory, gastroenterological, neurological, 
psychological, immunological, haematological, oncological, or 
renal disease. 
4) Has undergone another dental surgery within 60 days prior to the 
day of surgery. 
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5) A positive urine drugs of abuse screen or alcohol breathalyser test 
at screening and during the study (with the exception of a positive 
drugs of abuse screen that is a consequence of permitted 
prescription medicines). 
6) If female, has a positive pregnancy test at screening (serum) or on 
the day of surgery prior to surgery (urine), or is lactating. 
7) Has known or suspected, (in the opinion of the investigator), history 
of alcoholism or drug abuse within 2 years of screening or evidence 
of tolerance or physical dependence before dosing with study drug. 
8) Taking any concomitant medications that might confound 
assessments of pain relief, such as psychotropic drugs, 
antidepressants, sedative-hypnotics (other than those permitted for 
conscious sedation), or other analgesics taken within five times of 
their elimination half-lives. Selective serotonin reuptake inhibitors 
(SSRIs) and serotonin and noradrenaline reuptake inhibitors 
(SNRIs) are permitted if the subject has been on a stable dose for 
at least four weeks prior to Visit 1 (screening). 
9) Is considered by the investigator, for any reason (including, but not 
limited to the risks described as precautions, warnings and 
contraindications in the current version of the investigator’s 
brochure for 300 mg ibuprofen PR tablets), to be an unsuitable 
candidate to receive the study drug. 
10) Has a history of chronic use (defined as daily use for > 2 weeks) of 
nonsteroidal 
anti-inflammatory 
(NSAIDs), 
opiates, 
or 
glucocorticoids (except inhaled nasal steroids and topical 
corticosteroids), for any condition within 6 months before dosing 
with study drug.  
11) Has significant difficulties swallowing capsules or tablets or is 
unable to tolerate oral medication. 
12) Previously participated in another clinical study of 300 mg 
ibuprofen PR tablets, or received any investigational drug, device, 
or therapy within 90 days before screening. 
13) Enrolment of the Investigator, his / her family members, employees 
and other dependent persons. 
14) Failure to satisfy the investigator of fitness to participate for any 
other reason. 
Products to be 
Evaluated and 
Treatment 
Regimen: 
Test product:  
 
300 mg ibuprofen PR tablets for oral administration 
Reference products:  
 
200 mg ibuprofen IR tablets for oral administration 
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 
Placebo (for blinding purposes, two types of placebo tablets will 
be made; one to look like the test product and one to look like 
the reference product) 
Treatment regimens: 
Eligible subjects meeting all study entry criteria will be randomised to 
receive 1 of the following treatments: 
 
Treatment A: test product; 2×300 mg ibuprofen PR tablets, BID 
(total daily dose 1200 mg) 
 
Treatment B: reference product; 2×200 mg ibuprofen IR 
tablets, TID (total daily dose 1200 mg) 
 
Treatment C: matching placebo tablets 
Methodology: 
This is a single centre, randomised, double blind, double-dummy, 
parallel group-, multiple-dose, active and placebo controlled efficacy 
study to evaluate the efficacy and safety of ibuprofen 2×300 mg 
ibuprofen PR tablets in subjects with postoperative dental pain. 
Eligible subjects will complete all screening procedures within 28 days 
before the surgery and randomisation. 
At Screening, subjects will provide written informed consent to 
participate in the study before any protocol specified procedures or 
assessments are completed. On Day 1, subjects who continue to be 
eligible for study participation after completing screening procedures 
and assessments will undergo extraction of 2 or more third molars. At 
least 1 of the third molars must be a fully or partially bone impacted 
mandibular molar. If only 2 molars are removed, then they must be 
ipsilateral. 
All subjects will receive local anaesthesia (2% lidocaine with 
1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion 
of the investigator. Subjects who experience moderate to severe pain 
intensity (a score of ≥ 5 on a numeric rating scale [NRS] from 0-10 
where 0 = no pain, 10 = worst pain ever) within 6 hours after surgery 
and who continue to meet all study entry criteria will be randomised in 
a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets every 12 hours 
(Q12h), 2×200 mg ibuprofen IR tablets every 8 hours (Q8h), or 
placebo. The randomisation will be stratified by baseline pain category 
(moderate or severe) using a categorical scale that includes the 
categories of none (0), mild (1-4), moderate (5-7), and severe (8-10).  
Subjects will re-assess their baseline pain intensity using the NRS 
immediately before receiving study drug (pre-dose, Time 0) and their 
pain intensity (NRS) and pain relief (5-point categorical scale) at the 
following time points (pre-dose, if at one of the dosing timepoints of 0, 
8, 12 and/or 16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 
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6, 7, 8, 10, 12, 16, and 24 hours after Time 0; and immediately before 
each dose of rescue medication, if any. For assessments less than 
1 hour apart a window of +/-2 min is allowable whilst for assessments 
at least 1 hour apart a +/-5 min window is allowable. 
The double stopwatch method will be used to record the time to 
perceptible pain relief and time to meaningful pain relief during the 
8 hours following the first dose or until subject takes rescue 
medication. Subjects will complete a global evaluation of study drug 
24 hours (+/- 5 minutes) after Time 0 or immediately before the first 
dose of rescue medication (whichever occurs first). Vital signs will be 
recorded after the subject has been in a sitting position for 3 minutes 
at the following times: before surgery, within 30 minutes before Time 0, 
12 and 24 hours after Time 0, and/or immediately before the first dose 
of rescue medication. Adverse events (AEs) will be monitored and 
recorded from the time of signing of the informed consent form (ICF) 
until the Follow up- Visit (or Early Termination Visit). During the 
24 hours following Time 0, subjects will complete efficacy and safety 
assessments. Subjects will remain at the study site overnight and will 
be discharged on Day 2.  
Paracetamol / acetaminophen (1000 mg) will be permitted as the initial 
rescue medication. Subjects will be encouraged to wait at least 
60 minutes after receiving study drug before taking rescue medication. 
If acetaminophen rescue medication is not effective in relieving the 
subject’s pain, 5 mg oxycodone rescue medication may be 
administered at the discretion of the investigator. 
Subjects are not permitted to take any concomitant medications that 
might confound assessments of pain relief, such as psychotropic 
drugs, antidepressants, sedative-hypnotics (other than those permitted 
for conscious sedation), or other analgesics taken within five times of 
their elimination half-lives (other than those used at the surgery). 
Selective serotonin reuptake inhibitors (SSRIs) and serotonin and 
noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject 
has been on a stable dose for at least four weeks prior to Visit 1 
(screening).  
Other restrictions include the following: alcohol use is prohibited from 
24 hours before surgery until discharge on Day 2; nothing by mouth 
from midnight before surgery until 1 hour after surgery; clear liquids 
only are allowed starting 1 hour after surgery until 1 hour after dosing; 
1 hour after dosing, the subject’s diet may be advanced according to 
standard practice. 
Upon discharge from the study site, subjects may be prescribed pain 
medication for use at home according to the standard practice of the 
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study site. On Day 8 (± 2 days), subjects will return to the study site for 
an 
abbreviated 
confirmatory 
physical 
assessment 
and 
AE 
assessments. 
Statistical 
Evaluation: 
Analysis Populations 
The analysis populations include the following: 
 
The intent-to-treat (ITT) population will consist of all subjects 
who are treated with study drug and who have at least 1 pain 
relief assessment after Time 0. The ITT population is the 
primary population for the efficacy analysis. 
 
The per protocol- (PP) population will consist of all ITT subjects 
who do not incur a major protocol violation that would challenge 
the validity of their data. This population will be utilized to 
evaluate the sensitivity of the primary efficacy analysis. 
 
The safety population will include all subjects who are treated 
with study drug. The safety population is the population for all 
safety assessments. 
Subject Characteristics 
Demographic and baseline characteristics (including date of birth, sex, 
race, weight, height, BMI and medical history) will be summarized for 
each treatment group and for the overall population using descriptive 
statistics. No formal statistical analyses will be performed. 
Efficacy Analyses 
The primary efficacy null hypothesis is that SPID12 for placebo is equal 
to SPID12 for ibuprofen 2×300 mg PR tablets. The primary analysis 
will be an ANCOVA (Analysis of Covariance) model that includes the 
main effect of treatment and the baseline pain score as a covariate and 
will use windowed worst observation carried forward (WOCF) 
imputation for subjects who use rescue medication. The primary 
analysis will be based on a 2-sided test at the significance level of 0.05. 
All other comparisons between the treatment regimens, including 
ibuprofen 2×200 mg IR tablets versus placebo, will be considered 
secondary. No P value adjustment will be made for multiple endpoints 
or multiple comparisons. 
Each efficacy endpoint will be summarized descriptively by treatment 
group. 
For continuous secondary endpoints such as pain intensity score, 
SPID at each scheduled time point, peak pain intensity, TOTPAR4, 
TOTPAR8, TOTPAR12, TOTPAR24, SPID4, SPID8, SPID24, 
SPRID4, SPRID8, SPRID12, and SPRID24, descriptive statistics 
(such as mean, standard deviation, median, minimum, and maximum) 
will be provided for each treatment regimen. Nominal P values from 
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ANCOVA models comparing the placebo group with other treatment 
groups, including terms for treatment and baseline pain will be 
provided for SPID, SPRID, and TOTPAR variables, but no formal 
statistical inferences will be drawn on the basis of these tests. 
For ordinal secondary endpoints, such as pain intensity difference at 
each scheduled time point, pain relief at each scheduled time point, 
peak pain relief, response to study drug, and global evaluation of study 
drug, descriptive summaries will be provided and will include the 
number and percentage of subjects within each category for each 
treatment group. Nominal P values from Fisher’s exact tests (or 
chi-square- tests, as appropriate) comparing the placebo group with 
other treatment groups will be provided for peak pain relief and global 
evaluation of study drug, but no formal statistical inferences will be 
drawn on the basis of these tests. For each time to- event endpoint, 
Kaplan Meier methodology will be used to evaluate the treatment 
effect. Time to onset of analgesia (measured as time to perceptible 
pain relief confirmed by meaningful pain relief) will be based on data 
collected using the double stopwatch method. Time to onset of 
analgesia will be -right censored- at 8 hours for subjects who do not 
experience both perceptible pain relief and meaningful pain relief 
during the 8-hour interval after Time 0. For time to onset of analgesia, 
the comparison of interest will be the ibuprofen 2×300 mg PR group 
versus the ibuprofen 2×200 mg IR group. The summary tables will 
provide the number of subjects analysed, the number of subjects 
censored, estimates for the quartiles, and 95% confidence intervals 
(CIs) for the estimated median and the restricted mean estimate. 
P values from the Wilcoxon or log rank- tests (as appropriate) will also 
be used to compare placebo to the active treatments. 
For the responder analysis and the proportion of subjects using rescue 
medication, logistic regression models that adjust for baseline intensity 
and/or significant demographic variables, if appropriate, will be used to 
evaluate the treatment effect. 
Baseline values are defined as the last measurements taken before 
dosing with a study drug. 
Missing pain assessments for all efficacy analyses will be handled as 
follows: 
 
Missing pain assessments scheduled before the first observed 
assessment will be imputed with the subject’s worst observed 
pain assessment. 
 
Missing intermediate pain assessments will be replaced by 
linear interpolation. 
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 
Missing pain assessments at the end of the observation period 
due to premature discontinuation of pain assessments will be 
imputed by carrying forward the last observation prior to that 
missing. 
The primary analysis will use windowed worst observation carried 
forward (WOCF) methodology for subjects who use rescue medication. 
Any pain measurements taken during a period of time in which rescue 
medication is active (4 hours) will be replaced by the last pain 
measurement before the rescue medication was taken. A sensitivity 
analysis will also be performed, in which all pain assessments 
recorded after the first dose of rescue medication has been taken will 
be disregarded and the rules outlined above will be used for missing 
data. 
All data for assessments other than pain assessments will be analysed 
as collected; missing data due to premature termination or any other 
reason will be left as missing. 
Safety Analysis 
Data listings will be provided for protocol-specified safety data. The 
Medical Dictionary for Regulatory Activities (MedDRA) (Version 19.0 
or higher) will be used to classify all AEs with respect to system organ 
class and preferred term. Adverse event summaries will include only 
TEAEs, which will be summarized for each treatment group.  
For vital sign measurements, descriptive statistics will be provided at 
each scheduled time point for each treatment group. Changes from 
Baseline for vital signs will be calculated for each subject, and 
descriptive statistics will be provided on changes in vital signs from 
Baseline for each treatment group at each scheduled time point after 
Baseline. No formal statistical tests will be performed. 
 
 
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1 
BACKGROUND AND RATIONALE 
1.1 Background for the Study and Rationale 
Reckitt Benckiser (RB) is co-developing a new 300 mg ibuprofen prolonged release (PR) tablet 
with Strides Shasun Ltd. The product has been developed to meet consumer and patient needs 
to have access to longer acting over-the-counter analgesics. This PR formulation will reduce 
fluctuations in drug plasma concentrations and allow for a lower frequency of administration 
which is desirable in situations where pain duration is expected to be prolonged and require 
multiple doses of immediate release formulations. As a result, the product would be more 
consumer friendly, require less dosing and improve compliance with treatment. 
The proposed therapeutic indications of the PR product are for the short-term symptomatic 
treatment of mild to moderate pain such as dysmenorrhea, rheumatic pain, muscular pain, pain 
of non-serious arthritic conditions and backache. 
The proposed posology in adults over the age of 18 is: 
Ibuprofen 300 mg PR tablets.  Two tablets to be taken every 12 hours when required for pain 
relief. No more than 2 doses in 24 hours. The maximum daily dose is 1200 mg and there is 
no proposed indication in the paediatric population. 
 
Therefore, the purpose of the proposed study is to provide supporting pivotal efficacy evidence 
for European, Russian, and Australian applications and not to support any application in the 
USA. This efficacy study will provide further evidence on the safety and efficacy of the product 
in addition to the data obtained in two bioequivalence studies BE/17/279 and BE/17/281. 
1.2 Investigational Product 
Ibuprofen [2-(4-isobutylphenyl) propionic acid] is a non-steroidal anti-inflammatory drug 
(NSAID) with anti-inflammatory, analgesic and anti-pyretic properties(2). It was initially available 
in 1969 as a prescription only medicine, indicated for rheumatoid arthritis, osteoarthritis and 
other chronic painful conditions such as ankylosing spondylitis. Following further research and 
the establishment of a reassuring safety profile, it was launched in 1983 as an over-the-counter 
(OTC) medication, marketed as Nurofen®. 
Absorption of ibuprofen after oral administration is fairly rapid with peak serum concentrations 
occurring within 1 to 2 hours after administration. Ibuprofen is extensively bound to plasma 
proteins (99%) when administered at therapeutic levels and has a plasma half-life of about 
2 hours. Excretion by the kidney is both rapid and complete, but only a small proportion of drug 
is excreted unchanged in urine, the majority being extensively metabolised in the liver to 
2 major inactive metabolites. The pharmacokinetics of ibuprofen has been extensively 
reviewed by Davies(3). 
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1.3 Treatment Rationale 
The treatment of the test product is in line with the proposed posology of the final product and 
the treatment of the active comparator is in line with the posology provided in the label of the 
product. The treatments will be administered orally, as this is the standard route of 
administration for these products. 
 
The following are the treatment regimens of each product in the study: 
 
Treatment A: test product, 2x300 mg PR ibuprofen tablet, twice daily [total daily dose 
1200 mg] 
 
Treatment B: reference product, 2x200 mg IR ibuprofen tablet, three times a day [total 
daily dose 1200 mg] 
 
Treatment C: matching placebo tablets for both the test and reference regimens 
 
The active comparator (Treatment B) currently marketed in a number of geographies including 
a number of different European countries.  It has therefore been chosen to fulfil requirements 
that when it is included in a marketing authorisation dossier as a comparator that it is licenced 
within the EU.     
 
1.4 Study Population and Indication 
The following study population will be invited to participate in this clinical trial: 
Adult participants aged 18 to 50 requiring extraction of 2 or more third molars, at least 1 of 
which must be a fully or partially bone-impacted mandibular molar, (if only 2 molars are 
removed, then they must be ipsilateral), and who experience moderate to severe pain following 
surgery. 
Such population is expected to present pain levels that will allow for assessing the magnitude 
of treatment effect in a low variability setting. 
 
1.5 Non-Clinical Evidence 
No non-clinical evidence is available for the PR tablet.   
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1.6 Clinical Evidence to Date 
A total of 5 single and multiple-dose pharmacokinetic studies (139-15, BE-16-081, BE-16-295, 
BE-17-279, BE-17-281) have been performed with the test product.  These studies 
demonstrated the oral bioavailability (BA) of the ibuprofen PR tablets (dosed at 2x300 mg) is 
comparable to Brufen® (Ibuprofen) IR Tablets (dosed at 3x200 mg) after a single dose and at 
steady state conditions.  In terms of the release profile and absorption, Cmax tends to be slightly 
higher in the IR formulation when compared with the PR formulation [21.96 ±3.87 µg/mL vs 
14.51 ±3.1 µg/mL].  However the Cmax, (Maximum Observed Plasma Concentration), Tmax, 
(Time to Maximum Plasma Concentration) and AUC0-Tmax (Area Under the Plasma 
Concentration Curve) of the PR formulation suggest that’s the onset of action should not be 
any slower than the IR reference when considering the minimum effective concentration of 
ibuprofen(4).  In terms of total exposure (AUC0-∞) the concentration profile is bioequivalent 
between the PR test product and the IR reference product [163.41 ±43.0 µg.h/mL vs 168.59 
±37.7 µg.h/mL].  A food effect is demonstrated when the test product is taken in the fed state, 
with an expected increase in the absorption rate. 
In the 5 PK studies performed (over 200 subjects) only a limited number of mild, transient 
adverse events were reported.   
Summary Outcomes: 
 
The Clinical data available for this reformulation (Ibuprofen 300 mg PR) suggests an 
adequate pharmacokinetic profile to achieve a sufficient therapeutic effect in the 
proposed study 
 
There are no safety concerns with the test product 
 
Ibuprofen 300 mg PR had an increased rate of absorption when administered with food. 
 
Ibuprofen 300 mg PR tablets had a comparable concentration profile to the comparator 
IR product and was bioequivalent based on AUC0-∞ 
 
1.7 Risks / Benefits 
This study has been designed to confirm the therapeutic efficacy of ibuprofen 300 mg PR.  
Participants in this study are subjects aged 18-50 who require the extraction of 2 or more third 
molars, at least 1 of which must be a fully or partially bone impacted mandibular molar.  
Subjects will undergo dental surgery that is equivalent to that of the standard-of-care that would 
be expected for the above condition. They should be otherwise healthy and each subject 
will undergo a full health check as part of the enrolment into the study to confirm that they 
are healthy as defined in this protocol (see Section 4). 
Participants randomised into the placebo arm would not be expected to derive any therapeutic 
benefit from the administration of the placebo tablets. The placebo arm is essential to the study 
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design as it ensures that any conclusion of non-inferiority from the trial is a reflection of the 
true properties of the treatments; that is, it demonstrates the assay sensitivity of the study.  
However, this obviously leaves the participants without adequate analgesia in the post-
operative procedure and from an ethical perspective this is mitigated in the study design by 
the use of rescue medication that would be in line with standards of treatment. Although it is 
hypothesised that the investigational medicinal product (IMP) will provide adequate analgesia 
in the study, this cannot be guaranteed, and therefore the use of rescue medication also 
addresses the potential of reduced or lack of efficacy. 
Ibuprofen is an established pharmaceutical ingredient and the adverse reactions associated 
with administration of 1200 mg/24 hour (OTC doses) are well known and documented(2)(5).  The 
adverse reactions most frequently occurring with a single dose being nausea, gastrointestinal 
upset, vomiting, diarrhoea, light headedness, dizziness and headache. Rarely, more serious 
reactions have been reported including GI bleeding, ulceration and perforations, hypertension 
and renal failure. When OTC doses of ibuprofen (200-400 mg/dose; 1200 mg/day) are taken 
for acute episodes of pain there is an extremely low risk of causing serious gastrointestinal 
events(5).  
The specific 200mg Ibuprofen tablet to be used in this study as the active comparator 
(Treatment B) is marketed in the EU under the Nurofen brand and has an excellent safety 
profile.   
It is not anticipated that the safety profile of ibuprofen will be altered after administration of 
multiple single doses of ibuprofen 300 mg PR in the context of this study.  There are not 
expected to be any drug-drug interactions with the non-investigational medicinal products 
included within the study design. A washout period of at least 6 days is deemed to be sufficient 
prior to the Follow-up/Early Termination Visit to ensure adequate safety monitoring of the IMP. 
The investigation site will have adequate set up, experience and safety measures that would 
be expected of a centre able to perform regular molar extractions. They will also have adequate 
experience in the safety monitoring of participants post dose that would be expected in a 
clinical trial setting.  Therefore, it is considered that the risk related to study procedures are low 
and limited to common adverse events (AEs) related to the dental procedure, administration 
of routine anaesthetics, and discomfort from vital sign measurements.  Any subject that 
experiences immediate complications during the surgery will be excluded from the study. 
Therefore, the overall benefit-risk profile for the use of the investigational product as 
defined in this protocol is considered favourable. 
1.8 Ethical Conduct of the Study 
This study will be conducted in accordance with this protocol and the principles set out in the 
Declaration of Helsinki. It will comply with International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
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2 
STUDY OBJECTIVES 
Primary Objective:  
 
To evaluate the superiority of 2×300 mg ibuprofen PR tablets compared with placebo in 
subjects experiencing acute moderate to severe pain after third molar extraction over 
12 hours post initial dose.  
Key Secondary Objectives: 
 
To evaluate the analgesic performance of a total daily dose of 1200 mg of ibuprofen PR 
formulation compared to ibuprofen IR formulation over 24 hours post initial dose. 
 
To evaluate the safety and tolerability of 2×300 mg ibuprofen PR tablets. 
Additional Secondary Objectives: 
 
To evaluate the total analgesic effect, peak analgesic effect, onset and duration of action 
and the subject’s overall assessment of the study medications. 
3 
STUDY DESIGN AND RATIONALE FOR DESIGN 
This is a single centre randomised, double-blind, double dummy, parallel group, multiple-dose, 
active and placebo-controlled efficacy study to evaluate the efficacy and safety of 2×300 mg 
ibuprofen PR tablets in subjects with postoperative dental pain. 
The dental pain model used in this study is a robust and well established postsurgical pain 
model that produces pain that is predictable in its character, duration, and intensity(6). The 
model is widely accepted and has a proven record of assay sensitivity (i.e. separating active 
drugs from each other, as well as from placebo). The model is frequently used to evaluate 
NSAID type analgesics. Results from dental pain studies are accepted by the US Food and 
Drug Administration (FDA) and European authorities and have been widely extrapolated to 
other general pain conditions. 
The decision to conduct the study in the United States was taken as suitably qualified and 
experienced test sites could not be found in Europe.  The specific test site has been chosen 
to conduct the study as they have a proven history of quality and safety when conducting 
studies of this type. 
The placebo products have two purposes:  
1. To mask the treatment identify for PR and IR arms  
2. Act as a control arm 
The dose of the test product is the proposed posology of the final product and the dose of the 
active comparator is the posology provided in the label of the product. 
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Eligible subjects will be randomised in a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets 
Q12h, 2×200 mg ibuprofen IR tablets Q8h, or placebo. The randomisation will be stratified by 
baseline pain category (moderate or severe) using a categorical scale that includes the 
categories of none (0), mild (1-4), moderate (5-7), and severe (8-10). The randomisation 
schedule will be prepared by a statistician not otherwise involved in the study. Randomisation 
will be performed using an interactive web response system (IWRS). Access to the unblinding 
codes will be restricted to personnel not otherwise involved in the study and will be available 
to the investigator only in the case of a subject requiring unblinding prior to database lock. 
Figure 3.1 Study Design Schematic 
Screening 
Visit 
Day 
-28 to -1 
 
In-patient Surgical Stay 
 
Follow-up 
Visit 
Day 8± 2 d 
or Early 
Termination 
 
 
 
 
 
Day of Surgery (Day 1) 
Day 2 
 
→ Pre-
surgery 
Surgery 
Post-
surgery 
eligibility 
Randomisation 
& pre-dose 
(Baseline) 
assessments 
Dosing & 
post-dose 
assessments 
24 h 
post-dose 
assessments 
→
 
 
Note: Un-scheduled visits may occur at any point throughout the study 
 
Table 3-1 Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective: 
To evaluate the superiority of 2×300 mg 
ibuprofen PR tablets compared with placebo 
in subjects experiencing acute dental pain 
after third molar extraction over 12 hours 
post initial dose. 
Primary Endpoint:  
The primary efficacy endpoint is the summed 
pain intensity difference (SPID) over the 0 to 
12 hours (SPID12) after Time 0 and will be 
used to compare the test product (2x300 mg 
PR ibuprofen) and the placebo product.  
The clinical relevance of the difference 
between placebo and PR ibuprofen over 
12 hours after initial dose will be evaluated 
as confirmatory evidence (for the purposes 
of this study, a difference of 30% in PID 
scores over 12 hours after initial dose will be 
considered clinically relevant). 
Secondary Efficacy Objectives: 
 To evaluate the analgesic performance 
of a total daily dose of 1200 mg of 
ibuprofen PR formulation compared to 
ibuprofen IR formulation over 24 hours 
post initial dose.  
Key Secondary Efficacy Endpoints: 
 The summed pain intensity difference 
(SPID) over 0 to 24 hours (SPID24) will 
be used to compare the test product 
(2×300 mg ibuprofen PR tablets twice 
daily [BID]) and comparator product 
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 To evaluate the total analgesic effect, 
peak analgesic effect, onset and duration 
of action and the subject’s overall 
assessment of the study medications. 
(2×200 mg ibuprofen IR tablets three 
times a day [TID]). 
Efficacy Endpoints: 
 Summed pain intensity difference (SPID) 
over 0 to 4 hours (SPID4), over 0 to 
8 hours (SPID8), over 0 to 12 hours 
(SPID12), and over 0 to 24 hours 
(SPID24) after Time 0 
 Sum of total pain relief (TOTPAR) over 
0 to 4 hours (TOTPAR4), over 0 to 
8 hours (TOTPAR8), over 0 to 12 hours 
(TOTPAR12), and over 0 to 24 hours 
(TOTPAR24) after Time 0 
 Summed pain relief and intensity 
difference (sum of TOTPAR and SPID 
[SPRID]) over 0 to 4 hours (SPRID4), 
over 0 to 8 hours (SPRID8), over 0 to 
12 hours (SPRID12), and over 0 to 
24 hours (SPRID24) after Time 0 
 Response to study drug (a responder will 
be defined as a subject with ≥30% 
improvement in pain intensity without 
rescue medication during the first 
8 hours) 
 NRS pain intensity difference (PID) at 
each scheduled time point after Time 0 
 Pain intensity score at each scheduled 
time point 
 Pain relief score at each scheduled time 
point after Time 0 
 Peak pain relief 
 Time to onset of analgesia (measured as 
time to perceptible pain relief confirmed 
by time to meaningful pain relief) using 
double stopwatch 
 Time to first perceptible pain relief 
 Time to meaningful pain relief 
 Time to peak pain relief 
 Proportion of subjects using rescue 
medication 
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 Time to first use of rescue medication  
Exploratory Endpoint: 
 Patient’s global evaluation of study drug 
Safety Objective: 
To evaluate the safety and tolerability of 
2×300 mg ibuprofen PR tablets. 
Safety Endpoints: 
 Incidence of treatment-emergent 
adverse events (TEAEs) 
 Incidence of clinically relevant changes 
in vital sign measurements 
 
Subjects in the PR group will take 2×300 mg ibuprofen PR tablets at Hours 0 and 12. Subjects 
in the IR group will take 2×200 mg ibuprofen IR tablets at Hours 0, 8, and 16. To maintain 
double-blinding, at each dosing timepoint (Hours 0, 8, 12, and 16) all subjects will take a total 
of 4 tablets (placebo-only or active plus placebo, depending on randomised treatment group). 
Table 3-2 Treatment Regimens 
 
PR Group 
 
IR Group 
Placebo Group 
Hour 0 
2 PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 8 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 12 
2 PR, 
2 placebo for IR 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 placebo for IR 
Hour 16 
2 placebo for PR, 
2 placebo for IR 
2 placebo for PR, 
2 IR 
2 placebo for PR, 
2 placebo for IR 
Hour 24 
final assessments 
final assessments 
final assessments 
 
The study will enrol approximately 280 male and female subjects 18-50 years of age who 
experience moderate to severe pain intensity within 6 hours after dental surgery to remove 
2 or more third molars. At least 1 of the third molars must be a fully or partially bone impacted 
mandibular molar. If only 2 molars are removed, they must be ipsilateral. Subjects must satisfy 
all eligibility criteria including providing informed consent and willingness to remain at the clinic 
overnight. 
The study will be conducted in 1 study site in the United States.   
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 Study Population 
The study will enrol approximately 280 male and female subjects. 
 
4.2 Inclusion Criteria 
Only subjects to whom all of the following conditions apply will be included: 
1. Is male or female ≥ 18 and ≤ 50 years of age. 
2. Requires extraction of 2 or more third molars. At least 1 of the third molars must be a 
fully or partially bone-impacted mandibular molar. If only 2 molars are removed, then 
they must be ipsilateral. 
3. Experiences moderate to severe pain intensity within 6 hours after surgery, as 
measured by a numeric rating scale (NRS) score of ≥ 5 on a 0-10 scale. 
4. Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 35 kg/m2. 
5. Female subjects of child-bearing potential must be willing to use a highly effective 
method of contraception throughout the study. A highly effective method of birth 
control is defined as one which results in a low failure rate (i.e. less than 1% per year) 
when used consistently and correctly, such as the following: 
a. surgical sterilisation 
b. contraceptive implants or injectables 
c. combined oral contraceptives 
d. some IUDs (intrauterine devices) 
e. true sexual abstinence, when this is in line with the preferred and usual 
lifestyle of the subject (periodic abstinence such as calendar, ovulation, 
symptothermal, or post-ovulation methods; declaration of abstinence for the 
duration of the trial; or withdrawal are not acceptable methods of 
contraception), or  
f. vasectomised partner. 
To be considered not of child-bearing potential, females must be surgically sterile 
(defined as bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or post-
menopausal (defined as no menses for 12 months in women not using hormonal 
contraception or hormone replacement therapy, confirmed by a follicle stimulating 
hormone [FSH] level in the postmenopausal range at Screening). 
6. Free of clinically significant abnormal findings as determined by medical history, 
physical examination, vital signs, laboratory tests and ECG. 
7. Is able to provide written informed consent. 
8. Is willing and able to comply with study requirements (including diet and smoking 
restrictions), complete the pain evaluations, remain at the study site overnight, and 
return for follow-up 7 (± 2) days after surgery.  
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4.3 Exclusion Criteria 
A subject will not be eligible for study entry if any of the following exclusion criteria are met: 
1. Known hypersensitivity reactions or allergy (e.g., asthma, rhinitis, angioedema or 
urticaria) in response to nonsteroidal anti-inflammatory drugs (NSAIDs, including 
ibuprofen), acetylsalicylic acid (aspirin), ingredients of the study drug, or any other 
drugs used in the study, including anaesthetics and antibiotics that may be required 
on the day of surgery. 
2.  A history of active or previous peptic ulceration/ haemorrhage, gastrointestinal 
bleeding or perforation, heart failure, renal or hepatic failure, uncontrolled 
hypertension, asthma, nasal polyps, or chronic rhinitis. 
3. Has complications from the tooth extraction or any other clinically significant medical 
history that, in the opinion of the investigator, would affect the subject’s ability to 
comply or otherwise contraindicate study participation, including but not limited to the 
following: cardiac, respiratory, gastroenterological, neurological, psychological, 
immunological, haematological, oncological, or renal disease. 
4. Has undergone another dental surgery within 60 days prior to the day of surgery. 
5. A positive urine drugs of abuse screen or alcohol breathalyser test at screening and 
during the study (with the exception of a positive drugs of abuse screen that is a 
consequence of permitted prescription medicines). 
6. If female, has a positive pregnancy test at screening (serum) or on the day of surgery 
prior to surgery (urine), or is lactating. 
7. Has known or suspected, (in the opinion of the investigator), history of alcoholism or 
drug abuse within 2 years of screening or evidence of tolerance or physical 
dependence before dosing with study drug. 
8. Taking any concomitant medications that might confound assessments of pain relief, 
such as psychotropic drugs, antidepressants, sedative-hypnotics (other than those 
permitted for conscious sedation), or other analgesics taken within five times of their 
elimination half-lives. Selective serotonin reuptake inhibitors (SSRIs) and serotonin 
and noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject has been 
on a stable dose for at least four weeks prior to Visit 1 (screening). 
9. Is considered by the investigator, for any reason (including, but not limited to the risks 
described as precautions, warnings and contraindications in the current version of the 
investigator’s brochure [IB] for 300 mg ibuprofen PR tablets), to be an unsuitable 
candidate to receive the study drug. 
10. Has a history of chronic use (defined as daily use for > 2 weeks) of nonsteroidal anti-
inflammatory (NSAIDs), opiates, or glucocorticoids (except inhaled nasal steroids and 
topical corticosteroids), for any condition within 6 months before dosing with study 
drug.  
11. Has significant difficulties swallowing capsules or tablets or is unable to tolerate oral 
medication. 
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12. Previously participated in another clinical study of 300 mg ibuprofen PR tablets, or 
received any investigational drug, device, or therapy within 90 days before screening. 
13. Enrolment of the Investigator, his / her family members, employees and other 
dependent persons. 
14. Failure to satisfy the investigator of fitness to participate for any other reason. 
4.4 Subjects of Reproductive Potential 
Woman of childbearing potential must use a highly effective contraceptive method for the entire 
duration of study participation. 
A highly effective method of birth control is defined as one which results in a low failure rate 
(i.e. less than 1% per year) when used consistently and correctly, such as the following: 
 
Surgical sterilisation 
 
Established use of oral, injected or implanted hormonal methods of contraception 
 
Some intrauterine devices (IUDs) or intrauterine systems (IUSs) 
 
Male sterilisation (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). [For female subjects on the study, the vasectomised male 
partner should be the sole partner for that subject] 
 
True abstinence which is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence such as calendar, ovulation, symptothermal, or post-ovulation 
methods; declaration of abstinence for the duration of the trial; and withdrawal are not 
acceptable methods of contraception. 
4.5 Discontinuation / Withdrawal and Replacement of Subjects  
The Investigator may withdraw the subject from the study at any time. Reasons for removing 
a subject from the study include, but are not limited to: 
 
AEs that in the judgement of the Investigator may cause severe or permanent harm 
(significant clinical deterioration is an AE) 
 
Violation of the study protocol 
 
In the Investigator’s judgement, it is in the subject’s best interest 
 
Subject declines further study participation 
 
If applicable, randomisation code is broken 
If subjects choose to prematurely stop the study prior to the scheduled discharge at Hour 24, 
safety and tolerability assessments must be performed prior to discharge, and, if possible, 
efficacy assessments should be performed. 
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If subjects choose to prematurely stop the study after clinic discharge but prior to the follow-up 
visit, at least 2 documented attempts should be made to contact the subjects for follow-up 
assessments which will include the assessments described for the follow-up visit (Section 7.4). 
5 
STUDY TREATMENT 
5.1 Investigational Products 
Active Test Product 
Ibuprofen PR tablets 300 mg, single oral dose of 600 mg.  A yellow to pale yellow coloured, 
film coated, caplet shaped tablet, debossed as ‘N12’ on one side and plain on the other side. 
Table 5-1 Active Test Product 
Name of Ingredient 
Quantity/Tablet(mg) 
Function 
Reference 
Ibuprofen  
300.00 
Active 
Ph.Eur. 
Silicon dioxide 
3.00 
Glidant/Anti-adherent 
Ph.Eur. 
Hypromellose K4M 
Premium 
62.50 
Rate Controlling Polymer 
Ph.Eur. 
Hypromellose K100 LV 
32.50 
Rate Controlling Polymer 
Ph.Eur. 
Silicified Microcrystalline 
cellulose 50  
100.00 
Filler/Binder 
NF 
Silicified Microcrystalline 
cellulose 90 
50.00 
Filler/Binder 
NF 
Croscarmellose sodium 
17.50 
Disintegrant 
Ph.Eur. 
Glycine 
25.00 
Release Modifier 
Ph.Eur 
Silicon dioxide 
3.00 
Glidant/Anti-adherent 
Ph.Eur. 
Stearic acid 
6.00 
Lubricant 
Ph.Eur. 
Total weight of core 
tablet 
599.50 mg 
Film coating and Polishing  
Opadry Yellow 
15B520019 
7.50 
Coating agent 
In House 
Purified water# 
q.s. 
Coating vehicle 
Ph.Eur. 
Carnauba Wax   
0.025 
Polishing Agent 
Ph.Eur 
Total weight  
607.025 mg 
#   Removed during the process.  
 
 
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Placebo for Test Product 
A yellow to pale yellow coloured, film coated, caplet shaped tablet, debossed as ‘N12’ on one 
side and plain on the other side. 
Table 5-2 Placebo for Test Product 
Ingredient 
mg/tablet Function 
Reference 
Standard 
Core  
Hypromellose K4M Premium 
125.10 
Rate Controlling 
Polymer 
Ph. Eur. 
Hypromellose K100 Premium LV  
65.05 
Rate Controlling 
Polymer 
Ph. Eur. 
Silicified Microcrystalline Cellulose 50 
200.17 
Filler/ Binder 
NF 
Silicified Microcrystalline Cellulose 90 
100.08 
Filler/ Binder 
NF 
Croscarmellose Sodium  
35.03 
Disintegrant 
Ph. Eur. 
Glycine 
50.04 
Release Modifier 
Ph. Eur. 
Silica, Colloidal Hydrated 
12.02 
Glidant/ Anti-adherent 
Ph. Eur. 
Stearic Acid  
12.01 
Lubricant 
Ph. Eur. 
Coating and Polishing  
Opadry Yellow 15B520019 
7.50 
Coating Agent 
In house 
Carnauba Wax  
0.025 
Polishing Agent 
Ph. Eur. 
Processing agent 
Purified Water 
q.s.* 
Coating Vehicle 
Ph. Eur. 
Total 
607.025 
 
 
* Does not remain in final product except traces. Removed during the coating process.  
 
 
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Comparator Product 
Nurofen Ibuprofen acid tablets 200 mg, single oral dose of 400 mg.  A white to off white, 
biconvex, round, sugar coated tablet. 
Table 5-3 Comparator Product 
Name of Ingredient 
Unit Formula 
(mg/tablet) 
Function 
Reference to 
Standards 
Active Ingredient 
 
 
 
Ibuprofen 
200.0 
Active ingredient 
Ph.Eur. 
Other Ingredients 
 
 
 
Croscarmellose Sodium 
30.0 
Disintegrating agent 
Ph.Eur. 
Sodium Lauryl Sulphate 
0.5 
Tablet lubricant 
Ph.Eur. 
Sodium Citrate 
43.5 
Bulk filler 
Ph.Eur. 
Stearic Acid 
2.0 
Tablet lubricant 
Ph.Eur. 
Colloidal Anhydrous Silica 
1.0 
Granule flow aid 
Ph.Eur. 
Tablet Core Weight 
277.0 
 
 
Sugar Coat Ingredients 
 
 
 
Carmellose Sodium 
0.7 
Sugar coat binder 
Ph.Eur. 
Talc 
33.0 
Sugar coat bulking agent 
Ph.Eur. 
Acacia Spray Dried 
0.6 
Sugar coat binder 
Ph.Eur. 
Sucrose 
116.1 
Sugar coat 
Ph.Eur. 
Titanium Dioxide  
1.4 
Colour 
Ph.Eur. 
Macrogol 6000 
0.2 
Tablet polish 
Ph.Eur. 
Purified Water 
ND 
Sugar syrup solvent 
Ph.Eur. 
Coated Tablet Weight 
429.0 
 
 
 
 
Placebo for Comparator Product 
A white to off white, biconvex, round, sugar coated tablet. 
Table 5-4 Placebo for Comparator Product 
Ingredient 
Quantity (%w/w) 
Function 
Reference 
Standard 
Core 
Mannitol 
46.81 
Filler 
Ph. Eur 
Microcrystalline 
Cellulose 
16.14 
Filler 
USP/NF 
Magnesium Stearate 
1.61 
Lubricant 
Ph. Eur. 
Sugar coating 
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Carmellose Sodium 
0.16 
Sugar coat binder 
Ph. Eur 
Talc 
7.69 
Sugar coat bulking 
agent 
Ph. Eur 
Acacia Spray Dried 
0.14 
Sugar coat binder 
Ph. Eur 
Sucrose 
27.06 
Sugar coat 
Ph. Eur 
Titanium Dioxide 
0.33 
Colour 
Ph. Eur 
Macrogol 6000 
0.05 
Tablet polish 
Ph. Eur 
Purified Water* 
ND 
Sugar syrup solvent 
Ph. Eur 
 
Test Product and Placebo for Test Product will be manufactured and packed (primary pack) to 
Good Manufacturing Practice (GMP) standards by Strides Shasun Limited, R.S No 32-34 
PIMS Road, Periyakalpet, Kalapet, Pondicherry, 605014, India and shipped to Investigational 
Materials Supplies Unit (IMSU), RB, Dansom Lane, Hull, HU8 7DS. 
Nurofen Ibuprofen acid (Comparator) and the Placebo for Comparator tablets will be 
manufactured to GMP standards by Reckitt Benckiser, Thane Road, Nottingham, NG90 2DB, 
UK. Both active and placebo tablets will be unprinted for blinding purpose. 
Both the products (Comparator and Placebo) will be primary packed at Sharp Clinical Services, 
Elvicta Business Park, Crichowell, NP8 1DF, UK and shipped to Investigational Materials 
Supplies Unit (IMSU), RB, Dansom Lane, Hull, HU8 7DS. 
The Test Product, Placebo for Test Product, Comparator Product and the Placebo for 
Comparator product will be assembled to GMP standards by the IMSU, RB, Dansom Lane, 
Hull HU8 7DS, and bulk certified by RB Research and Development Qualified Person. All the 
products will be shipped directly from IMSU to the study site.  
5.2 Non-Investigational Products 
In preparation for the surgery, subjects will receive local anaesthesia (2% lidocaine with 
1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion of the investigator.  
5.3 Permitted Therapies 
After randomisation and administration of study drug, paracetamol / acetaminophen (1000 mg) 
will be permitted as the initial rescue medication. Subjects will be encouraged to wait at least 
60 minutes after receiving study drug before taking rescue medication. If acetaminophen 
rescue medication is not effective in relieving the subject’s pain, 5 mg oxycodone rescue 
medication may be administered at the discretion of the investigator.  
At the investigators discretion repeat doses of rescue medication may also be administered as 
required. 
The Investigator or designees will record all medication taken by the subject at the screening 
visit in the subject’s electronic Case Report Form (eCRF). Any medication taken by the subject 
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from the time of giving informed consent through to the end of the subject’s participation in the 
study (last assessment) will be recorded on the concomitant medication page in the eCRF. 
Upon discharge from the study site, subjects may be prescribed pain medication for use at 
home according to the standard practice of the study site.  
5.4 Treatment Compliance 
For the duration of each assessment the subject will remain at the study site under the 
supervision of the Investigator or designees. The Investigator or designees will provide 
supervised drug administration along with clear instructions and support to the subject to 
facilitate the best possible compliance with study requirements. Any non-compliance during 
the study will be observed and recorded by study site staff as a protocol deviation. 
5.5 Packaging and Labelling and Supply / Resupply 
For each subject one pack will be provided containing all required tablets for each dosing 
timepoint.  Each tablet will be held in a blister within the pack.  The pack will clearly show which 
tablets are to be taken at which timepoint. 
All packs regardless of treatment regimen will be the same except for a kit number and will 
therefore not identify the treatment. 
The IMP will be labelled in accordance with EudraLex Volume 4 Good Manufacturing Practice 
(GMP) Guidelines, Annex 13 - Manufacture of Investigational Medicinal Products, parts 26 to 
33 (Labelling) and in accordance with directive 2003/94/EC as amended and including any 
other applicable national/state legislation. The IMP will be labelled in English 
All IMP will be packed and labelled to GMP by the Investigational Material Supplies Unit 
(IMSU), Reckitt Benckiser Healthcare (UK) Ltd, Dansom Lane, Hull, HU8 7DS, UK. IMP will 
be shipped from the IMSU to the study site. 
5.6 Storage Conditions 
The Investigator or designated individual will keep all IMP(s) in a pharmacy or a secure storage 
facility, accessible only to those individuals authorised by the Investigator to dispense the 
medication. 
The Investigator or designated individual will maintain an inventory. This will include the 
description and quantity of IMP(s) received during the course of this study, as well as a record 
of the materials that are dispensed and returned (how much, to whom and when). This 
inventory (“Drug Dispensing Log”) will be subject to review by the study monitor during 
monitoring visits. 
The Investigator agrees not to supply IMP(s) to any person except study personnel and 
patients enrolled in this study. 
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The IMP should be stored between 8-25 °C and is not to be refrigerated or frozen. 
Temperatures must be constantly monitored and readings logged in a temperature log on 
working days.  
The temperature in the secure storage facility will be recorded using a minimum/maximum 
thermometer. If the temperature falls outside the specified range of 8-25 °C, the Sponsor 
should be notified immediately and appropriate action should be agreed and documented. The 
temperature log will be reviewed by the study monitor at each monitoring visit.  
5.7 Blinding 
This study is a double-blind, double dummy study.  There will be two placebo tablets designed 
to be comparable to each of the active products (PR and IR) in both shape, size, colour and 
weight. 
All subjects will receive 4 tablets at each dosing timepoint.  At each timepoint each subject will 
receive 2 tablets that may be either PR or the placebo made to look like PR and 2 tablets that 
may be IR or the placebo made to look like IR. See Table 3-2 Treatment Regimens.  This 
includes those in the placebo arm who will receive 2 placebo tablets designed to look like PR 
and 2 placebo tablets designed to look like IR at all dose timepoints. 
All subject packs will be designed and labelled to ensure blinding is maintained. 
Subjects, investigators and site staff will all be blind to the treatments. 
Unblinding will only occur after database lock or in the case of emergency unblinding, see 
Section 5.8. 
5.8 Emergency Unblinding Procedures 
Treatment unblinding is discouraged if knowledge of the treatment assignment will not 
materially change the planned management of a medical emergency. Unblinding will be 
permitted in a medical emergency that requires immediate knowledge of the subject’s 
treatment assignment. 
For emergency unblinding, study personnel will use the IWRS. If treatment assignment is 
unblinded for an individual subject, study personnel will be notified of that subject’s treatment 
assignment without unblinding the treatment assignments for the remaining subjects in the 
study. Thus, the overall study blind will not be compromised. If a subject’s treatment 
assignment is unblinded, he/she may or may not be asked to withdraw from the study. The 
investigator should make this decision after consultation with the medical monitor. 
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5.9 Drug Accountability 
The Investigator will keep all study medication (including rescue medication) in a pharmacy or 
a secure storage facility, accessible only to those individuals authorised by the Investigator to 
dispense the medication. 
The Investigator or designated individual will maintain an inventory. This will include the 
description and quantity of study drug received during the course of the study, as well as a 
record of the materials that are dispensed and returned (how much, to whom and when). This 
inventory will be subject to review by the study monitor during monitoring visits.  
The Investigator agrees not to supply study drug to any person except study personnel and 
subjects in this study.  
5.10 
Return and Destruction  
The Investigator agrees to conduct a drug-supply inventory, to record the results of this 
inventory (“IMP Removal from Site” form) and to ensure all original IMP containers whether 
empty or containing IMP are sent to RB’s representative at the end of the study. 
RBs representative will then arrange for the appropriate and timely destruction of all containers 
and unused IMP upon confirmation from RB following provision of a full reconciliation by 
Premier (on finalisation of the study report).   
6 
STUDY PROCEDURES BY VARIABLE 
6.1 Informed Consent 
Prior to conducting any study-related activities, written informed consent must be obtained 
from the subject (Section 12.2). 
6.2 Randomisation 
Eligible subjects will be randomised in a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets 
Q12h, 2x200 mg ibuprofen IR tablets Q8h, or placebo using permuted blocks of fixed size. The 
randomisation will be stratified by baseline pain category (moderate or severe) using a 
categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and 
severe (8-10). The randomisation schedule will be prepared by a statistician not otherwise 
involved in the study. Randomisation will be performed using an interactive web response 
system. Access to the unblinding codes will be restricted to personnel not otherwise involved 
in the study and will be available to the investigator only in the case of a subject requiring 
unblinding prior to database lock. 
6.3 Drug Administration 
Subjects will be dosed under clinic supervision to ensure compliance. Prior to dosing, each 
subject will be instructed by the Investigator or clinic staff on how to take the medication. 
 
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6.4 Demographics 
Demographic information will be recorded including gender, date of birth and race. 
6.5 Medical History and Concomitant Medication 
Relevant medical history, including history of current disease and information regarding 
underlying diseases will be recorded. The duration of surgery and all concomitant medication 
taken will be recorded as well as permitted therapies (see Section 5.3). 
6.6 Physical Examination 
A complete physical examination (excluding the genitourinary examination) will be performed 
at Screening. An abbreviated confirmatory physical assessment, including an examination of 
the subject’s mouth and neck, will be performed at the Follow-up Visit (or Early Termination 
Visit). 
Height, weight, and BMI will be assessed at Screening. 
6.7 Laboratory Tests 
The following fasting clinical laboratory tests will be performed at Screening.  
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea 
nitrogen, creatinine, glucose, sodium, potassium, chloride, bicarbonate, 
lactate dehydrogenase, uric acid, urea, inorganic phosphorous, 
cholesterol (total and High Density Lipoprotein (HDL)), triglycerides, 
gamma glutamyl transferase 
Coagulation: 
prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones, leucocyte 
esterase, nitrites (in the event that the dipstick test is positive, red blood 
cells, white blood cells, epithelial cells, crystals, bacteria and casts will 
be examined microscopically) 
Virology: 
hepatitis B, hepatitis C, HIV 
The following laboratory tests will also be performed: 
 
Alcohol breathalyzer test will be performed before surgery on Day 1. 
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 
Urine drug screen samples will be collected at Screening and before surgery on Day 1 to 
test for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine 
(PCP), and tetrahydrocannabinol (THC). 
 
For female subjects of childbearing potential, a blood sample for the serum pregnancy 
test will be collected at Screening and a urine pregnancy test sample will be collected 
before surgery on Day 1. 
Blood and urine samples for hematology, serum chemistry, and urinalysis will be prepared 
using standard procedures and will be sent to a central laboratory for analyses. 
6.8 Electrocardiograms 
A 12-lead electrocardiogram will be performed at Screening. 
6.9 Vital Signs 
Vital signs will be recorded after the subject has been in a sitting position for 3 minutes. Vital 
sign assessments will include blood pressure, heart rate, respiratory rate, and body 
temperature. Clinically significant abnormalities in vital signs should be recorded as AEs. 
6.10 
Blood Sampling 
Blood sampling will be performed according to the site’s standard practices, as described in 
the study manual or other site documentation. 
6.11 
Oral Radiography 
Oral radiographs (X-rays) will be taken at Screening (radiographs taken within 1 year before 
Screening will be acceptable and do not need to be repeated). 
6.12 
Pain Intensity  
Subjects will rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no 
pain and 10 = worst pain ever at the timepoints mentioned on Table 7-1. 
6.13 
Stopwatch Assessment  
Two stopwatches will be started immediately after the subject has swallowed the study drug 
with 8 ounces of water. Each subject will be instructed, “Stop the first stopwatch when you first 
feel any pain relief whatsoever. This does not mean you feel completely better, although you 
might, but when you first feel any relief in the pain you have now” (perceptible pain relief). The 
subject will also be instructed, “Stop the second stopwatch when you feel the pain relief is 
meaningful to you” (meaningful pain relief). If the subject does not press the stopwatches within 
8 hours after Time 0 the subject will discontinue use of the stopwatches. 
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6.14 
Pain Relief Scale  
Subjects will rate their pain relief relative to Time 0 using a 5-point categorical scale. Subjects 
will be asked “How much relief have you had since your starting pain?” with response choices 
of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. At each assessment time point, 
the pain intensity NRS assessment will be completed first and the pain relief assessment will 
be completed second. Subjects will not be able to compare their responses with their previous 
responses. 
6.15 
Subject’s Global Evaluation of Study Drug 
For the global evaluation of study drug, the subject will be asked “How effective do you think 
the study drug is as a treatment for pain?” with response choices of 0 = poor, 1 = fair, 2 = good, 
3 = very good, or 4 = excellent. Subjects will complete the global evaluation of study drug 
24 hours after Time 0 or immediately before the first dose of rescue medication (whichever 
occurs first). 
6.16 
Adverse Events  
During the study the Investigator will ask the subject: “Are you experiencing any symptoms or 
complaints?” at the baseline visit, and “Have you had any symptoms or complaints since the 
last time you were asked?” during the study. In addition, spontaneously reported AEs are 
collected. 
The observation period for an individual subject will start after giving informed consent and will 
finish at the last visit (follow-up visit) for the given individual subject. All AEs that arise during 
the observation period will be recorded and an assessment of the AE will be performed as per 
Section 8.2 by a medically qualified Investigator. If a subject has an AE that is still ongoing at 
the last visit, an attempt will be made by the Investigator to follow this up as per Section 8.4.   
If an untoward medical occurrence happens after the subject has signed the consent form but 
before administration of the IMP, it should be reported as an adverse event, including those 
associated with study procedures. 
7 
STUDY PROCEDURES BY VISIT 
7.1 Study Flow Chart / Table of Study Procedures and Assessments 
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Table 7-1 Schedule of Assessments 
 
Screening 
(Day -28 to 
Day -1) 
Surgery (Day 1) 
Day 2 
Follow-up 
(Day 8 ±2 days) or 
ETk 
 
 
Pre-
Surgery 
 
Post-op 
 
 
 
 
Pre-
dose 
0 h 
15, 30, 
45 min 
1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 
10 h 
12 h 
16 
h 
24h 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Assign a screening number 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xb 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
 
 
 
X 
 
X 
X 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (hematology, 
chemistry, urinalysis) 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test for female subjects of 
childbearing potentiale 
X 
X 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
Alcohol breathalyzer test 
 
X 
 
 
 
 
 
 
 
 
Oral radiographyf 
X 
 
 
 
 
 
 
 
 
 
Review study restrictions with subject 
X 
 
 
 
 
 
 
 
 
 
Pain intensity (NRS)g 
 
 
X 
 
X 
X 
X 
X 
X 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
Dosing with study drug 
 
 
 
0 h 
 
8 h 
12 h 
16h 
 
 
Stopwatch assessmenth 
 
 
 
X 
 
 
 
 
 
 
Pain relief (5-point categorical scale)g 
 
 
 
 
X 
X 
X 
 
X 
 
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Screening 
(Day -28 to 
Day -1) 
Surgery (Day 1) 
Day 2 
Follow-up 
(Day 8 ±2 days) or 
ETk 
 
 
Pre-
Surgery 
 
Post-op 
 
 
 
 
Pre-
dose 
0 h 
15, 30, 
45 min 
1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 
10 h 
12 h 
16 
h 
24h 
 
Global evaluation of study drugi 
 
 
 
 
 
 
 
 
X 
 
Concomitant medications 
 
Xb 
X 
X 
X 
X 
X 
 
X 
X 
Adverse eventsj 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Dispense/prescribe pain medication for use at 
home, as needed 
 
 
 
 
 
 
 
 
X 
 
Collect unused home pain medications, as 
needed 
 
 
 
 
 
 
 
 
 
X 
Discharge from study site 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: BMI=body mass index; ET=early termination; h=hour; min=minute; NRS=numeric rating scale; pre-op=pre-operative; post-op=post-operative. 
a Times listed are relative to dosing with study drug. 
b Medical history and concomitant medication use since Screening will be updated on Day 1 before surgery. 
c A complete physical examination (excluding the genitourinary examination) will be performed at Screening. An abbreviated confirmatory physical assessment, 
including an examination of the subject’s mouth and neck, will be performed at the Follow-up Visit (or Early Termination Visit). 
d Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at the following times: at Screening, before surgery, within 30 minutes 
before Time 0, 12 hours after Time 0, 24 hours after Time 0, and/or immediately before the first dose of rescue medication, and at the Follow-up Visit (or Early 
Termination Visit). 
e Serum pregnancy test at Screening and urine pregnancy test before surgery on Day 1 (female subjects of childbearing potential only). Test results must be 
negative for the subject to continue in the study. 
f 
Oral radiographs taken within 1 year before Screening will be acceptable and do not need to be repeated. 
g Pain assessments will be conducted (pre-dose, if at one of the dosing timepoints of 0, 8, 12 or 16 hours) at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 
8, 10, 12, 16 and 24 hours after Time 0 and immediately before each dose of rescue medication. Pain intensity will also be assessed pre-dose. At each 
assessment time point, the pain intensity assessment will be completed first and the pain relief assessment will be completed second. Subjects will not be 
able to compare their responses with their previous responses.  Note for assessments less than 1 hour apart a window of +/-2 min is allowable whilst for 
assessments at least 1 hour apart a +/-5 min window is allowable. 
h Two stopwatches will be started immediately after the subject has swallowed the first dose of study drug with 8 ounces of water (Time 0). Subjects will record 
the time to perceptible and meaningful pain relief, respectively, by stopping the stopwatches. 
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i 
Subjects will complete a global evaluation of study drug 24 hours after Time 0 or immediately before the first dose of rescue medication (whichever occurs 
first). 
j 
Adverse events will be monitored and recorded from the time of signing of the informed consent form until the Follow-up Visit (or Early Termination Visit). 
k If an unscheduled visit occurs the Investigator should follow the activities detailed in Section 7.5. 
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7.2 Screening Visit (Day -28 to Day -1) 
 
Written informed consent 
 
Assign a screening number 
 
Inclusion/exclusion criteria 
 
Demographics 
 
Medical history 
 
Complete physical examination (excluding the genitourinary examination) 
 
Vital signs 
 
Electrocardiogram 
 
Height, weight, and BMI 
 
Clinical laboratory tests (haematology, chemistry, urinalysis) 
 
Serum pregnancy test for female subjects of childbearing potential 
 
Urine drug screen 
 
Oral radiography (oral radiographs taken within 1 year before Screening will be 
acceptable and do not need to be repeated)  
 
Review study restrictions with subject 
 
Schedule surgery 
7.3 Day of Surgery (Day 1) 
 
Pre-Surgery 
 
Inclusion/exclusion criteria review 
 
Medical history review 
 
Vital signs 
 
Urine pregnancy test for female subjects of childbearing potential 
 
Urine drug screen 
 
Alcohol breathalyzer test 
 
Concomitant medications 
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 
Adverse events 
 
Surgery 
 
Subjects who continue to be eligible for study participation after completing screening 
procedures and assessments will undergo extraction of 2 or more third molars. At least 
1 of the third molars must be a fully or partially bone impacted mandibular molar. If only 
2 molars are removed, then they must be ipsilateral.  
 
All subjects will receive local anesthesia (2% lidocaine with 1:100,000 epinephrine).  
 
Nitrous oxide will be allowed at the discretion of the investigator. 
 
Post-surgery Eligibility Assessments and Randomisation 
 
Vital signs 
 
Concomitant medications 
 
Adverse events  
 
Pain intensity NRS  
 
Subjects who experience moderate to severe pain intensity (NRS score of ≥ 5) within 
6 hours after surgery and who continue to meet all study entry criteria will be randomised 
 
Dosing and Post-dose Assessments (Hour 0 through Hour 24) 
 
Subjects will re-assess their baseline pain intensity using the NRS immediately before 
receiving IMP (pre-dose, Time 0) 
 
Administer IMP at the timepoints in Table 3-2 
 
Subjects will assess their pain intensity (NRS) and pain relief (5 point categorical scale) 
at the following time points (pre-dose, if at one of the dosing timepoints of 0, 8, 12 or 
16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours 
after Time 0; and immediately before each dose of rescue medication, if any. For 
assessments less than 1 hour apart a window of +/-2 min is allowable whilst for 
assessments at least 1 hour apart a +/-5 min window is allowable. 
 
Subjects will use the double stopwatch method to record the time to perceptible pain 
relief and time to meaningful pain relief during the 8 hours following the first dose or until 
subject takes rescue medication 
 
Subjects will complete a global evaluation of study drug 24 hours after Time 0 or 
immediately before the first dose of rescue medication (whichever occurs first) 
 
Vital signs will be recorded after the subject has been in a sitting position for 3 minutes 
at the following times: before surgery, within 30 minutes before Time 0, 12 and 24 hours 
after Time 0, and/or immediately before the first dose of rescue medication 
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 
Concomitant medications 
 
Adverse events  
 
Subjects will remain at the study site overnight and will be discharged on Day 2.  
 
Upon discharge from the study site, dispense/prescribe pain medication.  
 
Schedule follow-up visit 
7.4 Follow-up Visit (Day 8 ± 2 days) or Early Termination 
 
Abbreviated confirmatory physical assessment, including an examination of the 
subject’s mouth and neck 
 
Vital signs 
 
Concomitant medications 
 
Collect unused pain medications 
 
Record any post discharge adverse events 
7.5 Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the reason for unscheduled visit, 
including any AEs, concomitant therapy changes, withdrawal (if deemed appropriate) and any 
clinical assessments deemed appropriate for the clinical care of the subject. Unscheduled 
visits should not alter the timing of the routine study schedule. 
7.6 Study Restrictions 
 
Prohibited Therapies 
Subjects are not permitted to take any concomitant medications that might confound 
assessments of pain relief, such as psychotropic drugs, antidepressants, sedative-hypnotics 
(other than those permitted for conscious sedation), or other analgesics taken within five times 
of their elimination half-lives (other than those used at the surgery). Selective serotonin 
reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are 
permitted if the subject has been on a stable dose for at least four weeks prior to Visit 1 
(screening).  
 
General and Dietary Restrictions 
Other restrictions include the following: alcohol use is prohibited from 24 hours before surgery 
until discharge on Day 2; nothing by mouth from midnight before surgery until 1 hour after 
surgery; clear liquids only are allowed starting 1 hour after surgery until 1 hour after dosing; 
1 hour after dosing, the subject’s diet may be advanced according to standard practice. 
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8 
SAFETY REPORTING 
8.1 Adverse Event Definitions 
An Adverse Event (AE)  
An adverse event (AE) is any untoward medical occurrence in a patient or a clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have a causal relationship with the study procedure. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. [ICH E6 1.2].  
Serious Adverse Event (SAE)  
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that:  
 
results in death  
 
is life-threatening 
 
requires in-patient hospitalization or prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity or  
 
is a congenital anomaly/birth defect 
In addition, important medical events that may not be immediately life-threatening or result in 
death, or require hospitalisation, but may jeopardise the patient or may require intervention to 
prevent one of the other outcomes listed above should also usually be considered serious.  
[ICH E2A] Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, 
or development of drug dependency or drug abuse.  
Note: If the event is related to the investigational product and is both serious and unexpected, 
it is classified as a suspected unexpected serious adverse reaction (SUSAR). In case of 
double-blinded studies, unblinding is needed in order to determine a SUSAR. 
8.2 Assessment of Adverse Events 
All AEs that arise after the subject has given informed consent will be recorded in the subject’s 
source documents and electronic case report forms (eCRFs). AEs can be reported 
spontaneously by the subject or in response to non-leading questioning or observation by the 
Investigator or be a significant laboratory abnormality. 
All adverse events (AE) and all serious adverse events (SAEs) are collected, fully investigated 
and documented.  
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As the study will be conducted on subjects who have been through removal of impacted third 
molars, it is expected that they will present post-surgical symptoms, for example: swelling and 
bruising. For the purposes of this study, when at normal/expected magnitude, such 
occurrences will not be reported as AEs as they are expected and, therefore, are not 
“untoward” as in the AE standard definition. 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at 
study termination will be further followed up until recovery or until stabilisation of the disease 
after termination. 
For each AE a causality assessment of the event to the study drug must be performed. The 
relationship to IMP must be determined by the Investigator (if medically qualified) or by a 
medically qualified Co-Investigator. 
Table 8-1 AE Relationship Descriptions 
Relationship 
Description 
Unassessable/ 
Unclassifiable 
Insufficient information to be able to make an assessment 
Conditional/ 
Unclassified 
Insufficient information to make an assessment at present (causality 
is conditional on additional information) 
Unrelated 
No possibility that the AE was caused by the IMP 
Unlikely 
Slight, but remote, chance that the AE was caused by the IMP, but 
the balance of judgement is that it was most likely not due to the IMP 
Possible 
Reasonable suspicion that the AE was caused by the IMP 
Probable 
Most likely that the AE was caused by the IMP 
Certain 
The AE was definitely caused by the IMP 
 
For each AE a severity description should be given. 
Table 8-2 AE Severity Descriptions 
Severity 
Description 
Mild 
The AE does not limit usual activities; the subject may experience 
slight discomfort 
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Severity 
Description 
Moderate 
The AE results in some limitation of usual activities; the subject may 
experience significant discomfort 
Severe 
The AE results in an inability to carry out usual activities; the subject 
may experience intolerable discomfort or pain 
 
Expectedness for each AE will be determined based on the information in Section 6.9 of the 
Investigator’s Brochure. 
All AEs will be coded by the Sponsor using the most up-to-date version of MedDRA. 
8.3 Reporting of Adverse Events 
In the event of a Serious Adverse Event (SAE), the Investigator must report the event using 
the SAE form to the Sponsor Global Vigilance Group (GVG), by contacting GVG by email: 
gvg@rb.com while copying in the contract research organisation (CRO) and Sponsor 
Project/Study Managers within 24 hours of knowledge of the event. 
The out of hours emergency phone number is +44 (0)1482 326151.  
This emergency phone number will be confirmed to the Investigator at the Study Initiation Visit.  
All SAE Forms must be provided via email. Any inconsistencies in the information received 
from the Investigator will be clarified using the Adverse Event Data Clarification Form. The 
Investigator must retain a copy of all the SAE forms in the Investigator Site File. 
The Investigator must inform their Institutional Review Board (IRB) of all SAEs occurring in the 
study within 7 days for fatal or life-threatening SAEs and 15 days for all other SAEs as per 
Sponsor instructions and as described in the Safety Management Plan.  
The Investigator should not break the randomisation code except when it is necessary to do 
so in order to ensure the subject receives appropriate medical care. 
SAEs and non-serious AEs will be reported to the appropriate regulatory authorities by the 
Sponsor in accordance with the authorities’ requirements. The Sponsor is responsible for 
expedited reporting of all SUSARs/ SAEs to relevant authorities and IECs/IRBs as required by 
regulations. If the event requires expedited reporting, a CIOMS (Council for International 
Organizations of Medical Sciences) form will be produced and GVG will take actions as per 
the study specific Safety Management Plan.  
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8.4 Follow-up of Adverse Events 
All SAEs and all AEs that have not resolved by the end of the study will be followed up by the 
Investigator until resolution or until the Investigator believes there will be no further change, 
whichever is the earlier. This may involve the subject making additional visits to the site.  
If a subject has unresolved AEs requiring follow-up, investigators must attempt to contact 
subjects by telephone or other means.  
8.5 Overdose, Abuse, Misuse and Medication Errors 
The Sponsor defines “overdose” as the administration of a quantity of an investigational IMP 
given per administration or cumulatively, which is above the maximum recommended dose 
according to the authorised product information. 
The Sponsor defines “abuse” as the persistent or sporadic, intentional excessive use of an 
IMP, which is intended to produce harmful physical or psychological effects e.g. intentional 
overdose to experience psychological effects. 
The Sponsor defines “misuse” as situations where the IMP is intentionally and inappropriately 
used not in accordance with the authorised product information. 
Overdoses, abuse, misuse are reportable to the Sponsor irrespective of the presence of an 
associated AE / SAE. The overdose, abuse, misuse and any associated AE / SAE will be 
captured on an AE CRF (Case Report Form) page / SAE form. 
Due to the full inpatient nature of this study, in which medication doses will be supervised by 
site staff, cases of overdose, abuse or misuse are not expected to occur.  
Medication errors are any unintentional errors in dispensing or administration of the IMP which 
relates to: 
 
Taking / being administered an incorrect IMP 
 
Taking / being administered a drug by the wrong route of administration e.g. swallowing 
a suppository 
 
The accidental administration of the IMP to a person who is not a subject within the 
study 
Medication errors are reportable to the Sponsor irrespective of the presence of an associated 
AE / SAE. Medication errors with or without an associated AE / SAE will be captured on the 
AE CRF page / SAE form. 
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8.6 Pregnancy 
Pregnancy both in a female subject or the female partner of a male subject is considered a 
collectable event and will be recorded as an AE in all cases. It will be qualified as an SAE only 
if it fulfils SAE criteria. 
Due to the full inpatient nature of this study, pregnancy cases are not expected to occur during 
the study.  
 
9 
STATISTICAL CONSIDERATIONS 
This section presents a summary of the planned statistical analyses. A statistical analysis plan 
(SAP) that describes the details of the analyses to be conducted will be written prior to 
database lock. 
Summary statistics for continuous variables will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, summary 
statistics will typically include the number and percentage of subjects in each category. All data 
will be presented in listings. 
Baseline values are defined as the last measurements taken before dosing with study drug. 
9.1 Determination of Sample Size 
The sample size determination is based on the primary efficacy variable, SPID12. According 
to Farrar 2001(1), a clinically important improvement in pain is represented by a 2 point 
reduction on an 11-point NRS. Based on a baseline pain score of 7 this corresponds to an 
approximate 30% reduction in pain. An average 2 point difference in pain scores between 
Ibuprofen PR and placebo across all 14 assessments up to 12 hours will correspond to a 
difference in SPID12 of 24 points. In a previous study(7), the pooled standard deviation (SD) 
for SPID12 was 31.65. Assuming the same variability in this study, a sample size of 40 subjects 
per group will have >90% power to detect a difference of 24 points in SPID12, between 
ibuprofen 2×300-mg PR tablets and placebo using a 2-sided test with an alpha level of 0.05. 
In order to provide a robust estimate of treatment effect differences between PR and IR, and 
to obtain a more precise estimate for this comparison, a 3:3:1 allocation ratio will be used, so 
that 120 subjects are randomised into each of the PR and IR groups. Thus 280 subjects will 
be enrolled into the study. 
9.2 Interim Analysis 
No interim analysis is planned.  
9.3 Analysis Datasets 
The analysis populations include the following: 
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 
The intent-to-treat (ITT) population will consist of all subjects who are treated with 
study drug and who have at least 1 pain relief assessment after Time 0. The ITT 
population is the primary population for the efficacy analysis. 
 
The per-protocol (PP) population will consist of all ITT subjects who do not incur a 
major protocol violation that would challenge the validity of their data. This population 
will be utilized to evaluate the sensitivity of the primary efficacy analysis. 
 
The safety population will include all subjects who are treated with study drug. The 
safety population is the population for all safety assessments. 
9.4 Subject Disposition and Characteristics 
The numbers of subjects randomised, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. Demographic and baseline characteristics (including date 
of birth, sex, race, weight, height, BMI, medical history, and surgery duration) will be 
summarized for each treatment group and for the overall population using descriptive statistics. 
No formal statistical analyses will be performed. 
9.5 Efficacy Analyses 
The comparison of primary interest is between PR ibuprofen and placebo. In addition, the 
comparison between IR ibuprofen and placebo will be presented with p-values to demonstrate 
study sensitivity. Point estimates and 95% confidence intervals will be used to evaluate the 
clinical relevance of any differences between the PR and IR formulations. All treatment 
differences will be presented with 95% confidence intervals. No P value adjustment will be 
made for multiple endpoints or multiple comparisons. In the event of model assumptions for 
normality being violated, non-parametric methods will be used. 
Each efficacy endpoint will be summarized descriptively by treatment group. 
 
Primary Endpoint(s) 
The primary endpoint, summed pain intensity difference (SPID) over 0 to 12 hours (SPID12), 
will be used to compare the test product (2×300 mg ibuprofen PR tablets) against the placebo 
product. 
9.5.1.1 
Primary Analysis 
The primary efficacy null hypothesis is that SPID12 for placebo is equal to SPID12 for ibuprofen 
2×300 mg PR tablets. The primary analysis will be an ANCOVA model that includes the main 
effect of treatment and a covariate of the baseline NRS pain score and will use windowed worst 
observation carried forward (WOCF) imputation for subjects who use rescue medication. The 
primary analysis will be based on a 2-sided test at the significance level of 0.05. 
9.5.1.2 
Secondary Analysis 
The clinical relevance of the difference between placebo and PR ibuprofen over 12 hours after 
initial dose will be evaluated. 
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Secondary Endpoints 
 
The summed pain intensity difference (SPID) over 0 to 24 hours (SPID24) will be 
used to compare the test product (2×300 mg ibuprofen PR tablets twice daily [BID]) 
and comparator product (2×200 mg ibuprofen IR tablets three times a day [TID]). 
 
Summed pain intensity difference (SPID) over 0 to 4 hours (SPID4), over 0 to 8 hours 
(SPID8), and over 0 to 12 hours (SPID12) after Time 0 
 
Sum of total pain relief (TOTPAR) over 0 to 4 hours (TOTPAR4), over 0 to 8 hours 
(TOTPAR8), over 0 to 12 hours (TOTPAR12), and over 0 to 24 hours (TOTPAR24) 
after Time 0 
 
Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) 
over 0 to 4 hours (SPRID4), over 0 to 8 hours (SPRID8), over 0 to 12 hours 
(SPRID12), and over 0 to 24 hours (SPRID24) after Time 0 
 
Response to study drug (a responder will be defined as a subject with ≥30% 
improvement in pain intensity without rescue medication during the first 8 hours) 
 
Numeric rating scale (NRS) pain intensity difference (PID) at each scheduled time 
point after Time 0 
 
Pain intensity score at each scheduled time point 
 
Pain relief score at each scheduled time point after Time 0 
 
Peak pain relief 
 
Time to onset of analgesia (measured as time to perceptible pain relief confirmed by 
time to meaningful pain relief) using double stopwatch 
 
Time to first perceptible pain relief 
 
Time to meaningful pain relief 
 
Time to peak pain relief 
 
Proportion of subjects using rescue medication 
 
Time to first use of rescue medication  
9.5.2.1 
Secondary Endpoint Analyses 
For continuous secondary endpoints such as pain intensity score, SPID at each scheduled 
time point, peak pain intensity, TOTPAR4, TOTPAR8, TOTPAR12, TOTPAR24, SPID4, 
SPID8, SPID24, SPRID4, SPRID8, SPRID12, and SPRID24, descriptive statistics (such as 
mean, standard deviation, median, minimum, and maximum) will be provided for each 
treatment regimen. P values from ANCOVA models comparing the placebo group with other 
treatment groups, including terms for treatment and a covariate for baseline pain will be 
provided for SPID, SPRID, and TOTPAR variables, but no formal statistical inferences will be 
drawn on the basis of these tests. In the event that normality assumptions are violated for a 
parameter, non-parametric analysis methods will be used.  
For ordinal secondary endpoints, such as pain intensity difference at each scheduled time 
point, pain relief at each scheduled time point, peak pain relief, and global evaluation of study 
drug, descriptive summaries will be provided and will include the number and percentage of 
subjects within each category for each treatment group. Nominal P values from Fisher’s exact 
tests (or chi-square tests, as appropriate) comparing the placebo group with other treatment 
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groups will be provided for peak pain relief and global evaluation of study drug, but no formal 
statistical inferences will be drawn on the basis of these tests. 
For each time-to-event endpoint, Kaplan-Meier methodology will be used to evaluate the 
treatment effect. Time to onset of analgesia (measured as time to perceptible pain relief 
confirmed by meaningful pain relief) will be based on data collected using the double stopwatch 
method. Time to onset of analgesia will be right-censored at 8 hours for subjects who do not 
experience both perceptible pain relief and meaningful pain relief during the 8-hour interval 
after Time 0. The summary tables will provide the number of subjects analysed, the number of 
subjects censored, estimates for the quartiles, and 95% confidence intervals (CIs) for the 
estimated median and the restricted mean estimate. P values comparing placebo to active 
treatment from Wilcoxon or log-rank tests (as appropriate) will also be used to examine 
treatment effect. 
For time to onset of analgesia, the comparison of interest will be the ibuprofen 2×300 mg PR 
group versus the ibuprofen 2×200 mg IR group. The summary table for this comparison will 
provide the number of subjects analysed, the number of subjects censored, estimates for the 
quartiles, and 95% confidence intervals (CIs) for the estimated median and the restricted mean 
estimate.  
For the proportion of subjects who are responders and the proportion of subjects using rescue 
medication, logistic regression models that adjust for baseline intensity and/or significant 
demographic variables, if appropriate, will be used to evaluate the treatment effect.   
For the responder analysis, subjects will be censored at 8 hours and for the use of rescue 
medication/time to first rescue subjects will be censored at 24 hours.  
9.6 Safety Analyses 
 
Safety Endpoint(s) 
 
Incidence of treatment-emergent adverse events (TEAEs) 
 
Incidence of changes in vital sign measurements 
9.6.1.1 
Safety Endpoint Analyses 
Data listings will be provided for protocol-specified safety data. The Medical Dictionary for 
Regulatory Activities (MedDRA) (Version 19.0 or higher) will be used to classify all AEs with 
respect to system organ class and preferred term. Adverse event summaries will include only 
TEAEs, which will be summarized for each treatment group.  
For vital sign measurements, descriptive statistics will be provided at each scheduled time 
point for each treatment group. Changes from Baseline for vital signs will be calculated for 
each subject, and descriptive statistics will be provided on changes in vital signs from Baseline 
for each treatment group at each scheduled time point after Baseline. No formal statistical tests 
will be performed. 
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9.7 Handling of Missing Data and Drop-outs 
Missing pain assessments for all efficacy analyses will be handled as follows: 
 
Missing pain assessments scheduled before the first observed assessment will be 
imputed with the subject’s worst observed pain assessment. 
 
Missing intermediate pain assessments will be replaced by linear interpolation. 
 
Missing pain assessments at the end of the observation period due to premature 
discontinuation of pain assessments will be imputed by carrying forward the last 
observation prior to that missing. 
 
The primary analysis will use windowed worst observation carried forward (WOCF) 
methodology for subjects who use rescue medication. Any pain measurements taken during a 
period of time in which rescue medication is active (4 hours) will be replaced by the last pain 
measurement before the rescue medication was taken. A sensitivity analysis will also be 
performed, in which all pain assessments recorded after the first dose of rescue medication 
has been taken will be disregarded and the rules outlined above will be used for missing data. 
 
All data for assessments other than pain assessments will be analysed as collected; missing 
data due to premature termination or any other reason will be left as missing. In the event of a 
notable difference between treatment groups in the number of subjects using rescue 
medication, other sensitivity analyses may be performed. These will be detailed in the 
Statistical Analysis Plan (SAP). 
 
9.8 Changes to the Original Statistical Plan 
If there are any deviations to the proposed statistical analysis as described in this protocol 
these will either be documented in the final SAP or in a protocol amendment prior to database 
lock with the rationale and impact of the changes addressed. 
10 
DATA HANDLING AND RECORD KEEPING 
10.1 
Case Report Forms (CRFs) 
Data will be recorded in an electronic Case Report Form (eCRF). For each enrolled study 
subject an eCRF is maintained. The Investigator or designees is responsible for the quality of 
the data record in the eCRF. eCRFs must be kept current to reflect subject status at each 
phase during the course of study. Subjects must not be identified in the eCRF by name or 
initials.  
In the eCRF subjects will be identified by a subject number in combination with date of birth 
only, i.e., not by their name or initials. eCRF entries must be completed by appropriately trained 
site staff only. A log of trained and authorised staff able to complete the eCRF will be kept. 
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10.2 
Specification of Source Documents 
Source data must be available at the site to document the existence of the study subjects. 
Source data must include the original documents relating to the study, as well as the medical 
treatment and medical history of the subject. The investigator and study monitor will identify 
the data that will be recorded directly on the eCRF and for this data the eCRF will be considered 
the source document (i.e., no prior written or electronic record of the data). The study monitor 
will document this at the screening and it will also be documented in the Data Management 
Plan.  
Source documents will include notes taken at the site and will include data such as 
demographic data, participation in study and ICF, medical history, SAEs, AEs and concomitant 
medication, results of examinations and assessments.  
Where source data are in the form of a computer printout (e.g. medical records, laboratory 
data) they will be signed and dated by the investigator or designated person, confirming that 
the print out is a true and faithful record of the data for that subject. These print-outs will be 
filed in the study files. 
The Investigator agrees to provide direct access to source data for study-related monitoring, 
audits, IRB review, and regulatory inspection(s). Direct access to source data requires that the 
subject gives written, documented consent to this. 
10.3 
Data Management 
The data management group at Premier Research will be responsible for data management 
and eCRF activities.  
Full details regarding data management will be described within the Data Management Plan.  
10.4 
Reporting of Protocol Deviations 
Site staff should make the study monitor aware of any deviation from the protocol as soon as 
possible after occurrence. Waivers for inclusion / exclusion criteria are not allowed. 
10.5 
Retention of Essential Documentation 
The Investigator should retain all essential documents (as defined in ICH E6 or according to 
other national and international regulations) until at least 5 years after the completion of the 
study (defined as last subject last visit in the study). These documents should be retained for 
a longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the Investigator 
when these documents no longer need to be retained. 
Subject files and other source data must be kept for the maximum period of time permitted by 
the Clinical Unit. The Investigator must notify the Sponsor of the retention period if this is 
shorter than described above. 
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11 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Monitoring 
The Sponsor will organise regular monitoring visits to be performed at intervals agreed with 
the Investigator. The anticipated monitoring frequency will be stated in the Monitoring Plan. 
Monitoring will also involve, as appropriate, correspondence and telephone contacts. 
On-site monitoring includes source data verification (SDV) which is the procedure whereby the 
data contained in the eCRFs are compared with the primary source data and thereby verified 
as accurate. It will be performed in such a way as to preserve subject confidentiality, taking 
into account all ethical and legislative requirements. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during the monitoring visit to review the data and resolve any queries and to allow direct 
access to the subject’s records for SDV).  
SDV will include as a minimum verification for all subjects, subject identity (date of birth, sex, 
initials and subject number), record of entry into the study and signature of the informed 
consent. In addition, details of SAEs in the subject’s notes will be verified. Details included in 
the subject’s notes as a minimum: 
 
Study number, brief description or title of study 
 
Date that the subject gave written consent 
 
All visit dates 
 
All SAEs 
 
All concomitant medications 
At a site visit the eCRFs should be complete and available in order that the accuracy of their 
completion may be checked. Each completed eCRF for each subject must be signed 
electronically by the Investigator, to verify the data and statements submitted. Similarly, all 
alterations on paper records must be initialled and dated by the Investigator or a designated 
person, explained as necessary, with the original mistake left legible. 
11.2 
Audits and Inspections 
For the purpose of ensuring compliance with the protocol, ICH GCP and applicable regulatory 
requirements, clinical studies sponsored by RB may be subject to an independent audit at the 
study site which will be conducted by personnel from an appropriate Quality Assurance Unit. 
Full consultation with the Investigator will be made prior to and during such audit, which will be 
conducted according to Quality Assurance Unit Standard Operating Procedures. 
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Study No: 5003601 
Protocol Version: 22 August 2018, draft 
Version 0.17 
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As soon as the Investigator is notified of a planned inspection by a Regulatory Authority, he / 
she must inform the Sponsor promptly and allow the Sponsor to participate in the inspection 
as permitted by applicable regulations and local laws. 
11.3 
Sponsor Policy on Fraud in Clinical Studies 
In accordance with GCP, it is the Sponsor’s policy to always follow-up suspected cases of 
fraud. 
12 
ETHICAL AND REGULATORY ASPECTS 
12.1 
Ethics Review and Regulatory Authority Approval 
Written approval to conduct the study by an independent and appropriately constituted IRB 
must be obtained and a copy provided to the Sponsor before any protocol-related procedures 
that do not form part of the subject’s normal clinical treatment are performed. The approval 
letter must contain: 
 
Name and address of the IRB. 
 
Date of meeting. 
 
Sufficient information to identify the version of the Protocol and subject 
information/informed consent. 
 
Sufficient information to identify the version of other documents reviewed. 
The investigator must also provide the Sponsor with a list of IRB members that includes each 
member’s name and profession. 
Any amendments to the Protocol must be submitted to the IRB for approval unless where 
necessary to eliminate apparent immediate hazards to study subjects, and any administrative 
changes must be notified.  
This study will be submitted to the applicable Regulatory Authorities. The study will only be 
undertaken when regulatory authorisation has been obtained by the Sponsor. 
The Sponsor will notify the Regulatory Authority within 90 days of the end of the study (within 
15 days if the study is terminated prematurely). 
Premier Research will notify the IRB within 90 days of the end of the study (within 15 days if 
the study is terminated prematurely). 
12.2 
Subject Information and Consent 
Informed consent should be obtained by means of a patient information sheet and ICF, 
prepared in accordance with ICH E6 (R2) section 4.8.10 and the applicable local regulations, 
written in a non-technical language.  All subjects will be provided with oral and written 
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CLINICAL STUDY PROTOCOL 
Study No: 5003601 
Protocol Version: 22 August 2018, draft 
Version 0.17 
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D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
information describing the nature and duration of the study and the procedures to be 
performed.  The subject will be asked to sign and date an ICF prior to any study-specific 
procedures being performed.  No subject can enter the study before his/her informed consent 
has been obtained.  A sample subject ICF used in the study will be included in the clinical study 
report for this protocol.  
As part of administering the informed consent document, the Investigator must explain to each 
subject the nature of the study, its purpose, the procedures involved, the expected duration, 
the potential risks and benefits involved, and any potential discomfort.  Each subject must be 
informed that participation in the study is voluntary and that he/she may withdraw from the 
study at any time and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician.  The subject should understand the study, 
patient information sheet, and ICF before signing and dating the ICF.  The Investigator or 
person obtaining consent must also sign and date the form.  Each subject will be given a copy 
of the signed informed consent and written information. 
12.3 
Early / Premature Termination of the Study 
In the unlikely event that this study generates an excessive frequency of adverse events, 
subjects’ termination or suspension may be requested by the sponsor or the IRB or the 
Regulatory Authority. 
The sponsor retains the right to terminate the study for non-safety reasons by giving an 
appropriate period of notice to all involved parties as per contractual agreements. 
Any decisions to terminate or suspend the study will be notified in writing to the Investigator or 
designees, the IRB, Regulatory Authority and the clinicaltrials.gov database. 
If the study is terminated early, study subjects who have attended screening will be informed 
that they are no longer required and if they have any questions, they should consult the study 
site staff. For subjects who have completed the study they will not be informed that the clinical 
study has been terminated. All data collected up to the point of study termination will be used 
in an abbreviated Clinical Investigation Report.  
13 
COMPENSATION, INDEMNITY AND INSURANCE 
13.1 
Clinical Study Agreement 
Before the study commences, a contract between the Sponsor and Premier Research, who 
contracts with the Investigator, will be signed in which financial aspects of the study (including 
financial disclosure) as well as responsibilities and obligations are described. 
13.2 
Compensation 
The Sponsor and the CRO carry insurance to pay compensation for injury, accident, ill health 
and death caused by participation in this study without regard to proof of negligence in 
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CLINICAL STUDY PROTOCOL 
Study No: 5003601 
Protocol Version: 22 August 2018, draft 
Version 0.17 
Page 62 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
accordance with the current local regulations and requirements. Details on finance and 
insurance will be provided in a separate agreement between the investigator and the sponsor.  
13.3 
Indemnity 
The Sponsor will provide appropriate indemnity for the Investigator and staff who conduct part 
or all of this study, upon request. The request must be received before the first subject is 
recruited. 
13.4 
Insurance 
If required and in accordance with applicable regulatory and legal requirements, the Sponsor 
will take out appropriate insurance policies on behalf of the Investigator and staff who conduct 
part or all of this study and/or on behalf of the subjects participating in the study. 
14 
REPORTING, PUBLICATION AND PRESENTATION 
A clinical study report will be prepared according to ICH E3 (Structure and Content of Clinical 
Study Reports) as part of the Sponsor’s commitment to Good Clinical Practice. The report will 
be a record of the total study conduct and findings and will be subject to approval by the 
Investigator who will sign the final report. 
The study data will be owned by the Sponsor. The Sponsor retains the right to publish the data 
independently of the Investigator. The Sponsor agrees that before it publishes the results, it 
will provide the Investigator with at least 30 days for full review prior to submission of the 
manuscript to the publisher. The Investigator must submit any proposed manuscript to the 
Sponsor for approval prior to submission for publication. 
15 
REFERENCES 
(1) Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of 
changes in chronic pain intensity measured on an 11-point numerical pain rating scale. 
Pain. 2001 Nov;94(2):149-58. 
(2) Summary of Product Characteristics for Nurofen 200 mg tablets Reckitt Benckiser 
Healthcare Ltd. (PL 00063/0385). 09 November 2015. 
(3) Davies, NM Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin. 
Pharmacokinet. 1998, 34 (2), 101-154. 
(4) Lisa Miles, Jessica Hall, Bartosz Jenner, Richard Addis & Simon Hutchings (2018) 
Predicting rapid analgesic onset of ibuprofen salts compared with ibuprofen acid: Tlag, 
Tlow, Tmed, and a novel parameter, TCmax Ref, Current Medical Research and 
Opinion, DOI: 10.1080/03007995.2018.1466697. 
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Study No: 5003601 
Protocol Version: 22 August 2018, draft 
Version 0.17 
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(5) Cooper SA, Desjardins PJ, Turk DC, et al. Research design considerations for single-
dose analgesic clinical trials in acute pain: IMMPACT recommendations. Pain. 2016 
Feb;157(2):288-301. doi: 10.1097/j.pain.0000000000000375. 
(6) Wyeth Consumer Healthcare. (2002). NDAC Meeting on Risks of NSAIDs. Available: 
https://www.fda.gov/ohrms/dockets/ac/02/briefing/3882b2_04_wyeth-ibuprophen.htm. 
Last accessed 13th March 2018 
(7) Singla, Neil Kumar et al. “A comparison of the clinical and experimental characteristics 
of four acute surgical pain models: Dental extraction, bunionectomy, joint replacement, 
and soft tissue surgery.” PAIN® 155 (2014): 441-456. 
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SAP_001.pdf: 
Reckitt Benckiser 
Study Information 
Clinical Study Report 5003601 
AD-MW-36.04 18-Jun-2019 
CONFIDENTIAL 
Documentation of Statistical Methods 
Statistical Analysis Plan, Amendment 3.0, dated 20-May-2020 
Table, Listing, and Figure Shells, Amendment 3.0, dated 20-May-2020 
Statistical Analysis Plan, Amendment 2.0, dated 18-May-2020 
Table, Listing, and Figure Shells, Amendment 2.0, dated 18-May-2020 
Statistical Analysis Plan, Amendment 1.0, dated 24-Feb-2020 
Table, Listing, and Figure Shells, Amendment 1.0, dated 28-Feb-2020 
Final Statistical Analysis Plan, Final Version 1.0, dated 07-Oct-2019
Page 1 of 351


I
Statistical Analysis Plan
Sponsor Reckitt Benckiser
Protocol Number 5003601
PCN Number RECK.177035
trremler 1
' re%ffarcn j
Sponsor
Reckitt Benckiser
Protocol Title:
A Randomized, Double-Blind, Double-Duffiffiy, Parallel-
Group, Multiple-Dose, Active and Placebo-Controlled
Efficacy Study of Ibuprofen Prolonged-Release Tablets for
the Treatment of Pain after Surgical Removal of Impacted
Third Molars
Pyotocol Number:
500360 1
Premier Research
PCN:
RECK.177035
Document Version:
Amendment 3.0
Document Date:
20-May-2020
Approvals
,Biostatistician
Premier Research
Print Name: Raghu Vishnubhotla
Sign Name:
Reckitt Benckiser
Representative
Print Name: Darren Tarsett
Ll-,tv|4vl*Lo2o
Sign Name:
21-May-2020 | 15:35:57 EDT
Page 2 of 351


Statistical   Analysis Plan,  
Sponsor Reckitt Benckiser 
Protocol Number 5003601 
PCN Number RECK.177035
Version 1.0  
 Page 2 of 42 
Document History 
Reasons for Amendment 1 
 The statistical analysis plan was amended in the following ways: 
1. The sensitivity analyses for the primary efficacy endpoint has been updated. A pattern-
mixture model with control-based pattern imputation will now be used.
2. A comparison of individual NRS pain intensity difference scores has been added. P-
values comparing the treatment arms (PR vs Placebo, IR vs Placebo) has been added.
3. Pain relief scores at each time point will be summarized and by p-values will be added
for treatment comparison.
Reasons for Amendment 2 
 The statistical analysis plan was amended in the following ways: 
1. Add clarification for how pain assessments recorded within 4-hours of rescue medication
and missing pain assessments are handled in the repeated measures analysis of pain
intensity difference and pain relief scores.
2. The sensitivity analyses for the primary efficacy endpoint have been further updated. A
multiple imputation model under a Missing at Random (MAR) assumption has been
added to account for missing data due to patient withdrawal, missing intermediate pain
assessments and pain assessments impacted by rescue medication.
3. Sensitivity analyses have been added for the key secondary endpoint SPID24.
4. Updated methodology for handling pain assessments post non-permitted rescue
medications. Added imputation windows for non-permitted rescue medications.
Reasons for Amendment 3 
 The statistical analysis plan was amended in the following ways: 
1.
Amend the analysis of pain relief at each time point to use a mixed model repeated
measures analysis. It is considered that the assumptions underlying the proportional
odds analysis at each and every time point is unlikely to be upheld. Since pain relief
is measured on a 5-point ordinal scale, it is deemed acceptable to treat this as a
continuous variable for purposes of analysis.
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Statistical   Analysis Plan,  
Sponsor Reckitt Benckiser 
Protocol Number 5003601 
PCN Number RECK.177035
Version 1.0  
 Page 3 of 42 
2.
Corrected a typographical error in section 6.1.4, where section 8.2.12 should be
referenced rather than 8.1.12.
3.
In the event that imposing a specified range for imputed values leads to an error in the
multiple imputation process, included the option to remove the restrictions on
imputed values as part of the multiple imputation process, and then enforce them
separately after the imputation is performed if necessary.
4.
Added that if the proportional odds assumptions are violated, a non-proportional odds
model will be explored. Also added clarification that in the proportional odds models,
the lowest level of the categorization of the dependent variable will be the reference
category, such that the probability of the higher response levels will be modelled.
5.
Updated the version of MedDRA that is used.
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Statistical   Analysis Plan,  
Sponsor Reckitt Benckiser 
Protocol Number 5003601 
PCN Number RECK.177035
Version 1.0  
 Page 4 of 42 
Table of Contents 
Approvals................................................................................................................................ 1 
Document History ................................................................................................................... 2 
Table of Contents .................................................................................................................... 4 
List of Tables .......................................................................................................................... 6 
1.
Overview ..................................................................................................................... 7 
2.
Study Objectives and Endpoints.................................................................................... 7 
2.1. 
Study Objectives .................................................................................................... 7 
2.1.1. Primary Objective................................................................................................... 7 
2.1.2. Secondary Objectives ............................................................................................. 7 
2.2. 
Study Endpoints ..................................................................................................... 8 
2.2.1. Safety Endpoints .................................................................................................... 8 
2.2.2. Efficacy Endpoints ................................................................................................. 8 
3.
Overall Study Design and Plan ..................................................................................... 9 
3.1. 
Overall Design ....................................................................................................... 9 
3.2. 
Sample Size and Power........................................................................................... 9 
3.3. 
Study Population .................................................................................................... 9 
3.4. 
Treatments Administered ........................................................................................ 9 
3.5. 
Method of Assigning Subjects to Treatment Groups ................................................ 9 
3.6. 
Blinding and Unblinding......................................................................................... 9 
3.7. 
Schedule of Events ................................................................................................11 
4.
Statistical Analysis and Reporting................................................................................14 
4.1. 
Introduction...........................................................................................................14 
4.2. 
Interim Analysis ....................................................................................................14 
5.
Analysis Populations ...................................................................................................14 
6.
General Issues for Statistical Analysis ..........................................................................15 
6.1. 
Statistical Definitions and Algorithms ....................................................................15 
6.1.1. Baseline ................................................................................................................15 
6.1.2. Adjustments for Covariates ....................................................................................15 
6.1.3. Multiple Comparisons ...........................................................................................15 
6.1.4. Handling of Dropouts or Missing Data ...................................................................15 
6.1.5. Adjustment of Pain Scores for Rescue Medication Use ...........................................16 
6.1.6. Sensitivity Analysis of SPID12 and SPID24 ...........................................................16 
6.1.7. Derived Variables..................................................................................................19 
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Statistical   Analysis Plan,  
Sponsor Reckitt Benckiser 
Protocol Number 5003601 
PCN Number RECK.177035
Version 1.0  
 Page 5 of 42 
6.1.8. Data Adjustments/Handling/Conventions ...............................................................23 
7.
Study Patients/Subjects and Demographics ..................................................................24 
7.1. 
Disposition of Patients/Subjects and Withdrawals ...................................................24 
7.2. 
Protocol Violations and Deviations ........................................................................24 
7.3. 
Demographics and Other Baseline Characteristics ..................................................24 
7.4. 
Exposure and Compliance......................................................................................24 
8.
Efficacy Analysis ........................................................................................................24 
8.1. 
Primary Efficacy Analysis .....................................................................................24 
8.2. 
Secondary Efficacy Analysis..................................................................................25 
8.2.1. SPID .....................................................................................................................25 
8.2.2. TOTPAR...............................................................................................................25 
8.2.3. SPRID ..................................................................................................................26 
8.2.4. Peak Pain Relief ....................................................................................................26 
8.2.5. Time to First Perceptible Pain Relief ......................................................................26 
8.2.6. Time to Meaningful Pain Relief .............................................................................26 
8.2.7. Time to onset of Analgesia.....................................................................................27 
8.2.8. Time to Peak Pain Relief .......................................................................................27 
8.2.9. Time to first use of Rescue Medication...................................................................27 
8.2.10. Proportion of Responders.......................................................................................28 
8.2.11. Numeric rating scale (NRS) pain intensity difference (PID) ....................................28 
8.2.12. Pain relief at each scheduled time point ..................................................................28 
8.2.13. Proportion of Subjects Rescue Medication..............................................................29 
8.3. 
Exploratory Efficacy Analysis................................................................................29 
8.3.1. Global Evaluation of Study Drug ...........................................................................29 
9.
Safety and Tolerability Analysis ..................................................................................29 
9.1. 
Adverse Events .....................................................................................................29 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................30 
9.1.2. Deaths and Serious Adverse Events........................................................................30 
9.2. 
Clinical Safety Laboratory Data .............................................................................30 
9.3. 
Vital Signs ............................................................................................................31 
9.4. 
Concomitant Medication........................................................................................31 
9.5. 
Rescue Medication use ..........................................................................................31 
10.
Changes to analysis planned in the protocol .................................................................31 
11.
References ..................................................................................................................31 
12.
Tables, Listings, and Figures .......................................................................................32 
12.1. 
Planned Table Descriptions....................................................................................33 
12.2. 
Efficacy Data ........................................................................................................33 
12.3. 
Safety Data............................................................................................................35 
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Statistical   Analysis Plan,  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 6 of 42 
 
12.4. 
Planned Listing Descriptions..................................................................................36 
12.5. 
Planned Figure Descriptions ..................................................................................37 
Appendix 1: Premier Research Library of Abbreviations..........................................................38 
 
 
 
List of Tables 
Table 1: Schedule of Events ....................................................................................................12 
Table 2 Planned Assessment Times .........................................................................................19 
Table 3: Demographic Data Summary Tables ..........................................................................33 
Table 4: Efficacy Tables .........................................................................................................33 
Table 5: Safety Tables ............................................................................................................35 
Table 6: Planned Listings........................................................................................................36 
Table 7: Planned Figures.........................................................................................................37 
 
 
 
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Statistical   Analysis Plan,  
Sponsor Reckitt Benckiser 
Protocol Number 5003601 
PCN Number RECK.177035
Version 1.0  
 Page 7 of 42 
1.
Overview
This statistical analysis plan (SAP) describes the planned analysis and reporting for Reckitt 
Benckiser protocol number 5003601 (A Randomized, Double-Blind, Double-Dummy, Parallel-
Group, Multiple-Dose, Active and Placebo-Controlled Efficacy Study of Ibuprofen Prolonged-
Release Tablets for the Treatment of Pain after Surgical Removal of Impacted Third Molars), 
dated 19-Nov-2019, version 3.0. Reference materials for this statistical plan include the protocol 
and the accompanying sample data collection documents. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials1. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to Reckitt Benckiser’s study 
5003601. 
2.
Study Objectives and Endpoints
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is: 
•
To evaluate the superiority of 2 x 300 mg ibuprofen PR tablets compared with placebo in
subjects experiencing acute moderate to severe pain after third molar extraction over 12
hours post initial dose.
2.1.2. Secondary Objectives 
The key secondary objectives are: 
•
To evaluate the analgesic performance of a total daily dose of 1200 mg of ibuprofen PR
formulation compared to ibuprofen immediate release (IR) formulation over 24 hours
post initial dose.
•
To evaluate the safety and tolerability of 2 x 300 mg ibuprofen PR tablets.
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Statistical   Analysis Plan,  
Sponsor Reckitt Benckiser 
Protocol Number 5003601 
PCN Number RECK.177035
Version 1.0  
 Page 8 of 42 
Additional secondary objectives include: 
•
To evaluate the total analgesic effect, peak analgesic effect, onset and duration of action
and the subject’s overall assessment of the study medications.
2.2. 
Study Endpoints 
2.2.1. Safety Endpoints 
The safety endpoints of this study include the following: 
•
Incidence of treatment-emergent adverse events (TEAEs)
•
Incidence of changes in vital sign measurements
2.2.2. Efficacy Endpoints 
2.2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the summed pain intensity difference (SPID) over 
0 to 12 hours (SPID12).  
2.2.2.2. 
Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints of this study include the following: 
•
Summed pain intensity difference (SPID) over 0 to 24 hours (SPID24) after Time 0.
•
SPID4, SPID8 and SPID12
•
Sum of total pain relief (TOTPAR) over 0 to 4 hours (TOTPAR4), over 0 to 8 hours
(TOTPAR8), over 0 to 12 hours (TOTPAR12) and over 0 to 24 hours (TOTPAR24) after
Time 0.
•
Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over
0 to 4 hours (SPRID4), over 0 to 8 hours (SPRID8), over 0 to 12 hours (SPRID12) and
over 0 to 24 hours (SPRID24) after Time 0.
•
Response to study drug
•
Numeric rating scale (NRS) pain intensity difference (PID) at each scheduled timepoint
after Time 0. NRS ranges from 0=no pain to 10=worst pain ever and pain relief is a 5
point categorical scale 0=none, 1=a little, 2=some, 3=a lot, 4=complete. PID is the
difference in NRS pain intensity between each time point and Time 0.
•
Pain intensity score at each scheduled time point after Time 0.
•
Pain relief at each schedule time point after Time 0.
•
Peak pain relief
•
Time to onset of analgesia
•
Time to first perceptible pain relief
•
Time to meaningful pain relief
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Statistical   Analysis Plan,  
Sponsor Reckitt Benckiser 
Protocol Number 5003601 
PCN Number RECK.177035
Version 1.0  
 Page 9 of 42 
•
Time to peak pain relief
•
Proportion of subjects using rescue medication
•
Time to first use of rescue medication
2.2.2.3. 
Exploratory Endpoint 
•
Patient’s global evaluation of study drug. It is measured on a scale of 0=poor, 1=fair,
2=good, 3=very good, 4=excellent
3.
Overall Study Design and Plan
3.1. 
Overall Design 
3.2. 
Sample Size and Power 
The sample size determination is based on the primary efficacy variable, SPID12.  According to 
Farrar 2001, a clinically important improvement in pain is represented by a 2 point reduction on 
an 11-point NRS.  Based on a baseline pain score of 7 this corresponds to an approximate 30% 
reduction in pain.  An average 2 point difference in pain scores between ibuprofen PR and 
placebo across all 14 assessments up to 12 hours will correspond to a difference in SPID12 of 24 
points.  In a previous study, the pooled standard deviation (SD) for SPID12 was 31.65.  
Assuming the same variability in this study, a sample size of 40 subjects per group will have 
>90% power to detect a difference of 24 points in SPID12, between ibuprofen 2x300-mg PR
tablets and placebo using a 2-sided test with an alpha level of 0.05.  In order to provide a robust
estimate of treatment effect differences between PR and IR, and to obtain a more precise
estimate for this comparison, a 3:3:1 allocation ratio will be used, so that 120 subjects are
randomized into each of the PR and IR groups.  Thus 280 subjects will be enrolled in the study.
3.3. 
Study Population 
Subjects with moderate to severe pain after extraction of 2 or more third molars will participate 
in this study. 
3.4. 
Treatments Administered 
Treatment A (test product): 2x300 mg ibuprofen PR tablets, BID (total daily dose 1200 mg) 
Treatment B (reference product): 2x200 mg ibuprofen IR tablets, TID (total daily dose 1200 mg) 
Treatment C: matching placebo tablets 
3.5. 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be randomized in a 3:3:1 ratio to receive 2x300 mg ibuprofen PR tablets 
Q12h, 2x200 mg ibuprofen IR Q8h, or placebo using permuted blocks of fixed size.  The 
randomization will be stratified by baseline pain category (moderate or severe) using a 
categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and severe 
(8-10).  The randomization schedule will be prepared by a statistician not otherwise involved in 
the study.  Randomization will be performed using an interactive response system (IRT).   
3.6. 
Blinding and Unblinding 
This is a double-blind, double-dummy study. There will be two placebo tablets designed to be 
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Statistical   Analysis Plan,  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 10 of 42 
 
comparable to each of the active products (PR and IR) in both shape, size, color and weight. 
All subjects will receive 4 tablets at each dosing timepoint.  All subject packs will be designed 
and labelled to ensure blinding is maintained. 
Access to the unblinding codes will be restricted to personnel not otherwise involved in the study 
and will be available to the investigator only in the case of a subject requiring unblinding prior to 
database lock.  
Unblinding will only occur after database lock or in the case of emergency unblinding. 
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Statistical   Analysis Plan,  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 11 of 42 
 
 
 
 
3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1. 
 
 
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Statistical   Analysis Plan,  
 
Sponsor Reckitt Benckiser 
 
Protocol Number 5003601 
 
PCN Number RECK.177035
Version 1.0  
 Page 12 of 42 
Table 1: Schedule of Events 
Page 13 of 351
I 
Sc,reening 
(Day -28 to 
Day -1) 
Pre-
Surgery 
Pre-
dose 
Written informed consent 
X 
Assign a screening number 
X 
In clu siontexclus ion criteria 
X 
X 
Demographics 
X 
Medical llistory 
X 
Xb 
Physical examination° 
X 
Vital signsd 
X 
X 
X 
Height, weighl and BMI 
X 
Clinical laboratory tests (hematology, 
X 
chemistry, urinalysis) 
Electrocardiogram 
X 
Pregnancy test for female subjects of 
X 
X 
childbearing potentiale 
Urine drug screen 
X 
X 
Alcohol breatllalyzer test 
X 
Oral radiography1 
X 
Review study restrictions with subject 
X 
Pain intensity (NRS )9' 
X 
Randomisation 
X 
Dosing with study drug 
Stopwatch assessment" 
Pain relief (5-point categoriic.al scale)g 
Surgery (Day 1) 
Post-op 
1, 1.5, 2, 3, 4, 
15, 30, 
5, 6, 7, 8, 
0 1!1 
45min 
10 h 
12 1!1 
X 
X 
X 
X 
Oh 
8h 
12 h 
X 
X 
X 
X 
Day2 
16 
Ill 
24h 
X 
X 
X 
16h 
X 
premier' 
research} 
Follow-up 
(Day 8 ±2 days) or 
ETk 
X 
X 


 
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I 
Sc,reening 
(Day -28 to 
Day -1) 
Pre-
Surge1ry 
Pre-
dose 
Global evaluation of study drug; 
Concomitant medications 
Xb 
X 
Adverse eventsi 
X 
X 
Dispense/prescribe pain medication for use at 
home, as needed 
Collect unused home pain medications, as 
needed 
Discharge from study site 
Surgery (Day 1) 
Post-op 
1, 1.5, 2, 3, 4, 
15, 30, 
5, 6, 7, 8, 
Oh 
45 min 
10 h 
X 
X 
X 
X 
X 
X 
12 h 
X 
X 
Day 2 
16 
premier' 
research} 
Follow-up 
(Day 8 ±2 days) or 
ETk 
h 
24h 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BMl=body mass index: ET=-early termination: h=hour, min=minute; NRS=numeiric rating scale; pre-op=pre-operative; post-op=post-operative _ 
a Times listed are relative to dosing wilh study drug. 
b Medical history and concomitant medication use since Screening will be updated on Day 1 before surgery 
c A complete physical examination (excluding the geniitourinary examination) will be performed at Screening. An abbreviated confirmatory physical assessment, 
including an exam ination of tile subject's mouth and neck, will be performed at tile Follow-up Visit (or Early Term ination Visit). 
d Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at tile following times: at screening, before surgery, within 30 minutes 
before Tiime 0, ·12 ti ours after Time 0_, 24 hours after Time O, and/or immediately before the first dose of rescue medication, and at tile Follow-up Visit (or Early 
Termination Visit). 
e Serum pregnancy test at Screening and urine pregnancy test before surgery on Day 1 (female subjects of childbearing potential only). Test results must be 
negative for the subject to continue in the study. 
f 
Oral radiographs taken within 1 year before Screening will be acceptable and do not need to be repeated. 
g Pain assessments will be conducted (pre-dose, if at one of tile dosing timepoints of O, 8, 12 or 16 hours) at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 
8, 10, 12, 16 and 24 llours after Time o and immediately before each dose of rescue medication. Pain intensity will also be assessed pre-dose. At each 
assessment time point, the pain intensity assessment will be completed first and the pain relief assessment will be completed second. Subjects will not be 
able to compare their responses with lheir previous responses. Note for assessments less than 1 hour apart a window of +/-2 min is allowable wll ilst for 
assessments at least 1 llour apart a +l-5 min window is allowable. 
h Two stopwatches will be started immediately after the subject has swallowed the first dose of study drng with 8 ounces of water {Time O). Subjects will record 
the time to perceptible and meaningful pain relief, respectively, by stopping the stopwatches. 


 
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4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population in each of the treatment arms, unless otherwise specified. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests. In addition to what is detailed in the SAP, other additional 
analyses may be conducted on the data which will only serve as exploratory evidence and the 
unplanned nature of these analyses will be made clear in the Clinical Study Report. 
4.2. 
Interim Analysis 
No interim analyses are planned. 
5. 
Analysis Populations 
The following analysis populations are planned for this study: 
• Safety Population (SAF): The Safety Population includes all subjects who receive any 
amount of planned study medication. Subjects will be assigned to treatment received. 
• Intent-To-Treat Population (ITT): The ITT population includes all subjects who are 
treated with study drug and who have at least 1 pain assessment after Time 0.  The ITT 
population is the primary population for the efficacy analysis. Subjects will be assigned 
to treatment randomized. 
• Per Protocol (PP): The PP Population will consist of all ITT subjects who do not incur a 
major protocol violation that would challenge the validity of their data.  This population 
will be determined at a data review meeting prior to database lock and used to evaluate 
the sensitivity of the primary efficacy analysis. Subjects will be assigned to treatment 
received. 
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6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last observation recorded prior to the first dose of study drug will be used as the baseline 
observation for all calculations of change from baseline.  
6.1.2. Adjustments for Covariates 
For the primary endpoint analysis, the baseline NRS pain score will be included as a covariate. 
For the secondary endpoint analyses, baseline pain will be included as a covariate for SPID, 
SPRID, and TOTPAR variables.   
For the proportion of subjects who are responders and the proportion of subjects using rescue 
medication, logistic regression models will adjust for baseline pain. 
For time to event endpoints, baseline pain will be included as a stratification factor.  
6.1.3. Multiple Comparisons 
No adjustment for multiplicity is required for the primary efficacy analysis – a single comparison 
of SPID12 for placebo versus SPID12 for ibuprofen PR. 
No adjustments will be made for multiple comparisons for other endpoints. 
6.1.4. Handling of Dropouts or Missing Data 
Missing pain assessments for all efficacy analyses will be handled as follows: 
• Missing pain assessments scheduled before the first observed assessment will be imputed 
with the subject’s worst observed pain assessment. 
• Missing intermediate pain assessments will be replaced by linear interpolation. 
• Missing pain assessments at the end of the observation period due to premature 
discontinuation of pain assessments will be imputed by carrying forward the last 
observation prior to that missing. 
All data for assessments other than pain assessments will be analyzed as collected; missing data 
due to premature termination or any other reason will be left as missing. Since this is a short-
term study and subjects remain at the study site throughout the 24-hour pain assessment period, 
the discontinuation rate and the amount of missing data is expected to be minimal.   
A number of sensitivity analyses will be performed in order to evaluate the efficacy under 
various different assumptions regarding missing data and are described in Section 6.1.6  
The exceptions to the above data handling rules are the descriptive summaries and repeated 
measures analyses by timepoint for pain intensity difference and pain relief, described in sections 
8.2.11 and 8.2.12. In these repeated measures analyses, missing values are indirectly imputed 
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under an assumption of missing at random, and so missing pain assessments will not be 
explicitly imputed prior to analysis. 
6.1.5.  Adjustment of Pain Scores for Rescue Medication Use 
Subjects are required to record their pain assessment (NRS and pain relief) immediately prior to 
each dose of rescue medication permitted in the protocol (1000mg paracetamol/acetaminophen or 
5mg oxycodone). The primary analysis will use windowed worst observation carried forward 
(WOCF) methodology for subjects who use rescue medication.  If a subject received rescue 
medication at time x, for any time point within x + 4 hours, the highest pain score from time 0 up 
until time x will be used. If the pain score for the windowed observation is higher than the worst 
observed score, it will not be replaced.  The same approach will be used for pain relief scores. 
Subject who received other drug and non-drug therapies during the treatment period will be 
evaluated on a case-by-case basis at a data review meeting, prior to database lock. If these therapies 
are considered to modulate the pain response, the same approach described above will be used to 
replace pain intensity and pain relief scores within a 4-hour time window after medication was 
taken. The windowed WOCF method to adjust pain scores for subjects who use rescue medication 
is consistent with the hypothetical strategy estimand, where the intercurrent event is use of rescue 
medication, and will be the approach used for the primary efficacy analysis [5]. 
6.1.6. Sensitivity Analysis of SPID12 and SPID24 
The following sensitivity analyses will also be performed for the primary endpoint SPID12 if any 
pain assessments are missing or if subjects take rescue medication. Each of these are consistent 
with the hypothetical strategy estimand, with the exception of analysis number 3, which uses the 
treatment policy strategy estimand. 
 
1. Missing data and values after rescue medication handled as per the main analysis but 
based on the PP population. 
2. Missing data imputed using WOCF (worst observed pain score at any timepoint, 
including baseline). Values after rescue medication handled as per the main analysis. 
3. Missing data handled as per the main analysis. Pain assessments are used regardless of 
whether rescue medication has been taken, and no adjustment is made for use of rescue 
medication.  In this analysis, the pain assessment recorded at the time of rescue 
medication is disregarded (unless it coincides with a planned pain assessment).  
4. Missing data handled as per the main analysis. All pain assessments recorded after the 
first dose of rescue medication has been taken will be disregarded. WOCF, LOCF (Last 
Observation Carried Forward) and multiple imputation methods will then be used to 
impute the disregarded data. 
a. WOCF - The worst (highest) pain assessment (including baseline) until first dose 
of rescue medication will be used to impute all subsequent pain assessments. In 
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other words, this method would be treating the subject as if they got no worse 
than their worst observed value prior to rescue medication.  
b. LOCF - In this LOCF analysis, the pain assessment taken immediately prior to/at 
the time of rescue medication will be taken as the last observed score, i.e., this 
method would be treating the subject as if they got no worse than their last 
observed value prior to rescue medication. 
c. Multiple Imputation under a MAR assumption. Data will be imputed separately 
for each treatment group, using a Markov Chain Monte Carlo (MCMC) method 
for full imputation, with covariates for baseline and pain scores observed at each 
assessment. The methodology described in sensitivity analysis 6 below will be 
used. In this analysis, the pain assessment recorded at the time of rescue 
medication is disregarded (unless it coincides with a planned pain assessment). 
5. Missing data imputed using multiple imputation (methodology described below). Values 
after rescue medication handled as per the main analysis. 
For sensitivity analysis 5, a pattern-mixture model with control-based pattern imputation will be 
used. This model assumes that after withdrawal from the study, subjects from the experimental 
group (no longer receiving active treatment) will exhibit the same future evolution of pain scores 
as subjects in the placebo group (who are also not exposed to active treatment). Subjects that 
discontinue from the placebo group are assumed to evolve in the same way as placebo subjects 
that remain in the study. This imputation assumes that intermittent missing values are missing at 
random (MAR), and that values that are missing due to withdrawal are missing not at random 
(MNAR). When data are MAR, the missingness of the data does not depend on the missing value 
after conditioning on the observed data (i.e., prior assessments and baseline covariates). Note 
that when the missingness of the data depends on the values of the missing variables after 
conditioning on the observed data, the data are called “missing not at random” (MNAR).  In 
order to assess the MAR assumption, a placebo-based pattern mixture model (PMM) will be 
utilized following the steps outlined in Ratitch B and O’Kelly, M.J. (2011) for SPID-12. 
 
Briefly, the strategy for implementing this approach is as follows for subjects with 
missing data: 
i. 
Impute all non-monotone (intermittent) missing data using the MCMC method of 
PROC MI.  Note that this imputation will sample data within each treatment 
group.  Note that PIi is the NRS pain intensity at time Ti as mentioned in Section 
6.1.7. SAS pseudo code is provided below. With MCMC option, SAS does 200 
burn-in iterations (default) before each imputation. 
PROC MI DATA=example seed = xxxx NIMPUTE = 20 OUT = outdata1 minimum=0 maximum=10; 
 
by <treatment>; 
 
MCMC chain=multiple impute=monotone; 
 
VAR  <PI0> <PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>; 
RUN; 
 
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ii. 
Using the imputed datasets from Step #1 that are now monotone missing (no 
intermittent missing data), a single call to PROC MI (including the MNAR 
statement) will be utilized to impute the monotone missing data.  Additional 
details are provided below. 
a. Within the call to PROC MI, one timepoint is imputed at a time.  The 
order in which pain scores are imputed will be PI0, then PI0.25...,PI12 
b. When imputing at timepoint t, the imputation step will include all placebo 
subjects, but only those from the active arms that have a value missing at 
timepoint t. Subjects with non-missing data that are on active arms will 
not contribute to the estimation for this step. 
c. Repeat the above step for all timepoints t. Thus, the data for timepoint t+1 
uses the data imputed from previous timepoints. 
SAS pseudo code is provided below.  SAS accomplishes this iterative process in one step.  Note 
that the treatment level 3 is the placebo treatment group. The MNAR statement imputes missing 
values for scenarios under the MNAR assumption. The MODEL option specifies that only 
observations in which treatment=3 are used to derive the imputation model for the pain score that 
time point. The minimum and maximum options are used to ensure that every pain score imputed 
ranges from 0-10. If forcing a specified range on the imputed values results in a SAS error of 
“imputed values to be out of range”, the minimum and maximum options will be removed in a 
step-wise way, and the imputed values will be unrestricted. Once all values have been imputed, 
the desired range limits will be enforced separately after the imputation is performed if 
necessary, by replacing values >10 with 10 and values <0 with 0. The rationale is to ensure that 
all values are clinically possible (i.e. in the range of possible values present on the 0-10 
numerical rating scale), and furthermore values outside the 0-10 range would likely have a larger 
impact on the resultant SPID values. 
PROC MI DATA=OUTDATA1 seed = xxxx NIMPUTE = 1 OUT = outdata2 MINIMUM=. 0..0   
MAXIMUM=. 10 10…10; 
BY _IMPUTATION_; 
CLASS <treatment>; 
MONOTONE REG (/ details); 
MNAR MODEL (PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>/ modelobs=(<treatment=’3’>)); 
VAR  <PI0> <PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>; 
RUN; 
 
 
 
iii. 
When all missing PI scores are imputed, SPID12 will be derived as described in 
6.1.7 and analyzed using the ANCOVA models as described in Section 8.1.  
PROC MIANALYZE will be used to combine the parameters from the analyses 
for inference. 
6. Missing data and values within the defined window after rescue medication are imputed 
using multiple imputation (methodology described below). 
For sensitivity analysis 6, a multiple imputation model under a MAR assumption will be used. 
This assumes that the missingness of the data does not depend on the missing observations after 
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conditioning on the observed data (i.e., prior assessments and baseline as covariates). This is 
considered a reasonable assumption since patients are encouraged to use rescue medication only 
if needed (i.e. high pain scores), and thus it can be expected that the intercurrent event of rescue 
medication depends on the observed data (i.e. rescue medication likely to be taken when the 
preceding pain scores were high). It can then be inferred that the pain scores post-rescue can be 
predicted from the observed variables, and therefore the response can be estimated without bias 
using the observed data. In this analysis, the pain assessment recorded at the time of rescue 
medication is disregarded (unless it coincides with a planned pain assessment). 
The strategy to be used is as follows: 
i. 
Set pain scores recorded within the defined window after rescue medication to 
missing. Impute all missing data (due to subject withdrawal, missing intermittent 
values and that set to missing due to rescue medication) using the MCMC method 
of PROC MI. Note that this imputation will sample data within each treatment 
group.  Note that PIi is the NRS pain intensity at time Ti as mentioned in Section 
6.1.7. SAS pseudo code is provided below. With the MCMC option, SAS does 
200 burn-in iterations (default) before each imputation. Twenty imputations will 
be performed. 
PROC MI DATA=example seed = xxxx NIMPUTE = 20 OUT = outdata1 minimum=0 … 0 
maximum=10 … 10; 
 
by <treatment>; 
 
MCMC chain=multiple; 
 
VAR  <PI0> <PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>; 
RUN; 
ii. 
When all missing PI scores are imputed, SPID12 will be derived as described in 
6.1.7 and analyzed using the ANCOVA models as described in Section 8.1.  
PROC MIANALYZE will be used to combine the parameters from the analyses 
for inference 
Sensitivity analyses 3 and 6 will also be performed for SPID24, with the necessary modifications 
to the SAS pseudo code in sensitivity analysis 6 to incorporate a covariate for PI24. 
6.1.7. Derived Variables 
At each assessment time point, subjects will complete the pain intensity NRS assessment first 
and the pain relief assessment second. 
Planned assessment time points are as follows: 0 (predose), 15, 30, and 45 minutes, and 1, 1.5, 2, 
3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours after Time 0.  Please see Table 2 below. 
 
 
Table 2 Planned Assessment Times 
i 
Ti (hours) 
0 
0 (predose) 
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1 
0.25 
2 
0.5 
3 
0.75 
4 
1 
5 
1.5 
6 
2 
7 
3 
8 
4 
9 
5 
10 
6 
11 
7 
12 
8 
13 
10 
14 
12 
15 
16 
16 
24 
 
• SPID-12 = summed pain intensity difference (change from Time 0) under the numeric 
rating scale (NRS)-time curve from 15 min through 12 hours calculated using the linear 
trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of 
study drug. Scheduled time points in Table 2 will be used when actual time is missing. 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷12 = ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑃𝑃𝑃𝑃𝐷𝐷𝑖𝑖
14
𝑖𝑖=1
 
 
Where T0 =0, Ti is the actual time, and PIDi is the PID score at time Ti  
PID is defined as  
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𝑃𝑃𝑃𝑃𝐷𝐷𝑖𝑖= 𝑃𝑃𝐼𝐼𝑖𝑖−𝑃𝑃𝐼𝐼0 
 
Where PI is the pain intensity as measured by the NRS scale. 
• SPID-x = summed pain intensity difference (change from Time 0) under the numeric rating 
scale (NRS)-time curve from 15 min through x hours calculated using the linear trapezoidal 
rule and the actual time points, where Time 0 is the time of the first dose of study drug. 
Scheduled time points in Table 2 will be used when actual time is missing. X = 4, 8, and 
24. 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥= ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑃𝑃𝑃𝑃𝐷𝐷𝑖𝑖
𝑦𝑦
𝑖𝑖=1
 
 
For x=4 y=8; x=8 y=12; x=24 y=16. 
• TOTPAR-x = total pain relief under the Pain Relief Scale (0 – 4) from 15 min through x 
hours calculated using the linear trapezoidal rule and actual time points, where Time 0 is 
the time of the first dose of study drug. Scheduled time points in Table 2 will be used when 
actual time is missing.  x = 4, 8, 12, and 24. 
 
 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑅𝑅𝑥𝑥=  ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑃𝑃𝑃𝑃𝑅𝑅𝑖𝑖
𝑦𝑦
𝑖𝑖=1
 
For x=4 y=8; x=8 y=12; x=12 y=14; x=24 y=16. PARi is the pain relief score on the Pain Relief 
Scale (0-4) at time Ti  
 
• SPRID-x = summed pain relief (TOTPAR) and intensity difference (SPID) from 15 min 
through x hours calculated using the linear trapezoidal rule and actual time points, where 
Time 0 is the time of the first dose of study drug. Scheduled time points in Table 2 will be 
used when actual time is missing. X = 4, 8, 12, and 24. 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥= 𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥+ 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑅𝑅𝑥𝑥 
 
• Responder: subject with ≥ 30% improvement in NRS pain intensity from T0 
(predose) without rescue medication during the first 8 hours. If a subject takes rescue 
medication prior to the 8-hour pain assessment or if the 8-hour assessment is not 
performed they will be considered a non-responder. i.e., 
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(𝑃𝑃𝐼𝐼0 −𝑃𝑃𝐼𝐼8)
𝑃𝑃𝐼𝐼0
∗100 ≥30 
Where PI0 and PI8 are the predose and 8-hour NRS pain intensity measurements 
respectively. 
• Time to onset of analgesia = If the subject has had meaningful pain relief (i.e., presses both 
stopwatches) then time to onset of analgesia is date/time of perceptible pain relief – 
date/time of the first dose of study drug. If subjects don’t experience both perceptible pain 
relief and meaningful pain relief during the 8-hour interval after Time 0, time to onset to 
analgesia will be right censored at the time of their last pain assessment in the first 8 hours. 
For subjects who take rescue medication prior to onset of analgesia during the 8-hour 
interval after Time 0, time to onset of analgesia will be right censored at the time rescue 
medication was taken. 
• Time to first perceptible pain relief = date/time of the first reported pain relief (any) as 
assessed by the subject (i.e. subject stops the first stopwatch (irrespective of the second 
stopwatch)) – date/time of the first dose of study drug. If subjects don’t experience 
perceptible pain relief during the 8-hour interval after Time 0, time to first perceptible pain 
relief will be right censored at the time of their last pain assessment in the first 8 hours. If 
the first stopwatch is not stopped but the second stopwatch is stopped, time will be left 
censored at the time that the second stopwatch is stopped. In other words, it is assumed that 
the first stopwatch measurement has already occurred but was missed/not recorded. For 
subjects who take rescue medication prior to first perceptible pain relief during the 8-hour 
interval after Time 0, time to first perceptible pain relief will be right censored at the time 
rescue medication was taken. 
• Time to meaningful pain relief = date/time of the first reported meaningful (subjective) 
pain relief as assessed by the subject (i.e. the subject stops the second stopwatch) – 
date/time of the first dose of study drug. If subjects don’t experience meaningful pain relief 
during the 8-hour interval after Time 0, time to meaningful pain relief will be right censored 
at the time of their last pain assessment in the first 8 hours. If the subject stops the second 
stopwatch but doesn’t stop the first stopwatch or the first stopwatch assessment is missing, 
then time to meaningful pain relief will be right censored at the time of their last pain 
assessment in the first 8 hours. For subjects who take rescue medication prior to achieving 
meaningful pain relief during the 8-hour interval after Time 0, time to meaningful pain 
relief will be right censored at the time rescue medication was taken. 
• Peak pain relief- Pain relief is measured on a scale from 0 (None) to 4 (Complete). If PRi 
is the pain relief measurement at time Ti , peak pain relief PPR is defined as 
 
𝑃𝑃𝑃𝑃𝑃𝑃= max{𝑃𝑃𝑅𝑅1,𝑃𝑃𝑅𝑅2,𝑃𝑃𝑅𝑅3,…, 𝑃𝑃𝑅𝑅16} 
 
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• Time to first use of rescue medication = date/time to the first dose of rescue medication – 
date/time of the first dose of study drug. If subjects don’t take rescue medication, subjects 
will be right censored at the time of their last pain assessment. 
• Time to peak pain relief = date/time of peak pain relief– date/time of the first dose of study 
drug. Time of peak pain relief is the time Ti when peak pain relief (PPR) first occurs. If no 
pain relief is observed then the time to peak pain relief will be right censored at the time of 
their last pain assessment. 
• Change from baseline = value at current time point – value at baseline.  
• TEAE = TEAE is defined as any event that started or worsened in intensity or relationship 
to treatment on or after the first dose of study drug. 
6.1.8. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
All P values will be displayed in four decimals and rounded using standard scientific notation (e.g., 
0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as <0.0001. 
Adverse events will be coded using the MedDRA version 23.0 thesaurus. 
A treatment related AE is any AE with a relationship to the study drug with possible, probable or 
certain causality to the study drug as determined by the Investigator. 
If partial dates occur, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if just day is missing then the day assigned is the first day of the month or 
the date of first dose (if in the same month), whichever is later; if just month is missing then the 
month assigned is the month of the first dose, unless that results in a date prior to the first dose in 
which case the month after the first dose is used; and if both month and day are missing then the 
month assigned is the month of the first dose and the day assigned is either the first day of the 
month or the first dose date, whichever is later. 
If partial times occur, the convention is as follows: if the missing time occurs on the day of the 
first dose and both the hour and minute are missing then the time assigned is the time of the first 
dose, otherwise if both the hour and minute are missing and the date is not the date of first dose 
the time assigned is 12:00; if the date is the same as the date of the first dose and only hour is 
missing the hour assigned is 12 or the hour of first dose, whichever is later, and if the date is the 
same as the date of first dose and only the minute is missing the minute assigned is 30 or the 
minute of first dose, whichever is later. Otherwise the hour assigned is 12 if the hour is missing 
and the date is not the same as the date of first dose and the minute assigned is 30 is the the date 
is not the same as the date of first dose. 
These conventions will be applied only to adverse event onset dates and times with the following 
precaution:  if the missing date and time reflect the date and time of onset of an adverse event, 
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the modified date and time will be constructed to match the first documented date/time post drug 
administration while preserving the order in which the AE was reported in the CRF. 
7. 
Study Patients/Subjects and Demographics 
7.1. 
Disposition of Patients/Subjects and Withdrawals 
Disposition will include tabulations of the number of subjects screened, number of subjects 
randomized into each treatment group, the number of subjects who received treatment, tabulated 
reasons for discontinuation from the study, and number of subjects in each analysis population. 
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be summarized by deviation type (major/minor) and listed. 
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, gender, race, ethnicity, height, weight, BMI, baseline pain category 
and baseline pain (continuous) will be presented by treatment groups and overall. For the 
continuous variables, the number of non-missing values and the mean, standard deviation, 
minimum, median and maximum will be tabulated.  
For the categorical variables, the counts and proportions of each value will be tabulated.    
These analyses will be conducted for the ITT, PP, and Safety populations. 
The number and percent of subjects reporting various medical histories, grouped by MedDRA 
system organ class and preferred term (coded using MedDRA v23.0), will be tabulated by 
treatment group. This analysis will be conducted for the Safety Population. Physical examination 
findings will also be summarized by body system and examination result- Normal, Abnormal – 
Clinically Significant, Abnormal-Not Clinically Significant. 
7.4. 
Exposure and Compliance 
The number of doses taken and treatment duration will be summarized by descriptive statistics. 
All study drug will be administered in clinic. The total number of tablets taken, and the number 
of tablets with active ingredient taken at each time point will be summarized. The dosage (in mg) 
of active ingredient taken and duration of exposure, from first dose to last dose of the study 
treatment will be summarized using descriptive statistics. Any deviations from the planned dose 
should be reported. 
8. 
Efficacy Analysis 
8.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the summed pain intensity difference (SPID) over 0 to 12 hours 
(SPID12).  The primary endpoint will be used to compare the test product (2x300 mg ibuprofen 
PR tablets) against placebo. 
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The primary efficacy hypothesis is that SPID12 for placebo is equal to SPID12 for ibuprofen 
2x300 mg PR tablets.  The primary analysis will be an ANCOVA model that includes the main 
effect of treatment and a covariate of the baseline NRS pain score and will use windowed worst 
observation carried forward (WOCF) imputation for subjects who use rescue medication.  The 
primary analysis will be based on a 2-sided test at the significance level of 0.05.  The treatment 
difference will be presented with a 95% confidence interval.   
Normality assumptions will be tested. If the data is considered non-normal, the Wilcoxon rank 
sum test will be used for the comparison between treatments, and the point estimate and 95% 
confidence interval will be calculated using the Hodges-Lehmann estimator. 
The primary efficacy analysis will be based on the ITT population. These analyses will be 
repeated for the PP population.  SPID-12 scores will also be summarized by baseline pain 
category (moderate or severe). 
8.2. 
Secondary Efficacy Analysis 
8.2.1. SPID 
Summed Pain Intensity Difference (SPID) will be calculated for secondary efficacy analysis as 
described in Section 6.1.7 at 4, 8, and 24 hours. Descriptive statistics by treatment regimen will 
be produced. 
ANCOVA models for comparing placebo with other treatment regimens with SPID as the 
dependent variable and treatment group and baseline pain as covariates will be generated. These 
models will be computed for SPID4, SPID8 and SPID12. The least square (LS) mean and 
standard error (SE) for each treatment group will be estimated and the difference in LS means 
and 95% confidence interval (CI) for the comparison of placebo with the IR and PR treatment 
regimens will be estimated. P-values will be reported but no formal statistical inferences will be 
made on the basis of these tests.  In addition, for the SPID24 endpoint, the difference in LS 
means and 95% CI for the IR versus PR groups will be presented. In the event that normality 
assumptions are violated for a parameter, non-parametric analysis methods will be used. 
8.2.2. TOTPAR 
Total pain relief (TOTPAR) will be calculated as described in Section 6.1.7 at 4, 8, 12 and 24 
hours. Descriptive statistics by treatment regimen will be produced. 
ANCOVA models for comparing placebo with other treatment regimens with TOTPAR as the 
dependent variable and treatment group and baseline pain as covariates will be generated. These 
models will be generated at TOTPAR4, TOTPAR8, TOTPAR12 and TOTPAR24. The LS mean 
and SE for each treatment group will be estimated and the difference in LS means and 95% CI 
for the comparison of placebo with the IR and PR treatment regimens will be estimated. P-values 
will be reported but no formal statistical inferences will be made on the basis of these tests. In 
the event that normality assumptions are violated for a parameter, non-parametric analysis 
methods will be used. 
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8.2.3. SPRID 
Summed pain relief and intensity difference is the sum of TOTPAR and SPID and will be 
calculated at 4, 8, and 12 and 24 hours as described in Section 6.1.7. 
Descriptive statistics by treatment regimen will be produced for SPRID at each planned 
assessment time point.  
ANCOVA models for comparing placebo with other treatment regimens with SPRID as the 
dependent variable and treatment group and baseline pain as covariates will be generated. The 
LS mean and SE for each treatment group will be estimated and the difference in LS means and 
95% CI for the comparison of placebo with the IR and PR treatment regimens will be estimated. 
P-values will be reported but no formal statistical inferences will be made on the basis of these 
tests. In the event that normality assumptions are violated for a parameter, non-parametric 
analysis methods will be used. 
8.2.4. Peak Pain Relief  
Peak pain relief will be calculated as described in Section 6.1.7 and will be summarized by 
counts (and percentages) for each pain relief score.  It will be analyzed using a proportional odds 
model (an extension of the logistic regression). This method allows for an ordinal response 
variable with more than two categories. This model will include a factor for treatment and 
baseline pain intensity as a continuous covariate. The lowest level of pain relief (0=none) will be 
used as the reference category, thus ensuring that the probability of the higher response levels 
will be modelled. For each of the PR and IR treatment regimens, the odds of being in a higher 
(better) pain relief category compared to placebo (odds ratio) will be presented with a 95% CI 
and associated p-value. If the proportional odds assumption does not hold, a non-proportional 
odds model will be considered.   
8.2.5. Time to First Perceptible Pain Relief 
Time to first perceptible pain relief will be summarized using Kaplan-Meier methods. The 
definition and censoring rules are described in Section 6.1.7. With baseline pain as a 
stratification factor, treatments will be compared to placebo using a stratified log-rank test or a 
stratified Wilcoxon test as appropriate. Summary tables will provide the number of subjects 
analyzed, the number of subjects censored, estimates for the 25th, 75th percentiles and median 
(including 95% CI), and associated p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated. 
8.2.6. Time to Meaningful Pain Relief  
Time to first meaningful pain relief will be summarized using Kaplan-Meier methods. The 
definition and censoring rules are described in Section 6.1.7. With baseline pain as a 
stratification factor, treatments will be compared to placebo using a stratified log-rank test or a 
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stratified Wilcoxon test. Summary tables will provide the number of subjects analyzed, the 
number of subjects censored, estimates for the 25th, 75th percentiles and median (including 95% 
CI), and associated p-value for comparisons versus placebo.   
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated.  
8.2.7. Time to onset of Analgesia 
Time to onset of analgesia will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 6.1.7. With baseline pain as a stratification factor, 
treatments will be compared to placebo and with each other (IR vs PR) using a stratified log-rank 
test or a stratified Wilcoxon test. The summary tables will provide the number of subjects 
analyzed, the number of subjects censored, estimates for the 25th, 75th percentiles and median 
(including 95% CI), and associated p-value for treatment comparisons.   
A measure of the treatment effect comparing each of the active arms with placebo and with each 
other (IR vs PR) will be obtained by calculating a hazard ratio and 95% CI by fitting a Cox 
proportional hazards model with a factor for treatment group and baseline pain as a continuous 
covariate. The assumption of proportional hazards will first be evaluated.  
8.2.8. Time to Peak Pain Relief 
Time to peak pain relief will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 6.1.7. With baseline pain as a stratification factor, 
treatments will be compared to placebo using a stratified log-rank test or a stratified Wilcoxon 
test. The summary tables will provide the number of subjects analyzed, the number of subjects 
censored, estimates for the 25th, 75th percentiles and median (including 95% CI), and associated 
p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated.  
8.2.9. Time to first use of Rescue Medication 
Time to first use of rescue medication will be summarized using Kaplan-Meier methods. The 
definition of time to first use of rescue medication and censoring rules for subjects who don’t 
take rescue medication are described in Section 6.1.7. With baseline pain as stratification factor, 
treatments will be compared to placebo using a stratified log-rank test or a stratified Wilcoxon 
test. The summary tables will provide the number of subjects analyzed, the number of subjects 
censored, estimates for the 25th, 75th percentiles and median (including 95% CI), and associated 
p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
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with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated. 
8.2.10.  Proportion of Responders 
For the proportion of subjects who are responders, a logistic regression model that adjusts for 
baseline pain (as a continuous covariate) and treatment arm will be used to evaluate the treatment 
effect. As a measure of treatment effect for each of the PR and IR groups versus placebo, odds 
ratios together with a 95% CI and p-values will be presented. 
8.2.11. Numeric rating scale (NRS) pain intensity difference (PID)  
PID at each time point will be calculated using the formula specified in Section 6.1.7, with pain 
scores recorded after rescue medication handled using the windowed WOCF method described 
in Section 6.1.5. Pain scores that are missing (assessment not performed or subject withdrew) 
will not be replaced. PID at each timepoint will be analyzed in a mixed model for repeated 
measures (MMRM) ANCOVA analysis. The model will include treatment, timepoint, treatment 
by timepoint, baseline and baseline by timepoint as fixed effects, and subject as a random effect. 
An unstructured covariance matrix will be used to model the within-subject correlations by 
timepoint. If the model fails to converge, alternative covariance structures, such as compound 
symmetry, will be tried instead. The model will be used to show estimated treatment effects at 
each timepoint. The LS mean and SE for each treatment group will be estimated and the 
difference in LS means and 95% CI for the comparison of placebo with the IR and PR treatment 
regimens will be estimated. P-values will be reported but no formal statistical inferences will be 
made on the basis of these tests. Descriptive summaries (including mean, SD, median, minimum 
and maximum) will be presented by treatment group.  
Pain intensity is measured using NRS at planned assessment time points. Descriptive summaries 
(including mean, SD, median, minimum and maximum) will also be presented by treatment 
group. Pain scores recorded after rescue medication will be handled using the windowed WOCF 
method described in Section 6.1.5. Pain scores that are missing (assessment not performed or 
subject withdrew) will not be replaced. 
8.2.12. Pain relief at each scheduled time point 
Pain relief scores at each scheduled time point will be summarized using descriptive statistics 
(including mean, SD, median, minimum and maximum) as well as counts (and percentages) for 
each pain relief score by treatment group. Pain relief scores recorded after rescue medication will 
be handled using the windowed WOCF method described in Section 6.1.5. Pain relief scores that 
are missing (assessment not performed or subject withdrew) will not be replaced. Treatment 
comparison will be done in the following way: 
• Pain relief at each timepoint will be analyzed in a mixed model for repeated 
measures (MMRM) ANCOVA analysis. The model will include treatment, 
timepoint, treatment by timepoint, baseline pain and baseline pain by timepoint as 
fixed effects, and subject as a random effect. An unstructured covariance matrix 
will be used to model the within-subject correlations by timepoint. If the model 
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fails to converge, alternative covariance structures, such as compound symmetry, 
will be tried instead. The model will be used to show estimated treatment effects at 
each timepoint. The LS mean and SE for each treatment group will be estimated 
and the difference in LS means and 95% CI for the comparison of placebo with the 
IR and PR treatment regimens will be estimated. P-values will be reported but no 
formal statistical inferences will be made on the basis of these tests. 
 
8.2.13. Proportion of Subjects Rescue Medication 
The definition of rescue medication use is presented in Section 6.1.5. The proportion of subjects 
using rescue medication for pain will be analyzed using logistic regression. The logistic 
regression model will include treatment arm and baseline pain (as a continuous covariate) as 
covariates. As a measure of treatment effect for each of the PR and IR groups versus placebo, 
odds ratios together with a 95% CI and p-values will be presented. 
8.3. 
Exploratory Efficacy Analysis  
8.3.1. Global Evaluation of Study Drug 
Subject’s global evaluation of study drug will be analyzed using a proportional odds model (an 
extension of the logistic regression). This method allows for an ordinal response variable with 
more than two categories. This model will include a factor for treatment group and baseline pain 
intensity as a continuous covariate. The lowest level of response (0=poor) will be used as the 
reference category, thus ensuring that the probability of the higher response levels will be 
modelled. For each of the PR and IR treatment regimens, the odds of being in a higher (better) 
evaluation category compared to placebo (odds ratio) will be presented with a 95% CI and 
associated p-value. If the proportional odds assumption does not hold, a non-proportional odds 
model will be considered. 
9. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported AEs, and changes in vital signs. 
All safety analyses will be performed on the Safety population. 
9.1. 
Adverse Events 
The number and percent of subjects reporting treatment emergent AEs, grouped by 
MedDRA system organ class and preferred term (coded using MedDRA v23.0), will 
be tabulated by severity and treatment group. In the case of multiple occurrences of the 
same TEAE within the same subject, each subject will only be counted once for each 
preferred term. 
The frequency and percentage of subjects reporting TEAEs, grouped by MedDRA SOC and PT, 
will be tabulated by treatment group for the SAF. Such summaries will be displayed for the 
following: 
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• TEAEs by SOC and PT 
• TEAEs by SOC, PT, and severity 
• TEAEs by SOC, PT, and relationship to the study medication 
• TEAEs leading to death by SOC, and PT 
• Serious TEAEs other than deaths by SOC, and PT 
• TEAEs leading to premature discontinuation by SOC, and PT 
• Listing of non-TEAEs 
In the case of multiple occurrences of the same AE within the same subject, each subject will 
only be counted once for each preferred term. In summaries of AE by SOC and PT, along with 
the number (%) of subjects with at least 1 AE in the category, the number of events will be 
displayed. In the summaries showing severity and relationship to study medication the event with 
the maximum severity or strongest relationship will be reported. If a particular event is missing 
the severity and/or relationship, then the strongest possible severity or relationship will be 
assumed for analysis (severity = severe, relationship = certain). 
Missing and partially missing AE start and/or stop dates will be imputed for the purpose of 
statistical analysis, according to the specifications described in Section 6.1.7. 
In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent will be 
flagged. 
9.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug, by treatment group, SOC, and preferred term will be prepared for the Safety 
Population. No inferential statistical tests will be performed. 
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and also tabulated by system organ class and preferred term 
and presented by treatment. 
9.2. 
Clinical Safety Laboratory Data 
Descriptive statistics for clinical safety laboratory data (laboratory data) recorded at screening 
will be presented overall and by treatment regimen. Summary tables by treatment regimen will 
be presented for each category of data separately. Routine clinical laboratory data will include 
hematology, serum chemistry, and urinalysis. Quantitative laboratory test result summaries will 
include N (population count for each regimen), n (number of subjects with non-missing values), 
mean, SD, median, and range. Qualitative tests (e.g., some urinalysis assessments) will be 
categorized accordingly. The set of laboratory parameters included in each table will correspond 
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to those requested in the study protocol. Urine drug screen, alcohol breath analyzer and urine 
pregnancy test results will be presented in listings.  
9.3. 
Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for supine 
systolic blood pressure, supine diastolic blood pressure, heart rate, respiratory rate, and oral body 
temperature, and will be presented by treatment regimen. Summary statistics for 12-lead ECG 
parameters and counts for ECG interpretations at screening will be presented. 
9.4. 
Concomitant Medication 
Prior and concomitant medications will be summarized descriptively by treatment using counts 
and percentages. 
Prior medications will be presented separately from concomitant medications. Medications that 
started prior to the first dose of study drug will be considered prior medications whether or not 
they were stopped prior to the first dose of study drug. Any medications continuing or starting 
post the first dose of study drug will be considered to be concomitant. If a medication starts prior 
to the first dose and continues after the first dose of study drug, it will be considered both prior 
and concomitant. Medications will be coded using March 2020 version of World Health 
Organization Drug Coding Dictionary (WHODD). 
9.5. 
Rescue Medication use  
The number of subjects taking rescue medication will be summarized by treatment group at the 
following post dose times -1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 
hours and 24 hours.  This will be done on the safety population.  
10. 
Changes to analysis planned in the protocol 
For the time to event endpoints an additional measure of the treatment effect comparing each of 
the active arms with placebo will be obtained by calculating a hazard ratio and 95% CI by fitting 
a Cox proportional hazards model with a factor for treatment group and baseline pain as a 
continuous covariate. The assumption of proportional hazards will first be evaluated. 
There has been a clarification to the definition of the ITT population to that stated in the 
protocol. The ITT population is defined as all subjects who are treated with study drug and who 
have at least 1 pain assessment after Time 0. In the protocol the ITT population was defined as 
subjects who have at least 1 pain relief assessment. 
11. 
References 
1. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
2. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
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3. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
4. Ratitich, B. and O’Kelly, M.J. (2011). Implementation of Pattern-Mixture Models Using 
Standard SAS / STAT Procedures. 
5. E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity 
Analysis in Clinical Trials 
 
12. 
Tables, Listings, and Figures 
All listings, tables, and graphs will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (CRF page or listing number). 
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12.1. Planned Table Descriptions 
The following are planned summary tables for protocol number 5003601. The table numbers and 
page numbers are place holders only and will be determined when the tables are produced. 
Table 3: Demographic Data Summary Tables  
Table Number 
Population 
Table Title/Summary 
14.1 Displays of Demographics and Disposition Data 
Table 14.1.1 
All Subjects 
Subject Disposition 
Table 14.1.2 
Safety Population 
Demographics and Baseline Characteristics 
Table 14.1.2.1 
ITT Population 
Demographics and Baseline Characteristics 
Table 14.1.3 
Safety Population 
Medical History  
Table 14.1.4 
 Safety Population 
Prior Medications  
Table 14.1.5 
 Safety Population 
Concomitant Medications  
Table 14.1.6 
 All Enrolled Subjects 
Summary of Protocol Deviations  
Table 14.1.7 
Safety Population 
Summary of Study Drug Exposure 
12.2. Efficacy Data  
Table 4: Efficacy Tables 
Table Number 
Population 
Table Title/Summary 
14.2.1  
ITT Population 
Analysis of SPID-12 Scores  
14.2.1.1 
PP Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 1  
14.2.1.2 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 2-WOCF 
14.2.1.3 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 3-No Rescue Adjustment 
14.2.1. 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 4a-Rescue WOCF 
14.2.1.5 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 4b-Rescue LOCF 
14.2.1.6 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 4c-Multiple Imputation-
Rescue Medication-MAR 
14.2.1.7 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 5-Multiple Imputation-PMM 
14.2.1.8 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 6-Multiple Imputation-MAR 
14.2.1.9 
ITT Population 
Summary of SPID-12 Scores by Baseline Pain Category 
14.2.2 
ITT Population 
Analysis of Summed Pain Intensity Difference Scores  
14.2.2.1 
ITT Population 
Analysis of SPID-24 Scores- Sensitivity Analysis 7-No Rescue Adjustment 
14.2.2.2 
ITT Population 
Analysis of SPID-24 Scores- Sensitivity Analysis 8-Multiple Imputation-MAR 
14.2.3 
ITT Population 
Analysis of Total Pain Relief Scores  
14.2.4 
ITT Population 
Analysis of Summed Pain Relief and Intensity Difference Scores  
14.2.5 
ITT Population 
Comparison of SPID-24 in Ibuprofen PR and IR arms 
14.2.5.1 
ITT Population 
Comparison of SPID-24 in Ibuprofen PR and IR arms-Sensitivity Analysis 7-
No Rescue Adjustment 
14.2.5.2 
ITT Population 
Comparison of SPID-24 in Ibuprofen PR and IR arms- Sensitivity Analysis 8-
Multiple Imputation-MAR 
14.2.6 
ITT Population 
Summary of Peak Pain Relief  
14.2.7 
ITT Population 
Time to First Perceptible Pain Relief  
14.2.8 
ITT Population 
Time to Meaningful Pain Relief  
14.2.9 
ITT Population 
Time to Onset of Analgesia  
14.2.10 
ITT Population 
Time to Peak Pain Relief  
14.2.11 
ITT Population 
Time to First use of Rescue Medication  
14.2.12 
ITT Population 
Proportion of Subjects Using Rescue Medication  
14.2.13 
ITT Population 
Proportion of Responders 
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14.2.14 
ITT Population 
Summary of NRS Pain Intensity Difference Score  
14.2.15 
ITT Population 
Summary of Pain Intensity Score at each Scheduled Time Point 
14.2.16 
ITT Population 
Summary of Pain Relief at each Scheduled Time Point 
14.2.17 
ITT Population 
Analysis of Patient Global Evaluation of Study Drug 
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12.3. Safety Data 
Table 5: Safety Tables 
Table Number 
Population 
Table Title/Summary 
14.3.1 Summary of Treatment Emergent Adverse Events 
Table 14.3.1.1 
 Safety Population 
Overall Summary of Treatment-Emergent Adverse Events  
Table 14.3.1.2 
Safety Population 
Summary of Treatment-Emergent Adverse Events  
Table 14.3.1.3 
Safety Population 
Summary of Treatment-Emergent Adverse Events by Maximum Severity  
Table 14.3.1.4 
Safety Population 
Summary of Treatment-Emergent Adverse Events by Relationship to 
Study Drug  
Table 14.3.1.5 
Safety Population 
Summary of Non-Serious Treatment-Emergent Adverse Events  
14.3.2 Summary of Deaths, Other Serious and Significant Adverse Events 
Table 14.3.2.1 
 Safety Population 
Summary of Serious Adverse Events  
Table 14.3.2.2 
Safety Population 
Summary of Treatment Emergent Adverse Events Leading to 
Discontinuation  
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 
Table 14.3.3.1 
Safety Population 
Listing of Serious Adverse Events  
Table 14.3.3.2 
Safety Population 
Listing of Treatment Emergent Adverse Events Leading to  
Study Drug Discontinuation 
14.3.4 Abnormal Laboratory Value  
Table 14.3.4.1 
Safety Population  
Listing of  Potentially Clinically Significant Abnormal Laboratory Values   
14.3.5 Laboratory Data Summary Tables 
Table 14.3.5.1 
Safety Population  
Summary of Serum Chemistry Laboratory Results  
14.3.6 Other Safety Data Summary Tables 
Table 14.3.6.1 
 Safety Population 
Summary of Vital Signs  
Table 14.3.6.2 
Safety Population 
Summary of Electrocardiogram (ECG) Interpretations  
Table 14.3.6.3 
Safety Population 
Summary of 12-Lead Electrocardiogram (ECG) Parameters 
Table 14.3.6.4 
Safety Population 
Summary of Physical Examination Findings 
Table 14.3.6.5 
Safety Population 
Rescue Medication use 
 
 
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12.4. Planned Listing Descriptions 
The following are planned data and patient/subject data listings for protocol number 5003601.  
In general, one listing will be produced per CRF domain. All listings will be sorted by treatment, 
site, and subject number. All calculated variables will be included in the listings. 
In all listings a blank line will be placed between each subject. Within a data listing, if an item 
appears line after line (e.g., repetition of subject number), then only the first occurrence will be 
displayed. 
In data listings, the information for one subject will be kept on one page if at all possible, rather 
than splitting a subject’s information across pages. 
Table 6: Planned Listings 
Data Listing Number 
Population 
Data Listing Title / Summary 
16.2.1 Subject Discontinuations/Completions 
 Listing 16.2.1 
All Subjects 
Subject Disposition 
16.2.2 Protocol Deviations 
Listing 16.2.2.1 
All Subjects  
Eligibility Criteria Not Met 
Listing 16.2.2.2 
All Subjects 
Screen Failures 
Listing 16.2.2.3 
All Subjects 
Protocol Deviations 
16.2.3 Subjects in Analysis Populations 
Listing 16.2.3 
All Subjects 
Analysis Populations 
16.2.4 Demographic Data and Other Baseline Characteristics 
Listing 16.2.4.1 
Safety Population 
Demographics and Baseline Characteristics 
Listing 16.2.4.2 
Safety Population 
Medical History 
Listing 16.2.4.3 
 All Randomized Subjects Listing of Subject Randomization  
Listing 16.2.4.4 
 Safety Population 
Study Drug Administration 
16.2.7 Adverse Event Listings (by Subject) 
Listing 16.2.7.1 
Safety Population 
Adverse Events  
Listing 16.2.7.2 
Safety Population 
Serious Adverse Events 
Listing 16.2.7.3 
Safety Population 
Treatment emergent Adverse Events Related to Study Drug 
Listing 16.2.7.4 
Safety Population 
Deaths 
16.2.8 Laboratory Values by Subject 
Listing 16.2.8.1 
Safety Population 
Clinical Laboratory Data: Serum Chemistry 
Listing 16.2.8.2 
Safety Population 
Clinical Laboratory Data: Hematology 
Listing 16.2.8.3 
Safety Population 
Clinical Laboratory Data: Urine 
Listing 16.2.8.4 
Safety Population 
Clinical Laboratory Data: Coagulation 
Listing 16.2.8.5 
Safety Population 
Serum and Urine Pregnancy Test 
16.2.9 Other Clinical Observations and Measurements (by Subject) 
Listing 16.2.9.1 
Safety Population 
Prior and Concomitant Medications 
Listing 16.2.9.1.1 
Safety Population 
Rescue Medications 
Listing 16.2.9.2 
Safety Population 
Vital Signs Measurements 
Listing 16.2.9.2.1 
Safety Population 
Physical Examination Findings 
Listing 16.2.9.3 
Safety Population 
12-lead Electrocardiogram Measurements  
Listing 16.2.9.3.1 
Safety Population 
Alcohol Breathalyzer Test 
Listing 16.2.9.4 
Safety Population 
NRS Pain Intensity Assessment 
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Data Listing Number 
Population 
Data Listing Title / Summary 
Listing 16.2.9.5 
Safety Population 
Pain Relief Scores  
Listing 16.2.9.6 
Safety Population 
Time to Pain Relief (Stopwatches) 
Listing 16.2.9.7 
Safety Population 
Subjects Global Evaluation of Study Drug 
 
 
 
12.5. Planned Figure Descriptions 
The following are planned summary figures for protocol number 5003601. The figure numbers 
and page numbers are place holders only and will be determined when the figures are produced. 
Table 7: Planned Figures 
Figure 14.4.1.1 
ITT Population 
Kaplan-Meier Plot of Time to First Perceptible Pain Relief 
Figure 14.4.1.2 
ITT Population 
Kaplan-Meier Plot of Time to Meaningful Pain Relief  
Figure 14.4.1.3 
ITT Population 
Kaplan-Meier Plot of Time to Onset Of Analgesia  
Figure 14.4.1.4 
ITT Population 
Kaplan-Meier Plot of Time to Peak Pain Relief 
Figure 14.4.1.5 
ITT Population 
Kaplan-Meier Plot of Time to First Use Of Rescue Medication 
Figure 14.4.1.6 
ITT Population 
Mean Pid Scores versus Time 
Figure 14.4.1.7 
ITT Population 
Mean Pain Relief Scores versus Time 
 
 
 
Figure Number 
Population 
Figure Title / Summary 
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Appendix 1: Premier Research Library of Abbreviations 
 
Abbreviation 
Definition 
aCRF  
annotated case report form 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
BSL 
biostatistician lead 
CCGs 
CRF completion guidelines 
CDISC 
clinical data interchange standards consortium 
CEC 
central ethics committee 
CFR 
code of federal regulations 
CI 
confidence intervals 
CM 
clinical manager 
CMP 
clinical monitoring plan 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CSR 
clinical study report 
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Abbreviation 
Definition 
CTA 
clinical trial administrator 
CTM 
clinical trial manager 
CTMS 
clinical trial management system 
DB 
database 
DBL 
database lock 
DM 
data management 
DMB 
data monitoring board 
DMC 
data monitoring committee 
DMP 
data management plan 
DSMB  
data safety monitoring board 
DSP 
data safety plan 
DSUR 
development safety update report 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eTMF 
electronic trial master file 
EU 
European Union 
FDA 
food and drug administration 
FPI 
first patient in 
GCP 
good clinical practice 
HR 
heart rate 
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Abbreviation 
Definition 
IB 
investigator’s brochure 
IC or ICF 
informed consent or informed consent form 
ICH 
international council for harmonization  
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
LPI 
last patient in 
LPLV 
last patient last visit 
LPO 
last patient out 
MedDRA 
medical dictionary for regulatory activities 
MHRA 
medicines and healthcare products regulatory agency 
MM 
medical monitor 
MMP 
medical monitoring plan 
MMRM 
mixed effect model repeat measurement 
N 
number 
NA 
not applicable 
NCS 
non-clinically significant 
NF 
non-functional 
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Abbreviation 
Definition 
PD 
protocol deviation 
PDGP 
protocol deviation guidance plan 
PE 
physical examination 
PI 
principal investigator 
PK 
pharmacokinetic 
PKAP 
pharmacokinetic analysis plan 
PM 
project manager 
PMP 
project management plan 
PP 
per-protocol 
PS 
project specialist 
PV 
pharmacovigilance 
PVG 
pharmacovigilance group 
QA 
quality assurance 
QARC 
quality assurance, risk and compliance 
QC 
quality control 
QOL 
quality of life 
SAE 
serious adverse event 
SAF 
Safety Population 
SAP 
statistical analysis plan 
SAS®  
a software system used for data analysis 
SBP 
systolic blood pressure 
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Abbreviation 
Definition 
SD 
standard deviation 
SDS 
study design specifications 
SDTM  
study data tabulation model  
SF 
screen failure 
SFT or SFTP 
secure file transfer or secure file transfer plan 
SIV 
site initiation visit 
SMP 
safety management plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
UAT 
user acceptance testing 
WHO 
world health organization 
WHO-DD 
world health organization drug dictionary 
WOCF 
worst observation carried forward 
 
 
Page 43 of 351


I
Statistical Analysis Plan,
Sponsor Reckitt Benckiser
Protocol Number 5003601
PCN NumberRECK.177035
premlEF r
' r"#ffiffiffi!*iltr:
Sponsor
Reckiu Benckiser
Protocol Title:
A Randomized, Double-Blind, Double-Duflffiy, Parallel-Group,
Multiple-Dose, Active and Placebo-Controlled Efficacy Study of
Ibuprofen Prolonged-Release Tablets for the Treatment of Pain
after Surgical Removal of Impacted Third Molars
Protocol Number:
5003601
Premier Research PCN:
RECK.177035
Document Version:
Amendment 3.0
Document Date:
20-May-2020
Approvals
Biostatistician
Premier Research
Print Name: Rashu Vishnubhotla
Sign Name:
Reckitt Benckiser
Representative
Print Name: Darren Tarsett
Ll ^a"1\ -'talc,
Sign Name:w
Version 1.0
Page 1 of 42
21-May-2020 | 15:53:27 EDT
Page 44 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
1.1. 
Planned Table Shells 
Table 14.1.1 
Subject Disposition 
All Randomized Subjects  
Disposition 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Study Populations [1]
Screened
XXX
Safety Population
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
ITT Population 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Per-Protocol Population
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Completion Status [2]
Completed Study
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Prematurely Discontinued Study Medication
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Prematurely Discontinued Study
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Reasons for discontinuation from Study
Lost to Follow-up
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Protocol Violation
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Adverse Event
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Non-Compliance with Study Drug
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Death
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Lack of Efficacy
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Withdrawal by Subject
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Pregnancy
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Physician Decision
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Study Terminated by Sponsor 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Other 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Abbreviation: ITT= Intent-to-Treat 
[1] Percentages are based on the number of randomized subjects.
[2] Percentages are based on the number of subjects in the Safety Population. 
Source: Listing 16.2.1
Page 45 of 351


Statistical Analysis Plan  
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Table 14.1.2 
Demographics and Baseline Characteristics 
Safety Population 
Variable 
   Statistic or Category 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Age (years) 
   n 
XX 
XX 
XX 
XX 
Mean
XX.X
XX.X
XX.X
XX.X
   Std Dev 
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
Gender 
   Male 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Female
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Ethnicity 
   Hispanic or Latino 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Not Hispanic or Latino
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Missing/Not Answered 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Race 
   American Indian/Alaska Native  
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Asian 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Black or African-American 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Native Hawaiian or Other Pacific Islander 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
White
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Missing/Not Answered 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Baseline Pain [1] 
n
XX
XX
XX
XX
   Mean 
XX.X
XX.X
XX.X
XX.X
Std Dev
XX.XX
XX.XX
XX.XX
XX.XX
   Median 
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, XX
XX, XX
XX, XX
XX, XX
Baseline Pain Category [2] 
Moderate
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Height (cm) 
n
XX
XX
XX
XX
   Mean 
XX.X
XX.X
XX.X
XX.X
   Std Dev 
XX.XX
XX.XX
XX.XX
XX.XX
   Median 
XX.X
XX.X
XX.X
XX.X
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Statistical Analysis Plan  
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Min, Max
XX, XX
XX, XX
XX, XX
XX, XX
Weight (kg) 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X
XX.X
XX.X
XX.X
   Std Dev 
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
BMI (kg/m2) 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X
XX.X
XX.X
XX.X
Std Dev
XX.XX
XX.XX
XX.XX
XX.XX
   Median 
XX.X
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
Surgery Duration (min) 
n
XX
XX
XX
XX
   Mean 
XX.X
XX.X
XX.X
XX.X
Std Dev
XX.XX
XX.XX
XX.XX
XX.XX
   Median 
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, XX
XX, XX
XX, XX
XX, XX
Abbreviation: BMI=Body Mass Index 
Note: Percentage are based on the number of subjects in the Safety Population. 
[1] Subjects rate their pain using a numeric rating scale (NRS) from 0 (no pain) to 10 (worst pain ever).
[2] NRS pain scores at baseline are categorized as moderate (5-7), and severe (8-10).
Source: Listing 16.2.4.1 
Table 14.1.2.1 
Demographics and Baseline Characteristics 
ITT Population 
Use Same Shell as Table 14.1.2 
Programming Note- Update footnote Note: Percentage are based on the number of subjects in the ITT Population. 
Page 47 of 351


 
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Table 14.1.3 
Medical History 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR 
  
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
  
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
Subjects with at least One Recorded Medical History 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
System Organ Class 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages are based on number of subjects in the Safety Population. 
Medical conditions were coded using MedDRA version 23.0 or later. Subjects were counted once for each system organ class (SOC) and once for each preferred term (PT). Medical 
history terms are displayed by descending frequency of SOC, then PT within SOC, and then alphabetically by PT. 
SOURCE: Listing 16.2.4.2 
Programming Note- Uncoded terms, if any, will be at the bottom of the table. They will have labels’ Not Coded’ for SOC and PT 
 
 
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Table 14.1.4 
Prior Medications 
Safety Population 
ATC Class Level 4 
   Preferred Term (ATC Class Level 5) 
Ibuprofen PR 
   
 (N=XX) 
Ibuprofen IR 
   
 (N=XX) 
Placebo   
 
 (N=XX) 
Overall 
 
 (N=XX) 
 
 
 
 
 
Subjects with at least one Prior Medication 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
ATC Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
ATC Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages are on number of subjects in the Safety Population.  
Medications are coded using WHO-DD B2E version March 2020.  
Medications that started prior to the first dose of study drug will be considered prior medications whether or not they were stopped prior to the first dose of study drug.. Medications are 
displayed by descending frequency of Anatomic Therapeutic Chemical (ATC) Level 4 classification, by Preferred Term (PT) within ATC and then alphabetically.  
Subjects were counted only once for each ATC and PT. 
SOURCE: Listing 16.2.9.1 
 
 
Table 14.1.5 
Concomitant Medications 
Safety Population 
Use same shell as Table 14.1.4 
Use this footnote for definition of concomitant medications- Any medications continuing or starting post the first dose of study drug will be considered as concomitant medications. 
 
 
 
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Statistical Analysis Plan  
 
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Table 14.1.6 
Summary of Protocol Deviations 
All Enrolled Subjects 
 
Deviation Category  
 Type of Deviation  
Ibuprofen PR 
   
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
 (N=XX) 
Overall 
 (N=XX) 
 
 
 
 
 
Subjects with any Protocol Deviation 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Subjects with Major Protocol Deviations 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
  Type of Protocol Deviation 
 
 
 
 
     Deviation type 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
     Deviation type 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
…… 
 
 
 
 
 
 
 
 
 
Subjects with Minor Protocol Deviations 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   Type of Protocol Deviation 
 
 
 
 
     Deviation type 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
     Deviation type 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
…. 
 
 
 
 
 
 
 
 
 
Notes: Subjects with one or more deviations within a deviation category (Major/Minor) or type of deviation were counted only once. 
Percentages are based on number of all enrolled subjects.  
SOURCE: Listing 16.2.2.3 
 
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Statistical Analysis Plan  
 
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Table 14.1.7 
Summary of Study Drug Exposure 
Safety Population 
 
Category 
  Statistic 
Ibuprofen PR 
   
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
 (N=XX) 
 
 
 
 
Number of Tables Taken 
 
 
 
   n 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
Number of Active Doses Taken [1] 
 
 
 
   n 
XX 
XX 
 
   Mean 
XX.X 
XX.X 
 
   Std Dev 
XX.XX 
XX.XX 
 
   Median 
XX.X 
XX.X 
 
   Min, Max 
XX, XX 
XX, XX 
 
 
 
 
 
Quantity of Active Drug Taken (mg) 
 
 
 
   n 
 
 
 
   Mean 
XX.X 
XX.X 
 
   Std Dev 
XX.XX 
XX.XX 
 
   Median 
XX.X 
XX.X 
 
   Min, Max 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
Treatment Duration (Hours) [2] 
 
 
 
   n 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
Note: Percentages are based on number of all enrolled subjects.  
[1] Active dose is a dose where the tablet taken has an active ingredient  
[2] Duration = date/time of last dose administered – date/time of first dose administered 
SOURCE: Listing 16.2.4.4.1 
 
Page 51 of 351


 
Statistical Analysis Plan  
 
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Table 14.3.1.1 
Overall Summary of Treatment Emergent Adverse Events  
Safety Population 
 
 
 
 
Ibuprofen PR  
 
 (N=XX) 
Ibuprofen PR 
 
 (N=XX) 
Placebo 
 (N=XX) 
Overall 
 
 (N=XX) 
 
 
 
 
 
   Subjects with at least one TEAE 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   TEAE by Maximum Severity 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   TEAE by Strongest Relationship  
 
 
 
 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   AE leading to Discontinuation 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   SAE 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
   AE leading to Death 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event; SAE = Serious Adverse Event. 
Notes: Percentages are based on number of subjects in the safety population.. 
TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug. Strongest possible severity or relationship will be 
assumed for TEAES with missing severity and/or relationship (severity=severe, relationship=certain) 
 
SOURCE: Listing 16.2.7.1 
 
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Table 14.3.1.2 
Summary of Treatment Emergent Adverse Events  
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
Subjects with at least One TEAE 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 2 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 3 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 2 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 3 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event. 
Notes: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. 
 
Percentages are based on number of subjects in the safety population. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  
TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug. 
AEs were coded using MedDRA version 23.0.  
 
SOURCE: Listing 16.2.7.1 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.1.3 
Summary of Treatment Emergent Adverse Events by Maximum Severity 
Safety Population 
 
System Organ Class 
   Preferred Term 
Maximum Severity [1] 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall  
 
 (N=XX) 
       
 
 
 
 
Subjects with at least One TEAE 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   Preferred Term 1 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event; SAE = Serious Adverse Event. 
[1] The severity shown is the greatest severity reported for a particular subject (Severe > Moderate > Mild). AEs with missing severity have been classified as Severe. 
Notes: Percentages are based on number of subjects in the safety population. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term. TEAE is 
defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug. AEs were coded using MedDRA version 23.0. 
SOURCE: Listing 16.2.7.1 
 
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Table 14.3.1.4 
Summary of Treatment Emergent Adverse Events by Relationship to Study Drug 
Safety Population 
 
System Organ Class 
   Preferred Term 
Greatest Relationship [1] 
Ibuprofen PR 
  
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall  
 (N=XX) 
       
 
 
 
 
Subjects with at least One TEAE 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
System Organ Class 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
[1] AE relation is marked in the CRF. The relationship shown is the strongest relationship reported for a particular subject. AEs with missing relationship have been classified as 
Certain. 
Abbreviations: TEAE = Treatment Emergent Adverse Event. 
Notes: Percentages are based on number of subjects in the safety population.. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term. TEAE is 
defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug.. AEs were coded using MedDRA version 23.0. 
SOURCE: Listing 16.2.7.1 
 
 
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Table 14.3.1.5 
Summary of Non-Serious Treatment Emergent Adverse Events  
Safety Population 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one non-
serious TEAE  
 
X (XX.X%) X 
 
X (XX.X%) X  
 
X (XX.X%) X 
 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event. 
Notes: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. Percentages are based on number of 
subjects in the safety population.. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.. TEAE is defined as any event that started or worsened in 
intensity or relationship to treatment on or after the first dose of study drug. AEs were coded using MedDRA version 23.0. 
SOURCE: Listing 16.2.7.1 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.2.1 
Summary of Serious Adverse Events 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one SAE 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
 
 
 
 
 
Abbreviation: SAE = Serious Adverse Event.  
Notes: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. 
 Percentages are based on number of subjects in the safety population. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  
  
AEs were coded using MedDRA version 23.0.  
SOURCE: Listing 16.2.7.1 
 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
Page 57 of 351


 
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Table 14.3.2.2 
Summary of Treatment Emergent Adverse Events Leading to Study Drug Discontinuation 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
 (N=XX) 
Ibuprofen IR 
 (N=XX) 
Placebo 
 (N=XX) 
Overall  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one TEAE that led to 
study drug discontinuation  
 
X (XX.X%) X 
 
X (XX.X%) X 
 
X (XX.X%) X 
 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
 
 
 
 
 
Abbreviation: TEAE = Treatment Emergent Adverse Event. 
 
Notes: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. 
 Percentages are based on number of subjects in the safety population. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  
 TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug.  
AEs were coded using MedDRA version 23.0.  
 
SOURCE: Listing 16.2.7.1 
 
 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.3.1 
Listing of Serious Adverse Events 
Safety Population 
 
 
Subject ID 
Treatment 
Group 
 
Gender 
Age 
(years) 
 
SAE 
System Organ Class/ 
Preferred Term/ Verbatim 
Term 
Start Date/Time (Study 
Day/ 
End Date/Time (Study 
Day) 
 
Severity/ 
Causality 
 
Outcome/ Action Taken 
XXXX 
  
M 
XX 
XXXX 
XXXX/XXX/XXX    
DDMMMYYYY/THH:MM 
(XX)/ 
DDMMMYYYY/THH:MM 
(XX) 
MILD/Related 
  XXX/XXX 
 
 
 
 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: SAE = Serious adverse event. 
Note: AEs were coded using MedDRA version 23.0.  
Study day is calculated relative to the date of first dose of study drug. 
Source: Listing 16.2.7.2 
 
Page 59 of 351


 
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Table 14.3.3.2 
Listing of Treatment Emergent Adverse Events Leading to Study Drug Discontinuation 
Safety Population 
 
 
Subject ID       
Treatment 
Group 
 
Gender 
Age 
(Years) 
 
TEAE 
System Organ Class/     
Preferred Term/ Verbatim 
Term 
Start Date/Time (Study 
Day)/ 
End Date/Time(Study 
Day) 
 
Severity/ 
Causality 
 
Outcome/  
   Action Taken 
XXXX 
XX 
F 
XX 
XXXX 
XXXX/XXX/XXX    
DDMMMYYYYTHH:MM 
(XX)/ 
DDMMMYYYYTHH:MM 
(XX) 
MILD/Related 
  XXX/XXX 
XXXX 
XX 
M 
 
XXXX 
XXXX/XXX/XXX    
DDMMMYYYYTHH:MM 
(XX)/ 
DDMMMYYYYTHH:MM 
(XX) 
MILD/Related 
  XXX/XXX 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event. 
Notes: AEs were coded using MedDRA version 23.0.  
 TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study 
drug.Study day is calculated relative to the date of first dose of study drug. 
 
Source: Listing 16.2.7.1
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Table 14.3.4.1 
Listing of Potentially Clinically Significant Abnormal Laboratory Values 
Safety Population 
 
 
 
 
Subject 
Number 
Treatment 
Group 
 
 
Gender 
Age 
(Years) 
Lab Category 
Lab Parameter 
(Units) 
 
Parameter 
Value 
Reference 
Range 
Test Result 
Assessment 
Date/Time of 
Collection 
(Study Day) 
XXXX 
XX 
M 
XX 
Hematology  
Hemoglobin 
 
XXXXX 
XX-XX 
High/Low 
XXXXX(XX) 
 
 
 
 
 
Haematocrit 
 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: NA=Not ApplicableNotes: Study day is calculated relative to the date of first dose of study drug.  
Source: Listings 16.2.8.1, 16.2.8.2, 16.2.8.3, 16.2.8.4 
Programming note- Category will be Hematology/Chemistry/Urinalysis/Coagulation. Sort by subject id, treatment group, and paramn.  
 
Page 61 of 351


 
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Table 14.3.5.1 
Summary of Clinical Laboratory Results  
Safety Population 
 
 
Lab Category: Chemistry/Hematology/Urinalysis 
 
Parameter:XXXX 
  Visit/ 
    Statistic 
 
 
 
 
 
Iburprofen 
PR 
(N=XX) 
Iburprofen PR 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
Lab Parameter: XXXXX 
 
 
 
 
   Screening  
 
 
 
 
     n 
XX 
XX 
XX 
XX 
    Mean 
XX.X 
XX.X 
XX.X 
XX.X 
    Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
XX.X 
XX.X 
    Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
Notes- Clinical laboratory tests (hematology, chemistry, urinalysis) tests are only done at Screening. 
 
SOURCE: Listing 16.2.8.1, 16.2.8.2, 16.2.8.3, 16.2.8.4 
Programming Note- Lab Category is Hematology or Chemistry or Urinalysis or Coagulation 
 
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Table 14.3.6.1 
Summary of Vital Signs  
Safety Population 
                     Parameter:XXXXX 
 
 
Visit/ 
Statistic 
 
 
 
 
 
Iburprofen PR 
(N=XX) 
Iburprofen IR 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Baseline 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
12 hours  
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Change from Baseline to 12 
hours 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
……. 
 
 
 
 
 
Notes- Baseline is defined as the last observation recorded prior to the first dose.  
Programming Note- Calculate summary stats and change from baseline for 12 hours, 24 hours and Day 8/ET visit. 
Source:Listing 16.2.9.2 
 
 
 
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Table 14.3.6.2 
Summary of Electrocardiogram (ECG) Interpretations  
Safety Population 
  
 
 
Visit 
   Category 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Overall 
 
(N=XX) 
Screening 
 
 
 
 
   Normal 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Abnormal - CS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Abnormal - NCS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CS = clinically significant; NCS = not clinically significant 
 
SOURCE: Listing 16.2.9.3 
 
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Table 14.3.6.3 
Summary of 12-Lead Electrocardiogram (ECG) Parameters  
Safety Population 
Parameter: XXXXXX 
 
 
Visit/ 
  Statistic 
 
 
 
 
Ibuprofen PR  
 (N=XX) 
Ibuprofen IR 
 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Screening 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOURCE: Listing 16.2.9.3. 
 
 
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Table 14.3.6.4 
Summary of Physical Examination Findings  
Safety Population 
Body System=XXXXXX 
 
Visit 
    Category 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Overall 
 
(N=XX) 
 Visit 
 
 
 
 
    Normal 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
    Abnormal - CS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
    Abnormal - NCS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
….. 
 
 
 
 
Abbreviations: CS = clinically significant; NCS = not clinically significant ET: end of treatment 
 
SOURCE: Listing 16.2.9.3 
 
 
Table 14.3.6.5 
Rescue Medication Use  
Safety Population 
 
 
Any rescue medication 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
Total 
 
 
 
 
 
At Any time 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
In the first 1 hour after dosing  
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
In the first 2 hours after dosing  
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
……….. 
 
 
 
 
 
 
 
 
 
 
Note: At each level of summarization subjects taking multiple rescue medication are counted only once. Percentage is based on number of subjects in the safety population.  
Programming note- Please complete table for the following time points 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours and 24 hours. 
 
 
 
 
 
 
 
 
 
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Table 14.2.1 
Analysis of SPID-12 Scores  
ITT Population 
 
Statistics 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
 
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.XX 
XX.XX 
XX.XX 
Std Dev 
XX.XXX 
XX.XXX 
XX.XXX 
Median 
XX.XX 
XX.XX 
XX.XX 
Min, Max 
XX.X,XX.X 
XX.X,XX.X 
XX.X,XX.X 
 
 
 
 
ANCOVA Statistics [1] 
 
 
 
LS Mean (SE) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
LS Mean Difference from Placebo (95% CI) 
p-value 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
 
 
 
 
 
 
 
 
 
….. 
 
 
 
  
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Notes: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 
10 = worst pain ever. Baseline pain is also recorded using the NRS scale. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. 
Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
Source: Listing 16.x.xx 
 
 
 
 
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Table 14.2.1.1 
Analysis of SPID-12 Scores – Sensitivity Analysis 1  
PP Population 
 
(Same Shell as Table 14.2.1) 
 
 
 
 
 
 
 
 
Table 14.2.1.2 
Analysis of SPID-12 Scores- Sensitivity Analysis 2-WOCF 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing 
pain assessments imputed by WOCF 
 
(Programming Note-This is sensitivity analysis # 2 in section 6.1.6 of the SAP.) 
 
 
Table 14.2.1.3 
Analysis of SPID-12 Scores- Sensitivity Analysis 3-No Rescue Adjustment 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. No adjustment made to pain scores after use of rescue medication. Missing intermediate pain assessments 
imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
(Programming Note-This is sensitivity analysis # 3 in section 6.1.6 of the SAP.) 
 
Table 14.2.1.4 
Analysis of SPID-12 Scores- Sensitivity Analysis 4a-Rescue WOCF 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. Worst observation carried forward (WOCF) is used to impute all subsequent pain scores after first use of rescue 
medication. Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
 
(Programming Note-This is sensitivity analysis # 4a in section 6.1.6 of the SAP.) 
 
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Table 14.2.1.5 
Analysis of SPID-12 Scores- Sensitivity Analysis 4b-Rescue LOCF 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. Last observation carried forward (LOCF) is used to impute all subsequent pain scores after first use of rescue 
medication. Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
(Programming Note-This is sensitivity analysis # 4b in section 6.1.6 of the SAP.) 
 
Table 14.2.1.6 
Analysis of SPID-12 Scores- Sensitivity Analysis 4c-Multiple Imputation-Rescue Medication-MAR 
 ITT Population 
(Same Shell as Table 14.2.1) 
Footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. All pain scores after rescue medication are imputed using an MCMC method under missing at random 
assumption. Intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
(Programming Note-This is sensitivity analysis # 4c in section 6.1.6 of the SAP.) 
 
 
 
Table 14.2.1.7 
Analysis of SPID-12 Scores- Sensitivity Analysis 5-Multiple Imputation-PMM 
 ITT Population 
(Same Shell as Table 14.2.1) 
Footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. 
Intermittent missing values are replaced by an MCMC method under a missing at random assumption. Missing pain assessments due to premature discontinuation are replaced using 
a pattern-mixture model with control-based imputation.  
 
 
(Programming Note-This is sensitivity analysis # 5 in section 6.1.6 of the SAP.) 
 
Table 14.2.1.8 
Analysis of SPID-12 Scores- Sensitivity Analysis 6-Multiple Imputation-MAR 
 ITT Population 
(Same Shell as Table 14.2.1) 
Footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating (NRS) from 0-10 where 0 = no pain and 10 = 
worst pain ever. Baseline pain is also recorded using the NRS scale. Missing pain scores and values within the defined window after rescue medication are imputed using multiple 
imputation under the MAR assumption. 
 
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(Programming Note-This is sensitivity analysis # 5 in section 6.1.6 of the SAP.) 
 
 
 
 
 
Table 14.2.1.9 
Summary of SPID-12 Scores by Baseline Pain Category 
ITT Population 
 
 
Category/Statistic 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Baseline  Pain Category-
Moderate 
 
 
 
    
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
Median 
XX 
XX 
XX 
Min, Max 
XX,XX 
XX,XX 
XX,XX 
 
 
 
 
…………. 
 
 
 
 
Notes- SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects will rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain 
and 10 = worst pain ever.  Baseline pain using a categorical scale that includes moderate (5-7), and severe (8-10). For subjects who use rescue medication, windowed worst 
observation carried forward (WOCF) is used. Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation 
imputed by LOCF. 
 
Programming Note- Please complete table for all baseline pain categories.  
 
 
                                                                    
 
 
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Table 14.2.2 
Analysis of Summed Pain Intensity Difference Scores  
ITT Population 
 
 
  
 
Category/Statistics 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
SPID-4 
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.XX 
XX.XX 
XX.XX 
Std Dev 
XX.XXX 
XX.XXX 
XX.XXX 
Median 
XX.XX 
XX.XX 
XX.XX 
Min, Max 
XX.X,XX.X 
XX.X,XX.X 
XX.X,XX.X 
 
 
 
 
ANCOVA Statistics [1] 
 
 
 
LS Mean (SE) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
LS Mean Difference from Placebo (95% CI) 
p-value 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
….. 
 
 
 
 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Notes: SPID-4/8/12 is summed pain intensity difference (SPID) over 0 to 4/8/12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no 
pain and 10 = worst pain ever. Baseline pain is also recorded using the NRS scale. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is 
used. Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
Programming Note- Please program for SPID-4 SPID-8 and SPID-24. 
 
Source: Listing 16.x.xx 
 
 
 
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Table 14.2.2.1 
Analysis of SPID-24 Scores- Sensitivity Analysis 7-No Rescue Adjustment 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. No adjustment made to pain scores after use of rescue medication. Missing intermediate pain assessments 
imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
Table 14.2.2.2 
Analysis of SPID-24 Scores- Sensitivity Analysis 8-Multiple Imputation-MAR 
 ITT Population 
(Same Shell as Table 14.2.1) 
Footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-24 is summed pain intensity difference (SPID) over 0 to 24 hours. Subjects rate their pain intensity using a numeric rating (NRS) from 0-10 where 0 = no pain and 10 = 
worst pain ever. Baseline pain is also recorded using the NRS scale. Missing pain scores and values within the defined window after rescue medication are imputed using multiple 
imputation under the MAR assumption 
 
 
 
Table 14.2.3 
Analysis of Total Pain Relief Scores  
ITT Population 
 
(Programming Note- Use same shell as Table 14.2.2. Please add the following footnote defining sum of total pain relief (TOTPAR) Note- Total pain relief (TOTPAR) is summed total 
pain relief under the Pain Relief Scale (0 – 4) from 15 min through 4/8/12/24 hours ) 
 
 
 
 
 
Table 14.2.4 
Analysis of Summed Pain Relief and Intensity Difference Scores  
ITT Population 
(Use same shell as Table 14.2.2) 
 
 
 
 
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Table 14.2.5 
Comparison of SPID-24 in Ibuprofen PR and IR arms 
ITT Population 
 
 
 
 
 
 
 
Category/Statistics 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
SPID-24 
 
 
ANCOVA Statistics [1] 
 
 
LS Mean (SE) 
XX.XX (XX.XX) 
XX.XX (XX.XX) 
 
 
 
 
 
 
 
 
 
LS Mean Difference (95% CI) 
p-value 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
 
 
 
 
….. 
 
 
 
 
 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error, SPID=summed pain intensity difference. 
[1] Estimates are from an analysis of covariance model with SPID-24/TOTPAR-24/SPRID-24 score as the dependent variable. Terms for treatment and baseline pain score were 
included as covariates.  
Notes-SPID-24 is summed pain intensity difference (SPID) over 0 to 24 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing intermediate pain assessments imputed by linear 
interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
 
Table 14.2.5.1 
Comparison of SPID-24 in Ibuprofen PR and IR arms-Sensitivity Analysis 7-No Rescue Adjustment 
ITT Population 
 
Use same shell as Table 14.2.5 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error, SPID=summed pain intensity difference. 
[1] Estimates are from an analysis of covariance model with SPID-24 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Notes-SPID-24 is summed pain intensity difference (SPID) over 0 to 24 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. No adjustment made to pain scores after use of rescue medication. Missing intermediate pain assessments imputed by linear interpolation. Missing pain 
assessments due to premature discontinuation imputed by LOCF. 
 
Table 14.2.5.2 
Comparison of SPID-24 in Ibuprofen PR and IR arms-Sensitivity Analysis 8- Multiple Imputation 
ITT Population 
 
Use same shell as Table 14.2.5 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error, SPID=summed pain intensity difference. 
[1] Estimates are from an analysis of covariance model with SPID-24 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Notes-SPID-24 is summed pain intensity difference (SPID) over 0 to 24 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
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= worst pain ever. No adjustment made to pain scores after use of rescue medication. Missing pain scores and values within the defined window after rescue medication are imputed 
using multiple imputation under the MAR assumption 
 
 
 
 
 
 
Table 14.2.6 
Summary of Peak Pain Relief  
ITT Population 
  
 
 
Category/Statistics 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
   None 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A Little Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Some Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A lot of Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Complete Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
Odds Ratio (vs placebo) [1] 
XX.XX 
XX.XX 
 
  95% CI 
(XX.XX,XX.XX) 
XX.XX,XX.XX) 
 
  p-value 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
 
 
 
Abbreviations: CI=Confidence Interval 
[1] From a proportional odds model treatment group and baseline pain as covariates. An odds ratio > 1 means that patients experienced higher peak pain relief than the placebo. 
Notes- Subjects rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. 
 
SOURCE: Listing 16.x.xx  
 
 
 
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Table 14.2.7 
Time to First Perceptible Pain Relief  
ITT Population 
  
 
 
Category/Statistic  
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Number of Subjects with First 
Perceptible Pain Relief 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Number of Subjects Censored  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Time to first perceptible pain relief 
(hours) [1] 
 
 
 
       Median (95% CI) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
        Q1  
XX.XX  
XX.XX  
XX.XX 
        Q3 
XX.XX  
XX.XX  
XX.XX 
        Range (Min-Max) 
XX.X-XX.X 
XX.X-XX.X 
XX-XX 
        p-value (vs placebo) [2] 
0.XXXX 
0.XXXX 
 
 
 
 
 
Hazard Ratio (vs placebo) [3] 
XX.XX 
XX.XX 
 
95% CI 
(XX.XX,XX.XX) 
(XX.XX,XX.XX) 
 
 
 
 
 
Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means 
that patients in the Ibuprofen groups achieved pain relief faster than the placebo.  
Notes- Time of first perceptible pain relief is the time of first reported pain relief as assessed by the subject (i.e. subject stops the first stopwatch (irrespective of the second 
stopwatch)). Pain scores at baseline are categorized as moderate (5-7), and severe (8-10). 
 
 
Table 14.2.8 
Time to Meaningful Pain Relief  
ITT Population 
 
Use same shell as Table 14.2.7 
(Programmers Note- Please add the following footnote- Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates.  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means 
that patients in the Ibuprofen groups achieved pain relief faster than the placebo. 
Notes- Time of meaningful pain relief is the time of the first reported meaningful (subjective) pain relief assessed by stopping the second stopwatch. Pain scores at baseline pain) are 
categorized as moderate (5-7), and severe (8-10 
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Table 14.2.9 
Time to Onset of Analgesia  
ITT Population 
 
 
Category/Statistic  
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Number of Subjects with First Perceptible Pain 
Relief and Meaningful Pain Relief 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Number of Subjects Censored  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Time to onset of analgesia (hours) [1] 
 
 
 
       Median (95% CI) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
        Q1  
XX.XX  
XX.XX  
XX.XX 
        Q3 
XX.XX  
XX.XX  
XX.XX 
        p-value (vs placebo) [2] 
0.XXXX 
0.XXXX 
 
        p-value (PR vs IR) [2] 
0.XXXX 
 
 
        Range (Min-Max) 
XX.X-XX.X 
XX.X-XX.X 
XX.X-XX.X 
 
 
 
 
Hazard Ratio (95% CI) (vs placebo) [3] 
XX.XX (XX.XX,XX.XX) 
XX.XX (XX.XX,XX.XX) 
 
Hazard Ratio (95% CI) (PR vs IR) [4] 
XX.XX (XX.XX,XX.XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 (Programmers Note- Please add the following footnote- Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. If hazard ratio <1 means 
that patients in the Ibuprofen groups achieved pain relief faster than the placebo  
[4] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. If hazard ratio <1 means 
that patients in the PR group achieved pain relief faster than the IR. 
Notes- If the subject has had meaningful pain relief (i.e., presses both stopwatches) then time to onset of analgesia is date/time when the first stopwatch is stopped. Pain scores at 
baseline are categorized as moderate (5-7), and severe (8-10). 
 
 
 
Table 14.2.10 
Time to Peak Pain Relief  
ITT Population 
Use same shell as Table 14.2.7 
 
(Programmers Note- Please add the following footnote- Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means 
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that patients in the Ibuprofen groups achieved pain relief faster than the placebo. 
Note- Time of peak pain relief is the time when pain relief, which is measured on a scale from 0 (none)-4 (complete), is maximum. Subjects who do not experience any pain relief are 
censored at the time of their last pain assessment.  
 
 
 
Table 14.2.11 
Time to First use of Rescue Medication  
ITT Population 
 
Use same shell as Table 14.2.7 
 
(Programmers Note- Please add the following footnote- Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of >1 means 
that patients in the Ibuprofen groups refrained from taking rescue medication for longer than the placebo. 
 
Notes- Subjects who do not take rescue medication are censored at the time of their last pain assessment. 
 
 
Table 14.2.12 
Proportion of Subjects Using Rescue Medication  
ITT Population 
  
 
 
Category/Statistic 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Number of subjects using Rescue Medication 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
Odds Ratio for Rescue Medication 
(Active/Placebo) [1] 
XX.XX 
XX.XX 
 
   (95% CI) 
(XX.XX,XX.XX) 
(XX.XX,XX.XX) 
 
p-value 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
Abbreviation: CI= Confidence Interval  
[1] Odds ratio, CI, and p-value are from a logistic regression model estimating the probability of using rescue medication with baseline pain and treatment arm 
as covariates in the model. An odds ratio < 1 means patients in the Ibuprofen groups are less likely to have used rescue medication compared to those in placebo. 
 
 
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 Table 14.2.13 
Proportion of Responders  
ITT Population 
 
(Use same shell as 14.2.12. Please use footnote below.) 
Abbreviation: CI=Confidence Interval  
Notes- A subject with ≥ 30% improvement in NRS pain intensity from T0 (predose) without rescue medication during the first 8 hours is considered a responder. 
[1] Odds ratio, CI, and p-value are from a logistic regression model estimating the probability of being a responder with baseline pain and treatment arm as covariates in the model. An 
odds ratio > 1 means patients in the Ibuprofen groups are more likely to be responders compared to those in placebo. 
 
 
 
 
 
Table 14.2.14 
Summary of NRS Pain Intensity Difference Score  
ITT Population 
  
 
 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
PID 15 mins after Time 0  
 
 
 
    
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
Median 
XX 
XX 
XX 
Min, Max 
XX,XX 
XX,XX 
XX,XX 
 
MMRM Statistics [1] 
 
 
 
LS Mean (SE) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
 
 
 
 
LS Mean Difference from 
Placebo (95% CI) 
XX.X (XX.X, XX.X) 
 
XX.X (XX.X, XX.X) 
 
 
p-value (vs Placebo) 
 
0.XXXX 
0.XXXX 
 
Abbreviations: MMRM = Mixed Model Repeated Measures, CI = confidence interval, LS=least-squares, SE = standard error, PID= Pain Intensity Difference NRS- Numeric Rating 
Scale. 
[1] Estimates are from a repeated measures mixed model with PID score as the dependent variable. Terms for treatment, timepoint, treatment by timepoint, baseline and baseline by 
timepoint as fixed effects, and subject as a random effect.  
Notes- Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever. Pain intensity difference score at a time point is the 
difference in NRS pain intensity from baseline to that time point. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing data 
due to missing intermediate assessments or premature discontinuation is not imputed. 
 
Programming Note- Please complete table for all scheduled time assessments. Only impute using wWOCF for assessments after rescue medication. Do not impute for missing data. 
 
 
Page 78 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.2.15 
Summary of Pain Intensity Score at each Scheduled Time Point 
ITT Population 
Use same shell as Table 14.2.14 
(Programmers please add the following footnote-  
Note- Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever. For subjects who use rescue medication, windowed 
worst observation carried forward (WOCF) is used. Missing data due to missing intermediate assessments or premature discontinuation is not imputed. 
Programming Note- Please complete table for all scheduled time assessments. No need for LS mean difference 95%CI and p value from 14.2.14 shell). Only impute using wWOCF for 
assessments after rescue medication. Do not impute for missing data. 
 
 
 
 
 
 
 
 
 
  
 
Page 79 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Table 14.2.16 
Summary of Pain Relief at each Scheduled Time Point 
ITT Population 
 
 
 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Pain Relief 5 mins after 
Time 0 
 
 
 
    
 
 
 
 
 
 
 
None 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
A Little Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Some Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
A lot of Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Complete Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
Median 
XX 
XX 
XX 
Min, Max 
XX,XX 
XX,XX 
XX,XX 
 
 
 
 
 
MMRM Statistics [1] 
 
 
 
LS Mean (SE) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
 
 
 
 
LS Mean Difference from 
Placebo (95% CI) 
XX.X (XX.X, XX.X) 
 
XX.X (XX.X, XX.X) 
 
 
p-value (vs Placebo) 
 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: MMRM = Mixed Model Repeated Measures, CI = confidence interval, LS=least-squares, SE = standard error. 
[1] Estimates are from a repeated measures mixed model with pain relief as the dependent variable. Terms for treatment, timepoint, treatment by timepoint, baseline pain and baseline 
pain by timepoint as fixed effects, and subject as a random effect. 
Notes- Subjects rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. For subjects who use rescue 
medication, windowed worst observation carried forward (WOCF) is used. Missing data due to missing intermediate assessments or premature discontinuation is not imputed. 
 
Programming Note- Please complete table for all scheduled time assessments. Only impute using wWOCF for assessments after rescue medication. Do not impute for missing data. 
 
 
 
Page 80 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
 
 
Table 14.2.17 
Analysis of Patient Global Evaluation of Study Drug 
ITT Population 
 
 
 
Category/Statistics 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Poor 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Fair 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Good 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Very Good 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Excellent 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
Odds Ratio (vs placebo) [1] 
XX.XX 
XX.XX 
 
95% CI 
(XX.XX,XX.XX) 
XX.XX,XX.XX) 
 
p-value 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
 
 
 
 
Notes- Patient’s global evaluation of study drug is measured on a scale of 0=poor, 1=fair, 2=good, 3=very good, 4=excellent. 
[1] From a proportional odds model treatment group and baseline pain as covariates. An odds ratio > 1 means that patients rated active arm more highly than placebo 
 
 
 
  
 
Page 81 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
1.2. 
Planned Listing Shells 
Listing 16.2.1 
Subject Disposition 
All Subjects 
Date of Last Dose 
Date of Completion/ 
Discontinuation 
 Subject 
Number 
Randomized? 
Patient 
Status 
(Study Day) 
(Study Day) 
Reason for Discontinuation 
Was blind broken? If yes, date and 
reason blind was broken 
XXXXXX 
Yes 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XX 
XXXXXX 
Yes 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XX 
XXXXXX 
Yes 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XX 
XXXXXX
No
DDMMMYYYY (X) 
DDMMMYYYY (X) 
XXXXXXXXXX: XXXXXXXXX
XX
XXXXXX 
No 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XXXXXXXXXXXXXXXXXXXXXX 
XX 
Abbreviation: NA=Not Applicable 
 Notes: Study day is calculated relative to the date of first dose of study drug 
Programming Note: If reason for early termination is other, concatenate the specify text as follows: “Other: XXXXXXXXX”. If additional details about reason for discontinuation are 
present in DSREASSP, then concatenate reason for discontinuation with “DSREASSP”. 
If reason for early termination is lost to follow-up, concatenate with date of last contact as follows: “Lost to follow-up: Lost-to follow-up comment (DSLFCOMT): date of last contact: 
DDMMMYYYY”. Lost to follow up comment DSLFCOMT will only be concatenated when present. 
If reason for discontinuation is a PI decision, concatenate PI decision reason as follows: “PI Decision: XXXXXXXXXXX 
Page 82 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.2.1 
Inclusion/ Exclusion Criteria 
All Subjects 
 
 
Date (Study Day)  
All Inclusion 
Criteria Met? 
Any Exclusion 
Criteria Met? 
Subject Number 
Gender 
Screening 
Informed Consent 
 
 
 
 
 
 
 
 
XXXXXX 
XXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
No 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
No: 02, 09 
No 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
No: 06 
No 
 
 
 
 
 
 
XXXXXX 
XXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
Yes: 06 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
No 
 
 
 
 
 
 
XXXXXX 
XXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
No 
 
 
 
 
 
 
Notes: Study day is calculated relative to the date of first dose of study drug. 
Programming note: If more than 1 inclusion or exclusion criterion number exists, concatenate with a comma. Decode any relevant criteria in the footnotes. 
 
Page 83 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.2.2 
Screen Failures 
Subject 
Number 
Gender 
Date of Birth 
Age 
Screen Fail Date 
Screen Fail Reason 
XXXXXX
XXXXXX
DDMMMYYYY
XX
DDMMMYYYY
Inclusion #2
XXXXXX
XXXXXX
DDMMMYYYY
XX
DDMMMYYYY
Inclusion #6
XXXXXX
XXXXXX
DDMMMYYYY
XX
DDMMMYYYY
Inclusion #4, Exclusion #6
XXXXXX
XXXXXX
DDMMMYYYY
XX
DDMMMYYYY
Other: XXXXXXXXXXXXX
Programming note: If more than 1 inclusion or exclusion criterion number exists, concatenate with a comma  
Programming note: If additional details about reason for screen failure are present in, then concatenate reason for screen failure reason with “DSSFOTRN”. 
Page 84 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.2.3 
Protocol Deviations 
All Subjects 
Subject 
Number 
Treatment
Group 
Event Date 
(Study day) 
Event Type 
Violation 
Level 
Description 
XXXXXX
XXXX
XXXX(XXX) 
XXXXXXXXXXX
MAJOR 
XXXXXXX
XXXXXXXXXXXXXX
MINOR 
XXXXXXXXXXXXXXX
XXXXXX
XXXX
XXXX(XXX) 
XXXXXXXXXXXX
MINOR 
XXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXX
MINOR 
XXXXXXXXXXX
XXXXXX
XXXX
XXXX(XXX) 
XXXXXXXXXXXX
MAJOR 
XXXXXXXXXXXXXXXXXXXX
Notes: Study day is calculated relative to the date of first dose of study drug. 
Page 85 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.3 
Analysis Populations 
All Subjects 
 Subject 
Number 
Treatment 
Group 
SAF 
PP 
ITT 
Primary Reason(s) for Exclusion 
XXXXXX
XXX
Yes 
No
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX.
XXXXXX
XXX
Yes 
Yes 
XXXXXX
XXXX
No
No
Abbreviations: PP = Per Protocol Population; SAF= Safety Population; ITT= Intent-to-treat population 
Page 86 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.4.1 
Demographics and Baseline Characteristics 
Safety Population 
 
 
 
 
 
Age 
 
 
Weight 
Height 
BMI 
Duration of 
Surgery 
 Subject 
Number 
Gender 
If Female, 
is she of 
childbearing 
potential? 
 
Treatment 
Group 
(years) 
Ethnicity 
Race 
(kg) 
(cm) 
(kg/m2) 
 
 
 
(hours) 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: BMI = Body mass index  
Notes: Height, weight, and BMI are the values at Screening. 
  
 
Page 87 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.4.2 
Medical History 
Safety Population 
Subject 
Number 
Treatment 
Group 
Any Medical 
History 
SOC/PT/VT    
Start date(Study Day) / 
End Date( Study Day) 
Ongoing? 
XXX
XX
XX
XXXX/XXX/XXX      
DDMMMYYYY/DDMMMYYYY(XXX) 
XXX
XX
XX
XXXX/XXX/XXX      
DDMMMYYYY/DDMMMYYYY(XXX) 
XXX
XX
XX
XXXX/XXX/XXX      
DDMMMYYYY/DDMMMYYYY(XXX) 
XXX
XX
XX
XXXX/XXX/XXX      
DDMMMYYYY/DDMMMYYYY(XXX) 
XXX
XX
XX
XXXX/XXX/XXX      
DDMMMYYYY/DDMMMYYYY(XXX) 
XXX
XX
XX
XXXX/XXX/XXX      
DDMMMYYYY/DDMMMYYYY(XXX) 
SOC = System Organ Class; PT = Preferred Term; VT = Verbatim Term. 
Notes: All medical history terms were coded using MedDRA dictionary version 21.1. Study day is calculated relative to the date of first dose of study drug 
Page 88 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.4.3 
Listing of Subject Randomization 
All Randomized Subjects 
Subject 
Number 
Randomization Date 
Randomization Time  
Randomization Number 
Kit Number Assigned 
Randomized Arm 
XXX
DDMMMYYYY
hh:mm
XXX
XXX
XX
XXX
DDMMMYYYY
hh:mm
XXX
XXX
XX
XXX
DDMMMYYYY
hh:mm
XXX
XXX
XX
XXX
DDMMMYYYY
hh:mm
XXX
XXX
XX
XXX
DDMMMYYYY
hh:mm
XXX
XXX
XX
Page 89 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.4.4 
Study Drug Administration 
Safety Population 
Subject 
Number 
Treatment 
Group 
Timepoint 
Was Study Drug 
Administered?  
Reason Not Administered 
Date of Administration 
Time of Administration 
XXX
XXX
0 hours 
Yes/no
XXXXXXXXXXXXX
DDMMMYYYY
hh:mm
XXX
XXX
8 hours 
Yes/no
XXXXXXXXXXXXX
DDMMMYYYY
hh:mm
XXX
XXX
12 hours 
Yes/no
XXXXXXXXXXXXX
DDMMMYYYY
hh:mm
XXX
XXX
16 hours 
Yes/no
XXXXXXXXXXXXX
DDMMMYYYY
hh:mm
Page 90 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.7.1 
Adverse Events 
Safety Population 
Subject 
Number 
Gender 
Treatment 
Group 
Any AEs 
reported? 
TEAE? 
SOC/PT/VT    
Start date 
time(Study Day) / 
End Date 
time(Study Day)  
Severity/ 
Relationship  
Medical 
Treatment 
Received? 
Outcome/ 
Action Taken  
Serious?  
XXX 
XXX 
XX 
XX 
NO 
XXXX/XXX/XXX  
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
No 
XXX 
XXX 
XX 
XX 
YES 
XXXX/XXX/XXX  
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
YES 
XXX 
XXX 
XX 
XX 
NO 
XXXX/XXX/XXX  
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
No 
XXX 
XXX 
XX 
XX 
YES 
XXXX/XXX/XXX  
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
No 
XXX 
XXX 
XX 
XX 
YES 
XXXX/XXX/XXX  
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
YES 
XXX 
XXX 
XX 
XX 
NO 
XXXX/XXX/XXX  
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
NO 
Abbreviation: TEAE-Treatment Emergent Adverse Event, SOC = System Organ Class; PT = Preferred Term; VT = Verbatim Term. 
Notes: AEs were coded using MedDRA dictionary version 21.1. TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose 
of study drug. Study day is calculated relative to the date of first dose of study drug. 
Programming note= Fatal/hospitalization/life threatening/persistent/congenital/important medical event can be concatenated to SAE when SAE=Y. Concatenate an abbreviated version 
of the term. Example – For Fatal use F etc. Add term to list of abbreviations if such abbreviation is used.  
Page 91 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.7.2 
Serious Adverse Events  
Safety Population 
(Same shell as Listing 16.2.7.1) 
Listing 16.2.7.3 
Treatment emergent Adverse Events Related to Study Drug 
Safety Population 
(Same shell as Listing 16.2.7.1) 
Page 92 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.7.4 
Deaths  
Safety Population 
Subject 
Number 
Gender 
Treatment 
Group 
Date of 
Death(Study Day) 
Cause of Death 
(Specify if Other) 
001-003
DDMMMYYYY(XX) 
XXXXXXXXXX
Notes-Study day is calculated relative to the date of first dose of study drug. 
Page 93 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.8.1 
Clinical Laboratory Data: Serum Chemistry 
Safety Population 
Subject 
Number 
Gender 
Treatment 
Group 
Was 
Sample 
Collected? 
Date/Time of 
Assessment 
Test Name 
Standard 
Results 
Units 
Abnormal? / 
If Yes, H or 
L 
Comments/Reason 
not Done 
XXX
XXX
XX
DDMMMYYYY(XX) 
XX
XX
NO
XXX
XXX
XX
DDMMMYYYY(XX) 
XX
XX
NO
XXX 
XXX 
XX 
DDMMMYYYY(XX) 
XX 
XX 
YES/ 
NO 
XXX 
XXX 
XX 
DDMMMYYYY(XX) 
XX 
XX 
YES/ 
YES 
XXX
XXX
XX
DDMMMYYYY(XX) 
XX
XX
NO
Abbreviation: H=High, L=Low 
Notes: Study day is calculated relative to the date of first dose of study drug. 
Page 94 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.8.2 
Clinical Laboratory Data: Hematology 
Safety Population 
(Same shell as Listing 16.2.8.1) 
Listing 16.2.8.3 
Clinical Laboratory Data: Urine 
Safety Population 
(Same shell as Listing 16.2.8.1) 
Listing 16.2.8.4 
Clinical Laboratory Data: Coagulation 
Safety Population 
(Same shell as Listing 16.2.8.1) 
Listing 16.2.8.5 
Serum and Urine Pregnancy Test 
Safety Population 
Subject 
Number 
Treatment 
Group 
Visit 
Was 
Sample 
Collected? 
Reason not 
collected 
Date of Assessment 
Time of 
Assessment
Serum or Urine Test ? 
Result of 
Pregnancy 
Test
001-
003 
DDMMMYYYY 
XXXXXXXXXX 
Page 95 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.1 
Prior and Concomitant Medications 
Safety Population 
Subject 
Number 
Treatment 
Group 
Prior, Concomitant 
or Both? 
ATC Class (Level 4)/ 
/PT /VT     
Start date time (Study 
Day)/ 
End date time(Study 
Day)  
Dose 
Unit  
Frequency  
Route 
Ongoing ? 
XXX 
XX 
Prior 
XXXX/XXX/XXX  
DDMMMYYYY(XX) / 
DDMMMYYYY(XX) 
XXX 
XXX 
XXX 
Both 
XXXX/XXX/XXX  
DDMMMYYYY(XX)  / 
DDMMMYYYY (XX) 
XXX 
XXX 
XXX 
Concomitant 
XXXX/XXX/XXX  
DDMMMYYYY(XX)  / 
DDMMMYYYY(XX) 
XXX 
XXX 
XXX 
XXXX/XXX/XXX  
DDMMMYYYY(XX)  / 
DDMMMYYYY (XX) 
XXX 
XXX 
XXX 
XXXX/XXX/XXX  
DDMMMYYYY (XX) / 
DDMMMYYYY(XX) 
XXX 
XXX 
XXX 
XXXX/XXX/XXX  
DDMMMYYYY(XX)  / 
DDMMMYYYY (XX) 
XXX 
XXX 
ATC = Anatomic Therapeutic Chemical; PT = Preferred Term; VT = Verbatim Term. 
Notes: Study day is calculated relative to the date of first dose of study drug.. Medications are coded using WHO-DD B2E version March 2020.  . Medications that started prior to the 
first dose of study drug will be considered prior medications whether or not they were stopped prior to the first dose of study drug. Any medications continuing or starting post the first 
dose of study drug will be considered to be concomitant. If a medication starts prior to the first dose and continues after the first dose of study drug, it will be considered both prior and 
concomitant. 
Page 96 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.1.1 
Rescue Medications 
Safety Population 
Subject 
Number 
Treatment 
Group 
Were 
any 
rescue 
medicati
ons 
reported
? 
Medicati
on  
Date time for 
pain 
relief/pain 
intensity 
(Study Day) 
NRS Pain 
intensity 
assessment 
Pain Relief 
Assessment 
ATC Class 
(Level 4)/ 
/PT /VT  
Start date 
time (Study 
Day) / End 
date 
time(Study 
Day) 
Dose 
Unit  
Frequency  
Route 
Ongoing ? 
XXX 
XX 
XX 
XXXX (XX) / 
XXXX(XX) 
XXXX/XXX/
XXX   
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
XXX 
XX 
XXXX (XX) / 
XXXX(XX) 
XXXX/XXX/
XXX   
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
XXX 
XX 
XXXX (XX) / 
XXXX(XX) 
XXXX/XXX/
XXX   
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
XXX 
XXXX (XX) / 
XXXX(XX) 
XXXX/XXX/
XXX   
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
XXX 
XXXX (XX) / 
XXXX(XX) 
XXXX/XXX/
XXX   
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
XXX 
XXXX (XX) / 
XXXX(XX) 
XXXX/XXX/
XXX   
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
Abbreviations: ATC = Anatomic Therapeutic Chemical; PT = Preferred Term; VT = Verbatim Term. 
Notes: Study day is calculated relative to the date of first dose of study drug.. Medications are coded using WHO-DD B2E version March 2020.  Pain assessments will be conducted 
immediately before each dose of rescue medication. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever and 
rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. 
Page 97 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.2 
Vital Signs Measurements 
Safety Population 
Subject 
Number 
Treatment Group 
Visit 
Timepoint  
Were Vital 
Signs 
Collected? 
Collection 
Date/Time 
(Study Day) 
Temperature 
(Units) 
Heart Rate (Units) 
Respiration Rate 
(Units) 
Systolic Blood Pressure 
(Units)   
Diastolic Blood 
Pressure (Units)  
XXX 
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX 
XXX 
XXX 
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX 
XXX 
XXX 
XXX   
XXX   
XXX   
XXX   
XXX   
XXX   
XXX   
XXX   
XXX 
XXX 
XXX 
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX 
XXX 
XXX 
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX  
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
Notes: Study day is calculated relative to the date of first dose of study drug. 
Page 98 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.2.1 
Physical Examination Findings 
Safety Population 
Subject 
Number 
Treatment 
Group 
Was Exam  
Performed? 
Visit 
Date/Time of 
Assessment (Study 
Day) 
Body 
System 
Standard 
Results 
If 
Abnormal, 
CS ? 
Abnormal 
findings 
descriptio
n 
Were mouth and 
neck examined? 
If no, 
reason 
Any CS abnormal 
findings that have 
been newly 
diagnosed or 
have worsened 
since the previous 
assessment? 
XXX 
XX 
Yes 
XX 
DDMMMYYYYThh:m
m(XX) 
XX 
Yes 
XX 
Yes 
XXX 
XX 
No 
XX 
DDMMMYYYYThh:m
m (XX) 
XX 
No 
XX 
No 
XXX 
XX 
Yes 
XX 
DDMMMYYYYThh:m
m(XX) 
XX 
YES 
Yes 
XX 
Yes 
XXX 
XX 
No 
XX 
DDMMMYYYYThh:m
m(XX) 
XX 
No 
XX 
No 
XXX 
XX 
No 
XX 
DDMMMYYYYThh:m
m(XX) 
XX 
No 
XX 
No 
Abbreviation: CS: Clinically Significant 
Notes: Study day is calculated relative to the date of first dose of study drug. 
Programming note: In the 'If Abnormal, CS ?' column, 'Yes' will only be populated when we the abnormal value is CS. 
Page 99 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.3 
12-Lead Electrocardiogram Measurements 
Safety Population  
Abbreviation: CS=Clinically Significant, NCS=Not Clinically Significant 
Notes: Study day is calculated relative to the date of first dose of study drug 
Subject 
Number 
Treatment 
Group 
Was ECG 
Performed? 
Date of Assessment 
(Study Day)  
Time of 
Assessment 
Heart Rate 
(Unit) 
RR Interval 
(Unit) 
PR Interval 
(Units) 
QRS (Unit) 
QT (Unit) 
QTc 
Interval 
(Unit) 
Investigator 
Interpretation 
XXX 
XXX 
XXX 
DDMMMYYYY(XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Normal 
XXX 
XXX 
XXX 
DDMMMYYYY (XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Abnormal-
NCS 
XXX 
XXX 
XXX 
DDMMMYYYY (XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Abnormal-
CS 
XXX 
XXX 
XXX 
DDMMMYYYY(XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Normal 
Page 100 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.3.1 
Alcohol Breathalyzer Test 
Safety Population 
Subject 
Number 
Treatment 
Was Alcohol 
Breathalyzer Test 
performed? 
Test Date/Time 
(Study Day) 
Alcohol 
Breathalyzer Test 
Result  
XXXX 
XX 
Yes 
DDMMMYYYYThh:mm(XX) 
XXXXXXX 
Notes: Study day is calculated relative to the date of first dose of study drug. 
Page 101 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.4 
NRS Pain Intensity Assessment 
Safety Population 
Subject 
Number 
Treatment 
Group 
Was NRS 
Pain 
Assessment 
collected? 
Reason not 
collected 
Timepoint 
Was Rescue 
Medication 
Taken? 
(Y/N) 
Date time post 
dose 
NRS Pain 
Intensity Score 
NRS Pain 
Intensity Score 
when rescue 
medication was 
taken 
Responder 
(Y/N) 
XXXX 
XX 
Yes 
XXXXXXXX 
XXX 
XXXX 
XXX 
XXX 
Notes- Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever. A subject with ≥ 30% improvement in NRS pain 
intensity from T0 (predose) without rescue medication during the first 8 hours is considered a responder. 
Programing Note- For those cases where “Was rescue medication taken?” is ‘Yes’, the datetime needs to be presented in the “Date time post dose” column.  
Page 102 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
 
 
 
Listing 16.2.9.5 
Pain Relief Scores 
Safety Population 
 
 
Subject 
Number 
 
 
Treatment 
Group 
 
 
Was 
assessment 
completed? 
 
 
Reason not 
collected  
 
 
 
Date of 
Assessment 
 
 
 
Date time 
pain relief 
collected 
 
 
Timepoint  
Was Rescue 
Medication 
Taken? 
(Y/N) 
Date time 
post dose 
 
How much 
relief have you 
had since your 
starting pain? 
How much 
pain relief 
have you 
had since 
your starting 
pain when 
rescue 
medication 
was taken? 
XXXX 
XX 
Yes 
XXXXXXXX 
 
 
XXX 
 
XXXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                Notes: Subjects rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. 
 
Programing Note- For those cases where “Was rescue medication taken?”  is ‘Yes’, the datetime needs to be presented in the “Date time post dose” column                 
Page 103 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.6 
Time to Pain Relief (Stopwatches) 
Safety Population 
Subject 
Number 
Treatment 
Group 
Which stopwatch 
pressed, perceptible or 
meaningful 
Hours on 
Stopwatch 
Minutes on 
stopwatch 
Seconds on 
stopwatch 
XXXX 
XX 
Perceptible/meaningful 
XX 
XXX 
XXX 
Notes: Perceptible pain relief stopwatch refers to the first stop watch and meaningful pain relief, the second stopwatch.
Page 104 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.7 
Subjects Global Evaluation of Study Drug 
Safety Population 
Subject 
Number 
Treatment 
Group 
Was Subject 
Global 
Evaluation of 
study drug 
completed 
Date/Time of 
evaluation 
Global evaluation 
score 
XXXX 
XX 
XXXX 
XX 
    Notes: Patient’s global evaluation of study drug is measured on a scale of 0=poor, 1=fair, 2=good, 3=very good, 4=excellent 
Page 105 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Figure 14.4.1.1 
Kaplan-Meier plot of time to first perceptible pain relief 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing first perceptible pain relief 
Figure 14.4.1.2 
Kaplan-Meier plot of time to Meaningful Pain Relief 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing meaningful pain relief 
Figure 14.4.1.3 
Kaplan-Meier plot of time to onset of analgesia 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing analgesia 
Figure 14.4.1.4 
Kaplan-Meier plot of time to peak pain relief 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing peak pain relief 
Figure 14.4.1.5 
Kaplan-Meier plot of time to first use of rescue medication 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients using rescue medication 
Figure 14.4.1.6 
Mean PID Scores versus Time 
Page 106 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
ITT Population 
x-axis Time (hours) 
y-axis- Mean PID score 
Present with error bars of +/- 1 standard error. 
Add footnote: For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing data due to missing intermediate assessments or 
premature discontinuation is not imputed. 
Figure 14.4.1.7 
Mean Pain Relief Scores versus Time 
ITT Population 
x-axis Time (hours) 
y-axis- Mean pain relief score 
Present with error bars of +/- 1 standard error. 
Add footnote: For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing data due to missing intermediate assessments or 
premature discontinuation is not imputed. 
Page 107 of 351


I
Statistical Analysis Plan
Sponsor Reckitt Benckiser
Protocol Number 5003601
PCN Number RECK.177035
trremter \
' fffi%ffiffirf,r} '
Sponsor
Reckitt Benckiser
Protocol Title:
A Randomized, Double-Blind, Double-Duffifity, Parallel,
Group, Multiple-Dose, Active and Placebo-Controlled
Efficacy Study of Ibuprofen Prolonged-Release Tablets for
the Treatment of Pain after Surgical Removal of Impacted
Third Molars
Protocol Number:
500360 1
Premier Research
PCN:
RECK.177035
Document Version:
Amendment 2.0
Document Date:
18-Mav-2020
Approvals
Biostatistician
Premier Research
Print Name: Raghu Vishnubhotla
Sign Name:
Reckitt Benckiser
Representative
Print Name: Darren Tarsett
11-rAAl -1r;1o
Sign Name:
Mqr
19-May-2020 | 22:39:31 EDT
Page 108 of 351


 
Statistical   Analysis Plan,  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 2 of 41 
 
Document History 
Reasons for Amendment 1 
 
 The statistical analysis plan was amended in the following ways: 
 
1. The sensitivity analyses for the primary efficacy endpoint has been updated. A pattern-
mixture model with control-based pattern imputation will now be used.  
2. A comparison of individual NRS pain intensity difference scores has been added. P-
values comparing the treatment arms (PR vs Placebo, IR vs Placebo) has been added. 
3. Pain relief scores at each time point will be summarized and by p-values will be added 
for treatment comparison.  
 
Reasons for Amendment 2 
 
 The statistical analysis plan was amended in the following ways: 
 
1. Add clarification for how pain assessments recorded within 4-hours of rescue medication 
and missing pain assessments are handled in the repeated measures analysis of pain 
intensity difference and pain relief scores. 
 
2. The sensitivity analyses for the primary efficacy endpoint have been further updated. A 
multiple imputation model under a Missing at Random (MAR) assumption has been 
added to account for missing data due to patient withdrawal, missing intermediate pain 
assessments and pain assessments impacted by rescue medication. 
 
3. Sensitivity analyses have been added for the key secondary endpoint SPID24. 
 
4. Updated methodology for handling pain assessments post non-permitted rescue 
medications. Added imputation windows for non-permitted rescue medications.  
 
 
 
 
 
 
 
 
 
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Statistical   Analysis Plan,  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 3 of 41 
 
 
 
Table of Contents 
Approvals................................................................................................................................ 1 
Document History ................................................................................................................... 2 
Table of Contents .................................................................................................................... 3 
List of Tables .......................................................................................................................... 5 
1. 
Overview ..................................................................................................................... 6 
2. 
Study Objectives and Endpoints.................................................................................... 6 
2.1. 
Study Objectives .................................................................................................... 6 
2.1.1. Primary Objective................................................................................................... 6 
2.1.2. Secondary Objectives ............................................................................................. 6 
2.2. 
Study Endpoints ..................................................................................................... 7 
2.2.1. Safety Endpoints .................................................................................................... 7 
2.2.2. Efficacy Endpoints ................................................................................................. 7 
3. 
Overall Study Design and Plan ..................................................................................... 8 
3.1. 
Overall Design ....................................................................................................... 8 
3.2. 
Sample Size and Power........................................................................................... 8 
3.3. 
Study Population .................................................................................................... 8 
3.4. 
Treatments Administered ........................................................................................ 8 
3.5. 
Method of Assigning Subjects to Treatment Groups ................................................ 8 
3.6. 
Blinding and Unblinding......................................................................................... 8 
3.7. 
Schedule of Events ................................................................................................10 
4. 
Statistical Analysis and Reporting................................................................................13 
4.1. 
Introduction...........................................................................................................13 
4.2. 
Interim Analysis ....................................................................................................13 
5. 
Analysis Populations ...................................................................................................13 
6. 
General Issues for Statistical Analysis ..........................................................................14 
6.1. 
Statistical Definitions and Algorithms ....................................................................14 
6.1.1. Baseline ................................................................................................................14 
6.1.2. Adjustments for Covariates ....................................................................................14 
6.1.3. Multiple Comparisons ...........................................................................................14 
6.1.4. Handling of Dropouts or Missing Data ...................................................................14 
6.1.5. Adjustment of Pain Scores for Rescue Medication Use ...........................................15 
6.1.6. Sensitivity Analysis of SPID12 and SPID24 ...........................................................15 
6.1.7. Derived Variables..................................................................................................18 
6.1.8. Data Adjustments/Handling/Conventions ...............................................................22 
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Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 4 of 41 
 
7. 
Study Patients/Subjects and Demographics ..................................................................23 
7.1. 
Disposition of Patients/Subjects and Withdrawals ...................................................23 
7.2. 
Protocol Violations and Deviations ........................................................................23 
7.3. 
Demographics and Other Baseline Characteristics ..................................................23 
7.4. 
Exposure and Compliance......................................................................................23 
8. 
Efficacy Analysis ........................................................................................................23 
8.1. 
Primary Efficacy Analysis .....................................................................................23 
8.2. 
Secondary Efficacy Analysis..................................................................................24 
8.2.1. SPID .....................................................................................................................24 
8.2.2. TOTPAR...............................................................................................................24 
8.2.3. SPRID ..................................................................................................................24 
8.2.4. Peak Pain Relief ....................................................................................................25 
8.2.5. Time to First Perceptible Pain Relief ......................................................................25 
8.2.6. Time to Meaningful Pain Relief .............................................................................25 
8.2.7. Time to onset of Analgesia.....................................................................................26 
8.2.8. Time to Peak Pain Relief .......................................................................................26 
8.2.9. Time to first use of Rescue Medication...................................................................26 
8.2.10. Proportion of Responders.......................................................................................26 
8.2.11. Numeric rating scale (NRS) pain intensity difference (PID) ....................................27 
8.2.12. Pain relief at each scheduled time point ..................................................................27 
8.2.13. Proportion of Subjects Rescue Medication..............................................................28 
8.3. 
Exploratory Efficacy Analysis................................................................................28 
8.3.1. Global Evaluation of Study Drug ...........................................................................28 
9. 
Safety and Tolerability Analysis ..................................................................................28 
9.1. 
Adverse Events .....................................................................................................28 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................29 
9.1.2. Deaths and Serious Adverse Events........................................................................29 
9.2. 
Clinical Safety Laboratory Data .............................................................................29 
9.3. 
Vital Signs ............................................................................................................29 
9.4. 
Concomitant Medication........................................................................................30 
9.5. 
Rescue Medication use ..........................................................................................30 
10. 
Changes to analysis planned in the protocol .................................................................30 
11. 
References ..................................................................................................................30 
12. 
Tables, Listings, and Figures .......................................................................................31 
12.1. 
Planned Table Descriptions....................................................................................32 
12.2. 
Efficacy Data ........................................................................................................32 
12.3. 
Safety Data............................................................................................................34 
12.4. 
Planned Listing Descriptions..................................................................................35 
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Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
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12.5. 
Planned Figure Descriptions ..................................................................................36 
Appendix 1: Premier Research Library of Abbreviations..........................................................37 
 
 
 
List of Tables 
Table 1: Schedule of Events ....................................................................................................11 
Table 2 Planned Assessment Times .........................................................................................18 
Table 3: Demographic Data Summary Tables ..........................................................................32 
Table 4: Efficacy Tables .........................................................................................................32 
Table 5: Safety Tables ............................................................................................................34 
Table 6: Planned Listings........................................................................................................35 
Table 7: Planned Figures.........................................................................................................36 
 
 
 
Page 112 of 351


Statistical   Analysis Plan,  
Sponsor Reckitt Benckiser 
Protocol Number 5003601 
PCN Number RECK.177035
Version 1.0  
 Page 6 of 41 
1.
Overview
This statistical analysis plan (SAP) describes the planned analysis and reporting for Reckitt 
Benckiser protocol number 5003601 (A Randomized, Double-Blind, Double-Dummy, Parallel-
Group, Multiple-Dose, Active and Placebo-Controlled Efficacy Study of Ibuprofen Prolonged-
Release Tablets for the Treatment of Pain after Surgical Removal of Impacted Third Molars), 
dated 19-Nov-2019, version 3.0. Reference materials for this statistical plan include the protocol 
and the accompanying sample data collection documents. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials1. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to Reckitt Benckiser’s study 
5003601. 
2.
Study Objectives and Endpoints
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is: 
•
To evaluate the superiority of 2 x 300 mg ibuprofen PR tablets compared with placebo in
subjects experiencing acute moderate to severe pain after third molar extraction over 12
hours post initial dose.
2.1.2. Secondary Objectives 
The key secondary objectives are: 
•
To evaluate the analgesic performance of a total daily dose of 1200 mg of ibuprofen PR
formulation compared to ibuprofen immediate release (IR) formulation over 24 hours
post initial dose.
•
To evaluate the safety and tolerability of 2 x 300 mg ibuprofen PR tablets.
Page 113 of 351


 
Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
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Additional secondary objectives include: 
• To evaluate the total analgesic effect, peak analgesic effect, onset and duration of action 
and the subject’s overall assessment of the study medications. 
2.2. 
Study Endpoints 
2.2.1. Safety Endpoints 
The safety endpoints of this study include the following: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of changes in vital sign measurements 
2.2.2. Efficacy Endpoints 
2.2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the summed pain intensity difference (SPID) over 
0 to 12 hours (SPID12).  
2.2.2.2. 
Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints of this study include the following:  
• Summed pain intensity difference (SPID) over 0 to 24 hours (SPID24) after Time 0. 
• SPID4, SPID8 and SPID12  
• Sum of total pain relief (TOTPAR) over 0 to 4 hours (TOTPAR4), over 0 to 8 hours 
(TOTPAR8), over 0 to 12 hours (TOTPAR12) and over 0 to 24 hours (TOTPAR24) after 
Time 0. 
• Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over 
0 to 4 hours (SPRID4), over 0 to 8 hours (SPRID8), over 0 to 12 hours (SPRID12) and 
over 0 to 24 hours (SPRID24) after Time 0. 
• Response to study drug 
• Numeric rating scale (NRS) pain intensity difference (PID) at each scheduled timepoint 
after Time 0. NRS ranges from 0=no pain to 10=worst pain ever and pain relief is a 5 
point categorical scale 0=none, 1=a little, 2=some, 3=a lot, 4=complete. PID is the 
difference in NRS pain intensity between each time point and Time 0. 
• Pain intensity score at each scheduled time point after Time 0. 
• Pain relief at each schedule time point after Time 0. 
• Peak pain relief 
• Time to onset of analgesia 
• Time to first perceptible pain relief 
• Time to meaningful pain relief 
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Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 8 of 41 
 
• Time to peak pain relief 
• Proportion of subjects using rescue medication 
• Time to first use of rescue medication 
2.2.2.3. 
Exploratory Endpoint 
• Patient’s global evaluation of study drug. It is measured on a scale of 0=poor, 1=fair, 
2=good, 3=very good, 4=excellent 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
3.2. 
Sample Size and Power 
The sample size determination is based on the primary efficacy variable, SPID12.  According to 
Farrar 2001, a clinically important improvement in pain is represented by a 2 point reduction on 
an 11-point NRS.  Based on a baseline pain score of 7 this corresponds to an approximate 30% 
reduction in pain.  An average 2 point difference in pain scores between ibuprofen PR and 
placebo across all 14 assessments up to 12 hours will correspond to a difference in SPID12 of 24 
points.  In a previous study, the pooled standard deviation (SD) for SPID12 was 31.65.  
Assuming the same variability in this study, a sample size of 40 subjects per group will have 
>90% power to detect a difference of 24 points in SPID12, between ibuprofen 2x300-mg PR 
tablets and placebo using a 2-sided test with an alpha level of 0.05.  In order to provide a robust 
estimate of treatment effect differences between PR and IR, and to obtain a more precise 
estimate for this comparison, a 3:3:1 allocation ratio will be used, so that 120 subjects are 
randomized into each of the PR and IR groups.  Thus 280 subjects will be enrolled in the study. 
3.3. 
Study Population 
Subjects with moderate to severe pain after extraction of 2 or more third molars will participate 
in this study. 
3.4. 
Treatments Administered 
Treatment A (test product): 2x300 mg ibuprofen PR tablets, BID (total daily dose 1200 mg) 
Treatment B (reference product): 2x200 mg ibuprofen IR tablets, TID (total daily dose 1200 mg) 
Treatment C: matching placebo tablets 
3.5. 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be randomized in a 3:3:1 ratio to receive 2x300 mg ibuprofen PR tablets 
Q12h, 2x200 mg ibuprofen IR Q8h, or placebo using permuted blocks of fixed size.  The 
randomization will be stratified by baseline pain category (moderate or severe) using a 
categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and severe 
(8-10).  The randomization schedule will be prepared by a statistician not otherwise involved in 
the study.  Randomization will be performed using an interactive response system (IRT).   
3.6. 
Blinding and Unblinding 
This is a double-blind, double-dummy study. There will be two placebo tablets designed to be 
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Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 9 of 41 
 
comparable to each of the active products (PR and IR) in both shape, size, color and weight. 
All subjects will receive 4 tablets at each dosing timepoint.  All subject packs will be designed 
and labelled to ensure blinding is maintained. 
Access to the unblinding codes will be restricted to personnel not otherwise involved in the study 
and will be available to the investigator only in the case of a subject requiring unblinding prior to 
database lock.  
Unblinding will only occur after database lock or in the case of emergency unblinding. 
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Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
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3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1. 
 
 
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Table 1: Schedule of Events 
 
 
 
 
Page 118 of 351
I 
Sc,reening 
(Day -28 to 
Day -1) 
Pre-
Surgery 
Pre-
dose 
Written informed consent 
X 
Assign a screening number 
X 
In clu siontexclus ion criteria 
X 
X 
Demographics 
X 
Medical llistory 
X 
Xb 
Physical examination° 
X 
Vital signsd 
X 
X 
X 
Height, weighl and BMI 
X 
Clinical laboratory tests (hematology, 
X 
chemistry, urinalysis) 
Electrocardiogram 
X 
Pregnancy test for female subjects of 
X 
X 
childbearing potentiale 
Urine drug screen 
X 
X 
Alcohol breatllalyzer test 
X 
Oral radiography1 
X 
Review study restrictions with subject 
X 
Pain intensity (NRS )9' 
X 
Randomisation 
X 
Dosing with study drug 
Stopwatch assessment" 
Pain relief (5-point categoriic.al scale)g 
Surgery (Day 1) 
Post-op 
1, 1.5, 2, 3, 4, 
15, 30, 
5, 6, 7, 8, 
0 1!1 
45min 
10 h 
12 1!1 
X 
X 
X 
X 
Oh 
8h 
12 h 
X 
X 
X 
X 
Day2 
16 
Ill 
24h 
X 
X 
X 
16h 
X 
premier' 
research} 
Follow-up 
(Day 8 ±2 days) or 
ETk 
X 
X 


 
Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 12 of 41 
 
 
 
Page 119 of 351
I 
Sc,reening 
(Day -28 to 
Day -1) 
Pre-
Surge1ry 
Pre-
dose 
Global evaluation of study drug; 
Concomitant medications 
Xb 
X 
Adverse eventsi 
X 
X 
Dispense/prescribe pain medication for use at 
home, as needed 
Collect unused home pain medications, as 
needed 
Discharge from study site 
Surgery (Day 1) 
Post-op 
1, 1.5, 2, 3, 4, 
15, 30, 
5, 6, 7, 8, 
Oh 
45 min 
10 h 
X 
X 
X 
X 
X 
X 
12 h 
X 
X 
Day 2 
16 
premier' 
research} 
Follow-up 
(Day 8 ±2 days) or 
ETk 
h 
24h 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BMl=body mass index: ET=-early termination: h=hour, min=minute; NRS=numeiric rating scale; pre-op=pre-operative; post-op=post-operative _ 
a Times listed are relative to dosing wilh study drug. 
b Medical history and concomitant medication use since Screening will be updated on Day 1 before surgery 
c A complete physical examination (excluding the geniitourinary examination) will be performed at Screening. An abbreviated confirmatory physical assessment, 
including an exam ination of tile subject's mouth and neck, will be performed at tile Follow-up Visit (or Early Term ination Visit). 
d Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at tile following times: at screening, before surgery, within 30 minutes 
before Tiime 0, ·12 ti ours after Time 0_, 24 hours after Time O, and/or immediately before the first dose of rescue medication, and at tile Follow-up Visit (or Early 
Termination Visit). 
e Serum pregnancy test at Screening and urine pregnancy test before surgery on Day 1 (female subjects of childbearing potential only). Test results must be 
negative for the subject to continue in the study. 
f 
Oral radiographs taken within 1 year before Screening will be acceptable and do not need to be repeated. 
g Pain assessments will be conducted (pre-dose, if at one of tile dosing timepoints of O, 8, 12 or 16 hours) at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 
8, 10, 12, 16 and 24 llours after Time o and immediately before each dose of rescue medication. Pain intensity will also be assessed pre-dose. At each 
assessment time point, the pain intensity assessment will be completed first and the pain relief assessment will be completed second. Subjects will not be 
able to compare their responses with lheir previous responses. Note for assessments less than 1 hour apart a window of +/-2 min is allowable wll ilst for 
assessments at least 1 llour apart a +l-5 min window is allowable. 
h Two stopwatches will be started immediately after the subject has swallowed the first dose of study drng with 8 ounces of water {Time O). Subjects will record 
the time to perceptible and meaningful pain relief, respectively, by stopping the stopwatches. 


 
Statistical   Analysis Plan,  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 13 of 41 
 
4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population in each of the treatment arms, unless otherwise specified. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests. In addition to what is detailed in the SAP, other additional 
analyses may be conducted on the data which will only serve as exploratory evidence and the 
unplanned nature of these analyses will be made clear in the Clinical Study Report. 
4.2. 
Interim Analysis 
No interim analyses are planned. 
5. 
Analysis Populations 
The following analysis populations are planned for this study: 
• Safety Population (SAF): The Safety Population includes all subjects who receive any 
amount of planned study medication. Subjects will be assigned to treatment received. 
• Intent-To-Treat Population (ITT): The ITT population includes all subjects who are 
treated with study drug and who have at least 1 pain assessment after Time 0.  The ITT 
population is the primary population for the efficacy analysis. Subjects will be assigned 
to treatment randomized. 
• Per Protocol (PP): The PP Population will consist of all ITT subjects who do not incur a 
major protocol violation that would challenge the validity of their data.  This population 
will be determined at a data review meeting prior to database lock and used to evaluate 
the sensitivity of the primary efficacy analysis. Subjects will be assigned to treatment 
received. 
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6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last observation recorded prior to the first dose of study drug will be used as the baseline 
observation for all calculations of change from baseline.  
6.1.2. Adjustments for Covariates 
For the primary endpoint analysis, the baseline NRS pain score will be included as a covariate. 
For the secondary endpoint analyses, baseline pain will be included as a covariate for SPID, 
SPRID, and TOTPAR variables.   
For the proportion of subjects who are responders and the proportion of subjects using rescue 
medication, logistic regression models will adjust for baseline pain. 
For time to event endpoints, baseline pain will be included as a stratification factor.  
6.1.3. Multiple Comparisons 
No adjustment for multiplicity is required for the primary efficacy analysis – a single comparison 
of SPID12 for placebo versus SPID12 for ibuprofen PR. 
No adjustments will be made for multiple comparisons for other endpoints. 
6.1.4. Handling of Dropouts or Missing Data 
Missing pain assessments for all efficacy analyses will be handled as follows: 
• Missing pain assessments scheduled before the first observed assessment will be imputed 
with the subject’s worst observed pain assessment. 
• Missing intermediate pain assessments will be replaced by linear interpolation. 
• Missing pain assessments at the end of the observation period due to premature 
discontinuation of pain assessments will be imputed by carrying forward the last 
observation prior to that missing. 
All data for assessments other than pain assessments will be analyzed as collected; missing data 
due to premature termination or any other reason will be left as missing. Since this is a short-
term study and subjects remain at the study site throughout the 24-hour pain assessment period, 
the discontinuation rate and the amount of missing data is expected to be minimal.   
A number of sensitivity analyses will be performed in order to evaluate the efficacy under 
various different assumptions regarding missing data and are described in Section 6.1.6  
The exceptions to the above data handling rules are the descriptive summaries and repeated 
measures analyses by timepoint for pain intensity difference and pain relief, described in sections 
8.2.11 and 8.1.12. In these repeated measures analyses, missing values are indirectly imputed 
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under an assumption of missing at random, and so missing pain assessments will not be 
explicitly imputed prior to analysis. 
6.1.5.  Adjustment of Pain Scores for Rescue Medication Use 
Subjects are required to record their pain assessment (NRS and pain relief) immediately prior to 
each dose of rescue medication permitted in the protocol (1000mg paracetamol/acetaminophen or 
5mg oxycodone). The primary analysis will use windowed worst observation carried forward 
(WOCF) methodology for subjects who use rescue medication.  If a subject received rescue 
medication at time x, for any time point within x + 4 hours, the highest pain score from time 0 up 
until time x will be used. If the pain score for the windowed observation is higher than the worst 
observed score, it will not be replaced.  The same approach will be used for pain relief scores. 
Subject who received other drug and non-drug therapies during the treatment period will be 
evaluated on a case-by-case basis at a data review meeting, prior to database lock. If these therapies 
are considered to modulate the pain response, the same approach described above will be used to 
replace pain intensity and pain relief scores within a 4-hour time window after medication was 
taken. The windowed WOCF method to adjust pain scores for subjects who use rescue medication 
is consistent with the hypothetical strategy estimand, where the intercurrent event is use of rescue 
medication, and will be the approach used for the primary efficacy analysis [5]. 
6.1.6. Sensitivity Analysis of SPID12 and SPID24 
The following sensitivity analyses will also be performed for the primary endpoint SPID12 if any 
pain assessments are missing or if subjects take rescue medication. Each of these are consistent 
with the hypothetical strategy estimand, with the exception of analysis number 3, which uses the 
treatment policy strategy estimand. 
 
1. Missing data and values after rescue medication handled as per the main analysis but 
based on the PP population. 
2. Missing data imputed using WOCF (worst observed pain score at any timepoint, 
including baseline). Values after rescue medication handled as per the main analysis. 
3. Missing data handled as per the main analysis. Pain assessments are used regardless of 
whether rescue medication has been taken, and no adjustment is made for use of rescue 
medication.  In this analysis, the pain assessment recorded at the time of rescue 
medication is disregarded (unless it coincides with a planned pain assessment).  
4. Missing data handled as per the main analysis. All pain assessments recorded after the 
first dose of rescue medication has been taken will be disregarded. WOCF, LOCF (Last 
Observation Carried Forward) and multiple imputation methods will then be used to 
impute the disregarded data. 
a. WOCF - The worst (highest) pain assessment (including baseline) until first dose 
of rescue medication will be used to impute all subsequent pain assessments. In 
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other words, this method would be treating the subject as if they got no worse 
than their worst observed value prior to rescue medication.  
b. LOCF - In this LOCF analysis, the pain assessment taken immediately prior to/at 
the time of rescue medication will be taken as the last observed score, i.e., this 
method would be treating the subject as if they got no worse than their last 
observed value prior to rescue medication. 
c. Multiple Imputation under a MAR assumption. Data will be imputed separately 
for each treatment group, using a Markov Chain Monte Carlo (MCMC) method 
for full imputation, with covariates for baseline and pain scores observed at each 
assessment. The methodology described in sensitivity analysis 6 below will be 
used. In this analysis, the pain assessment recorded at the time of rescue 
medication is disregarded (unless it coincides with a planned pain assessment). 
5. Missing data imputed using multiple imputation (methodology described below). Values 
after rescue medication handled as per the main analysis. 
For sensitivity analysis 5, a pattern-mixture model with control-based pattern imputation will be 
used. This model assumes that after withdrawal from the study, subjects from the experimental 
group (no longer receiving active treatment) will exhibit the same future evolution of pain scores 
as subjects in the placebo group (who are also not exposed to active treatment). Subjects that 
discontinue from the placebo group are assumed to evolve in the same way as placebo subjects 
that remain in the study. This imputation assumes that intermittent missing values are missing at 
random (MAR), and that values that are missing due to withdrawal are missing not at random 
(MNAR). When data are MAR, the missingness of the data does not depend on the missing value 
after conditioning on the observed data (i.e., prior assessments and baseline covariates). Note 
that when the missingness of the data depends on the values of the missing variables after 
conditioning on the observed data, the data are called “missing not at random” (MNAR).  In 
order to assess the MAR assumption, a placebo-based pattern mixture model (PMM) will be 
utilized following the steps outlined in Ratitch B and O’Kelly, M.J. (2011) for SPID-12. 
 
Briefly, the strategy for implementing this approach is as follows for subjects with 
missing data: 
i. 
Impute all non-monotone (intermittent) missing data using the MCMC method of 
PROC MI.  Note that this imputation will sample data within each treatment 
group.  Note that PIi is the NRS pain intensity at time Ti as mentioned in Section 
6.1.7. SAS pseudo code is provided below. With MCMC option, SAS does 200 
burn-in iterations (default) before each imputation. 
PROC MI DATA=example seed = xxxx NIMPUTE = 20 OUT = outdata1 minimum=0 maximum=10; 
 
by <treatment>; 
 
MCMC chain=multiple impute=monotone; 
 
VAR  <PI0> <PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>; 
RUN; 
 
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ii. 
Using the imputed datasets from Step #1 that are now monotone missing (no 
intermittent missing data), a single call to PROC MI (including the MNAR 
statement) will be utilized to impute the monotone missing data.  Additional 
details are provided below. 
a. Within the call to PROC MI, one timepoint is imputed at a time.  The 
order in which pain scores are imputed will be PI0, then PI0.25...,PI12 
b. When imputing at timepoint t, the imputation step will include all placebo 
subjects, but only those from the active arms that have a value missing at 
timepoint t. Subjects with non-missing data that are on active arms will 
not contribute to the estimation for this step. 
c. Repeat the above step for all timepoints t. Thus, the data for timepoint t+1 
uses the data imputed from previous timepoints. 
SAS pseudo code is provided below.  SAS accomplishes this iterative process in one step.  
Note that the treatment level 3 is the placebo treatment group. The MNAR statement 
imputes missing values for scenarios under the MNAR assumption. The MODEL option 
specifies that only observations in which treatment=3 are used to derive the imputation 
model for the pain score that time point. The minimum and maximum options are used to 
ensure that every pain score imputed ranges from 0-10. 
PROC MI DATA=OUTDATA1 seed = xxxx NIMPUTE = 1 OUT = outdata2 MINIMUM=. 0..0   
MAXIMUM=. 10 10…10; 
BY _IMPUTATION_; 
CLASS <treatment>; 
MONOTONE REG (/ details); 
MNAR MODEL (PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>/ modelobs=(<treatment=’3’>)); 
VAR  <PI0> <PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>; 
RUN; 
 
 
 
iii. 
When all missing PI scores are imputed, SPID12 will be derived as described in 
6.1.7 and analyzed using the ANCOVA models as described in Section 8.1.  
PROC MIANALYZE will be used to combine the parameters from the analyses 
for inference. 
6. Missing data and values within the defined window after rescue medication are imputed 
using multiple imputation (methodology described below). 
For sensitivity analysis 6, a multiple imputation model under a MAR assumption will be used. 
This assumes that the missingness of the data does not depend on the missing observations after 
conditioning on the observed data (i.e., prior assessments and baseline as covariates). This is 
considered a reasonable assumption since patients are encouraged to use rescue medication only 
if needed (i.e. high pain scores), and thus it can be expected that the intercurrent event of rescue 
medication depends on the observed data (i.e. rescue medication likely to be taken when the 
preceding pain scores were high). It can then be inferred that the pain scores post-rescue can be 
predicted from the observed variables, and therefore the response can be estimated without bias 
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using the observed data. In this analysis, the pain assessment recorded at the time of rescue 
medication is disregarded (unless it coincides with a planned pain assessment). 
The strategy to be used is as follows: 
i. 
Set pain scores recorded within the defined window after rescue medication to 
missing. Impute all missing data (due to subject withdrawal, missing intermittent 
values and that set to missing due to rescue medication) using the MCMC method 
of PROC MI. Note that this imputation will sample data within each treatment 
group.  Note that PIi is the NRS pain intensity at time Ti as mentioned in Section 
6.1.7. SAS pseudo code is provided below. With the MCMC option, SAS does 
200 burn-in iterations (default) before each imputation. Twenty imputations will 
be performed. 
PROC MI DATA=example seed = xxxx NIMPUTE = 20 OUT = outdata1 minimum=0 … 0 
maximum=10 … 10; 
 
by <treatment>; 
 
MCMC chain=multiple; 
 
VAR  <PI0> <PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>; 
RUN; 
ii. 
When all missing PI scores are imputed, SPID12 will be derived as described in 
6.1.7 and analyzed using the ANCOVA models as described in Section 8.1.  
PROC MIANALYZE will be used to combine the parameters from the analyses 
for inference 
Sensitivity analyses 3 and 6 will also be performed for SPID24, with the necessary modifications 
to the SAS pseudo code in sensitivity analysis 6 to incorporate a covariate for PI24. 
6.1.7. Derived Variables 
At each assessment time point, subjects will complete the pain intensity NRS assessment first 
and the pain relief assessment second. 
Planned assessment time points are as follows: 0 (predose), 15, 30, and 45 minutes, and 1, 1.5, 2, 
3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours after Time 0.  Please see Table 2 below. 
 
 
Table 2 Planned Assessment Times 
i 
Ti (hours) 
0 
0 (predose) 
1 
0.25 
2 
0.5 
3 
0.75 
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4 
1 
5 
1.5 
6 
2 
7 
3 
8 
4 
9 
5 
10 
6 
11 
7 
12 
8 
13 
10 
14 
12 
15 
16 
16 
24 
 
• SPID-12 = summed pain intensity difference (change from Time 0) under the numeric 
rating scale (NRS)-time curve from 15 min through 12 hours calculated using the linear 
trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of 
study drug. Scheduled time points in Table 2 will be used when actual time is missing. 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷12 = ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑃𝑃𝑃𝑃𝐷𝐷𝑖𝑖
14
𝑖𝑖=1
 
 
Where T0 =0, Ti is the actual time, and PIDi is the PID score at time Ti  
PID is defined as  
 
𝑃𝑃𝑃𝑃𝐷𝐷𝑖𝑖= 𝑃𝑃𝐼𝐼𝑖𝑖−𝑃𝑃𝐼𝐼0 
 
Where PI is the pain intensity as measured by the NRS scale. 
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• SPID-x = summed pain intensity difference (change from Time 0) under the numeric rating 
scale (NRS)-time curve from 15 min through x hours calculated using the linear trapezoidal 
rule and the actual time points, where Time 0 is the time of the first dose of study drug. 
Scheduled time points in Table 2 will be used when actual time is missing. X = 4, 8, and 
24. 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥= ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑃𝑃𝑃𝑃𝐷𝐷𝑖𝑖
𝑦𝑦
𝑖𝑖=1
 
 
For x=4 y=8; x=8 y=12; x=24 y=16. 
• TOTPAR-x = total pain relief under the Pain Relief Scale (0 – 4) from 15 min through x 
hours calculated using the linear trapezoidal rule and actual time points, where Time 0 is 
the time of the first dose of study drug. Scheduled time points in Table 2 will be used when 
actual time is missing.  x = 4, 8, 12, and 24. 
 
 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑅𝑅𝑥𝑥=  ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑃𝑃𝑃𝑃𝑅𝑅𝑖𝑖
𝑦𝑦
𝑖𝑖=1
 
For x=4 y=8; x=8 y=12; x=12 y=14; x=24 y=16. PARi is the pain relief score on the Pain Relief 
Scale (0-4) at time Ti  
 
• SPRID-x = summed pain relief (TOTPAR) and intensity difference (SPID) from 15 min 
through x hours calculated using the linear trapezoidal rule and actual time points, where 
Time 0 is the time of the first dose of study drug. Scheduled time points in Table 2 will be 
used when actual time is missing. X = 4, 8, 12, and 24. 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥= 𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥+ 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑅𝑅𝑥𝑥 
 
• Responder: subject with ≥ 30% improvement in NRS pain intensity from T0 
(predose) without rescue medication during the first 8 hours. If a subject takes rescue 
medication prior to the 8-hour pain assessment or if the 8-hour assessment is not 
performed they will be considered a non-responder. i.e., 
(𝑃𝑃𝐼𝐼0 −𝑃𝑃𝐼𝐼8)
𝑃𝑃𝐼𝐼0
∗100 ≥30 
Where PI0 and PI8 are the predose and 8-hour NRS pain intensity measurements 
respectively. 
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• Time to onset of analgesia = If the subject has had meaningful pain relief (i.e., presses both 
stopwatches) then time to onset of analgesia is date/time of perceptible pain relief – 
date/time of the first dose of study drug. If subjects don’t experience both perceptible pain 
relief and meaningful pain relief during the 8-hour interval after Time 0, time to onset to 
analgesia will be right censored at the time of their last pain assessment in the first 8 hours. 
For subjects who take rescue medication prior to onset of analgesia during the 8-hour 
interval after Time 0, time to onset of analgesia will be right censored at the time rescue 
medication was taken. 
• Time to first perceptible pain relief = date/time of the first reported pain relief (any) as 
assessed by the subject (i.e. subject stops the first stopwatch (irrespective of the second 
stopwatch)) – date/time of the first dose of study drug. If subjects don’t experience 
perceptible pain relief during the 8-hour interval after Time 0, time to first perceptible pain 
relief will be right censored at the time of their last pain assessment in the first 8 hours. If 
the first stopwatch is not stopped but the second stopwatch is stopped, time will be left 
censored at the time that the second stopwatch is stopped. In other words, it is assumed that 
the first stopwatch measurement has already occurred but was missed/not recorded. For 
subjects who take rescue medication prior to first perceptible pain relief during the 8-hour 
interval after Time 0, time to first perceptible pain relief will be right censored at the time 
rescue medication was taken. 
• Time to meaningful pain relief = date/time of the first reported meaningful (subjective) 
pain relief as assessed by the subject (i.e. the subject stops the second stopwatch) – 
date/time of the first dose of study drug. If subjects don’t experience meaningful pain relief 
during the 8-hour interval after Time 0, time to meaningful pain relief will be right censored 
at the time of their last pain assessment in the first 8 hours. If the subject stops the second 
stopwatch but doesn’t stop the first stopwatch or the first stopwatch assessment is missing, 
then time to meaningful pain relief will be right censored at the time of their last pain 
assessment in the first 8 hours. For subjects who take rescue medication prior to achieving 
meaningful pain relief during the 8-hour interval after Time 0, time to meaningful pain 
relief will be right censored at the time rescue medication was taken. 
• Peak pain relief- Pain relief is measured on a scale from 0 (None) to 4 (Complete). If PRi 
is the pain relief measurement at time Ti , peak pain relief PPR is defined as 
 
𝑃𝑃𝑃𝑃𝑃𝑃= max{𝑃𝑃𝑅𝑅1,𝑃𝑃𝑅𝑅2,𝑃𝑃𝑅𝑅3,…, 𝑃𝑃𝑅𝑅16} 
 
• Time to first use of rescue medication = date/time to the first dose of rescue medication – 
date/time of the first dose of study drug. If subjects don’t take rescue medication, subjects 
will be right censored at the time of their last pain assessment. 
• Time to peak pain relief = date/time of peak pain relief– date/time of the first dose of study 
drug. Time of peak pain relief is the time Ti when peak pain relief (PPR) first occurs. If no 
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pain relief is observed then the time to peak pain relief will be right censored at the time of 
their last pain assessment. 
• Change from baseline = value at current time point – value at baseline.  
• TEAE = TEAE is defined as any event that started or worsened in intensity or relationship 
to treatment on or after the first dose of study drug. 
6.1.8. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
All P values will be displayed in four decimals and rounded using standard scientific notation (e.g., 
0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as <0.0001. 
Adverse events will be coded using the MedDRA version 23.0 thesaurus. 
A treatment related AE is any AE with a relationship to the study drug with possible, probable or 
certain causality to the study drug as determined by the Investigator. 
If partial dates occur, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if just day is missing then the day assigned is the first day of the month or 
the date of first dose (if in the same month), whichever is later; if just month is missing then the 
month assigned is the month of the first dose, unless that results in a date prior to the first dose in 
which case the month after the first dose is used; and if both month and day are missing then the 
month assigned is the month of the first dose and the day assigned is either the first day of the 
month or the first dose date, whichever is later. 
If partial times occur, the convention is as follows: if the missing time occurs on the day of the 
first dose and both the hour and minute are missing then the time assigned is the time of the first 
dose, otherwise if both the hour and minute are missing and the date is not the date of first dose 
the time assigned is 12:00; if the date is the same as the date of the first dose and only hour is 
missing the hour assigned is 12 or the hour of first dose, whichever is later, and if the date is the 
same as the date of first dose and only the minute is missing the minute assigned is 30 or the 
minute of first dose, whichever is later. Otherwise the hour assigned is 12 if the hour is missing 
and the date is not the same as the date of first dose and the minute assigned is 30 is the the date 
is not the same as the date of first dose. 
These conventions will be applied only to adverse event onset dates and times with the following 
precaution:  if the missing date and time reflect the date and time of onset of an adverse event, 
the modified date and time will be constructed to match the first documented date/time post drug 
administration while preserving the order in which the AE was reported in the CRF. 
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7. 
Study Patients/Subjects and Demographics 
7.1. 
Disposition of Patients/Subjects and Withdrawals 
Disposition will include tabulations of the number of subjects screened, number of subjects 
randomized into each treatment group, the number of subjects who received treatment, tabulated 
reasons for discontinuation from the study, and number of subjects in each analysis population. 
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be listed. 
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, gender, race, ethnicity, height, weight, BMI, baseline pain category 
and baseline pain (continuous) will be presented by treatment groups and overall. For the 
continuous variables, the number of non-missing values and the mean, standard deviation, 
minimum, median and maximum will be tabulated.  
For the categorical variables, the counts and proportions of each value will be tabulated.    
These analyses will be conducted for the ITT, PP, and Safety populations. 
The number and percent of subjects reporting various medical histories, grouped by MedDRA 
system organ class and preferred term (coded using MedDRA v23.0), will be tabulated by 
treatment group. This analysis will be conducted for the Safety Population. Physical examination 
findings will also be summarized by body system and examination result- Normal, Abnormal – 
Clinically Significant, Abnormal-Not Clinically Significant. 
7.4. 
Exposure and Compliance 
The number of doses taken and treatment duration will be summarized by descriptive statistics. 
All study drug will be administered in clinic. The total number of tablets taken, and the number 
of tablets with active ingredient taken at each time point will be summarized. The dosage (in mg) 
of active ingredient taken and duration of exposure, from first dose to last dose of the study 
treatment will be summarized using descriptive statistics. Any deviations from the planned dose 
should be reported. 
8. 
Efficacy Analysis 
8.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the summed pain intensity difference (SPID) over 0 to 12 hours 
(SPID12).  The primary endpoint will be used to compare the test product (2x300 mg ibuprofen 
PR tablets) against placebo. 
The primary efficacy hypothesis is that SPID12 for placebo is equal to SPID12 for ibuprofen 
2x300 mg PR tablets.  The primary analysis will be an ANCOVA model that includes the main 
effect of treatment and a covariate of the baseline NRS pain score and will use windowed worst 
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observation carried forward (WOCF) imputation for subjects who use rescue medication.  The 
primary analysis will be based on a 2-sided test at the significance level of 0.05.  The treatment 
difference will be presented with a 95% confidence interval.   
Normality assumptions will be tested. If the data is considered non-normal, the Wilcoxon rank 
sum test will be used for the comparison between treatments, and the point estimate and 95% 
confidence interval will be calculated using the Hodges-Lehmann estimator. 
The primary efficacy analysis will be based on the ITT population. These analyses will be 
repeated for the PP population.  SPID-12 scores will also be summarized by baseline pain 
category (moderate or severe). 
8.2. 
Secondary Efficacy Analysis 
8.2.1. SPID 
Summed Pain Intensity Difference (SPID) will be calculated for secondary efficacy analysis as 
described in Section 6.1.7 at 4, 8, and 24 hours. Descriptive statistics by treatment regimen will 
be produced. 
ANCOVA models for comparing placebo with other treatment regimens with SPID as the 
dependent variable and treatment group and baseline pain as covariates will be generated. These 
models will be computed for SPID4, SPID8 and SPID12. The least square (LS) mean and 
standard error (SE) for each treatment group will be estimated and the difference in LS means 
and 95% confidence interval (CI) for the comparison of placebo with the IR and PR treatment 
regimens will be estimated. P-values will be reported but no formal statistical inferences will be 
made on the basis of these tests.  In addition, for the SPID24 endpoint, the difference in LS 
means and 95% CI for the IR versus PR groups will be presented. In the event that normality 
assumptions are violated for a parameter, non-parametric analysis methods will be used. 
8.2.2. TOTPAR 
Total pain relief (TOTPAR) will be calculated as described in Section 6.1.7 at 4, 8, 12 and 24 
hours. Descriptive statistics by treatment regimen will be produced. 
ANCOVA models for comparing placebo with other treatment regimens with TOTPAR as the 
dependent variable and treatment group and baseline pain as covariates will be generated. These 
models will be generated at TOTPAR4, TOTPAR8, TOTPAR12 and TOTPAR24. The LS mean 
and SE for each treatment group will be estimated and the difference in LS means and 95% CI 
for the comparison of placebo with the IR and PR treatment regimens will be estimated. P-values 
will be reported but no formal statistical inferences will be made on the basis of these tests. In 
the event that normality assumptions are violated for a parameter, non-parametric analysis 
methods will be used. 
8.2.3. SPRID 
Summed pain relief and intensity difference is the sum of TOTPAR and SPID and will be 
calculated at 4, 8, and 12 and 24 hours as described in Section 6.1.7. 
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Descriptive statistics by treatment regimen will be produced for SPRID at each planned 
assessment time point.  
ANCOVA models for comparing placebo with other treatment regimens with SPRID as the 
dependent variable and treatment group and baseline pain as covariates will be generated. The 
LS mean and SE for each treatment group will be estimated and the difference in LS means and 
95% CI for the comparison of placebo with the IR and PR treatment regimens will be estimated. 
P-values will be reported but no formal statistical inferences will be made on the basis of these 
tests. In the event that normality assumptions are violated for a parameter, non-parametric 
analysis methods will be used. 
8.2.4. Peak Pain Relief  
Peak pain relief will be calculated as described in Section 6.1.7 and will be summarized by 
counts (and percentages) for each pain relief score.  It will be analyzed using a proportional odds 
model (an extension of the logistic regression). This method allows for an ordinal response 
variable with more than two categories. This model will include a factor for treatment and 
baseline pain intensity as a continuous covariate. For each of the PR and IR treatment regimens, 
the odds of being in a higher (better) pain relief category compared to placebo (odds ratio) will 
be presented with a 95% CI and associated p-value.  
8.2.5. Time to First Perceptible Pain Relief 
Time to first perceptible pain relief will be summarized using Kaplan-Meier methods. The 
definition and censoring rules are described in Section 6.1.7. With baseline pain as a 
stratification factor, treatments will be compared to placebo using a stratified log-rank test or a 
stratified Wilcoxon test as appropriate. Summary tables will provide the number of subjects 
analyzed, the number of subjects censored, estimates for the 25th, 75th percentiles and median 
(including 95% CI), and associated p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated. 
8.2.6. Time to Meaningful Pain Relief  
Time to first meaningful pain relief will be summarized using Kaplan-Meier methods. The 
definition and censoring rules are described in Section 6.1.7. With baseline pain as a 
stratification factor, treatments will be compared to placebo using a stratified log-rank test or a 
stratified Wilcoxon test. Summary tables will provide the number of subjects analyzed, the 
number of subjects censored, estimates for the 25th, 75th percentiles and median (including 95% 
CI), and associated p-value for comparisons versus placebo.   
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated.  
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8.2.7. Time to onset of Analgesia 
Time to onset of analgesia will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 6.1.7. With baseline pain as a stratification factor, 
treatments will be compared to placebo and with each other (IR vs PR) using a stratified log-rank 
test or a stratified Wilcoxon test. The summary tables will provide the number of subjects 
analyzed, the number of subjects censored, estimates for the 25th, 75th percentiles and median 
(including 95% CI), and associated p-value for treatment comparisons.   
A measure of the treatment effect comparing each of the active arms with placebo and with each 
other (IR vs PR) will be obtained by calculating a hazard ratio and 95% CI by fitting a Cox 
proportional hazards model with a factor for treatment group and baseline pain as a continuous 
covariate. The assumption of proportional hazards will first be evaluated.  
8.2.8. Time to Peak Pain Relief 
Time to peak pain relief will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 6.1.7. With baseline pain as a stratification factor, 
treatments will be compared to placebo using a stratified log-rank test or a stratified Wilcoxon 
test. The summary tables will provide the number of subjects analyzed, the number of subjects 
censored, estimates for the 25th, 75th percentiles and median (including 95% CI), and associated 
p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated.  
8.2.9. Time to first use of Rescue Medication 
Time to first use of rescue medication will be summarized using Kaplan-Meier methods. The 
definition of time to first use of rescue medication and censoring rules for subjects who don’t 
take rescue medication are described in Section 6.1.7. With baseline pain as stratification factor, 
treatments will be compared to placebo using a stratified log-rank test or a stratified Wilcoxon 
test. The summary tables will provide the number of subjects analyzed, the number of subjects 
censored, estimates for the 25th, 75th percentiles and median (including 95% CI), and associated 
p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated. 
8.2.10.  Proportion of Responders 
For the proportion of subjects who are responders, a logistic regression model that adjusts for 
baseline pain (as a continuous covariate) and treatment arm will be used to evaluate the treatment 
effect. As a measure of treatment effect for each of the PR and IR groups versus placebo, odds 
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ratios together with a 95% CI and p-values will be presented. 
8.2.11. Numeric rating scale (NRS) pain intensity difference (PID)  
PID at each time point will be calculated using the formula specified in Section 6.1.7, with pain 
scores recorded after rescue medication handled using the windowed WOCF method described 
in Section 6.1.5. Pain scores that are missing (assessment not performed or subject withdrew) 
will not be replaced. PID at each timepoint will be analyzed in a mixed model for repeated 
measures (MMRM) ANCOVA analysis. The model will include treatment, timepoint, treatment 
by timepoint, baseline and baseline by timepoint as fixed effects, and subject as a random effect. 
An unstructured covariance matrix will be used to model the within-subject correlations by 
timepoint. If the model fails to converge, alternative covariance structures, such as compound 
symmetry, will be tried instead. The model will be used to show estimated treatment effects at 
each timepoint. The LS mean and SE for each treatment group will be estimated and the 
difference in LS means and 95% CI for the comparison of placebo with the IR and PR treatment 
regimens will be estimated. P-values will be reported but no formal statistical inferences will be 
made on the basis of these tests. Descriptive summaries (including mean, SD, median, minimum 
and maximum) will be presented by treatment group.  
Pain intensity is measured using NRS at planned assessment time points. Descriptive summaries 
(including mean, SD, median, minimum and maximum) will also be presented by treatment 
group. Pain scores recorded after rescue medication will be handled using the windowed WOCF 
method described in Section 6.1.5. Pain scores that are missing (assessment not performed or 
subject withdrew) will not be replaced. 
8.2.12. Pain relief at each scheduled time point 
Pain relief scores at each scheduled time point will be summarized using descriptive statistics 
(including mean, SD, median, minimum and maximum) as well as counts (and percentages) for 
each pain relief score by treatment group. Pain relief scores recorded after rescue medication will 
be handled using the windowed WOCF method described in Section 6.1.5. Pain relief scores that 
are missing (assessment not performed or subject withdrew) will not be replaced. Treatment 
comparison will be done in the following way: 
• Pain relief category at each timepoint will also be analyzed using a repeated 
measures proportional odds model (an extension of the logistic regression). This 
method allows for an ordinal response variable with more than two categories. 
Here the categories none = 0, a little = 1, some = 2, a lot = 3, and complete = 
4.This model will include the following covariate terms- treatment and baseline 
pain intensity (as a continuous covariate) timepoint, baseline by timepoint and 
treatment by timepoint. Subject will be the repeated measure in this model. For each 
of the PR and IR treatment regimens, the odds of being in a higher (better) pain 
relief category compared to placebo (odds ratio) will be presented with a 95% CI 
and associated p-value. 
 
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8.2.13. Proportion of Subjects Rescue Medication 
The definition of rescue medication use is presented in Section 6.1.5. The proportion of subjects 
using rescue medication for pain will be analyzed using logistic regression. The logistic 
regression model will include treatment arm and baseline pain (as a continuous covariate) as 
covariates. As a measure of treatment effect for each of the PR and IR groups versus placebo, 
odds ratios together with a 95% CI and p-values will be presented. 
8.3. 
Exploratory Efficacy Analysis  
8.3.1. Global Evaluation of Study Drug 
Subject’s global evaluation of study drug will be analyzed using a proportional odds model (an 
extension of the logistic regression). This method allows for an ordinal response variable with 
more than two categories. This model will include a factor for treatment group and baseline pain 
intensity as a continuous covariate. For each of the PR and IR treatment regimens, the odds of 
being in a higher (better) evaluation category compared to placebo (odds ratio) will be presented 
with a 95% CI and associated p-value. 
9. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported AEs, and changes in vital signs. 
All safety analyses will be performed on the Safety population. 
9.1. 
Adverse Events 
The number and percent of subjects reporting treatment emergent AEs, grouped by 
MedDRA system organ class and preferred term (coded using MedDRA v21.1), will 
be tabulated by severity and treatment group. In the case of multiple occurrences of the 
same TEAE within the same subject, each subject will only be counted once for each 
preferred term. 
The frequency and percentage of subjects reporting TEAEs, grouped by MedDRA SOC and PT, 
will be tabulated by treatment group for the SAF. Such summaries will be displayed for the 
following: 
• TEAEs by SOC and PT 
• TEAEs by SOC, PT, and severity 
• TEAEs by SOC, PT, and relationship to the study medication 
• TEAEs leading to death by SOC, and PT 
• Serious TEAEs other than deaths by SOC, and PT 
• TEAEs leading to premature discontinuation by SOC, and PT 
• Listing of non-TEAEs 
In the case of multiple occurrences of the same AE within the same subject, each subject will 
only be counted once for each preferred term. In summaries of AE by SOC and PT, along with 
the number (%) of subjects with at least 1 AE in the category, the number of events will be 
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displayed. In the summaries showing severity and relationship to study medication the event with 
the maximum severity or strongest relationship will be reported. If a particular event is missing 
the severity and/or relationship, then the strongest possible severity or relationship will be 
assumed for analysis (severity = severe, relationship = certain). 
Missing and partially missing AE start and/or stop dates will be imputed for the purpose of 
statistical analysis, according to the specifications described in Section 6.1.7. 
In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent will be 
flagged. 
9.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug, by treatment group, SOC, and preferred term will be prepared for the Safety 
Population. No inferential statistical tests will be performed. 
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and also tabulated by system organ class and preferred term 
and presented by treatment. 
9.2. 
Clinical Safety Laboratory Data 
Descriptive statistics for clinical safety laboratory data (laboratory data) recorded at screening 
will be presented overall and by treatment regimen. Summary tables by treatment regimen will 
be presented for each category of data separately. Routine clinical laboratory data will include 
hematology, serum chemistry, and urinalysis. Quantitative laboratory test result summaries will 
include N (population count for each regimen), n (number of subjects with non-missing values), 
mean, SD, median, and range. Qualitative tests (e.g., some urinalysis assessments) will be 
categorized accordingly. The set of laboratory parameters included in each table will correspond 
to those requested in the study protocol. Urine drug screen, alcohol breath analyzer and urine 
pregnancy test results will be presented in listings.  
9.3. 
Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for supine 
systolic blood pressure, supine diastolic blood pressure, heart rate, respiratory rate, and oral body 
temperature, and will be presented by treatment regimen. Summary statistics for 12-lead ECG 
parameters and counts for ECG interpretations at screening will be presented. 
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9.4. 
Concomitant Medication 
Prior and concomitant medications will be summarized descriptively by treatment using counts 
and percentages. 
Prior medications will be presented separately from concomitant medications. Medications that 
started prior to the first dose of study drug will be considered prior medications whether or not 
they were stopped prior to the first dose of study drug. Any medications continuing or starting 
post the first dose of study drug will be considered to be concomitant. If a medication starts prior 
to the first dose and continues after the first dose of study drug, it will be considered both prior 
and concomitant. Medications will be coded using March 2020 version of World Health 
Organization Drug Coding Dictionary (WHODD). 
9.5. 
Rescue Medication use  
The number of subjects taking rescue medication will be summarized by treatment group  at the 
following post dose times -1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 
hours and 24 hours.  This will be done on the safety population.  
10. 
Changes to analysis planned in the protocol 
For the time to event endpoints an additional measure of the treatment effect comparing each of 
the active arms with placebo will be obtained by calculating a hazard ratio and 95% CI by fitting 
a Cox proportional hazards model with a factor for treatment group and baseline pain as a 
continuous covariate. The assumption of proportional hazards will first be evaluated. 
There has been a clarification to the definition of the ITT population to that stated in the 
protocol. The ITT population is defined as all subjects who are treated with study drug and who 
have at least 1 pain assessment after Time 0. In the protocol the ITT population was defined as 
subjects who have at least 1 pain relief assessment. 
11. 
References 
1. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
2. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
3. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
4. Ratitich, B. and O’Kelly, M.J. (2011). Implementation of Pattern-Mixture Models Using 
Standard SAS / STAT Procedures. 
5. E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity 
Analysis in Clinical Trials 
 
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12. 
Tables, Listings, and Figures 
All listings, tables, and graphs will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (CRF page or listing number). 
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12.1. Planned Table Descriptions 
The following are planned summary tables for protocol number 5003601. The table numbers and 
page numbers are place holders only and will be determined when the tables are produced. 
Table 3: Demographic Data Summary Tables  
Table Number 
Population 
Table Title/Summary 
14.1 Displays of Demographics and Disposition Data 
Table 14.1.1 
All Subjects 
Subject Disposition 
Table 14.1.2 
Safety Population 
Demographics and Baseline Characteristics 
Table 14.1.2.1 
ITT Population 
Demographics and Baseline Characteristics 
Table 14.1.3 
Safety Population 
Medical History  
Table 14.1.4 
 Safety Population 
Prior Medications  
Table 14.1.5 
 Safety Population 
Concomitant Medications  
Table 14.1.6 
 All Enrolled Subjects 
Summary of Protocol Deviations  
Table 14.1.7 
Safety Population 
Summary of Study Drug Exposure 
12.2. Efficacy Data  
Table 4: Efficacy Tables 
Table Number 
Population 
Table Title/Summary 
14.2.1  
ITT Population 
Analysis of SPID-12 Scores  
14.2.1.1 
PP Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 1  
14.2.1.2 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 2-WOCF 
14.2.1.3 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 3-No Rescue Adjustment 
14.2.1. 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 4a-Rescue WOCF 
14.2.1.5 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 4b-Rescue LOCF 
14.2.1.6 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 4c-Multiple Imputation-
Rescue Medication-MAR 
14.2.1.7 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 5-Multiple Imputation-PMM 
14.2.1.8 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 6-Multiple Imputation-MAR 
14.2.1.9 
ITT Population 
Summary of SPID-12 Scores by Baseline Pain Category 
14.2.2 
ITT Population 
Analysis of Summed Pain Intensity Difference Scores  
14.2.2.1 
ITT Population 
Analysis of SPID-24 Scores- Sensitivity Analysis 7-No Rescue Adjustment 
14.2.2.2 
ITT Population 
Analysis of SPID-24 Scores- Sensitivity Analysis 8-Multiple Imputation-MAR 
14.2.3 
ITT Population 
Analysis of Total Pain Relief Scores  
14.2.4 
ITT Population 
Analysis of Summed Pain Relief and Intensity Difference Scores  
14.2.5 
ITT Population 
Comparison of SPID-24 in Ibuprofen PR and IR arms 
14.2.5.1 
ITT Population 
Comparison of SPID-24 in Ibuprofen PR and IR arms-Sensitivity Analysis 7-
No Rescue Adjustment 
14.2.5.2 
ITT Population 
Comparison of SPID-24 in Ibuprofen PR and IR arms- Sensitivity Analysis 8-
Multiple Imputation-MAR 
14.2.6 
ITT Population 
Summary of Peak Pain Relief  
14.2.7 
ITT Population 
Time to First Perceptible Pain Relief  
14.2.8 
ITT Population 
Time to Meaningful Pain Relief  
14.2.9 
ITT Population 
Time to Onset of Analgesia  
14.2.10 
ITT Population 
Time to Peak Pain Relief  
14.2.11 
ITT Population 
Time to First use of Rescue Medication  
14.2.12 
ITT Population 
Proportion of Subjects Using Rescue Medication  
14.2.13 
ITT Population 
Proportion of Responders 
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14.2.14 
ITT Population 
Summary of NRS Pain Intensity Difference Score  
14.2.15 
ITT Population 
Summary of Pain Intensity Score at each Scheduled Time Point 
14.2.16 
ITT Population 
Summary of Pain Relief at each Scheduled Time Point 
14.2.17 
ITT Population 
Analysis of Patient Global Evaluation of Study Drug 
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12.3. Safety Data 
Table 5: Safety Tables 
Table Number 
Population 
Table Title/Summary 
14.3.1 Summary of Treatment Emergent Adverse Events 
Table 14.3.1.1 
 Safety Population 
Overall Summary of Treatment-Emergent Adverse Events  
Table 14.3.1.2 
Safety Population 
Summary of Treatment-Emergent Adverse Events  
Table 14.3.1.3 
Safety Population 
Summary of Treatment-Emergent Adverse Events by Maximum Severity  
Table 14.3.1.4 
Safety Population 
Summary of Treatment-Emergent Adverse Events by Relationship to 
Study Drug  
Table 14.3.1.5 
Safety Population 
Summary of Non-Serious Treatment-Emergent Adverse Events  
14.3.2 Summary of Deaths, Other Serious and Significant Adverse Events 
Table 14.3.2.1 
 Safety Population 
Summary of Serious Adverse Events  
Table 14.3.2.2 
Safety Population 
Summary of Treatment Emergent Adverse Events Leading to 
Discontinuation  
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 
Table 14.3.3.1 
Safety Population 
Listing of Serious Adverse Events  
Table 14.3.3.2 
Safety Population 
Listing of Treatment Emergent Adverse Events Leading to  
Study Drug Discontinuation 
14.3.4 Abnormal Laboratory Value  
Table 14.3.4.1 
Safety Population  
Listing of  Potentially Clinically Significant Abnormal Laboratory Values   
14.3.5 Laboratory Data Summary Tables 
Table 14.3.5.1 
Safety Population  
Summary of Serum Chemistry Laboratory Results  
14.3.6 Other Safety Data Summary Tables 
Table 14.3.6.1 
 Safety Population 
Summary of Vital Signs  
Table 14.3.6.2 
Safety Population 
Summary of Electrocardiogram (ECG) Interpretations  
Table 14.3.6.3 
Safety Population 
Summary of 12-Lead Electrocardiogram (ECG) Parameters 
Table 14.3.6.4 
Safety Population 
Summary of Physical Examination Findings 
Table 14.3.6.5 
Safety Population 
Rescue Medication use 
 
 
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12.4. Planned Listing Descriptions 
The following are planned data and patient/subject data listings for protocol number 5003601.  
In general, one listing will be produced per CRF domain. All listings will be sorted by treatment, 
site, and subject number. All calculated variables will be included in the listings. 
In all listings a blank line will be placed between each subject. Within a data listing, if an item 
appears line after line (e.g., repetition of subject number), then only the first occurrence will be 
displayed. 
In data listings, the information for one subject will be kept on one page if at all possible, rather 
than splitting a subject’s information across pages. 
Table 6: Planned Listings 
Data Listing Number 
Population 
Data Listing Title / Summary 
16.2.1 Subject Discontinuations/Completions 
 Listing 16.2.1 
All Subjects 
Subject Disposition 
16.2.2 Protocol Deviations 
Listing 16.2.2.1 
All Subjects  
Eligibility Criteria Not Met 
Listing 16.2.2.2 
All Subjects 
Screen Failures 
Listing 16.2.2.3 
All Subjects 
Protocol Deviations 
16.2.3 Subjects in Analysis Populations 
Listing 16.2.3 
All Subjects 
Analysis Populations 
16.2.4 Demographic Data and Other Baseline Characteristics 
Listing 16.2.4.1 
Safety Population 
Demographics and Baseline Characteristics 
Listing 16.2.4.2 
Safety Population 
Medical History 
Listing 16.2.4.3 
 All Randomized Subjects Listing of Subject Randomization  
Listing 16.2.4.4 
 Safety Population 
Study Drug Administration 
16.2.7 Adverse Event Listings (by Subject) 
Listing 16.2.7.1 
Safety Population 
Adverse Events  
Listing 16.2.7.2 
Safety Population 
Serious Adverse Events 
Listing 16.2.7.3 
Safety Population 
Treatment emergent Adverse Events Related to Study Drug 
Listing 16.2.7.4 
Safety Population 
Deaths 
16.2.8 Laboratory Values by Subject 
Listing 16.2.8.1 
Safety Population 
Clinical Laboratory Data: Serum Chemistry 
Listing 16.2.8.2 
Safety Population 
Clinical Laboratory Data: Hematology 
Listing 16.2.8.3 
Safety Population 
Clinical Laboratory Data: Urine 
Listing 16.2.8.4 
Safety Population 
Clinical Laboratory Data: Coagulation 
Listing 16.2.8.5 
Safety Population 
Serum and Urine Pregnancy Test 
16.2.9 Other Clinical Observations and Measurements (by Subject) 
Listing 16.2.9.1 
Safety Population 
Prior and Concomitant Medications 
Listing 16.2.9.1.1 
Safety Population 
Rescue Medications 
Listing 16.2.9.2 
Safety Population 
Vital Signs Measurements 
Listing 16.2.9.2.1 
Safety Population 
Physical Examination Findings 
Listing 16.2.9.3 
Safety Population 
12-lead Electrocardiogram Measurements  
Listing 16.2.9.3.1 
Safety Population 
Alcohol Breathalyzer Test 
Listing 16.2.9.4 
Safety Population 
NRS Pain Intensity Assessment 
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Data Listing Number 
Population 
Data Listing Title / Summary 
Listing 16.2.9.5 
Safety Population 
Pain Relief Scores  
Listing 16.2.9.6 
Safety Population 
Time to Pain Relief (Stopwatches) 
Listing 16.2.9.7 
Safety Population 
Subjects Global Evaluation of Study Drug 
 
 
 
12.5. Planned Figure Descriptions 
The following are planned summary figures for protocol number 5003601. The figure numbers 
and page numbers are place holders only and will be determined when the figures are produced. 
Table 7: Planned Figures 
Figure 14.4.1.1 
ITT Population 
Kaplan-Meier Plot of Time to First Perceptible Pain Relief 
Figure 14.4.1.2 
ITT Population 
Kaplan-Meier Plot of Time to Meaningful Pain Relief  
Figure 14.4.1.3 
ITT Population 
Kaplan-Meier Plot of Time to Onset Of Analgesia  
Figure 14.4.1.4 
ITT Population 
Kaplan-Meier Plot of Time to Peak Pain Relief 
Figure 14.4.1.5 
ITT Population 
Kaplan-Meier Plot of Time to First Use Of Rescue Medication 
Figure 14.4.1.6 
ITT Population 
Mean Pid Scores versus Time 
Figure 14.4.1.7 
ITT Population 
Mean Pain Relief Scores versus Time 
 
 
 
Figure Number 
Population 
Figure Title / Summary 
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Appendix 1: Premier Research Library of Abbreviations 
 
Abbreviation 
Definition 
aCRF  
annotated case report form 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
BSL 
biostatistician lead 
CCGs 
CRF completion guidelines 
CDISC 
clinical data interchange standards consortium 
CEC 
central ethics committee 
CFR 
code of federal regulations 
CI 
confidence intervals 
CM 
clinical manager 
CMP 
clinical monitoring plan 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CSR 
clinical study report 
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Abbreviation 
Definition 
CTA 
clinical trial administrator 
CTM 
clinical trial manager 
CTMS 
clinical trial management system 
DB 
database 
DBL 
database lock 
DM 
data management 
DMB 
data monitoring board 
DMC 
data monitoring committee 
DMP 
data management plan 
DSMB  
data safety monitoring board 
DSP 
data safety plan 
DSUR 
development safety update report 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eTMF 
electronic trial master file 
EU 
European Union 
FDA 
food and drug administration 
FPI 
first patient in 
GCP 
good clinical practice 
HR 
heart rate 
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Abbreviation 
Definition 
IB 
investigator’s brochure 
IC or ICF 
informed consent or informed consent form 
ICH 
international council for harmonization  
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
LPI 
last patient in 
LPLV 
last patient last visit 
LPO 
last patient out 
MedDRA 
medical dictionary for regulatory activities 
MHRA 
medicines and healthcare products regulatory agency 
MM 
medical monitor 
MMP 
medical monitoring plan 
MMRM 
mixed effect model repeat measurement 
N 
number 
NA 
not applicable 
NCS 
non-clinically significant 
NF 
non-functional 
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Abbreviation 
Definition 
PD 
protocol deviation 
PDGP 
protocol deviation guidance plan 
PE 
physical examination 
PI 
principal investigator 
PK 
pharmacokinetic 
PKAP 
pharmacokinetic analysis plan 
PM 
project manager 
PMP 
project management plan 
PP 
per-protocol 
PS 
project specialist 
PV 
pharmacovigilance 
PVG 
pharmacovigilance group 
QA 
quality assurance 
QARC 
quality assurance, risk and compliance 
QC 
quality control 
QOL 
quality of life 
SAE 
serious adverse event 
SAF 
Safety Population 
SAP 
statistical analysis plan 
SAS®  
a software system used for data analysis 
SBP 
systolic blood pressure 
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Abbreviation 
Definition 
SD 
standard deviation 
SDS 
study design specifications 
SDTM  
study data tabulation model  
SF 
screen failure 
SFT or SFTP 
secure file transfer or secure file transfer plan 
SIV 
site initiation visit 
SMP 
safety management plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
UAT 
user acceptance testing 
WHO 
world health organization 
WHO-DD 
world health organization drug dictionary 
WOCF 
worst observation carried forward 
 
 
Page 148 of 351


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Statistical AnalysisPlan,
Sponsor Reckitt Benckiser
Protocol Number 5003601
PCN Number RECK.117035
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Sponsor
Reckitt Benckiser
Protocol Title:
A Randomized, Double-Blind, Double-Duffiffiy, parallel_Group,
Multiple-Dose, Active and placebo-controlled Efficacy Study of
Ibuprofen Prolonged-Release Tablets for the Treatment of pain
after Surgical Removal of Impacted Third Molars
5003601
RECK.17703s
Amendment 2.0
18-May-2020
Protocol Number:
Premier Research PCN:
Document Version:
Document Date:
Approvals
Biostatistician
Premier Research
Print Name: Raghu Vishnubhotla
Sign Name:
Reckitt Benckiser
Representative
Print Name: Darren Tarsett
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Sign Name:
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Version 1.0
Page 1 of4l
19-May-2020 | 22:39:31 EDT
Page 149 of 351


Statistical Analysis Plan  
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PCN Number RECK.177035
1.1. 
Planned Table Shells 
Table 14.1.1 
Subject Disposition 
All Randomized Subjects  
Disposition 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Study Populations [1]
Screened
XXX
Safety Population
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
ITT Population 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Per-Protocol Population
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Completion Status [2]
Completed Study
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Prematurely Discontinued Study Medication
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Prematurely Discontinued Study
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Reasons for discontinuation from Study
Lost to Follow-up
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Protocol Violation
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Adverse Event
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Non-Compliance with Study Drug
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Death
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Lack of Efficacy
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Withdrawal by Subject
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Pregnancy
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Physician Decision
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Study Terminated by Sponsor 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Other 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Abbreviation: ITT= Intent-to-Treat 
[1] Percentages are based on the number of randomized subjects.
[2] Percentages are based on the number of subjects in the Safety Population. 
Source: Listing 16.2.1
Page 150 of 351


 
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Table 14.1.2 
Demographics and Baseline Characteristics 
Safety Population 
 
Variable 
   Statistic or Category 
Ibuprofen PR  
 
(N=XX) 
Ibuprofen IR 
  
(N=XX) 
Placebo 
  
(N=XX) 
Overall 
  
(N=XX) 
Age (years) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
 
 
XX, XX 
XX, XX 
XX, XX 
Gender 
 
 
 
 
   Male 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Female 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Ethnicity 
 
 
 
 
   Hispanic or Latino 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Not Hispanic or Latino 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Missing/Not Answered 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Race 
 
 
 
 
   American Indian/Alaska Native  
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Asian 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Black or African-American 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Native Hawaiian or Other Pacific Islander 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   White 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Missing/Not Answered 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Baseline Pain [1] 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Baseline Pain Category [2] 
 
 
 
 
 
   Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Height (cm) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
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   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Weight (kg) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Surgery Duration (min) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
Abbreviation: BMI=Body Mass Index 
Note: Percentage are based on the number of subjects in the Safety Population. 
[1] Subjects rate their pain using a numeric rating scale (NRS) from 0 (no pain) to 10 (worst pain ever).  
[2] NRS pain scores at baseline are categorized as moderate (5-7), and severe (8-10). 
 
Source: Listing 16.2.4.1 
 
Table 14.1.2.1 
Demographics and Baseline Characteristics 
ITT Population 
Use Same Shell as Table 14.1.2 
Programming Note- Update footnote Note: Percentage are based on the number of subjects in the ITT Population. 
 
 
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Table 14.1.3 
Medical History 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR 
  
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
  
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
Subjects with at least One Recorded Medical History 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
System Organ Class 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages are based on number of subjects in the Safety Population. 
Medical conditions were coded using MedDRA version 23.0 or later. Subjects were counted once for each system organ class (SOC) and once for each preferred term (PT). Medical 
history terms are displayed by descending frequency of SOC, then PT within SOC, and then alphabetically by PT. 
SOURCE: Listing 16.2.4.2 
Programming Note- Uncoded terms, if any, will be at the bottom of the table. They will have labels’ Not Coded’ for SOC and PT 
 
 
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Table 14.1.4 
Prior Medications 
Safety Population 
ATC Class Level 4 
   Preferred Term (ATC Class Level 5) 
Ibuprofen PR 
   
 (N=XX) 
Ibuprofen IR 
   
 (N=XX) 
Placebo   
 
 (N=XX) 
Overall 
 
 (N=XX) 
 
 
 
 
 
Subjects with at least one Prior Medication 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
ATC Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
ATC Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages are on number of subjects in the Safety Population.  
Medications are coded using WHO-DD B2E version March 2020.  
Medications that started prior to the first dose of study drug will be considered prior medications whether or not they were stopped prior to the first dose of study drug.. Medications are 
displayed by descending frequency of Anatomic Therapeutic Chemical (ATC) Level 4 classification, by Preferred Term (PT) within ATC and then alphabetically.  
Subjects were counted only once for each ATC and PT. 
SOURCE: Listing 16.2.9.1 
 
 
Table 14.1.5 
Concomitant Medications 
Safety Population 
Use same shell as Table 14.1.4 
Use this footnote for definition of concomitant medications- Any medications continuing or starting post the first dose of study drug will be considered as concomitant medications. 
 
 
 
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Table 14.1.6 
Summary of Protocol Deviations 
All Enrolled Subjects 
 
Deviation Category  
 Type of Deviation  
Ibuprofen PR 
   
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
 (N=XX) 
Overall 
 (N=XX) 
 
 
 
 
 
Subjects with any Protocol Deviation 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Subjects with Major Protocol Deviations 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
  Type of Protocol Deviation 
 
 
 
 
     Deviation type 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
     Deviation type 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
…… 
 
 
 
 
 
 
 
 
 
Subjects with Minor Protocol Deviations 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   Type of Protocol Deviation 
 
 
 
 
     Deviation type 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
     Deviation type 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
…. 
 
 
 
 
 
 
 
 
 
Notes: Subjects with one or more deviations within a deviation category (Major/Minor) or type of deviation were counted only once. 
Percentages are based on number of all enrolled subjects.  
SOURCE: Listing 16.2.2.3 
 
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Table 14.1.7 
Summary of Study Drug Exposure 
Safety Population 
 
Category 
  Statistic 
Ibuprofen PR 
   
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
 (N=XX) 
 
 
 
 
Number of Tables Taken 
 
 
 
   n 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
Number of Active Doses Taken [1] 
 
 
 
   n 
XX 
XX 
 
   Mean 
XX.X 
XX.X 
 
   Std Dev 
XX.XX 
XX.XX 
 
   Median 
XX.X 
XX.X 
 
   Min, Max 
XX, XX 
XX, XX 
 
 
 
 
 
Quantity of Active Drug Taken (mg) 
 
 
 
   n 
 
 
 
   Mean 
XX.X 
XX.X 
 
   Std Dev 
XX.XX 
XX.XX 
 
   Median 
XX.X 
XX.X 
 
   Min, Max 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
Treatment Duration (Hours) [2] 
 
 
 
   n 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
Note: Percentages are based on number of all enrolled subjects.  
[1] Active dose is a dose where the tablet taken has an active ingredient  
[2] Duration = date/time of last dose administered – date/time of first dose administered 
SOURCE: Listing 16.2.4.4.1 
 
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Table 14.3.1.1 
Overall Summary of Treatment Emergent Adverse Events  
Safety Population 
 
 
 
 
Ibuprofen PR  
 
 (N=XX) 
Ibuprofen PR 
 
 (N=XX) 
Placebo 
 (N=XX) 
Overall 
 
 (N=XX) 
 
 
 
 
 
   Subjects with at least one TEAE 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   TEAE by Maximum Severity 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   TEAE by Strongest Relationship  
 
 
 
 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   AE leading to Discontinuation 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   SAE 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
   AE leading to Death 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event; SAE = Serious Adverse Event. 
Notes: Percentages are based on number of subjects in the safety population.. 
TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug. Strongest possible severity or relationship will be 
assumed for TEAES with missing severity and/or relationship (severity=severe, relationship=certain) 
 
SOURCE: Listing 16.2.7.1 
 
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Table 14.3.1.2 
Summary of Treatment Emergent Adverse Events  
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
Subjects with at least One TEAE 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 2 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 3 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 2 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 3 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event. 
Notes: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. 
 
Percentages are based on number of subjects in the safety population. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  
TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug. 
AEs were coded using MedDRA version 23.0.  
 
SOURCE: Listing 16.2.7.1 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
Page 158 of 351


 
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Table 14.3.1.3 
Summary of Treatment Emergent Adverse Events by Maximum Severity 
Safety Population 
 
System Organ Class 
   Preferred Term 
Maximum Severity [1] 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall  
 
 (N=XX) 
       
 
 
 
 
Subjects with at least One TEAE 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   Preferred Term 1 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event; SAE = Serious Adverse Event. 
[1] The severity shown is the greatest severity reported for a particular subject (Severe > Moderate > Mild). AEs with missing severity have been classified as Severe. 
Notes: Percentages are based on number of subjects in the safety population. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term. TEAE is 
defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug. AEs were coded using MedDRA version 23.0. 
SOURCE: Listing 16.2.7.1 
 
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Table 14.3.1.4 
Summary of Treatment Emergent Adverse Events by Relationship to Study Drug 
Safety Population 
 
System Organ Class 
   Preferred Term 
Greatest Relationship [1] 
Ibuprofen PR 
  
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall  
 (N=XX) 
       
 
 
 
 
Subjects with at least One TEAE 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
System Organ Class 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
[1] AE relation is marked in the CRF. The relationship shown is the strongest relationship reported for a particular subject. AEs with missing relationship have been classified as 
Certain. 
Abbreviations: TEAE = Treatment Emergent Adverse Event. 
Notes: Percentages are based on number of subjects in the safety population.. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term. TEAE is 
defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug.. AEs were coded using MedDRA version 23.0. 
SOURCE: Listing 16.2.7.1 
 
 
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Table 14.3.1.5 
Summary of Non-Serious Treatment Emergent Adverse Events  
Safety Population 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one non-
serious TEAE  
 
X (XX.X%) X 
 
X (XX.X%) X  
 
X (XX.X%) X 
 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event. 
Notes: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. Percentages are based on number of 
subjects in the safety population.. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.. TEAE is defined as any event that started or worsened in 
intensity or relationship to treatment on or after the first dose of study drug. AEs were coded using MedDRA version 23.0. 
SOURCE: Listing 16.2.7.1 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.2.1 
Summary of Serious Adverse Events 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one SAE 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
 
 
 
 
 
Abbreviation: SAE = Serious Adverse Event.  
Notes: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. 
 Percentages are based on number of subjects in the safety population. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  
  
AEs were coded using MedDRA version 23.0.  
SOURCE: Listing 16.2.7.1 
 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.2.2 
Summary of Treatment Emergent Adverse Events Leading to Study Drug Discontinuation 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
 (N=XX) 
Ibuprofen IR 
 (N=XX) 
Placebo 
 (N=XX) 
Overall  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one TEAE that led to 
study drug discontinuation  
 
X (XX.X%) X 
 
X (XX.X%) X 
 
X (XX.X%) X 
 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
 
 
 
 
 
Abbreviation: TEAE = Treatment Emergent Adverse Event. 
 
Notes: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. 
 Percentages are based on number of subjects in the safety population. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  
 TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study drug.  
AEs were coded using MedDRA version 23.0.  
 
SOURCE: Listing 16.2.7.1 
 
 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.3.1 
Listing of Serious Adverse Events 
Safety Population 
 
 
Subject ID 
Treatment 
Group 
 
Gender 
Age 
(years) 
 
SAE 
System Organ Class/ 
Preferred Term/ Verbatim 
Term 
Start Date/Time (Study 
Day/ 
End Date/Time (Study 
Day) 
 
Severity/ 
Causality 
 
Outcome/ Action Taken 
XXXX 
  
M 
XX 
XXXX 
XXXX/XXX/XXX    
DDMMMYYYY/THH:MM 
(XX)/ 
DDMMMYYYY/THH:MM 
(XX) 
MILD/Related 
  XXX/XXX 
 
 
 
 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: SAE = Serious adverse event. 
Note: AEs were coded using MedDRA version 23.0.  
Study day is calculated relative to the date of first dose of study drug. 
Source: Listing 16.2.7.2 
 
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Table 14.3.3.2 
Listing of Treatment Emergent Adverse Events Leading to Study Drug Discontinuation 
Safety Population 
 
 
Subject ID       
Treatment 
Group 
 
Gender 
Age 
(Years) 
 
TEAE 
System Organ Class/     
Preferred Term/ Verbatim 
Term 
Start Date/Time (Study 
Day)/ 
End Date/Time(Study 
Day) 
 
Severity/ 
Causality 
 
Outcome/  
   Action Taken 
XXXX 
XX 
F 
XX 
XXXX 
XXXX/XXX/XXX    
DDMMMYYYYTHH:MM 
(XX)/ 
DDMMMYYYYTHH:MM 
(XX) 
MILD/Related 
  XXX/XXX 
XXXX 
XX 
M 
 
XXXX 
XXXX/XXX/XXX    
DDMMMYYYYTHH:MM 
(XX)/ 
DDMMMYYYYTHH:MM 
(XX) 
MILD/Related 
  XXX/XXX 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event. 
Notes: AEs were coded using MedDRA version 23.0.  
 TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose of study 
drug.Study day is calculated relative to the date of first dose of study drug. 
 
Source: Listing 16.2.7.1
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Table 14.3.4.1 
Listing of Potentially Clinically Significant Abnormal Laboratory Values 
Safety Population 
 
 
 
 
Subject 
Number 
Treatment 
Group 
 
 
Gender 
Age 
(Years) 
Lab Category 
Lab Parameter 
(Units) 
 
Parameter 
Value 
Reference 
Range 
Test Result 
Assessment 
Date/Time of 
Collection 
(Study Day) 
XXXX 
XX 
M 
XX 
Hematology  
Hemoglobin 
 
XXXXX 
XX-XX 
High/Low 
XXXXX(XX) 
 
 
 
 
 
Haematocrit 
 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: NA=Not ApplicableNotes: Study day is calculated relative to the date of first dose of study drug.  
Source: Listings 16.2.8.1, 16.2.8.2, 16.2.8.3, 16.2.8.4 
Programming note- Category will be Hematology/Chemistry/Urinalysis/Coagulation. Sort by subject id, treatment group, and paramn.  
 
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Table 14.3.5.1 
Summary of Clinical Laboratory Results  
Safety Population 
 
 
Lab Category: Chemistry/Hematology/Urinalysis 
 
Parameter:XXXX 
  Visit/ 
    Statistic 
 
 
 
 
 
Iburprofen 
PR 
(N=XX) 
Iburprofen PR 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
Lab Parameter: XXXXX 
 
 
 
 
   Screening  
 
 
 
 
     n 
XX 
XX 
XX 
XX 
    Mean 
XX.X 
XX.X 
XX.X 
XX.X 
    Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
XX.X 
XX.X 
    Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
Notes- Clinical laboratory tests (hematology, chemistry, urinalysis) tests are only done at Screening. 
 
SOURCE: Listing 16.2.8.1, 16.2.8.2, 16.2.8.3, 16.2.8.4 
Programming Note- Lab Category is Hematology or Chemistry or Urinalysis or Coagulation 
 
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Table 14.3.6.1 
Summary of Vital Signs  
Safety Population 
                     Parameter:XXXXX 
 
 
Visit/ 
Statistic 
 
 
 
 
 
Iburprofen PR 
(N=XX) 
Iburprofen IR 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Baseline 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
12 hours  
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Change from Baseline to 12 
hours 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
……. 
 
 
 
 
 
Notes- Baseline is defined as the last observation recorded prior to the first dose.  
Programming Note- Calculate summary stats and change from baseline for 12 hours, 24 hours and Day 8/ET visit. 
Source:Listing 16.2.9.2 
 
 
 
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Table 14.3.6.2 
Summary of Electrocardiogram (ECG) Interpretations  
Safety Population 
  
 
 
Visit 
   Category 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Overall 
 
(N=XX) 
Screening 
 
 
 
 
   Normal 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Abnormal - CS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Abnormal - NCS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CS = clinically significant; NCS = not clinically significant 
 
SOURCE: Listing 16.2.9.3 
 
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Table 14.3.6.3 
Summary of 12-Lead Electrocardiogram (ECG) Parameters  
Safety Population 
Parameter: XXXXXX 
 
 
Visit/ 
  Statistic 
 
 
 
 
Ibuprofen PR  
 (N=XX) 
Ibuprofen IR 
 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Screening 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOURCE: Listing 16.2.9.3. 
 
 
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Table 14.3.6.4 
Summary of Physical Examination Findings  
Safety Population 
Body System=XXXXXX 
 
Visit 
    Category 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Overall 
 
(N=XX) 
 Visit 
 
 
 
 
    Normal 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
    Abnormal - CS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
    Abnormal - NCS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
….. 
 
 
 
 
Abbreviations: CS = clinically significant; NCS = not clinically significant ET: end of treatment 
 
SOURCE: Listing 16.2.9.3 
 
 
Table 14.3.6.5 
Rescue Medication Use  
Safety Population 
 
 
Any rescue medication 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
Total 
 
 
 
 
 
At Any time 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
In the first 1 hour after dosing  
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
In the first 2 hours after dosing  
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
……….. 
 
 
 
 
 
 
 
 
 
 
Note: At each level of summarization subjects taking multiple rescue medication are counted only once. Percentage is based on number of subjects in the safety population.  
Programming note- Please complete table for the following time points 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours and 24 hours. 
 
 
 
 
 
 
 
 
 
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Table 14.2.1 
Analysis of SPID-12 Scores  
ITT Population 
 
Statistics 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
 
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.XX 
XX.XX 
XX.XX 
Std Dev 
XX.XXX 
XX.XXX 
XX.XXX 
Median 
XX.XX 
XX.XX 
XX.XX 
Min, Max 
XX.X,XX.X 
XX.X,XX.X 
XX.X,XX.X 
 
 
 
 
ANCOVA Statistics [1] 
 
 
 
LS Mean (SE) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
LS Mean Difference from Placebo (95% CI) 
p-value 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
 
 
 
 
 
 
 
 
 
….. 
 
 
 
  
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Notes: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 
10 = worst pain ever. Baseline pain is also recorded using the NRS scale. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. 
Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
Source: Listing 16.x.xx 
 
 
 
 
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Table 14.2.1.1 
Analysis of SPID-12 Scores – Sensitivity Analysis 1  
PP Population 
 
(Same Shell as Table 14.2.1) 
 
 
 
 
 
 
 
 
Table 14.2.1.2 
Analysis of SPID-12 Scores- Sensitivity Analysis 2-WOCF 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing 
pain assessments imputed by WOCF 
 
(Programming Note-This is sensitivity analysis # 2 in section 6.1.6 of the SAP.) 
 
 
Table 14.2.1.3 
Analysis of SPID-12 Scores- Sensitivity Analysis 3-No Rescue Adjustment 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. No adjustment made to pain scores after use of rescue medication. Missing intermediate pain assessments 
imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
(Programming Note-This is sensitivity analysis # 3 in section 6.1.6 of the SAP.) 
 
Table 14.2.1.4 
Analysis of SPID-12 Scores- Sensitivity Analysis 4a-Rescue WOCF 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. Worst observation carried forward (WOCF) is used to impute all subsequent pain scores after first use of rescue 
medication. Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
 
(Programming Note-This is sensitivity analysis # 4a in section 6.1.6 of the SAP.) 
 
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Table 14.2.1.5 
Analysis of SPID-12 Scores- Sensitivity Analysis 4b-Rescue LOCF 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. Last observation carried forward (LOCF) is used to impute all subsequent pain scores after first use of rescue 
medication. Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
(Programming Note-This is sensitivity analysis # 4b in section 6.1.6 of the SAP.) 
 
Table 14.2.1.6 
Analysis of SPID-12 Scores- Sensitivity Analysis 4c-Multiple Imputation-Rescue Medication-MAR 
 ITT Population 
(Same Shell as Table 14.2.1) 
Footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. All pain scores after rescue medication are imputed using an MCMC method under missing at random 
assumption. Intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
(Programming Note-This is sensitivity analysis # 4c in section 6.1.6 of the SAP.) 
 
 
 
Table 14.2.1.7 
Analysis of SPID-12 Scores- Sensitivity Analysis 5-Multiple Imputation-PMM 
 ITT Population 
(Same Shell as Table 14.2.1) 
Footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. 
Intermittent missing values are replaced by an MCMC method under a missing at random assumption. Missing pain assessments due to premature discontinuation are replaced using 
a pattern-mixture model with control-based imputation.  
 
 
(Programming Note-This is sensitivity analysis # 5 in section 6.1.6 of the SAP.) 
 
Table 14.2.1.8 
Analysis of SPID-12 Scores- Sensitivity Analysis 6-Multiple Imputation-MAR 
 ITT Population 
(Same Shell as Table 14.2.1) 
Footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating (NRS) from 0-10 where 0 = no pain and 10 = 
worst pain ever. Baseline pain is also recorded using the NRS scale. Missing pain scores and values within the defined window after rescue medication are imputed using multiple 
imputation under the MAR assumption. 
 
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(Programming Note-This is sensitivity analysis # 5 in section 6.1.6 of the SAP.) 
 
 
 
 
 
Table 14.2.1.9 
Summary of SPID-12 Scores by Baseline Pain Category 
ITT Population 
 
 
Category/Statistic 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Baseline  Pain Category-
Moderate 
 
 
 
    
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
Median 
XX 
XX 
XX 
Min, Max 
XX,XX 
XX,XX 
XX,XX 
 
 
 
 
…………. 
 
 
 
 
Notes- SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects will rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain 
and 10 = worst pain ever.  Baseline pain using a categorical scale that includes moderate (5-7), and severe (8-10). For subjects who use rescue medication, windowed worst 
observation carried forward (WOCF) is used. Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation 
imputed by LOCF. 
 
Programming Note- Please complete table for all baseline pain categories.  
 
 
                                                                    
 
 
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Table 14.2.2 
Analysis of Summed Pain Intensity Difference Scores  
ITT Population 
 
 
  
 
Category/Statistics 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
SPID-4 
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.XX 
XX.XX 
XX.XX 
Std Dev 
XX.XXX 
XX.XXX 
XX.XXX 
Median 
XX.XX 
XX.XX 
XX.XX 
Min, Max 
XX.X,XX.X 
XX.X,XX.X 
XX.X,XX.X 
 
 
 
 
ANCOVA Statistics [1] 
 
 
 
LS Mean (SE) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
LS Mean Difference from Placebo (95% CI) 
p-value 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
….. 
 
 
 
 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Notes: SPID-4/8/12 is summed pain intensity difference (SPID) over 0 to 4/8/12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no 
pain and 10 = worst pain ever. Baseline pain is also recorded using the NRS scale. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is 
used. Missing intermediate pain assessments imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
Programming Note- Please program for SPID-4 SPID-8 and SPID-24. 
 
Source: Listing 16.x.xx 
 
 
 
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Table 14.2.2.1 
Analysis of SPID-24 Scores- Sensitivity Analysis 7-No Rescue Adjustment 
 ITT Population 
(Same Shell as Table 14.2.1) 
Please add these footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. No adjustment made to pain scores after use of rescue medication. Missing intermediate pain assessments 
imputed by linear interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
Table 14.2.2.2 
Analysis of SPID-24 Scores- Sensitivity Analysis 8-Multiple Imputation-MAR 
 ITT Population 
(Same Shell as Table 14.2.1) 
Footnotes: Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-24 is summed pain intensity difference (SPID) over 0 to 24 hours. Subjects rate their pain intensity using a numeric rating (NRS) from 0-10 where 0 = no pain and 10 = 
worst pain ever. Baseline pain is also recorded using the NRS scale. Missing pain scores and values within the defined window after rescue medication are imputed using multiple 
imputation under the MAR assumption 
 
 
 
Table 14.2.3 
Analysis of Total Pain Relief Scores  
ITT Population 
 
(Programming Note- Use same shell as Table 14.2.2. Please add the following footnote defining sum of total pain relief (TOTPAR) Note- Total pain relief (TOTPAR) is summed total 
pain relief under the Pain Relief Scale (0 – 4) from 15 min through 4/8/12/24 hours ) 
 
 
 
 
 
Table 14.2.4 
Analysis of Summed Pain Relief and Intensity Difference Scores  
ITT Population 
(Use same shell as Table 14.2.2) 
 
 
 
 
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Table 14.2.5 
Comparison of SPID-24 in Ibuprofen PR and IR arms 
ITT Population 
 
 
 
 
 
 
 
Category/Statistics 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
SPID-24 
 
 
ANCOVA Statistics [1] 
 
 
LS Mean (SE) 
XX.XX (XX.XX) 
XX.XX (XX.XX) 
 
 
 
 
 
 
 
 
 
LS Mean Difference (95% CI) 
p-value 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
 
 
 
 
….. 
 
 
 
 
 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error, SPID=summed pain intensity difference. 
[1] Estimates are from an analysis of covariance model with SPID-24/TOTPAR-24/SPRID-24 score as the dependent variable. Terms for treatment and baseline pain score were 
included as covariates.  
Notes-SPID-24 is summed pain intensity difference (SPID) over 0 to 24 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing intermediate pain assessments imputed by linear 
interpolation. Missing pain assessments due to premature discontinuation imputed by LOCF. 
 
 
 
Table 14.2.5.1 
Comparison of SPID-24 in Ibuprofen PR and IR arms-Sensitivity Analysis 7-No Rescue Adjustment 
ITT Population 
 
Use same shell as Table 14.2.5 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error, SPID=summed pain intensity difference. 
[1] Estimates are from an analysis of covariance model with SPID-24 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Notes-SPID-24 is summed pain intensity difference (SPID) over 0 to 24 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. No adjustment made to pain scores after use of rescue medication. Missing intermediate pain assessments imputed by linear interpolation. Missing pain 
assessments due to premature discontinuation imputed by LOCF. 
 
Table 14.2.5.2 
Comparison of SPID-24 in Ibuprofen PR and IR arms-Sensitivity Analysis 8- Multiple Imputation 
ITT Population 
 
Use same shell as Table 14.2.5 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error, SPID=summed pain intensity difference. 
[1] Estimates are from an analysis of covariance model with SPID-24 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Notes-SPID-24 is summed pain intensity difference (SPID) over 0 to 24 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
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= worst pain ever. No adjustment made to pain scores after use of rescue medication. Missing pain scores and values within the defined window after rescue medication are imputed 
using multiple imputation under the MAR assumption 
 
 
 
 
 
 
Table 14.2.6 
Summary of Peak Pain Relief  
ITT Population 
  
 
 
Category/Statistics 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
   None 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A Little Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Some Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A lot of Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Complete Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
Odds Ratio (vs placebo) [1] 
XX.XX 
XX.XX 
 
  95% CI 
(XX.XX,XX.XX) 
XX.XX,XX.XX) 
 
  p-value 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
 
 
 
Abbreviations: CI=Confidence Interval 
[1] From a proportional odds model treatment group and baseline pain as covariates. An odds ratio > 1 means that patients experienced higher pain relief than the placebo. 
Notes- Subjects rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. 
 
SOURCE: Listing 16.x.xx  
 
 
 
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Table 14.2.7 
Time to First Perceptible Pain Relief  
ITT Population 
  
 
 
Category/Statistic  
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Number of Subjects with First 
Perceptible Pain Relief 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Number of Subjects Censored  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Time to first perceptible pain relief 
(hours) [1] 
 
 
 
       Median (95% CI) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
        Q1  
XX.XX  
XX.XX  
XX.XX 
        Q3 
XX.XX  
XX.XX  
XX.XX 
        Range (Min-Max) 
XX.X-XX.X 
XX.X-XX.X 
XX-XX 
        p-value (vs placebo) [2] 
0.XXXX 
0.XXXX 
 
 
 
 
 
Hazard Ratio (vs placebo) [3] 
XX.XX 
XX.XX 
 
95% CI 
(XX.XX,XX.XX) 
(XX.XX,XX.XX) 
 
 
 
 
 
Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means 
that patients in the Ibuprofen groups achieved pain relief faster than the placebo.  
Notes- Time of first perceptible pain relief is the time of first reported pain relief as assessed by the subject (i.e. subject stops the first stopwatch (irrespective of the second 
stopwatch)). Pain scores at baseline are categorized as moderate (5-7), and severe (8-10). 
 
 
Table 14.2.8 
Time to Meaningful Pain Relief  
ITT Population 
 
Use same shell as Table 14.2.7 
(Programmers Note- Please add the following footnote- Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates.  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means 
that patients in the Ibuprofen groups achieved pain relief faster than the placebo. 
Notes- Time of meaningful pain relief is the time of the first reported meaningful (subjective) pain relief assessed by stopping the second stopwatch. Pain scores at baseline pain) are 
categorized as moderate (5-7), and severe (8-10 
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Table 14.2.9 
Time to Onset of Analgesia  
ITT Population 
 
 
Category/Statistic  
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Number of Subjects with First Perceptible Pain 
Relief and Meaningful Pain Relief 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Number of Subjects Censored  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Time to onset of analgesia (hours) [1] 
 
 
 
       Median (95% CI) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
        Q1  
XX.XX  
XX.XX  
XX.XX 
        Q3 
XX.XX  
XX.XX  
XX.XX 
        p-value (vs placebo) [2] 
0.XXXX 
0.XXXX 
 
        p-value (PR vs IR) [2] 
0.XXXX 
 
 
        Range (Min-Max) 
XX.X-XX.X 
XX.X-XX.X 
XX.X-XX.X 
 
 
 
 
Hazard Ratio (95% CI) (vs placebo) [3] 
XX.XX (XX.XX,XX.XX) 
XX.XX (XX.XX,XX.XX) 
 
Hazard Ratio (95% CI) (PR vs IR) [4] 
XX.XX (XX.XX,XX.XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 (Programmers Note- Please add the following footnote- Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. If hazard ratio <1 means 
that patients in the Ibuprofen groups achieved pain relief faster than the placebo  
[4] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. If hazard ratio <1 means 
that patients in the PR group achieved pain relief faster than the IR. 
Notes- If the subject has had meaningful pain relief (i.e., presses both stopwatches) then time to onset of analgesia is date/time when the first stopwatch is stopped. Pain scores at 
baseline are categorized as moderate (5-7), and severe (8-10). 
 
 
 
Table 14.2.10 
Time to Peak Pain Relief  
ITT Population 
Use same shell as Table 14.2.7 
 
(Programmers Note- Please add the following footnote- Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means 
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that patients in the Ibuprofen groups achieved pain relief faster than the placebo. 
Note- Time of peak pain relief is the time when pain relief, which is measured on a scale from 0 (none)-4 (complete), is maximum. Subjects who do not experience any pain relief are 
censored at the time of their last pain assessment.  
 
 
 
Table 14.2.11 
Time to First use of Rescue Medication  
ITT Population 
 
Use same shell as Table 14.2.7 
 
(Programmers Note- Please add the following footnote- Abbreviation- Q1- 25
th Percentile, Q3- 75
th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of >1 means 
that patients in the Ibuprofen groups refrained from taking rescue medication for longer than the placebo. 
 
Notes- Subjects who do not take rescue medication are censored at the time of their last pain assessment. 
 
 
Table 14.2.12 
Proportion of Subjects Using Rescue Medication  
ITT Population 
  
 
 
Category/Statistic 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Number of subjects using Rescue Medication 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
Odds Ratio for Rescue Medication 
(Active/Placebo) [1] 
XX.XX 
XX.XX 
 
   (95% CI) 
(XX.XX,XX.XX) 
(XX.XX,XX.XX) 
 
p-value 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
Abbreviation: CI= Confidence Interval  
[1] Odds ratio, CI, and p-value are from a logistic regression model estimating the probability of using rescue medication with baseline pain and treatment arm 
as covariates in the model. An odds ratio < 1 means patients in the Ibuprofen groups are less likely to have used rescue medication compared to those in placebo. 
 
 
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 Table 14.2.13 
Proportion of Responders  
ITT Population 
 
(Use same shell as 14.2.12. Please use footnote below.) 
Abbreviation: CI=Confidence Interval  
Notes- A subject with ≥ 30% improvement in NRS pain intensity from T0 (predose) without rescue medication during the first 8 hours is considered a responder. 
[1] Odds ratio, CI, and p-value are from a logistic regression model estimating the probability of being a responder with baseline pain and treatment arm as covariates in the model. An 
odds ratio > 1 means patients in the Ibuprofen groups are more likely to be responders compared to those in placebo. 
 
 
 
 
 
Table 14.2.14 
Summary of NRS Pain Intensity Difference Score  
ITT Population 
  
 
 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
PID 15 mins after Time 0  
 
 
 
    
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
Median 
XX 
XX 
XX 
Min, Max 
XX,XX 
XX,XX 
XX,XX 
 
LS Mean Difference from 
Placebo (95% CI)[1] 
XX.XX (XX.XX, XX.XX) 
 
XX.XX (XX.XX, XX.XX) 
 
 
p-value (vs Placebo) 
 
0.XXXX 
0.XXXX 
 
Abbreviations: PID= Pain Intensity Difference NRS- Numeric Rating Scale. 
Notes- Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever. Pain intensity difference score at a time point is the 
difference in NRS pain intensity from baseline to that time point. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing data 
due to missing intermediate assessments or premature discontinuation is not imputed. 
[1] From a repeated measures mixed model with treatment, timepoint, treatment by timepoint, baseline and baseline by timepoint as fixed effects, and subject as a random effect.  
 
Programming Note- Please complete table for all scheduled time assessments. Only impute using wWOCF for assessments after rescue medication. Do not impute for missing data. 
 
 
 
 
 
 
 
 
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Table 14.2.15 
Summary of Pain Intensity Score at each Scheduled Time Point 
ITT Population 
Use same shell as Table 14.2.14 
(Programmers please add the following footnote-  
Note- Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever. For subjects who use rescue medication, windowed 
worst observation carried forward (WOCF) is used. Missing data due to missing intermediate assessments or premature discontinuation is not imputed. 
Programming Note- Please complete table for all scheduled time assessments. No need for LS mean difference 95%CI and p value from 14.2.14 shell). Only impute using wWOCF for 
assessments after rescue medication. Do not impute for missing data. 
 
 
 
 
 
 
 
 
 
  
 
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Table 14.2.16 
Summary of Pain Relief at each Scheduled Time Point 
ITT Population 
 
 
 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Pain Relief 5 mins after 
Time 0 
 
 
 
    
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
Median 
XX 
XX 
XX 
Min, Max 
XX,XX 
XX,XX 
XX,XX 
 
   None 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A Little Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Some Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A lot of Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Complete Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
Odds Ratio (vs placebo) [1] 
XX.XX 
XX.XX 
 
  95% CI 
(XX.XX,XX.XX) 
XX.XX,XX.XX) 
 
  p-value 
0.XXXX 
0.XXXX 
 
 
 
 (Programmers please add the following footnote-  
1] From a repeated measures proportional odds model with treatment, timepoint, treatment by timepoint, baseline and baseline by timepoint as fixed effects, and subject as a random 
effect. An odds ratio > 1 means that patients experienced higher pain relief than the placebo. 
Notes- Subjects rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. For subjects who use rescue 
medication, windowed worst observation carried forward (WOCF) is used. Missing data due to missing intermediate assessments or premature discontinuation is not imputed. 
 
Programming Note- Please complete table for all scheduled time assessments. Only impute using wWOCF for assessments after rescue medication. Do not impute for missing data. 
 
 
 
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Table 14.2.17 
Analysis of Patient Global Evaluation of Study Drug 
ITT Population 
 
 
 
Category/Statistics 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Poor 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Fair 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Good 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Very Good 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Excellent 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
Odds Ratio (vs placebo) [1] 
XX.XX 
XX.XX 
 
95% CI 
(XX.XX,XX.XX) 
XX.XX,XX.XX) 
 
p-value 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
 
 
 
 
Notes- Patient’s global evaluation of study drug is measured on a scale of 0=poor, 1=fair, 2=good, 3=very good, 4=excellent. 
[1] From a proportional odds model treatment group and baseline pain as covariates. An odds ratio > 1 means that patients rated active arm more highly than placebo 
 
 
 
  
 
Page 186 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
1.2. 
Planned Listing Shells 
Listing 16.2.1 
Subject Disposition 
All Subjects 
Date of Last Dose 
Date of Completion/ 
Discontinuation 
 Subject 
Number 
Randomized? 
Patient 
Status 
(Study Day) 
(Study Day) 
Reason for Discontinuation 
Was blind broken? If yes, date and 
reason blind was broken 
XXXXXX 
Yes 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XX 
XXXXXX 
Yes 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XX 
XXXXXX 
Yes 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XX 
XXXXXX
No
DDMMMYYYY (X) 
DDMMMYYYY (X) 
XXXXXXXXXX: XXXXXXXXX
XX
XXXXXX 
No 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XXXXXXXXXXXXXXXXXXXXXX 
XX 
Abbreviation: NA=Not Applicable 
 Notes: Study day is calculated relative to the date of first dose of study drug 
Programming Note: If reason for early termination is other, concatenate the specify text as follows: “Other: XXXXXXXXX”. If additional details about reason for discontinuation are 
present in DSREASSP, then concatenate reason for discontinuation with “DSREASSP”. 
If reason for early termination is lost to follow-up, concatenate with date of last contact as follows: “Lost to follow-up: Lost-to follow-up comment (DSLFCOMT): date of last contact: 
DDMMMYYYY”. Lost to follow up comment DSLFCOMT will only be concatenated when present. 
If reason for discontinuation is a PI decision, concatenate PI decision reason as follows: “PI Decision: XXXXXXXXXXX 
Page 187 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.2.1 
Inclusion/ Exclusion Criteria 
All Subjects 
 
 
Date (Study Day)  
All Inclusion 
Criteria Met? 
Any Exclusion 
Criteria Met? 
Subject Number 
Gender 
Screening 
Informed Consent 
 
 
 
 
 
 
 
 
XXXXXX 
XXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
No 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
No: 02, 09 
No 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
No: 06 
No 
 
 
 
 
 
 
XXXXXX 
XXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
Yes: 06 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
No 
 
 
 
 
 
 
XXXXXX 
XXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
No 
 
 
 
 
 
 
Notes: Study day is calculated relative to the date of first dose of study drug. 
Programming note: If more than 1 inclusion or exclusion criterion number exists, concatenate with a comma. Decode any relevant criteria in the footnotes. 
 
Page 188 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.2.2 
Screen Failures 
 
 
 
Subject 
Number 
Gender 
 
Date of Birth 
Age 
Screen Fail Date 
Screen Fail Reason  
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY 
XX 
DDMMMYYYY 
Inclusion #2 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY 
XX 
DDMMMYYYY 
Inclusion #6 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY 
XX 
DDMMMYYYY 
Inclusion #4, Exclusion #6 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY 
XX 
DDMMMYYYY 
Other: XXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: If more than 1 inclusion or exclusion criterion number exists, concatenate with a comma  
Programming note: If additional details about reason for screen failure are present in, then concatenate reason for screen failure reason with “DSSFOTRN”. 
 
Page 189 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.2.3 
Protocol Deviations 
All Subjects 
 
 
Subject 
Number 
Treatment
Group 
Event Date 
(Study day) 
Event Type 
Violation 
Level 
Description 
 
 
 
 
 
 
XXXXXX 
XXXX 
              XXXX(XXX) 
XXXXXXXXXXX 
MAJOR 
XXXXXXX 
 
 
 
XXXXXXXXXXXXXX 
MINOR 
XXXXXXXXXXXXXXX 
 
 
 
 
 
 
XXXXXX 
XXXX 
XXXX(XXX) 
XXXXXXXXXXXX 
MINOR 
XXXXXXXXXXXXXXXXXXX 
 
 
 
XXXXXXXXXXXXXXXX 
MINOR 
XXXXXXXXXXX 
 
 
 
 
 
 
XXXXXX 
XXXX 
XXXX(XXX) 
XXXXXXXXXXXX 
MAJOR 
XXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
Notes: Study day is calculated relative to the date of first dose of study drug. 
 
Page 190 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.3 
Analysis Populations 
All Subjects 
 
 Subject 
Number 
Treatment 
Group 
SAF 
 
PP 
 
ITT 
 
Primary Reason(s) for Exclusion 
 
 
 
 
 
 
XXXXXX 
XXX 
Yes 
No 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX. 
 
 
 
 
 
 
XXXXXX 
XXX 
Yes 
Yes 
 
 
 
 
 
 
 
 
XXXXXX 
XXXX 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: PP = Per Protocol Population; SAF= Safety Population; ITT= Intent-to-treat population 
 
 
Page 191 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.4.1 
Demographics and Baseline Characteristics 
Safety Population 
 
 
 
 
 
Age 
 
 
Weight 
Height 
BMI 
Duration of 
Surgery 
 Subject 
Number 
Gender 
If Female, 
is she of 
childbearing 
potential? 
 
Treatment 
Group 
(years) 
Ethnicity 
Race 
(kg) 
(cm) 
(kg/m2) 
 
 
 
(hours) 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: BMI = Body mass index  
Notes: Height, weight, and BMI are the values at Screening. 
  
 
Page 192 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.4.2 
Medical History 
Safety Population 
 
Subject 
Number 
 
Treatment 
Group 
Any Medical  
History 
SOC/PT/VT     
Start date(Study Day) / 
End Date( Study Day) 
Ongoing? 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
SOC = System Organ Class; PT = Preferred Term; VT = Verbatim Term. 
Notes: All medical history terms were coded using MedDRA dictionary version 21.1. Study day is calculated relative to the date of first dose of study drug 
 
 
Page 193 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.4.3 
Listing of Subject Randomization 
All Randomized Subjects 
 
Subject 
Number 
Randomization Date 
Randomization Time   
Randomization Number 
Kit Number Assigned 
Randomized Arm 
XXX 
DDMMMYYYY 
hh:mm       
XXX 
XXX 
XX 
XXX 
DDMMMYYYY 
hh:mm    
XXX 
XXX 
XX 
XXX 
DDMMMYYYY 
hh:mm          
XXX 
XXX 
XX 
XXX 
DDMMMYYYY 
hh:mm        
XXX 
XXX 
XX 
XXX 
DDMMMYYYY 
hh:mm         
XXX 
XXX 
XX 
 
 
Page 194 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.4.4 
Study Drug Administration 
Safety Population 
Subject 
Number 
Treatment 
Group 
Timepoint 
Was Study Drug 
Administered?   
Reason Not Administered 
Date of Administration 
Time of Administration 
XXX 
XXX 
0 hours 
Yes/no       
XXXXXXXXXXXXX 
DDMMMYYYY 
hh:mm    
XXX 
XXX 
8 hours 
Yes/no       
XXXXXXXXXXXXX 
DDMMMYYYY 
hh:mm    
XXX 
XXX 
12 hours 
Yes/no       
XXXXXXXXXXXXX 
DDMMMYYYY 
hh:mm    
XXX 
XXX 
16 hours 
Yes/no       
XXXXXXXXXXXXX 
DDMMMYYYY 
hh:mm    
 
 
 
 
 
 
 
 
 
 
 
 
Page 195 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
 
Listing 16.2.7.1 
Adverse Events 
Safety Population 
 
Subject 
Number 
Gender 
Treatment 
Group 
 
 
Any AEs 
reported? 
TEAE? 
SOC/PT/VT     
Start date 
time(Study Day) / 
End Date 
time(Study Day)  
Severity/ 
Relationship   
Medical  
Treatment 
Received? 
Outcome/ 
Action Taken   
Serious?   
XXX 
XXX 
XX 
XX 
NO 
XXXX/XXX/XXX    
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
No 
XXX 
XXX 
XX 
XX 
YES 
XXXX/XXX/XXX    
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
YES 
XXX 
XXX 
XX 
XX 
NO 
XXXX/XXX/XXX    
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
No 
XXX 
XXX 
XX 
XX 
YES 
XXXX/XXX/XXX    
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
No 
XXX 
XXX 
XX 
XX 
YES 
XXXX/XXX/XXX    
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
YES 
XXX 
XXX 
XX 
XX 
NO 
XXXX/XXX/XXX    
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
NO 
Abbreviation: TEAE-Treatment Emergent Adverse Event, SOC = System Organ Class; PT = Preferred Term; VT = Verbatim Term. 
Notes: AEs were coded using MedDRA dictionary version 21.1. TEAE is defined as any event that started or worsened in intensity or relationship to treatment on or after the first dose 
of study drug. Study day is calculated relative to the date of first dose of study drug. 
Programming note= Fatal/hospitalization/life threatening/persistent/congenital/important medical event can be concatenated to SAE when SAE=Y. Concatenate an abbreviated version 
of the term. Example – For Fatal use F etc. Add term to list of abbreviations if such abbreviation is used.  
 
Page 196 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.7.2 
Serious Adverse Events  
Safety Population 
 
(Same shell as Listing 16.2.7.1) 
 
 
Listing 16.2.7.3 
Treatment emergent Adverse Events Related to Study Drug 
Safety Population 
 
(Same shell as Listing 16.2.7.1) 
 
 
Page 197 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.7.4 
Deaths  
Safety Population 
 
Subject 
Number 
 
 
 
Gender 
 
 
 
Treatment 
Group 
Date of 
Death(Study Day) 
Cause of Death 
(Specify if Other) 
001-003 
 
 
DDMMMYYYY(XX) 
XXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes-Study day is calculated relative to the date of first dose of study drug. 
 
Page 198 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
 
Listing 16.2.8.1 
Clinical Laboratory Data: Serum Chemistry 
Safety Population 
 
Subject 
Number 
Gender 
Treatment 
Group 
Was 
Sample 
Collected? 
Date/Time of 
Assessment  
 
Test Name 
Standard 
Results 
Units 
Abnormal? / 
If Yes, H or 
L 
Comments/Reason 
not Done 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
NO 
 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
NO 
 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
YES/ 
NO 
 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
YES/ 
YES 
 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
NO 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: H=High, L=Low 
Notes: Study day is calculated relative to the date of first dose of study drug. 
 
Page 199 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.8.2 
Clinical Laboratory Data: Hematology 
Safety Population 
 
(Same shell as Listing 16.2.8.1) 
 
 
Listing 16.2.8.3 
Clinical Laboratory Data: Urine 
Safety Population 
 
(Same shell as Listing 16.2.8.1) 
 
Listing 16.2.8.4 
Clinical Laboratory Data: Coagulation 
Safety Population 
 
(Same shell as Listing 16.2.8.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.8.5 
Serum and Urine Pregnancy Test  
Safety Population 
 
Subject 
Number 
 
 
 
Treatment 
Group 
 
 
 
Visit 
 
 
 
Was 
Sample  
Collected? 
 
 
 
 
Reason not 
collected  
Date of Assessment  
 
Time of 
Assessment 
Serum or Urine Test ? 
 
Result of 
Pregnancy 
Test 
001-
003 
 
 
 
 
DDMMMYYYY 
 
XXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 200 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.9.1 
Prior and Concomitant Medications 
Safety Population 
 
Subject 
Number 
 
Treatment 
Group 
Prior, Concomitant 
or Both? 
ATC Class (Level 4)/ 
/PT /VT     
Start date time (Study 
Day)/ 
End date time(Study 
Day)  
 
Dose 
Unit   
Frequency    
 
Route 
Ongoing ? 
XXX 
 
XX 
Prior 
XXXX/XXX/XXX       
DDMMMYYYY(XX) / 
DDMMMYYYY(XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
Both 
XXXX/XXX/XXX       
DDMMMYYYY(XX)  / 
DDMMMYYYY (XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
Concomitant 
XXXX/XXX/XXX       
DDMMMYYYY(XX)  / 
DDMMMYYYY(XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
 
XXXX/XXX/XXX       
DDMMMYYYY(XX)  / 
DDMMMYYYY (XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
 
XXXX/XXX/XXX       
DDMMMYYYY (XX) / 
DDMMMYYYY(XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
 
XXXX/XXX/XXX       
DDMMMYYYY(XX)  / 
DDMMMYYYY (XX) 
 
XXX 
XXX 
 
 
ATC = Anatomic Therapeutic Chemical; PT = Preferred Term; VT = Verbatim Term. 
Notes: Study day is calculated relative to the date of first dose of study drug.. Medications are coded using WHO-DD B2E version March 2020.  . Medications that started prior to the 
first dose of study drug will be considered prior medications whether or not they were stopped prior to the first dose of study drug. Any medications continuing or starting post the first 
dose of study drug will be considered to be concomitant. If a medication starts prior to the first dose and continues after the first dose of study drug, it will be considered both prior and 
concomitant. 
 
 
 
 
Page 201 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.9.1.1 
Rescue Medications 
Safety Population 
 
Subject 
Number 
 
Treatment 
Group 
Were 
any 
rescue 
medicati
ons 
reported
? 
Medicati
on  
Date time for 
pain 
relief/pain 
intensity 
(Study Day) 
NRS Pain 
intensity 
assessment 
Pain Relief 
Assessment 
ATC Class 
(Level 4)/ 
/PT /VT     
Start date 
time (Study 
Day) / End 
date 
time(Study 
Day) 
Dose 
Unit   
Frequency    
 
Route 
 
 
Ongoing ? 
XXX 
 
XX 
XX 
 
XXXX (XX) / 
XXXX(XX) 
 
 
XXXX/XXX/
XXX       
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
 
 
XXX 
 
 
XX 
 
XXXX (XX) / 
XXXX(XX) 
 
 
XXXX/XXX/
XXX       
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
 
 
XXX 
 
 
XX 
 
XXXX (XX) / 
XXXX(XX) 
 
 
XXXX/XXX/
XXX       
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
 
 
XXX 
 
 
 
 
XXXX (XX) / 
XXXX(XX) 
 
 
XXXX/XXX/
XXX       
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
 
 
XXX 
 
 
 
 
XXXX (XX) / 
XXXX(XX) 
 
 
XXXX/XXX/
XXX       
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
 
 
XXX 
 
 
 
 
XXXX (XX) / 
XXXX(XX) 
 
 
XXXX/XXX/
XXX       
XXXX (XX) / 
XXXX(XX) 
XXX 
XXX 
 
 
Abbreviations: ATC = Anatomic Therapeutic Chemical; PT = Preferred Term; VT = Verbatim Term. 
Notes: Study day is calculated relative to the date of first dose of study drug.. Medications are coded using WHO-DD B2E version March 2020.  Pain assessments will be conducted 
immediately before each dose of rescue medication. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever and 
rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. 
 
 
Page 202 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.9.2 
Vital Signs Measurements 
Safety Population 
 
Subject 
Number 
 
Treatment Group 
Visit 
Timepoint  
Were Vital 
Signs 
Collected? 
Collection 
Date/Time 
(Study Day) 
Temperature 
(Units) 
Heart Rate (Units) 
Respiration Rate 
(Units) 
Systolic Blood Pressure 
(Units)   
Diastolic Blood 
Pressure (Units)   
XXX 
 
XXX      
XXX      
XXX      
XXX      
XXX      
XXX      
XXX      
XXX      
XXX 
XXX 
XXX 
 
XXX      
XXX      
XXX      
XXX      
XXX      
XXX      
XXX      
XXX      
XXX 
XXX 
XXX 
 
XXX       
XXX       
XXX       
XXX       
XXX       
XXX       
XXX       
XXX       
XXX 
XXX 
XXX 
 
XXX     
XXX     
XXX     
XXX     
XXX     
XXX     
XXX     
XXX     
XXX 
XXX 
XXX 
 
XXX   
XXX   
XXX   
XXX   
XXX   
XXX   
XXX   
XXX   
XXX 
XXX 
XXX 
 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
Notes: Study day is calculated relative to the date of first dose of study drug. 
 
Page 203 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.9.2.1 
Physical Examination Findings 
Safety Population 
 
Subject 
Number 
 
Treatment 
Group 
Was Exam  
Performed? 
Visit 
Date/Time of 
Assessment (Study 
Day) 
 
Body 
System 
Standard 
Results 
If 
Abnormal, 
CS ? 
 
Abnormal 
findings 
descriptio
n 
Were mouth and 
neck examined? 
 
If no, 
reason 
Any CS abnormal 
findings that have 
been newly 
diagnosed or 
have worsened 
since the previous 
assessment? 
XXX 
 
XX 
Yes 
XX 
DDMMMYYYYThh:m
m(XX) 
 
XX 
 
 
Yes 
XX 
Yes 
XXX 
 
XX 
No 
XX 
DDMMMYYYYThh:m
m (XX) 
 
XX 
 
 
No 
XX 
No 
XXX 
 
XX 
Yes 
XX 
DDMMMYYYYThh:m
m(XX) 
 
XX 
YES 
 
 
Yes 
XX 
Yes 
XXX 
 
XX 
No 
XX 
DDMMMYYYYThh:m
m(XX) 
 
XX 
 
 
No 
XX 
No 
XXX 
 
XX 
No 
XX 
DDMMMYYYYThh:m
m(XX) 
 
XX 
 
 
No 
XX 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: CS: Clinically Significant 
Notes: Study day is calculated relative to the date of first dose of study drug. 
Programming note: In the 'If Abnormal, CS ?' column, 'Yes' will only be populated when we the abnormal value is CS. 
 
Page 204 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.9.3 
12-Lead Electrocardiogram Measurements 
Safety Population  
 
 
Abbreviation: CS=Clinically Significant, NCS=Not Clinically Significant 
 
Notes: Study day is calculated relative to the date of first dose of study drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
Number 
 
 
 
Treatment 
Group 
 
Was ECG 
Performed? 
Date of Assessment 
(Study Day)  
 
Time of 
Assessment 
Heart Rate 
(Unit) 
RR Interval 
(Unit) 
PR Interval 
(Units) 
QRS (Unit) 
QT (Unit) 
QTc 
Interval 
(Unit) 
Investigator 
Interpretation 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX 
 
XXX 
XXX 
DDMMMYYYY(XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX 
 
XXX 
XXX 
DDMMMYYYY (XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Abnormal-
NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX 
 
XXX 
XXX 
DDMMMYYYY (XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Abnormal-
CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX 
 
XXX 
XXX 
DDMMMYYYY(XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 205 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.9.3.1 
Alcohol Breathalyzer Test 
Safety Population 
 
 
Subject 
Number 
 
 
Treatment 
 
 
Was Alcohol 
Breathalyzer Test 
performed? 
 
Test Date/Time 
(Study Day) 
 
 
Alcohol 
Breathalyzer Test 
Result  
 
XXXX 
XX 
Yes 
DDMMMYYYYThh:mm(XX) 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Study day is calculated relative to the date of first dose of study drug. 
Page 206 of 351


 
Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
 
Listing 16.2.9.4 
NRS Pain Intensity Assessment 
Safety Population 
 
 
Subject 
Number 
 
 
 
Treatment 
Group 
 
 
Was NRS 
Pain 
Assessment 
collected? 
 
 
Reason not 
collected  
 
 
Timepoint  
Was Rescue 
Medication 
Taken? 
(Y/N) 
Date time post 
dose 
 
NRS Pain 
Intensity Score 
 
NRS Pain 
Intensity Score 
when rescue 
medication was 
taken  
Responder 
(Y/N) 
XXXX 
 
XX 
Yes 
XXXXXXXX 
XXX 
 
XXXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes- Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever. A subject with ≥ 30% improvement in NRS pain 
intensity from T0 (predose) without rescue medication during the first 8 hours is considered a responder. 
 
Programing Note- For those cases where “Was rescue medication taken?” is ‘Yes’, the datetime needs to be presented in the “Date time post dose” column.  
 
 
Page 207 of 351


 
Statistical Analysis Plan  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
 
 
 
 
Listing 16.2.9.5 
Pain Relief Scores 
Safety Population 
 
 
Subject 
Number 
 
 
Treatment 
Group 
 
 
Was 
assessment 
completed? 
 
 
Reason not 
collected  
 
 
 
Date of 
Assessment 
 
 
 
Date time 
pain relief 
collected 
 
 
Timepoint  
Was Rescue 
Medication 
Taken? 
(Y/N) 
Date time 
post dose 
 
How much 
relief have you 
had since your 
starting pain? 
How much 
pain relief 
have you 
had since 
your starting 
pain when 
rescue 
medication 
was taken? 
XXXX 
XX 
Yes 
XXXXXXXX 
 
 
XXX 
 
XXXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                Notes: Subjects rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. 
 
Programing Note- For those cases where “Was rescue medication taken?”  is ‘Yes’, the datetime needs to be presented in the “Date time post dose” column                 
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Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.6 
Time to Pain Relief (Stopwatches) 
Safety Population 
Subject 
Number 
Treatment 
Group 
Which stopwatch 
pressed, perceptible or 
meaningful 
Hours on 
Stopwatch 
Minutes on 
stopwatch 
Seconds on 
stopwatch 
XXXX 
XX 
Perceptible/meaningful 
XX 
XXX 
XXX 
Notes: Perceptible pain relief stopwatch refers to the first stop watch and meaningful pain relief, the second stopwatch.
Page 209 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Listing 16.2.9.7 
Subjects Global Evaluation of Study Drug 
Safety Population 
Subject 
Number 
Treatment 
Group 
Was Subject 
Global 
Evaluation of 
study drug 
completed 
Date/Time of 
evaluation 
Global evaluation 
score 
XXXX 
XX 
XXXX 
XX 
    Notes: Patient’s global evaluation of study drug is measured on a scale of 0=poor, 1=fair, 2=good, 3=very good, 4=excellent 
Page 210 of 351


Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Figure 14.4.1.1 
Kaplan-Meier plot of time to first perceptible pain relief 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing first perceptible pain relief 
Figure 14.4.1.2 
Kaplan-Meier plot of time to Meaningful Pain Relief 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing meaningful pain relief 
Figure 14.4.1.3 
Kaplan-Meier plot of time to onset of analgesia 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing analgesia 
Figure 14.4.1.4 
Kaplan-Meier plot of time to peak pain relief 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing peak pain relief 
Figure 14.4.1.5 
Kaplan-Meier plot of time to first use of rescue medication 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients using rescue medication 
Figure 14.4.1.6 
Mean PID Scores versus Time 
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Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
ITT Population 
x-axis Time (hours) 
y-axis- Mean PID score 
Present with error bars of +/- 1 standard error. 
Add footnote: For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing data due to missing intermediate assessments or 
premature discontinuation is not imputed. 
Figure 14.4.1.7 
Mean Pain Relief Scores versus Time 
ITT Population 
x-axis Time (hours) 
y-axis- Mean pain relief score 
Present with error bars of +/- 1 standard error. 
Add footnote: For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. Missing data due to missing intermediate assessments or 
premature discontinuation is not imputed. 
Page 212 of 351


I
Statistical Analysis Plan,
Sponsor Reckitt Benckiser
Protocol Number 5003601
PCN Number RECK.177035
trremler
I 
."qlrg* 
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t:"*i .l, ll". i. :' i : . ;
Sponsor
Reckitt Benckiser
Protocol Title:
A Randomized, Double-Blind, Double-Duffiffiy, Parallel-Group,
Multiple-Dose, Active and Placebo-Controlled Efficacy Study of
Ibuprofen Prolonged-Release Tablets for the Treatment of Pain
after Surgical Removal of Impacted Third Molars
Protocol Number:
s003601
Premier Research PCN:
RECK.177035
Document Version:
Amendment 1.0
Document Date:
24-Feb-2020
Approvals
Biostatistician
Premier Research
Print Name: Raghu Vishnubhotla
Sign Name:
Reckitt Benckiser
Representative
Print Name: Darren Targett
2.5 e+A LoZo,
SignName'[{%t}r
Version 1.0
Page 1 of39
25-Feb-2020 | 10:23:40 EST
Page 213 of 351


 
Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
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Document History 
Reasons for Amendment 1 
 
 The statistical analysis plan was amended in the following ways: 
 
1. The sensitivity analyses for the primary efficacy endpoint has been updated. A pattern-
mixture model with control-based pattern imputation will now be used.  
2. A comparison of individual NRS pain intensity difference scores has been added. P-
values comparing the treatment arms (PR vs Placebo, IR vs Placebo) has been added. 
3. Pain relief scores at each time point will be summarized and by p-values will be added 
for treatment comparison.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table of Contents 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
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Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 2 
List of Tables .................................................................................................................................. 5 
1. 
Overview ............................................................................................................................. 6 
2. 
Study Objectives and Endpoints ......................................................................................... 6 
2.1. 
Study Objectives ........................................................................................................... 6 
2.1.1. Primary Objective ......................................................................................................... 6 
2.1.2. Secondary Objectives.................................................................................................... 6 
2.2. 
Study Endpoints ............................................................................................................ 7 
2.2.1. Safety Endpoints ........................................................................................................... 7 
2.2.2. Efficacy Endpoints ........................................................................................................ 7 
3. 
Overall Study Design and Plan ........................................................................................... 8 
3.1. 
Overall Design .............................................................................................................. 8 
3.2. 
Sample Size and Power ................................................................................................. 8 
3.3. 
Study Population ........................................................................................................... 8 
3.4. 
Treatments Administered .............................................................................................. 8 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................... 8 
3.6. 
Blinding and Unblinding............................................................................................... 8 
3.7. 
Schedule of Events ...................................................................................................... 10 
4. 
Statistical Analysis and Reporting .................................................................................... 13 
4.1. 
Introduction ................................................................................................................. 13 
4.2. 
Interim Analysis .......................................................................................................... 13 
5. 
Analysis Populations ......................................................................................................... 13 
6. 
General Issues for Statistical Analysis .............................................................................. 14 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 14 
6.1.1. Baseline ....................................................................................................................... 14 
6.1.2. Adjustments for Covariates......................................................................................... 14 
6.1.3. Multiple Comparisons ................................................................................................. 14 
6.1.4. Handling of Dropouts or Missing Data ....................................................................... 14 
6.1.5. Adjustment of Pain Scores for Rescue Medication Use ............................................. 15 
6.1.6. Sensitivity Analysis of SPID12 .................................................................................. 15 
6.1.7. Derived Variables ....................................................................................................... 17 
6.1.8. Data Adjustments/Handling/Conventions .................................................................. 20 
7. 
Study Patients/Subjects and Demographics ...................................................................... 21 
7.1. 
Disposition of Patients/Subjects and Withdrawals ..................................................... 21 
7.2. 
Protocol Violations and Deviations ............................................................................ 21 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 21 
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7.4. 
Exposure and Compliance .......................................................................................... 22 
8. 
Efficacy Analysis .............................................................................................................. 22 
8.1. 
Primary Efficacy Analysis .......................................................................................... 22 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 22 
8.2.1. SPID ............................................................................................................................ 22 
8.2.2. TOTPAR ..................................................................................................................... 23 
8.2.3. SPRID ......................................................................................................................... 23 
8.2.4. Peak Pain Relief .......................................................................................................... 23 
8.2.5. Time to First Perceptible Pain Relief .......................................................................... 24 
8.2.6. Time to Meaningful Pain Relief ................................................................................. 24 
8.2.7. Time to onset of Analgesia ......................................................................................... 24 
8.2.8. Time to Peak Pain Relief ............................................................................................ 25 
8.2.9. Time to first use of Rescue Medication ...................................................................... 25 
8.2.10. Proportion of Responders ........................................................................................... 25 
8.2.11. Numeric rating scale (NRS) pain intensity difference (PID) ...................................... 25 
8.2.12. Pain relief at each scheduled time point ..................................................................... 26 
8.2.13. Proportion of Subjects Rescue Medication ................................................................. 26 
8.3. 
Exploratory Efficacy Analysis .................................................................................... 26 
8.3.1. Global Evaluation of Study Drug ............................................................................... 26 
9. 
Safety and Tolerability Analysis ....................................................................................... 27 
9.1. 
Adverse Events ........................................................................................................... 27 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 27 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 28 
9.2. 
Clinical Safety Laboratory Data ................................................................................. 28 
9.3. 
Vital Signs ................................................................................................................... 28 
9.4. 
Concomitant Medication ............................................................................................. 28 
10. 
Changes to analysis planned in the protocol ..................................................................... 28 
11. 
References ......................................................................................................................... 29 
12. 
Tables, Listings, and Figures ............................................................................................ 29 
12.1. Planned Table Descriptions ........................................................................................ 30 
12.2. Efficacy Data .............................................................................................................. 30 
12.3. Safety Data .................................................................................................................. 32 
12.4. Planned Listing Descriptions ...................................................................................... 33 
12.5. Planned Figure Descriptions ....................................................................................... 34 
Appendix 1: Premier Research Library of Abbreviations ............................................................ 35 
 
 
 
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Version 1.0     
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List of Tables 
Table 1: Schedule of Events ......................................................................................................... 11 
Table 2: Planned Assessment Times............................................................................................. 17 
Table 3: Demographic Data Summary Tables .............................................................................. 30 
Table 4: Efficacy Tables ............................................................................................................... 30 
Table 5: Safety Tables .................................................................................................................. 32 
Table 6: Planned Listings.............................................................................................................. 33 
Table 7: Planned Figures .............................................................................................................. 34 
 
 
 
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Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
 Page 6 of 39 
 
 
1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Reckitt 
Benckiser protocol number 5003601 (A Randomized, Double-Blind, Double-Dummy, Parallel-
Group, Multiple-Dose, Active and Placebo-Controlled Efficacy Study of Ibuprofen Prolonged-
Release Tablets for the Treatment of Pain after Surgical Removal of Impacted Third Molars), 
dated 19-Nov-2019, version 3.0. Reference materials for this statistical plan include the protocol 
and the accompanying sample data collection documents. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials1. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to Reckitt Benckiser’s study 
5003601. 
2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is: 
• To evaluate the superiority of 2 x 300 mg ibuprofen PR tablets compared with placebo in 
subjects experiencing acute moderate to severe pain after third molar extraction over 12 
hours post initial dose. 
2.1.2. Secondary Objectives 
The key secondary objectives are: 
• To evaluate the analgesic performance of a total daily dose of 1200 mg of ibuprofen PR 
formulation compared to ibuprofen immediate release (IR) formulation over 24 hours 
post initial dose. 
• To evaluate the safety and tolerability of 2 x 300 mg ibuprofen PR tablets. 
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Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
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Version 1.0     
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Additional secondary objectives include: 
• To evaluate the total analgesic effect, peak analgesic effect, onset and duration of action 
and the subject’s overall assessment of the study medications. 
2.2. 
Study Endpoints 
2.2.1. Safety Endpoints 
The safety endpoints of this study include the following: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of changes in vital sign measurements 
2.2.2. Efficacy Endpoints 
2.2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the summed pain intensity difference (SPID) over 
0 to 12 hours (SPID12).  
2.2.2.2. 
Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints of this study include the following:  
• Summed pain intensity difference (SPID) over 0 to 24 hours (SPID24) after Time 0. 
• SPID4, SPID8 and SPID12  
• Sum of total pain relief (TOTPAR) over 0 to 4 hours (TOTPAR4), over 0 to 8 hours 
(TOTPAR8), over 0 to 12 hours (TOTPAR12) and over 0 to 24 hours (TOTPAR24) after 
Time 0. 
• Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over 
0 to 4 hours (SPRID4), over 0 to 8 hours (SPRID8), over 0 to 12 hours (SPRID12) and 
over 0 to 24 hours (SPRID24) after Time 0. 
• Response to study drug 
• Numeric rating scale (NRS) pain intensity difference (PID) at each scheduled timepoint 
after Time 0. NRS ranges from 0=no pain to 10=worst pain ever and pain relief is a 5 
point categorical scale 0=none, 1=a little, 2=some, 3=a lot, 4=complete. PID is the 
difference in NRS pain intensity between each time point and Time 0. 
• Pain intensity score at each scheduled time point after Time 0. 
• Peak pain relief 
• Time to onset of analgesia 
• Time to first perceptible pain relief 
• Time to peak pain relief 
• Proportion of subjects using rescue medication 
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• Time to first use of rescue medication 
2.2.2.3. 
Exploratory Endpoint 
• Patient’s global evaluation of study drug. It is measured on a scale of 0=poor, 1=fair, 
2=good, 3=very good, 4=excellent 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
3.2. 
Sample Size and Power 
The sample size determination is based on the primary efficacy variable, SPID12.  According to 
Farrar 2001, a clinically important improvement in pain is represented by a 2 point reduction on 
an 11-point NRS.  Based on a baseline pain score of 7 this corresponds to an approximate 30% 
reduction in pain.  An average 2 point difference in pain scores between ibuprofen PR and 
placebo across all 14 assessments up to 12 hours will correspond to a difference in SPID12 of 24 
points.  In a previous study, the pooled standard deviation (SD) for SPID12 was 31.65.  
Assuming the same variability in this study, a sample size of 40 subjects per group will have 
>90% power to detect a difference of 24 points in SPID12, between ibuprofen 2x300-mg PR 
tablets and placebo using a 2-sided test with an alpha level of 0.05.  In order to provide a robust 
estimate of treatment effect differences between PR and IR, and to obtain a more precise 
estimate for this comparison, a 3:3:1 allocation ratio will be used, so that 120 subjects are 
randomized into each of the PR and IR groups.  Thus 280 subjects will be enrolled in the study. 
3.3. 
Study Population 
Subjects with moderate to severe pain after extraction of 2 or more third molars will participate 
in this study. 
3.4. 
Treatments Administered 
Treatment A (test product): 2x300 mg ibuprofen PR tablets, BID (total daily dose 1200 mg) 
Treatment B (reference product): 2x200 mg ibuprofen IR tablets, TID (total daily dose 1200 mg) 
Treatment C: matching placebo tablets 
3.5. 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be randomized in a 3:3:1 ratio to receive 2x300 mg ibuprofen PR tablets 
Q12h, 2x200 mg ibuprofen IR Q8h, or placebo using permuted blocks of fixed size.  The 
randomization will be stratified by baseline pain category (moderate or severe) using a 
categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and severe 
(8-10).  The randomization schedule will be prepared by a statistician not otherwise involved in 
the study.  Randomization will be performed using an interactive response system (IRT).   
3.6. 
Blinding and Unblinding 
This is a double-blind, double-dummy study. There will be two placebo tablets designed to be 
comparable to each of the active products (PR and IR) in both shape, size, color and weight. 
All subjects will receive 4 tablets at each dosing timepoint.  All subject packs will be designed 
and labelled to ensure blinding is maintained. 
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Access to the unblinding codes will be restricted to personnel not otherwise involved in the study 
and will be available to the investigator only in the case of a subject requiring unblinding prior to 
database lock.  
Unblinding will only occur after database lock or in the case of emergency unblinding. 
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Version 1.0     
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3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1. 
 
 
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Table 1: Schedule of Events 
 
 
 
 
Page 223 of 351
I 
Sc,reening 
(Day -28 to 
Day -1) 
Pre-
Surgery 
Pre-
dose 
Written informed consent 
X 
Assign a screening number 
X 
In clu siontexclus ion criteria 
X 
X 
Demographics 
X 
Medical llistory 
X 
Xb 
Physical examination° 
X 
Vital signsd 
X 
X 
X 
Height, weighl and BMI 
X 
Clinical laboratory tests (hematology, 
X 
chemistry, urinalysis) 
Electrocardiogram 
X 
Pregnancy test for female subjects of 
X 
X 
childbearing potentiale 
Urine drug screen 
X 
X 
Alcohol breatllalyzer test 
X 
Oral radiography1 
X 
Review study restrictions with subject 
X 
Pain intensity (NRS)9' 
X 
Randomisation 
X 
Dosing with study drug 
Stopwatch assessment" 
Pain relief (5-point categoriic.al scale)g 
Surgery (Day 1) 
Post-op 
1, 1.5, 2, 3, 4, 
15, 30, 
5, 6, 7, 8, 
0 1!1 
45min 
10 h 
12 1!1 
X 
X 
X 
X 
Oh 
8h 
12 h 
X 
X 
X 
X 
Day2 
16 
Ill 
24h 
X 
X 
X 
16h 
X 
premier' 
research} 
Follow-up 
(Day 8 ±2 days) or 
ETk 
X 
X 


 
Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
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Version 1.0     
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Page 224 of 351
I 
Sc,reening 
(Day -28 to 
Day -1) 
Pre-
Surge1ry 
Pre-
dose 
Global evaluation of study drug; 
Concomitant medications 
Xb 
X 
Adverse eventsi 
X 
X 
Dispense/prescribe pain medication for use at 
home, as needed 
Collect unused home pain medications, as 
needed 
Discharge from study site 
Surgery (Day 1) 
Post-op 
1, 1.5, 2, 3, 4, 
15, 30, 
5, 6, 7, 8, 
Oh 
45 min 
10 h 
X 
X 
X 
X 
X 
X 
12 h 
X 
X 
Day 2 
16 
premier' 
research} 
Follow-up 
(Day 8 ±2 days) or 
ETk 
h 
24h 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BMl=body mass index: ET=-early termination: h=hour, min=minute; NRS=numeiric rating scale; pre-op=pre-operative; post-op=post-operative _ 
a Times listed are relative to dosing wilh study drug. 
b Medical history and concomitant medication use since Screening will be updated on Day 1 before surgery 
c A complete physical examination (excluding the geniitourinary examination) will be performed at Screening. An abbreviated confirmatory physical assessment, 
including an exam ination of tile subject's mouth and neck, will be performed at tile Follow-up Visit (or Early Term ination Visit). 
d Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at tile following times: at screening, before surgery, within 30 minutes 
before Tiime 0, ·12 ti ours after Time 0_, 24 hours after Time O, and/or immediately before the first dose of rescue medication, and at tile Follow-up Visit (or Early 
Termination Visit). 
e Serum pregnancy test at Screening and urine pregnancy test before surgery on Day 1 (female subjects of childbearing potential only). Test results must be 
negative for the subject to continue in the study. 
f 
Oral radiographs taken within 1 year before Screening will be acceptable and do not need to be repeated. 
g Pain assessments will be conducted (pre-dose, if at one of tile dosing timepoints of O, 8, 12 or 16 hours) at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 
8, 10, 12, 16 and 24 llours after Time o and immediately before each dose of rescue medication. Pain intensity will also be assessed pre-dose. At each 
assessment time point, the pain intensity assessment will be completed first and the pain relief assessment will be completed second. Subjects will not be 
able to compare their responses with lheir previous responses. Note for assessments less than 1 hour apart a window of +/-2 min is allowable wll ilst for 
assessments at least 1 llour apart a +l-5 min window is allowable. 
h Two stopwatches will be started immediately after the subject has swallowed the first dose of study drng with 8 ounces of water {Time O). Subjects will record 
the time to perceptible and meaningful pain relief, respectively, by stopping the stopwatches. 


Statistical   Analysis Plan,  
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Protocol Number 5003601  
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Version 1.0    
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4.
Statistical Analysis and Reporting
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population in each of the treatment arms, unless otherwise specified. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests. In addition to what is detailed in the SAP, other additional 
analyses may be conducted on the data which will only serve as exploratory evidence and the 
unplanned nature of these analyses will be made clear in the Clinical Study Report. 
4.2. 
Interim Analysis 
No interim analyses are planned. 
5.
Analysis Populations
The following analysis populations are planned for this study: 
•
Safety Population (SAF): The Safety Population includes all subjects who receive any
amount of planned study medication. Subjects will be assigned to treatment received.
•
Intent-To-Treat Population (ITT): The ITT population includes all subjects who are
treated with study drug and who have at least 1 pain assessment after Time 0.  The ITT
population is the primary population for the efficacy analysis. Subjects will be assigned
to treatment randomized.
•
Per Protocol (PP): The PP Population will consist of all ITT subjects who do not incur a
major protocol violation that would challenge the validity of their data.  This population
will be determined at a data review meeting prior to database lock and used to evaluate
the sensitivity of the primary efficacy analysis. Subjects will be assigned to treatment
received.
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6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last observation recorded prior to the first dose of study drug will be used as the baseline 
observation for all calculations of change from baseline.  
6.1.2. Adjustments for Covariates 
For the primary endpoint analysis, the baseline NRS pain score will be included as a covariate. 
For the secondary endpoint analyses, baseline pain will be included as a covariate for SPID, 
SPRID, and TOTPAR variables.   
For the proportion of subjects who are responders and the proportion of subjects using rescue 
medication, logistic regression models will adjust for baseline pain. 
For time to event endpoints, baseline pain will be included as a stratification factor.  
6.1.3. Multiple Comparisons 
No adjustment for multiplicity is required for the primary efficacy analysis – a single comparison 
of SPID12 for placebo versus SPID12 for ibuprofen PR. 
No adjustments will be made for multiple comparisons for other endpoints. 
6.1.4. Handling of Dropouts or Missing Data 
Missing pain assessments for all efficacy analyses will be handled as follows: 
• Missing pain assessments scheduled before the first observed assessment will be imputed 
with the subject’s worst observed pain assessment. 
• Missing intermediate pain assessments will be replaced by linear interpolation. 
• Missing pain assessments at the end of the observation period due to premature 
discontinuation of pain assessments will be imputed by carrying forward the last 
observation prior to that missing. 
All data for assessments other than pain assessments will be analyzed as collected; missing data 
due to premature termination or any other reason will be left as missing. Since this is a short-
term study and subjects remain at the study site throughout the 24-hour pain assessment period, 
the discontinuation rate and the amount of missing data is expected to be minimal.   
 
A number of sensitivity analyses will be performed in order to evaluate the efficacy under 
various different assumptions regarding missing data and are described in Section 6.1.6  
 
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6.1.5.  Adjustment of Pain Scores for Rescue Medication Use 
Subjects are required to record their pain assessment (NRS and pain relief) immediately prior to 
each dose of rescue medication. The primary analysis will use windowed worst observation carried 
forward (WOCF) methodology for subjects who use rescue medication.  If a subject received 
rescue medication at time x, for any time point within x + 4 hours, the highest pain score from time 
0 up until time x will be used. If the pain score for the windowed observation is higher than the 
worst observed score, it will not be replaced.  The same approach will be used for pain relief scores. 
6.1.6. Sensitivity Analysis of SPID12 
The following sensitivity analyses will also be performed for the primary endpoint SPID12 if any 
pain assessments are missing or if subjects take rescue medication: 
 
1. Missing data and values after rescue medication handled as per the main analysis but 
based on the PP population. 
2. Missing data imputed using WOCF (worst observed pain score at any timepoint, 
including baseline). Values after rescue medication handled as per the main analysis. 
3. Missing data handled as per the main analysis. Pain assessments are used regardless of 
whether rescue medication has been taken, and no adjustment is made for use of rescue 
medication.  In this analysis, the pain assessment recorded at the time of rescue 
medication is disregarded (unless it coincides with a planned pain assessment).  
4. Missing data handled as per the main analysis. All pain assessments recorded after the 
first dose of rescue medication has been taken will be disregarded. WOCF and LOCF 
(Last Observation Carried Forward) imputation methods will then be used to impute the 
disregarded data. 
a. WOCF - The worst (highest) pain assessment (including baseline) until first dose 
of rescue medication will be used to impute all subsequent pain assessments. In 
other words, this method would be treating the subject as if they got no worse 
than their worst observed value prior to rescue medication.  
b. LOCF - In this LOCF analysis, the pain assessment taken immediately prior to/at 
the time of rescue medication will be taken as the last observed score, i.e., this 
method would be treating the subject as if they got no worse than their last 
observed value prior to rescue medication.  
5. Missing data imputed using multiple imputation (methodology described below). Values 
after rescue medication handled as per the main analysis. 
 
For sensitivity analysis 5, a pattern-mixture model with control-based pattern imputation will be 
used. This model assumes that after withdrawal from the study, subjects from the experimental 
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group (no longer receiving active treatment) will exhibit the same future evolution of pain scores 
as subjects in the placebo group (who are also not exposed to active treatment). Subjects that 
discontinue from the placebo group are assumed to evolve in the same way as placebo subjects 
that remain in the study. This imputation assumes that intermittent missing values are missing at 
random (MAR), and that values that are missing due to withdrawal are missing not at random 
(MNAR). When data are MAR, the missingness of the data does not depend on the missing value 
after conditioning on the observed data (i.e., prior assessments and baseline covariates). Note 
that when the missingness of the data depends on the values of the missing variables after 
conditioning on the observed data, the data are called “missing not at random” (MNAR).  In 
order to assess the MAR assumption, a placebo-based pattern mixture model (PMM) will be 
utilized following the steps outlined in Ratitch B and O’Kelly, M.J. (2011) for SPID-12. 
 
Briefly, the strategy for implementing this approach is as follows for subjects with 
missing data: 
i. 
Impute all non-monotone (intermittent) missing data using the MCMC method of 
PROC MI.  Note that this imputation will sample data within each treatment 
group.  Note that PIi is the NRS pain intensity at time Ti as mentioned in Section 
6.1.7. SAS pseudo code is provided below. With MCMC option, SAS does 200 
burn-in iterations (default) before each imputation. 
PROC MI DATA=example seed = xxxx NIMPUTE = 20 OUT = outdata1 minimum=0 maximum=10; 
 
by <treatment>; 
 
MCMC chain=multiple impute=monotone; 
 
VAR  <PI0> <PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>; 
RUN; 
 
ii. 
Using the imputed datasets from Step #1 that are now monotone missing (no 
intermittent missing data), a single call to PROC MI (including the MNAR 
statement) will be utilized to impute the monotone missing data.  Additional 
details are provided below. 
a. Within the call to PROC MI, one timepoint is imputed at a time.  The 
order in which pain scores are imputed will be PI0, then PI0.25...,PI12 
b. When imputing at timepoint t, the imputation step will include all placebo 
subjects, but only those from the active arms that have a value missing at 
timepoint t. Subjects with non-missing data that are on active arms will 
not contribute to the estimation for this step. 
c. Repeat the above step for all timepoints t. Thus, the data for timepoint t+1 
uses the data imputed from previous timepoints. 
SAS pseudo code is provided below.  SAS accomplishes this iterative process in one step.  
Note that the treatment level 3 is the placebo treatment group. The MNAR statement 
imputes missing values for scenarios under the MNAR assumption. The MODEL option 
specifies that only observations in which treatment=3 are used to derive the imputation 
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model for the pain score that time point. The minimum and maximum options are used to 
ensure that every pain score imputed ranges from 0-10. 
PROC MI DATA=OUTDATA1 seed = xxxx NIMPUTE = 1 OUT = outdata2 MINIMUM=. 1..1 MAXIMUM=. 10 10…10; 
BY _IMPUTATION_; 
CLASS <treatment>; 
MONOTONE REG (/ details); 
MNAR MODEL (PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>/ modelobs=(<treatment=’3’>)); 
VAR  <PI0> <PI0.25> <PI0.5> <PI0.75><PI1> …..<PI12>; 
RUN; 
 
 
 
iii. 
When all missing PI scores are imputed, SPID12 will be derived as described in 
6.1.7 and analyzed using the ANCOVA models as described in Section 8.1.  
PROC MIANALYZE will be used to combine the parameters from the analyses 
for inference. 
6.1.7. Derived Variables 
At each assessment time point, subjects will complete the pain intensity NRS assessment first 
and the pain relief assessment second. 
Planned assessment time points are as follows: 0 (predose), 15, 30, and 45 minutes, and 1, 1.5, 2, 
3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours after Time 0.  Please see Table 2 below. 
 
Table 2: Planned Assessment Times 
i 
Ti (hours) 
0 
0 (predose) 
1 
0.25 
2 
0.5 
3 
0.75 
4 
1 
5 
1.5 
6 
2 
7 
3 
8 
4 
9 
5 
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10 
6 
11 
7 
12 
8 
13 
10 
14 
12 
15 
16 
16 
24 
 
• SPID-12 = summed pain intensity difference (change from Time 0) under the numeric 
rating scale (NRS)-time curve from 15 min through 12 hours calculated using the linear 
trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of 
study drug. Scheduled time points in Table 2 will be used when actual time is missing. 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷12 = ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑃𝑃𝑃𝑃𝐷𝐷𝑖𝑖
14
𝑖𝑖=1
 
 
Where T0 =0, Ti is the actual time, and PIDi is the PID score at time Ti  
PID is defined as  
 
𝑃𝑃𝑃𝑃𝐷𝐷𝑖𝑖= 𝑃𝑃𝐼𝐼𝑖𝑖−𝑃𝑃𝐼𝐼0 
 
Where PI is the pain intensity as measured by the NRS scale. 
• SPID-x = summed pain intensity difference (change from Time 0) under the numeric rating 
scale (NRS)-time curve from 15 min through x hours calculated using the linear trapezoidal 
rule and the actual time points, where Time 0 is the time of the first dose of study drug. 
Scheduled time points in Table 2 will be used when actual time is missing. X = 4, 8, and 
24. 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥= ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑃𝑃𝑃𝑃𝐷𝐷𝑖𝑖
𝑦𝑦
𝑖𝑖=1
 
 
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For x=4 y=8; x=8 y=12; x=24 y=16. 
• TOTPAR-x = total pain relief under the Pain Relief Scale (0 – 4) from 15 min through x 
hours calculated using the linear trapezoidal rule and actual time points, where Time 0 is 
the time of the first dose of study drug. Scheduled time points in Table 2 will be used when 
actual time is missing.  x = 4, 8, 12, and 24. 
 
 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑅𝑅𝑥𝑥= ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑃𝑃𝑃𝑃𝑅𝑅𝑖𝑖
𝑦𝑦
𝑖𝑖=1
 
For x=4 y=8; x=8 y=12; x=12 y=14; x=24 y=16. PARi is the pain relief score on the Pain Relief 
Scale (0-4) at time Ti  
 
• SPRID-x = summed pain relief (TOTPAR) and intensity difference (SPID) from 15 min 
through x hours calculated using the linear trapezoidal rule and actual time points, where 
Time 0 is the time of the first dose of study drug. Scheduled time points in Table 2 will be 
used when actual time is missing. X = 4, 8, 12, and 24. 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥= 𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥+ 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑅𝑅𝑥𝑥 
 
• Responder: subject with ≥ 30% improvement in NRS pain intensity from T0 (predose) 
without rescue medication during the first 8 hours. If a subject takes rescue medication 
prior to the 8-hour pain assessment or if the 8-hour assessment is not performed they will 
be considered a non-responder. i.e., 
(𝑃𝑃𝐼𝐼0 −𝑃𝑃𝐼𝐼8)
𝑃𝑃𝐼𝐼0
∗100 ≥30 
Where PI0 and PI8 are the predose and 8-hour NRS pain intensity measurements 
respectively. 
• Time to onset of analgesia = If the subject has had meaningful pain relief (i.e., presses both 
stopwatches) then time to onset of analgesia is date/time of perceptible pain relief – 
date/time of the first dose of study drug. If subjects don’t experience both perceptible pain 
relief and meaningful pain relief during the 8-hour interval after Time 0, time to onset to 
analgesia will be right censored at the time of their last pain assessment in the first 8 hours. 
For subjects who take rescue medication prior to onset of analgesia during the 8-hour 
interval after Time 0, time to onset of analgesia will be right censored at the time rescue 
medication was taken. 
• Time to first perceptible pain relief = date/time of the first reported pain relief (any) as 
assessed by the subject (i.e. subject stops the first stopwatch (irrespective of the second 
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stopwatch)) – date/time of the first dose of study drug. If subjects don’t experience 
perceptible pain relief during the 8-hour interval after Time 0, time to first perceptible pain 
relief will be right censored at the time of their last pain assessment in the first 8 hours. If 
the first stopwatch is not stopped but the second stopwatch is stopped, time will be left 
censored at the time that the second stopwatch is stopped. In other words, it is assumed that 
the first stopwatch measurement has already occurred but was missed/not recorded. For 
subjects who take rescue medication prior to first perceptible pain relief during the 8-hour 
interval after Time 0, time to first perceptible pain relief will be right censored at the time 
rescue medication was taken. 
• Time to meaningful pain relief = date/time of the first reported meaningful (subjective) 
pain relief as assessed by the subject (i.e. the subject stops the second stopwatch) – 
date/time of the first dose of study drug. If subjects don’t experience meaningful pain relief 
during the 8-hour interval after Time 0, time to meaningful pain relief will be right censored 
at the time of their last pain assessment in the first 8 hours. If the subject stops the second 
stopwatch but doesn’t stop the first stopwatch or the first stopwatch assessment is missing, 
then time to meaningful pain relief will be right censored at the time of their last pain 
assessment in the first 8 hours. For subjects who take rescue medication prior to achieving 
meaningful pain relief during the 8-hour interval after Time 0, time to meaningful pain 
relief will be right censored at the time rescue medication was taken. 
• Peak pain relief- Pain relief is measured on a scale from 0 (None) to 4 (Complete). If PRi 
is the pain relief measurement at time Ti , peak pain relief PPR is defined as 
 
𝑃𝑃𝑃𝑃𝑃𝑃= max{𝑃𝑃𝑅𝑅1, 𝑃𝑃𝑅𝑅2, 𝑃𝑃𝑅𝑅3, … , 𝑃𝑃𝑅𝑅16} 
 
• Time to first use of rescue medication = date/time to the first dose of rescue medication – 
date/time of the first dose of study drug. If subjects don’t take rescue medication, subjects 
will be right censored at the time of their last pain assessment. 
• Time to peak pain relief = date/time of peak pain relief– date/time of the first dose of study 
drug. Time of peak pain relief is the time Ti when peak pain relief (PPR) first occurs. If no 
pain relief is observed then the time to peak pain relief will be right censored at the time of 
their last pain assessment. 
• Change from baseline = value at current time point – value at baseline.  
• TEAE = TEAE is defined as any event that started or worsened in intensity or relationship 
to treatment on or after the first dose of study drug. 
6.1.8. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
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All P values will be displayed in four decimals and rounded using standard scientific notation (e.g., 
0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as <0.0001. 
Adverse events will be coded using the MedDRA version 21.1 thesaurus. 
A treatment related AE is any AE with a relationship to the study drug with possible, probable or 
certain causality to the study drug as determined by the Investigator. 
If partial dates occur, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if just day is missing then the day assigned is the first day of the month or 
the date of first dose (if in the same month), whichever is later; if just month is missing then the 
month assigned is the month of the first dose, unless that results in a date prior to the first dose in 
which case the month after the first dose is used; and if both month and day are missing then the 
month assigned is the month of the first dose and the day assigned is either the first day of the 
month or the first dose date, whichever is later. 
If partial times occur, the convention is as follows: if the missing time occurs on the day of the 
first dose and both the hour and minute are missing then the time assigned is the time of the first 
dose, otherwise if both the hour and minute are missing and the date is not the date of first dose 
the time assigned is 12:00; if the date is the same as the date of the first dose and only hour is 
missing the hour assigned is 12 or the hour of first dose, whichever is later, and if the date is the 
same as the date of first dose and only the minute is missing the minute assigned is 30 or the 
minute of first dose, whichever is later. Otherwise the hour assigned is 12 if the hour is missing 
and the date is not the same as the date of first dose and the minute assigned is 30 is the the date 
is not the same as the date of first dose. 
These conventions will be applied only to adverse event onset dates and times with the following 
precaution:  if the missing date and time reflect the date and time of onset of an adverse event, 
the modified date and time will be constructed to match the first documented date/time post drug 
administration while preserving the order in which the AE was reported in the CRF. 
7. 
Study Patients/Subjects and Demographics 
7.1. 
Disposition of Patients/Subjects and Withdrawals 
Disposition will include tabulations of the number of subjects screened, number of subjects 
randomized into each treatment group, the number of subjects who received treatment, tabulated 
reasons for discontinuation from the study, and number of subjects in each analysis population. 
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be listed. 
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, gender, race, ethnicity, height, weight, BMI, baseline pain category 
and baseline pain (continuous) will be presented by treatment groups and overall. For the 
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continuous variables, the number of non-missing values and the mean, standard deviation, 
minimum, median and maximum will be tabulated.  
For the categorical variables, the counts and proportions of each value will be tabulated.    
These analyses will be conducted for the ITT, PP, and Safety populations. 
The number and percent of subjects reporting various medical histories, grouped by MedDRA 
system organ class and preferred term (coded using MedDRA v21.1), will be tabulated by 
treatment group. This analysis will be conducted for the Safety Population. Physical examination 
findings will also be summarized by body system and examination result- Normal, Abnormal – 
Clinically Significant, Abnormal-Not Clinically Significant. 
7.4. 
Exposure and Compliance 
The number of doses taken and treatment duration will be summarized by descriptive statistics. 
All study drug will be administered in clinic. The total number of tablets taken, and the number 
of tablets with active ingredient taken at each time point will be summarized. The dosage (in mg) 
of active ingredient taken and duration of exposure, from first dose to last dose of the study 
treatment will be summarized using descriptive statistics. Any deviations from the planned dose 
should be reported. 
8. 
Efficacy Analysis 
8.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the summed pain intensity difference (SPID) over 0 to 12 hours 
(SPID12).  The primary endpoint will be used to compare the test product (2x300 mg ibuprofen 
PR tablets) against placebo. 
The primary efficacy hypothesis is that SPID12 for placebo is equal to SPID12 for ibuprofen 
2x300 mg PR tablets.  The primary analysis will be an ANCOVA model that includes the main 
effect of treatment and a covariate of the baseline NRS pain score and will use windowed worst 
observation carried forward (WOCF) imputation for subjects who use rescue medication.  The 
primary analysis will be based on a 2-sided test at the significance level of 0.05.  The treatment 
difference will be presented with a 95% confidence interval.   
Normality assumptions will be tested. If the data is considered non-normal, the Wilcoxon rank 
sum test will be used for the comparison between treatments, and the point estimate and 95% 
confidence interval will be calculated using the Hodges-Lehmann estimator. 
The primary efficacy analysis will be based on the ITT population. These analyses will be 
repeated for the PP population.  SPID-12 scores will also be summarized by baseline pain 
category (moderate or severe). 
8.2. 
Secondary Efficacy Analysis 
8.2.1. SPID 
Summed Pain Intensity Difference (SPID) will be calculated for secondary efficacy analysis as 
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described in Section 6.1.7 at 4, 8, and 24 hours. Descriptive statistics by treatment regimen will 
be produced. 
ANCOVA models for comparing placebo with other treatment regimens with SPID as the 
dependent variable and treatment group and baseline pain as covariates will be generated. These 
models will be computed for SPID4, SPID8 and SPID12. The least square (LS) mean and 
standard error (SE) for each treatment group will be estimated and the difference in LS means 
and 95% confidence interval (CI) for the comparison of placebo with the IR and PR treatment 
regimens will be estimated. P-values will be reported but no formal statistical inferences will be 
made on the basis of these tests.  In addition, for the SPID24 endpoint, the difference in LS 
means and 95% CI for the IR versus PR groups will be presented. In the event that normality 
assumptions are violated for a parameter, non-parametric analysis methods will be used. 
8.2.2. TOTPAR 
Total pain relief (TOTPAR) will be calculated as described in Section 6.1.7 at 4, 8, 12 and 24 
hours. Descriptive statistics by treatment regimen will be produced. 
ANCOVA models for comparing placebo with other treatment regimens with TOTPAR as the 
dependent variable and treatment group and baseline pain as covariates will be generated. These 
models will be generated at TOTPAR4, TOTPAR8, TOTPAR12 and TOTPAR24. The LS mean 
and SE for each treatment group will be estimated and the difference in LS means and 95% CI 
for the comparison of placebo with the IR and PR treatment regimens will be estimated. P-values 
will be reported but no formal statistical inferences will be made on the basis of these tests. In 
the event that normality assumptions are violated for a parameter, non-parametric analysis 
methods will be used. 
8.2.3. SPRID 
Summed pain relief and intensity difference is the sum of TOTPAR and SPID and will be 
calculated at 4, 8, and 12 and 24 hours as described in Section 6.1.7. 
Descriptive statistics by treatment regimen will be produced for SPRID at each planned 
assessment time point.  
ANCOVA models for comparing placebo with other treatment regimens with SPRID as the 
dependent variable and treatment group and baseline pain as covariates will be generated. The 
LS mean and SE for each treatment group will be estimated and the difference in LS means and 
95% CI for the comparison of placebo with the IR and PR treatment regimens will be estimated. 
P-values will be reported but no formal statistical inferences will be made on the basis of these 
tests. In the event that normality assumptions are violated for a parameter, non-parametric 
analysis methods will be used. 
8.2.4. Peak Pain Relief  
Peak pain relief will be calculated as described in Section 6.1.7 and will be summarized by 
counts (and percentages) for each pain relief score.  It will be analyzed using a proportional odds 
model (an extension of the logistic regression). This method allows for an ordinal response 
variable with more than two categories. This model will include a factor for treatment and 
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baseline pain intensity as a continuous covariate. For each of the PR and IR treatment regimens, 
the odds of being in a higher (better) pain relief category compared to placebo (odds ratio) will 
be presented with a 95% CI and associated p-value.  
8.2.5. Time to First Perceptible Pain Relief 
Time to first perceptible pain relief will be summarized using Kaplan-Meier methods. The 
definition and censoring rules are described in Section 6.1.7. With baseline pain as a 
stratification factor, treatments will be compared to placebo using a stratified log-rank test or a 
stratified Wilcoxon test as appropriate. Summary tables will provide the number of subjects 
analyzed, the number of subjects censored, estimates for the 25th, 75th percentiles and median 
(including 95% CI), and associated p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated. 
8.2.6. Time to Meaningful Pain Relief  
Time to first meaningful pain relief will be summarized using Kaplan-Meier methods. The 
definition and censoring rules are described in Section 6.1.7. With baseline pain as a 
stratification factor, treatments will be compared to placebo using a stratified log-rank test or a 
stratified Wilcoxon test. Summary tables will provide the number of subjects analyzed, the 
number of subjects censored, estimates for the 25th, 75th percentiles and median (including 95% 
CI), and associated p-value for comparisons versus placebo.   
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated.  
8.2.7. Time to onset of Analgesia 
Time to onset of analgesia will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 6.1.7. With baseline pain as a stratification factor, 
treatments will be compared to placebo and with each other (IR vs PR) using a stratified log-rank 
test or a stratified Wilcoxon test. The summary tables will provide the number of subjects 
analyzed, the number of subjects censored, estimates for the 25th, 75th percentiles and median 
(including 95% CI), and associated p-value for treatment comparisons.   
A measure of the treatment effect comparing each of the active arms with placebo and with each 
other (IR vs PR) will be obtained by calculating a hazard ratio and 95% CI by fitting a Cox 
proportional hazards model with a factor for treatment group and baseline pain as a continuous 
covariate. The assumption of proportional hazards will first be evaluated.  
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8.2.8. Time to Peak Pain Relief 
Time to peak pain relief will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 6.1.7. With baseline pain as a stratification factor, 
treatments will be compared to placebo using a stratified log-rank test or a stratified Wilcoxon 
test. The summary tables will provide the number of subjects analyzed, the number of subjects 
censored, estimates for the 25th, 75th percentiles and median (including 95% CI), and associated 
p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated.  
8.2.9. Time to first use of Rescue Medication 
Time to first use of rescue medication will be summarized using Kaplan-Meier methods. The 
definition of time to first use of rescue medication and censoring rules for subjects who don’t 
take rescue medication are described in Section 6.1.7. With baseline pain as stratification factor, 
treatments will be compared to placebo using a stratified log-rank test or a stratified Wilcoxon 
test. The summary tables will provide the number of subjects analyzed, the number of subjects 
censored, estimates for the 25th, 75th percentiles and median (including 95% CI), and associated 
p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated. 
8.2.10.  Proportion of Responders 
For the proportion of subjects who are responders, a logistic regression model that adjusts for 
baseline pain (as a continuous covariate) and treatment arm will be used to evaluate the treatment 
effect. As a measure of treatment effect for each of the PR and IR groups versus placebo, odds 
ratios together with a 95% CI and p-values will be presented. 
8.2.11. Numeric rating scale (NRS) pain intensity difference (PID)  
PID at each time point will be calculated using the formula specified in Section 6.1.7. PID at 
each timepoint will be analyzed in a mixed model for repeated measures (MMRM) ANCOVA 
analysis. The model will include treatment, timepoint, treatment by timepoint, baseline and 
baseline by timepoint as fixed effects, and subject as a random effect. An unstructured 
covariance matrix will be used to model the within-subject correlations by timepoint. If the 
model fails to converge, alternative covariance structures, such as compound symmetry, will be 
tried instead. The model will be used to show estimated treatment effects at each timepoint. The 
LS mean and SE for each treatment group will be estimated and the difference in LS means and 
95% CI for the comparison of placebo with the IR and PR treatment regimens will be estimated. 
P-values will be reported but no formal statistical inferences will be made on the basis of these 
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tests. Descriptive summaries (including mean, SD, median, minimum and maximum) will be 
presented by treatment group. Pain intensity score at each scheduled time point  
Pain intensity is measured using NRS at planned assessment time points. Descriptive summaries 
(including mean, SD, median, minimum and maximum) will also be presented by treatment 
group. 
8.2.12. Pain relief at each scheduled time point 
Pain relief scores at each scheduled time point will be summarized using descriptive statistics 
(including mean, SD, median, minimum and maximum) as well as counts (and percentages) for 
each pain relief score by treatment group. Treatment comparison will be done in the following 
way: 
• Pain relief category at each timepoint will also be analyzed using a repeated 
measures proportional odds model (an extension of the logistic regression). This 
method allows for an ordinal response variable with more than two categories. 
Here the categories none = 0, a little = 1, some = 2, a lot = 3, and complete = 
4.This model will include the following covariate terms- treatment and baseline 
pain intensity (as a continuous covariate) timepoint, baseline by timepoint and 
treatment by timepoint. Subject will be the repeated measure in this model. For each 
of the PR and IR treatment regimens, the odds of being in a higher (better) pain 
relief category compared to placebo (odds ratio) will be presented with a 95% CI 
and associated p-value. 
 
8.2.13. Proportion of Subjects Rescue Medication 
The definition of rescue medication use is presented in Section 6.1.7. The proportion of subjects 
using rescue medication for pain will be analyzed using logistic regression. The logistic 
regression model will include treatment arm and baseline pain (as a continuous covariate) as 
covariates. As a measure of treatment effect for each of the PR and IR groups versus placebo, 
odds ratios together with a 95% CI and p-values will be presented. 
8.3. 
Exploratory Efficacy Analysis  
8.3.1. Global Evaluation of Study Drug 
Subject’s global evaluation of study drug will be analyzed using a proportional odds model (an 
extension of the logistic regression). This method allows for an ordinal response variable with 
more than two categories. This model will include a factor for treatment group and baseline pain 
intensity as a continuous covariate. For each of the PR and IR treatment regimens, the odds of 
being in a higher (better) evaluation category compared to placebo (odds ratio) will be presented 
with a 95% CI and associated p-value. 
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9. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported AEs, and changes in vital signs. 
All safety analyses will be performed on the Safety population. 
9.1. 
Adverse Events 
The number and percent of subjects reporting treatment emergent AEs, grouped by 
MedDRA system organ class and preferred term (coded using MedDRA v21.1), will 
be tabulated by severity and treatment group. In the case of multiple occurrences of the 
same TEAE within the same subject, each subject will only be counted once for each 
preferred term. 
The frequency and percentage of subjects reporting TEAEs, grouped by MedDRA SOC and PT, 
will be tabulated by treatment group for the SAF. Such summaries will be displayed for the 
following: 
• TEAEs by SOC and PT 
• TEAEs by SOC, PT, and severity 
• TEAEs by SOC, PT, and relationship to the study medication 
• TEAEs leading to death by SOC, and PT 
• Serious TEAEs other than deaths by SOC, and PT 
• TEAEs leading to premature discontinuation by SOC, and PT 
• Listing of non-TEAEs 
In the case of multiple occurrences of the same AE within the same subject, each subject will 
only be counted once for each preferred term. In summaries of AE by SOC and PT, along with 
the number (%) of subjects with at least 1 AE in the category, the number of events will be 
displayed. In the summaries showing severity and relationship to study medication the event with 
the maximum severity or strongest relationship will be reported. If a particular event is missing 
the severity and/or relationship, then the strongest possible severity or relationship will be 
assumed for analysis (severity = severe, relationship = certain). 
Missing and partially missing AE start and/or stop dates will be imputed for the purpose of 
statistical analysis, according to the specifications described in Section 6.1.7. 
In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent will be 
flagged. 
9.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug, by treatment group, SOC, and preferred term will be prepared for the Safety 
Population. No inferential statistical tests will be performed. 
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
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9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and also tabulated by system organ class and preferred term 
and presented by treatment. 
9.2. 
Clinical Safety Laboratory Data 
Descriptive statistics for clinical safety laboratory data (laboratory data) recorded at screening 
will be presented overall and by treatment regimen. Summary tables by treatment regimen will 
be presented for each category of data separately. Routine clinical laboratory data will include 
hematology, serum chemistry, and urinalysis. Quantitative laboratory test result summaries will 
include N (population count for each regimen), n (number of subjects with non-missing values), 
mean, SD, median, and range. Qualitative tests (e.g., some urinalysis assessments) will be 
categorized accordingly. The set of laboratory parameters included in each table will correspond 
to those requested in the study protocol. Urine drug screen, alcohol breath analyzer and urine 
pregnancy test results will be presented in listings.  
9.3. 
Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for supine 
systolic blood pressure, supine diastolic blood pressure, heart rate, respiratory rate, and oral body 
temperature, and will be presented by treatment regimen. Summary statistics for 12-lead ECG 
parameters and counts for ECG interpretations at screening will be presented. 
9.4. 
Concomitant Medication 
Prior and concomitant medications will be summarized descriptively by treatment using counts 
and percentages. 
Prior medications will be presented separately from concomitant medications. Medications that 
started prior to the first dose of study drug will be considered prior medications whether or not 
they were stopped prior to the first dose of study drug. Any medications continuing or starting 
post the first dose of study drug will be considered to be concomitant. If a medication starts prior 
to the first dose and continues after the first dose of study drug, it will be considered both prior 
and concomitant. Medications will be coded using Sept 2018 version of World Health 
Organization Drug Coding ASDFK Dictionary (WHODD). 
10. 
Changes to analysis planned in the protocol 
For the time to event endpoints an additional measure of the treatment effect comparing each of 
the active arms with placebo will be obtained by calculating a hazard ratio and 95% CI by fitting 
a Cox proportional hazards model with a factor for treatment group and baseline pain as a 
continuous covariate. The assumption of proportional hazards will first be evaluated. 
There has been a clarification to the definition of the ITT population to that stated in the 
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protocol. The ITT population is defined as all subjects who are treated with study drug and who 
have at least 1 pain assessment after Time 0. In the protocol the ITT population was defined as 
subjects who have at least 1 pain relief assessment. 
11. 
References 
1. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
2. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
3. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
4. Ratitich, B. and O’Kelly, M.J. (2011). Implementation of Pattern-Mixture Models Using 
Standard SAS / STAT Procedures. 
 
12. 
Tables, Listings, and Figures 
All listings, tables, and graphs will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (CRF page or listing number). 
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12.1. Planned Table Descriptions 
The following are planned summary tables for protocol number 5003601. The table numbers and 
page numbers are place holders only and will be determined when the tables are produced. 
Table 3: Demographic Data Summary Tables  
Table Number 
Population 
Table Title/Summary 
14.1 Displays of Demographics and Disposition Data 
Table 14.1.1 
All Subjects 
Subject Disposition 
Table 14.1.2 
Safety Population 
Demographics and Baseline Characteristics 
Table 14.1.2.1 
ITT Population 
Demographics and Baseline Characteristics 
Table 14.1.3 
Safety Population 
Medical History  
Table 14.1.4 
 Safety Population 
Prior Medications  
Table 14.1.5 
 Safety Population 
Concomitant Medications  
Table 14.1.6 
 All Enrolled Subjects 
Summary of Protocol Deviations  
Table 14.1.7 
Safety Population 
Summary of Study Drug Exposure 
12.2. Efficacy Data  
Table 4: Efficacy Tables 
 
 
 
Table Number 
Population 
Table Title/Summary 
14.2.1  
ITT Population 
Analysis of SPID-12 Scores  
14.2.1.1 
PP Population 
Analysis of SPID-12 Scores  
14.2.1.2 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis-WOCF 
14.2.1.3 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis-No Rescue Adjustment 
14.2.1.4 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis-Rescue WOCF 
14.2.1.5 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis-Rescue LOCF 
14.2.1.6 
ITT Population 
Analysis of SPID-12 Scores- Sensitivity Analysis-Multiple Imputation 
14.2.1.7 
ITT Population 
Summary of SPID-12 Scores by Baseline Pain 
14.2.2 
ITT Population 
Analysis of Summed Pain Intensity Difference Scores  
14.2.3 
ITT Population 
Analysis of Total Pain Relief Scores  
14.2.4 
ITT Population 
Analysis of Summed Pain Relief and Intensity Difference Scores  
14.2.5 
ITT Population 
Comparison of SPID-24 in Ibuprofen PR and IR arms 
14.2.6 
ITT Population 
Summary of Peak Pain Relief  
14.2.7 
ITT Population 
Time to First Perceptible Pain Relief  
14.2.8 
ITT Population 
Time to Meaningful Pain Relief  
14.2.9 
ITT Population 
Time to Onset of Analgesia  
14.2.10 
ITT Population 
Time to Peak Pain Relief  
14.2.11 
ITT Population 
Time to First use of Rescue Medication  
14.2.12 
ITT Population 
Proportion of Subjects Using Rescue Medication  
14.2.13 
ITT Population 
Proportion of Responders 
14.2.14 
ITT Population 
Summary of NRS Pain Intensity Difference Score  
14.2.15 
ITT Population 
Summary of Pain Intensity Score at each Scheduled Time Point 
14.2.16 
ITT Population 
Summary of Pain Relief at each Scheduled Time Point 
14.2.17 
ITT Population 
Analysis of Patient Global Evaluation of Study Drug 
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12.3. Safety Data 
Table 5: Safety Tables 
Table Number 
Population 
Table Title/Summary 
14.3.1 Summary of Treatment Emergent Adverse Events 
Table 14.3.1.1 
 Safety Population 
Overall Summary of Treatment-Emergent Adverse Events  
Table 14.3.1.2 
Safety Population 
Summary of Treatment-Emergent Adverse Events  
Table 14.3.1.3 
Safety Population 
Summary of Treatment-Emergent Adverse Events by Maximum Severity  
Table 14.3.1.4 
Safety Population 
Summary of Treatment-Emergent Adverse Events by Relationship to 
Study Drug  
Table 14.3.1.5 
Safety Population 
Summary of Non-Serious Treatment-Emergent Adverse Events  
14.3.2 Summary of Deaths, Other Serious and Significant Adverse Events 
Table 14.3.2.1 
 Safety Population 
Summary of Serious Adverse Events  
Table 14.3.2.2 
Safety Population 
Summary of Treatment Emergent Adverse Events Leading to 
Discontinuation  
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 
Table 14.3.3.1 
Safety Population 
Listing of Serious Adverse Events  
Table 14.3.3.2 
Safety Population 
Listing of Treatment Emergent Adverse Events Leading to  
Study Drug Discontinuation 
14.3.4 Abnormal Laboratory Value  
Table 14.3.4.1 
Safety Population  
Listing of  Potentially Clinically Significant Abnormal Laboratory Values   
14.3.5 Laboratory Data Summary Tables 
Table 14.3.5.1 
Safety Population  
Summary of Serum Chemistry Laboratory Results  
14.3.6 Other Safety Data Summary Tables 
Table 14.3.6.1 
 Safety Population 
Summary of Vital Signs  
Table 14.3.6.2 
Safety Population 
Summary of Electrocardiogram (ECG) Interpretations  
Table 14.3.6.3 
Safety Population 
Summary of 12-Lead Electrocardiogram (ECG) Parameters 
Table 14.3.6.4 
Safety Population 
Summary of Physical Examination Findings 
 
 
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12.4. Planned Listing Descriptions 
The following are planned data and patient/subject data listings for protocol number 5003601.  
In general, one listing will be produced per CRF domain. All listings will be sorted by treatment, 
site, and subject number. All calculated variables will be included in the listings. 
In all listings a blank line will be placed between each subject. Within a data listing, if an item 
appears line after line (e.g., repetition of subject number), then only the first occurrence will be 
displayed. 
In data listings, the information for one subject will be kept on one page if at all possible, rather 
than splitting a subject’s information across pages. 
Table 6: Planned Listings 
Data Listing Number 
Population 
Data Listing Title / Summary 
16.2.1 Subject Discontinuations/Completions 
 Listing 16.2.1 
All Subjects 
Subject Disposition 
16.2.2 Protocol Deviations 
Listing 16.2.2.1 
All Subjects  
Eligibility Criteria Not Met 
Listing 16.2.2.2 
All Subjects 
Screen Failures 
Listing 16.2.2.3 
All Subjects 
Protocol Deviations 
16.2.3 Subjects in Analysis Populations 
Listing 16.2.3 
All Subjects 
Analysis Populations 
16.2.4 Demographic Data and Other Baseline Characteristics 
Listing 16.2.4.1 
Safety Population 
Demographics and Baseline Characteristics 
Listing 16.2.4.2 
Safety Population 
Medical History 
Listing 16.2.4.3 
 All Randomized Subjects Listing of Subject Randomization  
Listing 16.2.4.4 
 Safety Population 
Study Drug Administration 
16.2.7 Adverse Event Listings (by Subject) 
Listing 16.2.7.1 
Safety Population 
Adverse Events  
Listing 16.2.7.2 
Safety Population 
Serious Adverse Events 
Listing 16.2.7.3 
Safety Population 
Treatment emergent Adverse Events Related to Study Drug 
Listing 16.2.7.4 
Safety Population 
Deaths 
16.2.8 Laboratory Values by Subject 
Listing 16.2.8.1 
Safety Population 
Clinical Laboratory Data: Serum Chemistry 
Listing 16.2.8.2 
Safety Population 
Clinical Laboratory Data: Hematology 
Listing 16.2.8.3 
Safety Population 
Clinical Laboratory Data: Urine 
Listing 16.2.8.4 
Safety Population 
Clinical Laboratory Data: Coagulation 
Listing 16.2.8.5 
Safety Population 
Serum and Urine Pregnancy Test 
16.2.9 Other Clinical Observations and Measurements (by Subject) 
Listing 16.2.9.1 
Safety Population 
Prior and Concomitant Medications 
Listing 16.2.9.1.1 
Safety Population 
Rescue Medications 
Listing 16.2.9.2 
Safety Population 
Vital Signs Measurements 
Listing 16.2.9.2.1 
Safety Population 
Physical Examination Findings 
Listing 16.2.9.3 
Safety Population 
12-lead Electrocardiogram Measurements  
Listing 16.2.9.3.1 
Safety Population 
Alcohol Breathalyzer Test 
Listing 16.2.9.4 
Safety Population 
NRS Pain Intensity Assessment 
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Data Listing Number 
Population 
Data Listing Title / Summary 
Listing 16.2.9.5 
Safety Population 
Pain Relief Scores  
Listing 16.2.9.6 
Safety Population 
Time to Pain Relief (Stopwatches) 
Listing 16.2.9.7 
Safety Population 
Subjects Global Evaluation of Study Drug 
 
 
 
12.5. Planned Figure Descriptions 
The following are planned summary figures for protocol number 5003601. The figure numbers 
and page numbers are place holders only and will be determined when the figures are produced. 
Table 7: Planned Figures 
Figure 14.4.1.1 
ITT Population 
Kaplan-Meier Plot of Time to First Perceptible Pain Relief 
Figure 14.4.1.2 
ITT Population 
Kaplan-Meier Plot of Time to Meaningful Pain Relief  
Figure 14.4.1.3 
ITT Population 
Kaplan-Meier Plot of Time to Onset Of Analgesia  
Figure 14.4.1.4 
ITT Population 
Kaplan-Meier Plot of Time to Peak Pain Relief 
Figure 14.4.1.5 
ITT Population 
Kaplan-Meier Plot of Time to First Use Of Rescue Medication 
Figure 14.4.1.6 
ITT Population 
Mean Pid Scores versus Time 
Figure 14.4.1.7 
ITT Population 
Mean Pain Relief Scores versus Time 
 
 
 
Figure Number 
Population 
Figure Title / Summary 
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Appendix 1: Premier Research Library of Abbreviations 
 
Abbreviation 
Definition 
aCRF  
annotated case report form 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
BSL 
biostatistician lead 
CCGs 
CRF completion guidelines 
CDISC 
clinical data interchange standards consortium 
CEC 
central ethics committee 
CFR 
code of federal regulations 
CI 
confidence intervals 
CM 
clinical manager 
CMP 
clinical monitoring plan 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CSR 
clinical study report 
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Abbreviation 
Definition 
CTA 
clinical trial administrator 
CTM 
clinical trial manager 
CTMS 
clinical trial management system 
DB 
database 
DBL 
database lock 
DM 
data management 
DMB 
data monitoring board 
DMC 
data monitoring committee 
DMP 
data management plan 
DSMB  
data safety monitoring board 
DSP 
data safety plan 
DSUR 
development safety update report 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eTMF 
electronic trial master file 
EU 
European Union 
FDA 
food and drug administration 
FPI 
first patient in 
GCP 
good clinical practice 
HR 
heart rate 
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Abbreviation 
Definition 
IB 
investigator’s brochure 
IC or ICF 
informed consent or informed consent form 
ICH 
international council for harmonization  
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LLOQ 
lower limit of quantification 
LPI 
last patient in 
LPLV 
last patient last visit 
LPO 
last patient out 
MedDRA 
medical dictionary for regulatory activities 
MHRA 
medicines and healthcare products regulatory agency 
MM 
medical monitor 
MMP 
medical monitoring plan 
MMRM 
mixed effect model repeat measurement 
N 
number 
NA 
not applicable 
NCS 
non-clinically significant 
NF 
non-functional 
PD 
protocol deviation 
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Abbreviation 
Definition 
PDGP 
protocol deviation guidance plan 
PE 
physical examination 
PI 
principal investigator 
PK 
pharmacokinetic 
PKAP 
pharmacokinetic analysis plan 
PM 
project manager 
PMP 
project management plan 
PP 
per-protocol 
PS 
project specialist 
PV 
pharmacovigilance 
PVG 
pharmacovigilance group 
QA 
quality assurance 
QARC 
quality assurance, risk and compliance 
QC 
quality control 
QOL 
quality of life 
SAE 
serious adverse event 
SAF 
Safety Population 
SAP 
statistical analysis plan 
SAS®  
a software system used for data analysis 
SBP 
systolic blood pressure 
SD 
standard deviation 
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Abbreviation 
Definition 
SDS 
study design specifications 
SDTM  
study data tabulation model  
SF 
screen failure 
SFT or SFTP 
secure file transfer or secure file transfer plan 
SIV 
site initiation visit 
SMP 
safety management plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
UAT 
user acceptance testing 
WHO 
world health organization 
WHO-DD 
world health organization drug dictionary 
 
 
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Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
Sponsor 
Reckitt Benckiser 
Protocol Title: 
A Randomized, Double-Blind, Double-Dummy, Parallel-
Group, Multiple-Dose, Active and Placebo-Controlled 
Efficacy Study of Ibuprofen Prolonged-Release Tablets for 
the Treatment of Pain after Surgical Removal of Impacted 
Third Molars 
Protocol Number: 
5003601 
Premier Research 
PCN: 
RECK.177035 
Document Version: 
Amendment 1.0 
Document Date: 
28-Feb-2020
Approvals 
Role 
Signatures 
Date (dd-Mmm-
yyyy) 
Biostatistician 
Premier Research 
Print Name: Raghu Vishnubhotla 
 
Sign Name: 
Reckitt Benckiser 
Representative 
Print Name: Darren Targett 
Sign Name: 
28-Feb-2020 | 10:03:19 EST
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Statistical Analysis Plan  
Sponsor Reckitt Benckiser  
Protocol Number 5003601  
PCN Number RECK.177035
1.1. 
Planned Table Shells 
Table 14.1.1 
Subject Disposition 
All Randomized Subjects 
Disposition 
Ibuprofen PR  
(N=XX) 
Ibuprofen IR  
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Study Populations [1] 
Screened 
XXX 
Safety Population 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
ITT Population 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Per-Protocol Population 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Completion Status [2] 
  Completed Study 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Prematurely Discontinued Study Medication 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Prematurely Discontinued Study 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
  Reasons for discontinuation from Study 
 Lost to Follow-up 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 Protocol Violation 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 Adverse Event 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 Non-Compliance with Study Drug 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 Death 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 Withdrawal 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 Pregnancy 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 Physician Decision 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 Study Terminated by Sponsor 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 Other 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
[1] Percentages are based on the number of randomized subjects.
[2] Percentages are based on the number of subjects in the Safety Population.
Source: Listing 16.2.1
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Table 14.1.2 
Demographics and Baseline Characteristics 
Safety Population 
 
Variable 
   Statistic or Category 
Ibuprofen PR  
 
(N=XX) 
Ibuprofen IR 
  
(N=XX) 
Placebo 
  
(N=XX) 
Overall 
  
(N=XX) 
Age (years) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
 
 
XX, XX 
XX, XX 
XX, XX 
Gender 
 
 
 
 
   Male 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Female 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Ethnicity 
 
 
 
 
   Hispanic or Latino 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Not Hispanic or Latino 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Race 
 
 
 
 
   Asian 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Black or African-American 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Native Hawaiian or Other Pacific Islander 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   White 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Baseline Pain [1] 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Baseline Pain Category [2] 
 
 
 
 
 
   Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Height (cm) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Weight (kg) 
 
 
 
 
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   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Surgery Duration (min) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
Note: Percentage are based on the number of subjects in the Safety Population. 
[1] Subjects rate their pain using a numeric rating scale (NRS) from 0 (no pain) to 10 (worst pain ever).  
[2] NRS pain scores at baseline are categorized as moderate (5-7), and severe (8-10). 
 
Source: Listing 16.2.4.1 
 
Table 14.1.2.1 
Demographics and Baseline Characteristics 
ITT Population 
Use Same Shell as Table 14.1.2 
 
 
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Table 14.1.3 
Medical History 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR 
  
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
  
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
Subjects with at least One Recorded Medical History 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
System Organ Class 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are based on number of subjects in the Safety Population. 
Medical conditions were coded using MedDRA version 21.1 or later. Subjects were counted once for each system organ class (SOC) and once for each preferred term (PT). Medical 
history terms are displayed by descending frequency of SOC, then PT within SOC, and then alphabetically by PT. 
SOURCE: Listing 16.2.4.2 
 
 
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Table 14.1.4 
Prior Medications 
Safety Population 
ATC Class Level 4 
   Preferred Term (ATC Class Level 5) 
Ibuprofen PR 
   
 (N=XX) 
Ibuprofen IR 
   
 (N=XX) 
Placebo   
 
 (N=XX) 
Overall 
 
 (N=XX) 
 
 
 
 
 
Subjects with at least one Prior Medication 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
ATC Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
ATC Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 2 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Preferred Term 3 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are on number of subjects in the Safety Population.  
Medications coded using WHO-DD B2E version September 2018.  
Prior medications are all medications taken before the date of the first dose of study drug.  
Medications are displayed by descending frequency of Anatomic Therapeutic Chemical (ATC) Level 4 classification, by Preferred Term (PT) within ATC and then alphabetically.  
Subjects were counted only once for each ATC and PT. 
SOURCE: Listing 16.2.9.1 
 
 
Table 14.1.5 
Concomitant Medications 
Safety Population 
Use same shell as Table 14.1.4 
 
 
 
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Table 14.1.6 
Summary of Protocol Deviations 
All Enrolled Subjects 
 
Deviations 
Ibuprofen PR 
   
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
 (N=XX) 
Overall 
 (N=XX) 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXXXX 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXXXXX 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are based on number of all enrolled subjects.  
SOURCE: Listing 16.2.2.3 
 
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Table 14.1.7 
Summary of Study Drug Exposure 
Safety Population 
 
Drug Exposure 
Ibuprofen PR 
   
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
 (N=XX) 
 
 
 
 
Number of Tables Taken 
 
 
 
   n 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
Number of Active Doses Taken [1] 
 
 
 
   n 
XX 
XX 
 
   Mean 
XX.X 
XX.X 
 
   Std Dev 
XX.XX 
XX.XX 
 
   Median 
XX.X 
XX.X 
 
   Min, Max 
XX, XX 
XX, XX 
 
 
 
 
 
Quantity of Active Drug Taken (mg) 
 
 
 
   n 
 
 
 
   Mean 
XX.X 
XX.X 
 
   Std Dev 
XX.XX 
XX.XX 
 
   Median 
XX.X 
XX.X 
 
   Min, Max 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
Treatment Duration (Hours) [2] 
 
 
 
   n 
XX 
XX 
XX 
   Mean 
XX.X 
XX.X 
XX.X 
   Std Dev 
XX.XX 
XX.XX 
XX.XX 
   Median 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
Note: Percentages are based on number of all enrolled subjects.  
[1] Active dose is a dose where the tablet taken has an active ingredient  
[2] Duration = date/time of last dose administered – date/time of first dose administered 
SOURCE: Listing 16.2.4.4.1 
 
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Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events  
Safety Population 
 
 
 
Subjects with at least one 
Ibuprofen PR  
 
 (N=XX) 
Ibuprofen PR 
 
 (N=XX) 
Placebo 
 (N=XX) 
Overall 
 
 (N=XX) 
 
 
 
 
 
   TEAE 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   TEAE by Maximum Severity 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   TEAE by Strongest Relationship  
 
 
 
 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   AE leading to Discontinuation 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   SAE 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
   AE leading to Death 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment emergent adverse event; SAE = Serious adverse event. 
Note: Percentages are 100*n/N.  
TEAEs are defined as AEs occurring or worsening with an onset at the time of or following the start of treatment with study medication.  
 
SOURCE: Listing 16.2.7.1 
 
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Table 14.3.1.2 
Summary of Treatment Emergent Adverse Events  
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
Subjects with at least One TEAE 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 2 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 3 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 2 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
   Preferred Term 3 
X (XX.X%)  [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
X (XX.X%) [X] 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment emergent adverse event. 
Note: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. 
 
Percentages are 100*n/N. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  
TEAEs are defined as AEs occurring or worsening with an onset at the time of or following the start of treatment with study medication.  
AEs were coded using MedDRA version 21.1.  
 
SOURCE: Listing 16.2.7.1 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.1.3 
Summary of Treatment Emergent Adverse Events by Maximum Severity 
Safety Population 
 
System Organ Class 
   Preferred Term 
Maximum Severity [1] 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall  
 
 (N=XX) 
       
 
 
 
 
Subjects with at least One TEAE 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   Preferred Term 1 
 
 
 
 
      Mild 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Moderate 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
      Severe 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
Abbreviations: TEAE = Treatment emergent adverse event; SAE = Serious adverse event. 
[1] The severity shown is the greatest severity reported for a particular subject (Severe > Moderate > Mild). AEs with missing severity have been classified as Severe. 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term. TEAEs are defined as AEs occurring or worsening with an 
onset at the time of or following the start of treatment with study medication. AEs were coded using MedDRA version 21.1. 
SOURCE: Listing 16.2.7.1 
 
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Table 14.3.1.4 
Summary of Treatment-Emergent Adverse Events by Relationship to Study Drug 
Safety Population 
 
System Organ Class 
   Preferred Term 
Greatest Relationship [1] 
Ibuprofen PR 
  
 (N=XX) 
Ibuprofen IR 
  
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall  
 (N=XX) 
       
 
 
 
 
Subjects with at least One TEAE 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
System Organ Class 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
   Preferred Term 1 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unassessable/Unclassifiable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Conditional/Unclassified 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unrelated 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Unlikely 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Possible 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Probable 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Certain 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
[1] AE relation is marked in the CRF. The relationship shown is the strongest relationship reported for a particular subject. AEs with missing relationship have been classified as 
Certain. 
Abbreviations: TEAE = Treatment emergent adverse event. 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term. TEAEs are defined as AEs occurring or worsening with an 
onset at the time of or following the start of treatment with study medication. AEs were coded using MedDRA version 21.1. 
SOURCE: Listing 16.2.7.1 
 
 
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Table 14.3.1.5 
Summary of Non-Serious Treatment Emergent Adverse Events  
Safety Population 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one non-
serious TEAE  
 
X (XX.X%) X 
 
X (XX.X%) X  
 
X (XX.X%) X 
 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment emergent adverse event. 
Note: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. Percentages are 100*n/N. Subjects 
were counted only once for each System Organ Class (SOC) or Preferred Term. TEAEs are defined as AEs occurring or worsening with an onset at the time of or following the start of 
treatment with study medication. AEs were coded using MedDRA version 21.1. 
SOURCE: Listing 16.2.7.1 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.2.1 
Summary of Serious Adverse Events 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
  
 (N=XX) 
Ibuprofen IR  
 
 (N=XX) 
Placebo 
 
 (N=XX) 
Overall 
  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one SAE 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SAE = Serious adverse event. TEAE = Treatment emergent adverse event. 
Note: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. 
 Percentages are 100*n/N. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  
TEAEs are defined as AEs occurring or worsening with an onset at the time of or following the start of treatment with study medication.  
AEs were coded using MedDRA version 21.1.  
SOURCE: Listing 16.2.7.1 
 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.2.2 
Summary of Treatment Emergent Adverse Events Leading to Study Drug Discontinuation 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Ibuprofen PR  
 (N=XX) 
Ibuprofen IR 
 (N=XX) 
Placebo 
 (N=XX) 
Overall  
 (N=XX) 
 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one TEAE that led to 
study drug discontinuation  
 
X (XX.X%) X 
 
X (XX.X%) X 
 
X (XX.X%) X 
 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
   Preferred Term 1 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 2 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
   Preferred Term 3 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
X (XX.X%) X 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment emergent adverse event. 
 
Note: The first number (n) corresponds to the count of unique subjects and percentage, while the second is the count of the number of events. 
 Percentages are 100*n/N. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  
TEAEs are defined as AEs occurring or worsening with an onset at the time of or following the start of treatment with study medication.  
AEs were coded using MedDRA version 21.1.  
 
SOURCE: Listing 16.2.7.1 
 
 
Programmers Note- Ensure there is some space between the Number of subject (%) count and the number of events in the table  
 
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Table 14.3.3.1 
Listing of Serious Adverse Events 
Safety Population 
 
 
Subject ID 
Treatment 
Group 
 
Gender 
Age 
(Units) 
 
SAE 
System Organ Class/ 
Preferred Term/ Verbatim 
Term 
Start Date/ 
End Date (Study Day) 
 
Severity/ 
Causality 
 
Outcome/ Action Taken 
XXXX 
  
M 
XX 
XXXX 
XXXX/XXX/XXX    
DDMMMYYYY/ 
DDMMMYYYY () 
MILD/Related 
  XXX/XXX 
 
 
 
 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SAE = Serious adverse event. 
AEs were coded using MedDRA version 21.1.  
Study day is calculated relative to the date of first dose of study drug. 
Source- Listing 16.2.7.2 
 
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Table 14.3.3.2 
Listing of Treatment Emergent Adverse Events Leading to Study Drug Discontinuation 
Safety Population 
 
 
Subject ID       
Treatment 
Group 
 
Gender 
Age 
(Units) 
 
TEAE 
System Organ Class/ Preferred 
Term/ Verbatim Term 
Start Date/ 
End Date (Study Day) 
 
Severity/ 
Causality 
 
Outcome/ Action Taken 
XXXX 
XX 
F 
XX 
XXXX 
XXXX/XXX/XXX    
DDMMMYYYY/ 
DDMMMYYYY () 
MILD/Related 
  XXX/XXX 
XXXX 
XX 
M 
 
XXXX 
XXXX/XXX/XXX    
DDMMMYYYY/ 
DDMMMYYYY () 
MILD/Related 
  XXX/XXX 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment Emergent Adverse Event. 
AEs were coded using MedDRA version 21.1.  
TEAE= AEs that started or changed in the intensity or relationship to treatment on or after the first dose of study drug. 
Study day is calculated relative to the date of first dose of study drug. 
 
Source- Listing 16.2.7.3
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Table 14.3.4.1 
Listing of Potentially Clinically Significant Abnormal Laboratory Values 
Safety Population 
 
 
 
 
Subject 
Number 
Treatment 
Group 
 
 
Gender 
Age 
(Units) 
Lab Parameter 
 
Parameter Value 
Reference Range 
Test Result 
Assessment 
Date/Time of 
Collection (Study 
Day) 
XXXX 
XX 
M 
XX 
Hemoglobin 
 
XXXXX 
XX-XX 
High/Low 
XXXXX(XX) 
 
 
 
 
Haematocrit 
 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study day is calculated relative to the date of first dose of study drug. 
Source: Listing 16.2.8.2 
 
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Table 14.3.5.1 
Summary of Clinical Laboratory Results  
Safety Population 
 
 
Hematology/Chemistry/Urinalysis Lab Parameter:XXXXXX 
 
Visit/ 
Statistic 
 
 
 
 
 
Iburprofen PR 
(N=XX) 
Iburprofen PR 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Screening 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
Note- Clinical laboratory tests (hematology, chemistry, urinalysis) tests are only done at Screening. 
 
SOURCE: Listing 16.2.8.1 
 
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Table 14.3.6.1 
Summary of Vital Signs  
Safety Population 
                     Parameter:XXXXX 
 
 
Visit/ 
Statistic 
 
 
 
 
 
Iburprofen PR 
(N=XX) 
Iburprofen IR 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Baseline 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
12 hours  
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Change from Baseline to 12 
hours 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
……. 
 
 
 
 
 
Note- Baseline is defined as the last observation recorded prior to the first dose.  
Programming Note- Calculate summary stats and change from baseline for 12 hours, 24 hours and Day 8/ET visit. 
Source-Listing 16.2.9.2 
 
 
 
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Table 14.3.6.2 
Summary of Electrocardiogram (ECG) Interpretations  
Safety Population 
  
 
 
Visit/ 
Categories 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Overall 
 
(N=XX) 
Screening 
 
 
 
 
   Normal 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Abnormal - CS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Abnormal - NCS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CS = clinically significant; NCS = not clinically significant 
 
SOURCE: Listing 16.2.9.3 
 
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Table 14.3.6.3 
Summary of 12-Lead Electrocardiogram (ECG) Parameters  
Safety Population 
Parameter: XXXXXX 
 
 
Visit/ 
Stat 
 
 
 
 
Ibuprofen PR  
 (N=XX) 
Ibuprofen IR 
 
(N=XX) 
Placebo 
(N=XX) 
Overall 
(N=XX) 
Screening 
 
 
 
 
n 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOURCE: Listing 16.2.9.3. 
 
 
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Table 14.3.6.4 
Summary of Physical Examination Findings  
Safety Population 
Visit- Screening/Day 8/ET 
 
 
Body System/ 
Categories 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Overall 
 
(N=XX) 
Body System-XXXX 
 
 
 
 
   Normal 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Abnormal - CS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Abnormal - NCS 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
 
….. 
 
 
 
 
Abbreviations: CS = clinically significant; NCS = not clinically significant ET: end of treatment 
 
SOURCE: Listing 16.2.9.3 
 
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Table 14.2.1 
Analysis of SPID-12 Scores  
ITT Population 
 
Statistics 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
 
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.XX 
XX.XX 
XX.XX 
Std Dev 
XX.XXX 
XX.XXX 
XX.XXX 
Median 
XX.XX 
XX.XX 
XX.XX 
Min, Max 
XX.X,XX.X 
XX.X,XX.X 
XX.X,XX.X 
 
 
 
 
ANCOVA Statistics [1] 
 
 
 
LS Mean (SE) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
LS Mean Difference from Placebo (95% CI) 
p-value 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
….. 
 
 
 
  
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID-12 score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever. Baseline pain is also recorded using the NRS scale. For subjects who use rescue medication, windowed worst observation carried forward (WOCF) is used. 
 
Source: Listing 16.x.xx 
 
 
 
 
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Table 14.2.1.1 
Analysis of SPID-12 Scores  
PP Population 
 
(Same Shell as Table 14.2.1) 
 
 
 
 
 
 
 
 
Table 14.2.1.2 
Analysis of SPID-12 Scores- Sensitivity Analysis-WOCF 
 ITT Population 
(Same Shell as Table 14.2.1) 
 
(Programming Note-This is sensitivity analysis # 2 in section 6.1.6 of the SAP.) 
 
 
Table 14.2.1.3 
Analysis of SPID-12 Scores- Sensitivity Analysis-No Rescue Adjustment 
 ITT Population 
(Same Shell as Table 14.2.1) 
 
(Programming Note-This is sensitivity analysis # 3 in section 6.1.6 of the SAP.) 
 
Table 14.2.1.4 
Analysis of SPID-12 Scores- Sensitivity Analysis-Rescue WOCF 
 ITT Population 
(Same Shell as Table 14.2.1) 
 
(Programming Note-This is sensitivity analysis # 4a in section 6.1.6 of the SAP.) 
 
 
Table 14.2.1.5 
Analysis of SPID-12 Scores- Sensitivity Analysis-Rescue LOCF 
 ITT Population 
(Same Shell as Table 14.2.1) 
 
(Programming Note-This is sensitivity analysis # 4b in section 6.1.6 of the SAP.) 
 
Table 14.2.1.6 
Analysis of SPID-12 Scores- Sensitivity Analysis-Multiple Imputation 
 ITT Population 
(Same Shell as Table 14.2.1) 
 
(Programming Note-This is sensitivity analysis # 5 in section 6.1.6 of the SAP.) 
 
 
 
 
Table 14.2.1.7 
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Summary of SPID-12 Scores by Baseline Pain 
ITT Population 
 
 
Category/Statistic 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Baseline  Pain Category-
Moderate 
 
 
 
    
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
Median 
XX 
XX 
XX 
Min, Max 
XX,XX 
XX,XX 
XX,XX 
 
 
 
 
…………. 
 
 
 
 
Note- SPID-12 is summed pain intensity difference (SPID) over 0 to 12 hours. Subjects will rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 
10 = worst pain ever.  Baseline pain using a categorical scale that includes moderate (5-7), and severe (8-10). 
Programming Note- Please complete table for all baseline pain categories.  
 
 
                                                                    
 
 
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Table 14.2.2 
Analysis of Summed Pain Intensity Difference Scores  
ITT Population 
 
 
  
 
Category/Statistics 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
(N=XX) 
SPID-4 
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.XX 
XX.XX 
XX.XX 
Std Dev 
XX.XXX 
XX.XXX 
XX.XXX 
Median 
XX.XX 
XX.XX 
XX.XX 
Min, Max 
XX.X,XX.X 
XX.X,XX.X 
XX.X,XX.X 
 
 
 
 
ANCOVA Statistics [1] 
 
 
 
LS Mean (SE) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
LS Mean Difference from Placebo (95% CI) 
p-value 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
….. 
 
 
 
 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error. 
[1] Estimates are from an analysis of covariance model with SPID score as the dependent variable. Terms for treatment and baseline pain score were included as covariates.  
Note: SPID-4/8/12 is summed pain intensity difference (SPID) over 0 to 4/8/12 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain 
and 10 = worst pain ever. Baseline pain is also recorded using the NRS scale. 
 
Programming Note- Please program for SPID-4 SPID-8 and SPID-24. 
 
Source: Listing 16.x.xx 
 
 
 
 
 
 
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Table 14.2.3 
Analysis of Total Pain Relief Scores  
ITT Population 
 
(Programming Note- Use same shell as Table 14.2.2. Please add the following footnote defining sum of total pain relief (TOTPAR) Note- Total pain relief (TOTPAR) is summed total 
pain relief under the Pain Relief Scale (0 – 4) from 15 min through 4/8/12/24 hours ) 
 
 
 
 
 
Table 14.2.4 
Analysis of Summed Pain Relief and Intensity Difference Scores  
ITT Population 
(Use same shell as Table 14.2.2) 
 
 
Table 14.2.5 
Comparison of SPID-24 in Ibuprofen PR and IR arms 
ITT Population 
 
 
 
 
 
 
 
Category/Statistics 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
SPID-24 
 
 
ANCOVA Statistics [1] 
 
 
LS Mean (SE) 
XX.XX (XX.XX) 
XX.XX (XX.XX) 
 
 
 
 
 
 
 
 
 
LS Mean Difference (95% CI) 
p-value 
XX.XX (XX.XX, XX.XX) 
0.XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
….. 
 
 
 
 
 
Abbreviations:  ANCOVA = analysis of covariance, CI = confidence interval; LS = least-squares, SE = standard error, SPID=summed pain intensity difference. 
[1] Estimates are from an analysis of covariance model with SPID-24/TOTPAR-24/SPRID-24 score as the dependent variable. Terms for treatment and baseline pain score were 
included as covariates.  
Note-SPID-24 is summed pain intensity difference (SPID) over 0 to 24 hours. Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 
= worst pain ever 
 
 
 
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Table 14.2.6 
Summary of Peak Pain Relief  
ITT Population 
  
 
 
Category/Statistics 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
   None 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A Little Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Some Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A lot of Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Complete Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
Odds Ratio (vs placebo) [1] 
XX.XX 
XX.XX 
 
  95% CI 
(XX.XX,XX.XX) 
XX.XX,XX.XX) 
 
  p-value 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
 
 
 
Abbreviations: CI=Confidence Interval 
[1] From a proportional odds model treatment group and baseline pain as covariates. An odds ratio > 1 means that patients experienced higher pain relief than the placebo. 
Note- Subjects rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. 
 
SOURCE: Listing 16.x.xx  
 
 
 
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Table 14.2.7 
Time to First Perceptible Pain Relief  
ITT Population 
  
 
 
Category/Statistic  
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Number of Subjects with First 
Perceptible Pain Relief 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Number of Subjects Censored  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Time to first perceptible pain relief 
(hours) [1] 
 
 
 
       Median (95% CI) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
        Q1  
XX.XX  
XX.XX  
XX.XX 
        Q3 
XX.XX  
XX.XX  
XX.XX 
        Range (Min-Max) 
XX.X-XX.X 
XX.X-XX.X 
XX-XX 
        p-value (vs placebo) [2] 
0.XXXX 
0.XXXX 
 
 
 
 
 
Hazard Ratio (vs placebo) [3] 
XX.XX 
XX.XX 
 
95% CI 
(XX.XX,XX.XX) 
(XX.XX,XX.XX) 
 
 
 
 
 
Abbreviation- Q1- 25th Percentile, Q3- 75th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means 
that patients in the Ibuprofen groups achieved pain relief faster than the placebo.  
Note- Time of first perceptible pain relief is the time of first reported pain relief as assessed by the subject (i.e. subject stops the first stopwatch (irrespective of the second stopwatch)). 
Pain scores at baseline are categorized as moderate (5-7), and severe (8-10). 
 
 
Table 14.2.8 
Time to Meaningful Pain Relief  
ITT Population 
 
Use same shell as Table 14.2.4 
(Programmers Note- Please add the following footnote- Abbreviation- Q1- 25th Percentile, Q3- 75th Percentile  
[1] From Kaplan-Meier Estimates.  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means 
that patients in the Ibuprofen groups achieved pain relief faster than the placebo. 
Note- Time of meaningful pain relief is the time of the first reported meaningful (subjective) pain relief assessed by stopping the second stopwatch. Pain scores at baseline pain) are 
categorized as moderate (5-7), and severe (8-10 
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Table 14.2.9 
Time to Onset of Analgesia  
ITT Population 
 
 
Category/Statistic  
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Number of Subjects with First Perceptible Pain 
Relief and Meaningful Pain Relief 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Number of Subjects Censored  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Time to onset of analgesia (hours) [1] 
 
 
 
       Median (95% CI) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
XX.XX (XX.XX, XX.XX) 
        Q1  
XX.XX  
XX.XX  
XX.XX 
        Q3 
XX.XX  
XX.XX  
XX.XX 
        p-value (vs placebo) [2] 
0.XXXX 
0.XXXX 
 
        p-value (PR vs IR) [2] 
0.XXXX 
 
 
        Range (Min-Max) 
XX.X-XX.X 
XX.X-XX.X 
XX.X-XX.X 
 
 
 
 
Hazard Ratio (95% CI) (vs placebo) [3] 
XX.XX (XX.XX,XX.XX) 
XX.XX (XX.XX,XX.XX) 
 
Hazard Ratio (95% CI) (PR vs IR) [4] 
XX.XX (XX.XX,XX.XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 (Programmers Note- Please add the following footnote- Abbreviation- Q1- 25th Percentile, Q3- 75th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. If hazard ratio <1 means 
that patients in the Ibuprofen groups achieved pain relief faster than the placebo  
[4] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. If hazard ratio <1 means 
that patients in the PR group achieved pain relief faster than the IR. 
Note- If the subject has had meaningful pain relief (i.e., presses both stopwatches) then time to onset of analgesia is date/time when the first stopwatch is stopped. Pain scores at 
baseline are categorized as moderate (5-7), and severe (8-10). 
 
 
 
Table 14.2.10 
Time to Peak Pain Relief  
ITT Population 
Use same shell as Table 14.2.7 
 
(Programmers Note- Please add the following footnote- Abbreviation- Q1- 25th Percentile, Q3- 75th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means 
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that patients in the Ibuprofen groups achieved pain relief faster than the placebo. 
Note- Time of peak pain relief is the time when pain relief, which is measured on a scale from 0 (none)-4 (complete), is maximum. Subjects who do not experience any pain relief are 
censored at the time of their last pain assessment.  
 
 
 
Table 14.2.11 
Time to First use of Rescue Medication  
ITT Population 
 
Use same shell as Table 14.2.7 
 
(Programmers Note- Please add the following footnote- Abbreviation- Q1- 25th Percentile, Q3- 75th Percentile  
[1] From Kaplan-Meier Estimates  
[2] From Log-rank/Wilcoxon test stratified by baseline pain. 
[3] Hazard Ratio calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of >1 means 
that patients in the Ibuprofen groups refrained from taking rescue medication for longer than the placebo. 
 
Note- Subjects who do not take rescue medication are censored at the time of their last pain assessment. 
 
 
Table 14.2.12 
Proportion of Subjects Using Rescue Medication  
ITT Population 
  
 
 
Category/Statistic 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Number of subjects using Rescue Medication 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
Odds Ratio for Rescue Medication 
(Active/Placebo) [1] 
XX.XX 
XX.XX 
 
   (95% CI) 
(XX.XX,XX.XX) 
(XX.XX,XX.XX) 
 
p-value 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
Abbreviation: CI= Confidence Interval  
[1] Odds ratio, CI, and p-value are from a logistic regression model estimating the probability of using rescue medication with baseline pain and treatment arm 
as covariates in the model. An odds ratio < 1 means patients in the Ibuprofen groups are less likely to have used rescue medication compared to those in placebo. 
 
 
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 Table 14.2.13 
Proportion of Responders  
ITT Population 
 
(Use same shell as 14.2.12. Please use footnote below.) 
Abbreviation: CI=Confidence Interval  
Note- A subject with ≥ 30% improvement in NRS pain intensity from T0 (predose) without rescue medication during the first 8 hours is considered a responder. 
[1] Odds ratio, CI, and p-value are from a logistic regression model estimating the probability of being a responder with baseline pain and treatment arm as covariates in the model. An 
odds ratio > 1 means patients in the Ibuprofen groups are more likely to be responders compared to those in placebo. 
 
 
 
 
 
Table 14.2.14 
Summary of NRS Pain Intensity Difference Score  
ITT Population 
  
 
 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
PID 15 mins after Time 0  
 
 
 
    
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
Median 
XX 
XX 
XX 
Min, Max 
XX,XX 
XX,XX 
XX,XX 
 
LS Mean Difference from 
Placebo (95% CI)[1] 
XX.XX (XX.XX, XX.XX) 
 
XX.XX (XX.XX, XX.XX) 
 
 
p-value (vs Placebo) 
 
0.XXXX 
0.XXXX 
 
Abbreviations: PID= Pain Intensity Difference NRS- Numeric Rating Scale. 
Note- Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever. Pain intensity difference score at a time point is the 
difference in NRS pain intensity from baseline to that time point. 
[1] From a repeated measures mixed model with treatment, timepoint, treatment by timepoint, baseline and baseline by timepoint as fixed effects, and subject as a random effect.  
 
Programming Note- Please complete table for all scheduled time assessments. 
 
 
 
 
 
 
 
 
 
Page 284 of 351


 
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Table 14.2.15 
Summary of Pain Intensity Score at each Scheduled Time Point 
ITT Population 
Use same shell as Table 14.2.14 
(Programmers please add the following footnote-  
Note- Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever.  
Programming Note- Please complete table for all scheduled time assessments. No need for LS mean difference 95%CI and p value from 14.2.14 shell) 
 
 
 
 
 
 
 
 
 
Table 14.2.16 
Summary of Pain Relief at each Scheduled Time Point 
ITT Population 
 
 
 
 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
Pain Relief 5 mins after 
Time 0 
 
 
 
    
 
 
 
n 
XX 
XX 
XX 
Mean  
XX.X 
XX.X 
XX.X 
Std Dev 
XX.XX 
XX.XX 
XX.XX 
Median 
XX 
XX 
XX 
Min, Max 
XX,XX 
XX,XX 
XX,XX 
 
   None 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A Little Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Some Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   A lot of Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
   Complete Relief 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
Odds Ratio (vs placebo) [1] 
XX.XX 
XX.XX 
 
  95% CI 
(XX.XX,XX.XX) 
XX.XX,XX.XX) 
 
  p-value 
0.XXXX 
0.XXXX 
 
 
 
Page 285 of 351


 
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 (Programmers please add the following footnote-  
1] From a repeated measures proportional odds model with treatment, timepoint, treatment by timepoint, baseline and baseline by timepoint as fixed effects, and subject as a random 
effect. An odds ratio > 1 means that patients experienced higher pain relief than the placebo. 
Note- Subjects rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4.  
Programming Note- Please complete table for all scheduled time assessments.) 
 
 
 
Page 286 of 351


 
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Table 14.2.17 
Analysis of Patient Global Evaluation of Study Drug 
ITT Population 
 
 
 
Category/Statistics 
Ibuprofen PR 
(N=XX) 
Ibuprofen IR 
(N=XX) 
Placebo 
 
(N=XX) 
 
 
 
 
Poor 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Fair 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Good 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Very Good 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
Excellent 
X (XX.X%) 
X (XX.X%) 
X (XX.X%) 
 
 
 
 
Odds Ratio (vs placebo) [1] 
XX.XX 
XX.XX 
 
95% CI 
(XX.XX,XX.XX) 
XX.XX,XX.XX) 
 
p-value 
0.XXXX 
0.XXXX 
 
 
 
 
 
 
 
 
 
 
Note- Patient’s global evaluation of study drug is measured on a scale of 0=poor, 1=fair, 2=good, 3=very good, 4=excellent. 
[1] From a proportional odds model treatment group and baseline pain as covariates. An odds ratio > 1 means that patients rated active arm more highly than placebo 
 
 
 
  
 
Page 287 of 351


Statistical Analysis Plan  
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1.2. 
Planned Listing Shells 
Listing 16.2.1 
Subject Disposition 
All Subjects 
Date of Last Dose 
Date of Completion/ 
Discontinuation 
 Subject 
Number 
Randomized? 
Patient 
Status 
(Study Day) 
(Study Day) 
Reason for Discontinuation 
Was blind broken? 
XXXXXX 
Yes 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XX 
XXXXXX 
Yes 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XX 
XXXXXX 
Yes 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XX 
XXXXXX 
No 
DDMMMYYYY (X) 
DDMMMYYYY (X) 
XXXXXXXXXX: XXXXXXXXX 
XX 
XXXXXX 
No 
DDMMMYYYY 
(XX) 
DDMMMYYYY (XX) 
XXXXXXXXXXXXXXXXXXXXXX 
XX 
 Note: Study day is calculated relative to the date of first dose of study drug 
Programming Note: If reason for early termination is other, concatenate the specify text as follows: “Other: XXXXXXXXX”. If additional details about reason for discontinuation are 
present in DSREASSP, then concatenate reason for discontinuation with “DSREASSP”. 
If reason for early termination is lost to follow-up, concatenate with date of last contact as follows: “Lost to follow-up; date of last contact: DDMMMYYYY”.  
If reason for discontinuation is a PI decision, concatenate PI decision reason as follows: “PI Decision: XXXXXXXXXXX 
Page 288 of 351


 
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Listing 16.2.2.1 
Eligibility Criteria Not Met 
All Subjects 
 
 
Date (Study Day)  
All Inclusion 
Criteria Met? 
Any Exclusion 
Criteria Met? 
Subject Number 
Gender 
Screening 
Informed Consent 
 
 
 
 
 
 
 
 
XXXXXX 
XXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
No 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
No: 02, 09 
No 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
No: 06 
No 
 
 
 
 
 
 
XXXXXX 
XXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
Yes: 06 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
No 
 
 
 
 
 
 
XXXXXX 
XXXX 
DDMMMYYYY (-X) 
DDMMMYYYY (-X) 
Yes 
No 
 
 
 
 
 
 
Note: Study day is calculated relative to the date of first dose of study drug 
Programming note: If more than 1 inclusion or exclusion criterion number exists, concatenate with a comma. Decode any relevant criteria in the footnotes. 
 
Page 289 of 351


 
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Listing 16.2.2.2 
Screen Failures 
 
 
 
Subject 
Number 
Gender 
 
Date of Birth 
Age 
Screen Fail Date 
Screen Fail Reason  
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY 
XX 
DDMMMYYYY 
Inclusion #2 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY 
XX 
DDMMMYYYY 
Inclusion #6 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY 
XX 
DDMMMYYYY 
Inclusion #4, Exclusion #6 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
DDMMMYYYY 
XX 
DDMMMYYYY 
Other: XXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: If more than 1 inclusion or exclusion criterion number exists, concatenate with a comma  
Programming note: If additional details about reason for screen failure are present in, then concatenate reason for screen failure reason with “DSSFOTRN”. 
 
Page 290 of 351


 
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Listing 16.2.2.3 
Protocol Deviations 
All Subjects 
 
 
Subject 
Number 
Treatment 
Group 
Event Date 
(Study day) 
Event Type 
Violation 
Level 
Description 
 
 
 
 
 
 
XXXXXX 
XXXX 
              XXXX(XXX) 
XXXXXXXXXXX 
MAJOR 
XXXXXXX 
 
 
 
XXXXXXXXXXXXXX 
MINOR 
XXXXXXXXXXXXXXX 
 
 
 
 
 
 
XXXXXX 
XXXX 
XXXX(XXX) 
XXXXXXXXXXXX 
MINOR 
XXXXXXXXXXXXXXXXXXX 
 
 
 
XXXXXXXXXXXXXXXX 
MINOR 
XXXXXXXXXXX 
 
 
 
 
 
 
XXXXXX 
XXXX 
XXXX(XXX) 
XXXXXXXXXXXX 
MAJOR 
XXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
Note: Study day is calculated relative to the date of first dose of study drug. 
 
Page 291 of 351


 
Statistical Analysis Plan  
 
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Listing 16.2.3 
Analysis Populations 
All Subjects 
 
 Subject 
Number 
Treatment 
Group 
SAF 
 
PP 
 
ITT 
 
Primary Reason(s) for Exclusion 
 
 
 
 
 
 
XXXXXX 
XXX 
Yes 
No 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX. 
 
 
 
 
 
 
XXXXXX 
XXX 
Yes 
Yes 
 
 
 
 
 
 
 
 
XXXXXX 
XXXX 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: PP = Per Protocol Population; SAF= Safety Population; ITT= Intent-to-treat population 
 
 
Page 292 of 351


 
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Listing 16.2.4.1 
Demographics and Baseline Characteristics 
Safety Population 
 
 
 
 
 
Age 
 
 
Weight 
Height 
BMI 
Duration of 
Surgery 
 Subject 
Number 
Gender 
If Female, 
is she of 
childbearing 
potential? 
 
Treatment 
Group 
(years) 
Ethnicity 
Race 
(kg) 
(cm) 
(kg/m2) 
 
 
 
(hours) 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
XX.XX 
XXXXXX 
XX 
XX 
XX 
XX 
XXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.XX 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: BMI = Body mass index  
Note: Height, weight, and BMI are the values at Screening. 
  
 
Page 293 of 351


 
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Listing 16.2.4.2 
Medical History 
Safety Population 
 
Subject 
Number 
 
Treatment 
Group 
Any Medical  
History 
SOC/PT/VT     
Start date(Study Day) / 
End Date( Study Day) 
Ongoing? 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
XXX 
 
XX 
XX 
XXXX/XXX/XXX       
DDMMMYYYY/DDMMMYYYY(XXX) 
 
SOC = System Organ Class; PT = Preferred Term; VT = Verbatim Term. 
Note: All medical history terms are coded using MedDRA dictionary version 21.1. Study day is calculated relative to the date of first dose of study drug 
 
 
Page 294 of 351


 
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Listing 16.2.4.3 
Listing of Subject Randomization 
All Randomized Subjects 
 
Subject 
Number 
Randomization Date 
Randomization Time   
Randomization Number 
Kit Number Assigned 
Randomized Arm 
XXX 
DDMMMYYYY 
hh:mm       
XXX 
XXX 
XX 
XXX 
DDMMMYYYY 
hh:mm    
XXX 
XXX 
XX 
XXX 
DDMMMYYYY 
hh:mm          
XXX 
XXX 
XX 
XXX 
DDMMMYYYY 
hh:mm        
XXX 
XXX 
XX 
XXX 
DDMMMYYYY 
hh:mm         
XXX 
XXX 
XX 
 
 
Page 295 of 351


 
Statistical Analysis Plan  
 
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Listing 16.2.4.4 
Study Drug Administration 
Safety Population 
Subject 
Number 
Treatment 
Group 
Timepoint 
Was Study Drug 
Administered?   
Reason Not Administered 
Date of Administration 
Time of Administration 
XXX 
XXX 
0 hours 
Yes/no       
XXXXXXXXXXXXX 
DDMMMYYYY 
hh:mm    
XXX 
XXX 
8 hours 
Yes/no       
XXXXXXXXXXXXX 
DDMMMYYYY 
hh:mm    
XXX 
XXX 
12 hours 
Yes/no       
XXXXXXXXXXXXX 
DDMMMYYYY 
hh:mm    
XXX 
XXX 
16 hours 
Yes/no       
XXXXXXXXXXXXX 
DDMMMYYYY 
hh:mm    
 
 
 
 
 
 
 
 
 
 
 
 
Page 296 of 351


 
Statistical Analysis Plan  
 
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Listing 16.2.7.1 
Adverse Events 
Safety Population 
 
Subject 
Number 
Gender 
Treatment 
Group 
 
 
Any AEs 
reported? 
TEAE? 
SOC/PT/VT     
Start date 
time(Study Day) / 
End Date 
time(Study Day)  
Severity/ 
Relationship   
Medical  
Treatment 
Received? 
Outcome/ 
Action Taken   
Other 
Action 
Taken 
Serious?   Relationship 
to study 
drug 
XXX 
XXX 
XX 
XX 
NO 
XXXX/XXX/XXX   
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
 
No 
XX 
XXX 
XXX 
XX 
XX 
YES 
XXXX/XXX/XXX   
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
 
YES 
XX 
XXX 
XXX 
XX 
XX 
NO 
XXXX/XXX/XXX   
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
 
No 
XX 
XXX 
XXX 
XX 
XX 
YES 
XXXX/XXX/XXX   
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
 
No 
XX 
XXX 
XXX 
XX 
XX 
YES 
XXXX/XXX/XXX   
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
 
YES 
XX 
XXX 
XXX 
XX 
XX 
NO 
XXXX/XXX/XXX   
XXXX(XXX)/ 
XXXX(XXX) 
XXXXX/ 
XXXXX 
XX 
XXXX/ 
XXXX 
 
NO 
XX 
SOC = System Organ Class; PT = Preferred Term; VT = Verbatim Term. 
Abbreviation: TEAE-Treatment Emergent Adverse Event. 
Note: AEs are coded using MedDRA dictionary version 21.1. TEAE is defined as any AE that occurs or worsens in severity or frequency on or after the initiation of treatment. Study 
day is calculated relative to the date of first dose of study drug 
Programming note= Fatal/hospitalization/life threatening/persistent/congenital/important medical event 
 
Page 297 of 351


 
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Listing 16.2.7.2 
Serious Adverse Events  
Safety Population 
 
(Same shell as Listing 16.2.7.1) 
 
 
Listing 16.2.7.3 
Treatment emergent Adverse Events Related to Study Drug 
Safety Population 
 
(Same shell as Listing 16.2.7.1) 
 
 
Page 298 of 351


 
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Listing 16.2.7.4 
Deaths  
Safety Population 
 
Subject 
Number 
 
 
 
Gender 
 
 
 
Treatment 
Group 
Date of 
Death(Study Day) 
Cause of Death 
(Specify if Other) 
001-003 
 
 
DDMMMYYYY(XX) 
XXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note-Study day is calculated relative to the date of first dose of study drug. 
 
Page 299 of 351


 
Statistical Analysis Plan  
 
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Listing 16.2.8.1 
Clinical Laboratory Data: Serum Chemistry 
Safety Population 
 
Subject 
Number 
Gender 
Treatment 
Group 
Was 
Sample 
Collected? 
Date/Time of 
Assessment  
 
Test Name 
Standard 
Results 
Units 
Abnormal? / 
If Yes, H or 
L 
Comments/Reason 
not Done 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
NO 
 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
NO 
 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
YES/ 
NO 
 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
YES/ 
YES 
 
XXX 
XXX 
XX 
 
DDMMMYYYY(XX) 
 
XX 
XX 
NO 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation:H=High, L=Low 
Note: Study day is calculated relative to the date of first dose of study drug. 
 
Page 300 of 351


 
Statistical Analysis Plan  
 
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Listing 16.2.8.2 
Clinical Laboratory Data: Hematology 
Safety Population 
 
(Same shell as Listing 16.2.8.1) 
 
 
Listing 16.2.8.3 
Clinical Laboratory Data: Urine 
Safety Population 
 
(Same shell as Listing 16.2.8.1) 
 
Listing 16.2.8.4 
Clinical Laboratory Data: Coagulation 
Safety Population 
 
(Same shell as Listing 16.2.8.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 301 of 351


 
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Listing 16.2.8.5 
Serum and Urine Pregnancy Test  
Safety Population 
 
Subject 
Number 
 
 
 
Treatment 
Group 
 
 
 
Visit 
 
 
 
Was 
Sample  
Collected? 
 
 
 
 
Reason not 
collected  
Date of Assessment  
 
Time of 
Assessment 
Serum or Urine Test ? 
 
Result of 
Pregnancy 
Test 
001-
003 
 
 
 
 
DDMMMYYYY 
 
XXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 302 of 351


 
Statistical Analysis Plan  
 
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Listing 16.2.9.1 
Prior and Concomitant Medications 
Safety Population 
 
Subject 
Number 
 
Treatment 
Group 
Prior, Concomitant 
or Both? 
ATC Class (Level 4)/ 
/PT /VT     
Start date (Study Day)/ 
End Date (Study Day)  
 
Dose 
Unit   
Frequency    
 
Route 
Ongoing ? 
XXX 
 
XX 
Prior 
XXXX/XXX/XXX       
DDMMMYYYY(XX) / 
DDMMMYYYY(XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
Both 
XXXX/XXX/XXX       
DDMMMYYYY(XX)  / 
DDMMMYYYY (XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
Conmed 
XXXX/XXX/XXX       
DDMMMYYYY(XX)  / 
DDMMMYYYY(XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
 
XXXX/XXX/XXX       
DDMMMYYYY(XX)  / 
DDMMMYYYY (XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
 
XXXX/XXX/XXX       
DDMMMYYYY (XX) / 
DDMMMYYYY(XX) 
 
XXX 
XXX 
 
 
XXX 
 
 
 
XXXX/XXX/XXX       
DDMMMYYYY(XX)  / 
DDMMMYYYY (XX) 
 
XXX 
XXX 
 
 
ATC = Anatomic Therapeutic Chemical; PT = Preferred Term; VT = Verbatim Term. 
Note: Study day is calculated relative to the date of first dose of study drug. Medications are coded using WHO-DD Enhanced version MMM YYYY. Prior medications are defined as 
medications with start date/time before the administration of study drug. Concomitant medications are defined as any medication starting on or after the first dose of the study drug or 
starting before the first dose of the study drug and continuing after the first dose.  
 
 
 
Page 303 of 351


 
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Listing 16.2.9.1.1 
Rescue Medications 
Safety Population 
 
Subject 
Number 
 
Treatment 
Group 
Were 
any 
rescue 
medicati
ons 
reported
? 
Medicati
on  
Date for pain 
relief/pain 
intensity  
NRS Pain 
intensity 
assessment 
Pain Relief 
Assessment 
ATC Class 
(Level 4)/ 
/PT /VT     
Start datetime  
Dose 
Unit   
Frequency    
 
Route 
 
 
Ongoing ? 
XXX 
 
XX 
XX 
 
 
 
 
XXXX/XXX/
XXX       
XXXX 
XXX 
XXX 
 
 
XXX 
 
 
XX 
 
 
 
 
XXXX/XXX/
XXX       
XXXX 
XXX 
XXX 
 
 
XXX 
 
 
XX 
 
 
 
 
XXXX/XXX/
XXX       
XXXX 
XXX 
XXX 
 
 
XXX 
 
 
 
 
 
 
 
XXXX/XXX/
XXX       
XXXX 
XXX 
XXX 
 
 
XXX 
 
 
 
 
 
 
 
XXXX/XXX/
XXX       
XXXX 
XXX 
XXX 
 
 
XXX 
 
 
 
 
 
 
 
XXXX/XXX/
XXX       
XXXX 
XXX 
XXX 
 
 
ATC = Anatomic Therapeutic Chemical; PT = Preferred Term; VT = Verbatim Term. 
Note: Medications are coded using WHO-DD Enhanced version MMM YYYY.  
 
Page 304 of 351


 
Statistical Analysis Plan  
 
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Listing 16.2.9.2 
Vital Signs Measurements 
Safety Population 
 
Subject 
Number 
 
Treatment 
Group 
Were Vital 
Signs 
Collected? 
Temperature 
(Units) 
Heart Rate (Units) 
Respiration Rate 
(Units) 
Systolic Blood Pressure 
(Units)   
Diastolic Blood 
Pressure (units)   
XXX 
 
XX 
 
XXX 
XXX      
XXX      
XXX 
XXX 
XXX 
 
 
 
XXX 
XXX      
XXX      
XXX 
XXX 
XXX 
 
 
 
XXX 
XXX       
XXX       
XXX 
XXX 
XXX 
 
 
 
 
XXX     
XXX     
XXX 
XXX 
XXX 
 
 
 
 
XXX   
XXX   
XXX 
XXX 
XXX 
 
 
 
 
XXX 
XXX 
XXX 
XXX 
 
 
Note: Study day is calculated relative to the date of first dose of study drug. 
 
Page 305 of 351


 
Statistical Analysis Plan  
 
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Listing 16.2.9.2.1 
Physical Examination Findings 
Safety Population 
 
Subject 
Number 
 
Treatment 
Group 
Was 
Sample 
Collected? 
Date/Time of Assessment  
 
Were 
mouth and 
neck 
examined
? 
If no, 
reason 
Body 
System 
Standard 
Results 
Abnormal? / 
If Yes, CS 
Comments/Reason not 
Done 
XXX 
 
XX 
 
DDMMMYYYYThh:mm(XX) 
 
 
 
XX 
NO 
 
XXX 
 
XX 
 
DDMMMYYYYThh:mm (XX) 
 
 
 
XX 
NO 
 
XXX 
 
XX 
 
DDMMMYYYYThh:mm(XX) 
 
 
 
XX 
YES/ 
NO 
 
XXX 
 
XX 
 
DDMMMYYYYThh:mm(XX) 
 
 
 
XX 
YES/ 
YES 
 
XXX 
 
XX 
 
DDMMMYYYYThh:mm(XX) 
 
 
 
XX 
NO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Study day is calculated relative to the date of first dose of study drug. 
 
Page 306 of 351


 
Statistical Analysis Plan  
 
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Listing 16.2.9.3 
12-Lead Electrocardiogram Measurements 
Safety Population  
 
 
Abbreviation: CS=Clinically Significant, NCS=Not Clinically Significant 
 
Note: Study day is calculated relative to the date of first dose of study drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
Number 
 
 
 
Treatment 
Group 
 
Was ECG 
Performed? 
Date of Assessment 
(Study Day)  
 
Time of 
Assessment 
Heart Rate 
(Unit) 
RR Interval 
(Unit) 
PR Interval 
(Units) 
QRS (Unit) 
QT (Unit) 
QTc 
Interval 
(Unit) 
Investigator 
Interpretation 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX 
 
XXX 
XXX 
DDMMMYYYY(XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX 
 
XXX 
XXX 
DDMMMYYYY (XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Abnormal-
NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX 
 
XXX 
XXX 
DDMMMYYYY (XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Abnormal-
CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX 
 
XXX 
XXX 
DDMMMYYYY(XX) 
HH:MM 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
 
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Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
PCN Number RECK.177035 
 
Listing 16.2.9.3.1 
Alcohol Breathalyzer Test 
Safety Population 
 
 
Subject 
Number 
 
 
Treatment 
 
 
Was Alcohol 
Breathalyzer Test 
performed? 
 
Test Date/Time 
(Study Day) 
 
 
Alcohol 
Breathalyzer Test 
Result  
 
XXXX 
XX 
Yes 
DDMMMYYYYThh:mm(XX) 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Study day is calculated relative to the date of first dose of study drug. 
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Listing 16.2.9.4 
NRS Pain Intensity Assessment 
Safety Population 
 
 
Subject 
Number 
 
 
 
Treatment 
Group 
 
 
Was NRS 
Pain 
Assessment 
collected? 
 
 
Reason not 
collected  
 
 
Timepoint  
Was Rescue 
Medication 
Taken? 
(Y/N) 
Date time post 
dose 
 
NRS Pain 
Intensity Score 
 
NRS Pain 
Intensity Score 
when rescue 
medication was 
taken  
Responder 
(Y/N) 
XXXX 
 
XX 
Yes 
XXXXXXXX 
XXX 
 
XXXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note- Subjects rate their pain intensity using a numeric rating scale (NRS) from 0-10 where 0 = no pain and 10 = worst pain ever. A subject with ≥ 30% improvement in NRS pain 
intensity from T0 (predose) without rescue medication during the first 8 hours is considered a responder. 
 
Programing Note- For those cases where “Was rescue medication taken?” is ‘Yes’, the datetime needs to be presented in the “Date time post dose” column.  
 
 
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Statistical Analysis Plan  
 
Sponsor Reckitt Benckiser  
 
Protocol Number 5003601  
 
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Listing 16.2.9.5 
Pain Relief Scores 
Safety Population 
 
 
Subject 
Number 
 
 
Treatment 
Group 
 
 
Was 
assessment 
completed? 
 
 
Reason not 
collected  
 
 
 
Date of 
Assessment 
 
 
 
Date time pain 
relief collected 
 
 
Timepoint  
Was Rescue 
Medication 
Taken? 
(Y/N) 
Date time post 
dose 
 
How much relief 
have you had 
since your 
starting pain? 
XXXX 
XX 
Yes 
XXXXXXXX 
 
 
XXX 
 
XXXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                Note: Subjects rate their pain relief relative to Time 0 using a 5-point categorical scale, none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. 
 
Programing Note- For those cases where “Was rescue medication taken?”  is ‘Yes’, the datetime needs to be presented in the “Date time post dose” column                 
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Statistical Analysis Plan  
 
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Protocol Number 5003601  
 
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Listing 16.2.9.6 
Time to Pain Relief (Stopwatches)  
Safety Population 
 
 
Subject 
Number 
 
 
 
Treatment 
Group 
 
 
Which stopwatch 
pressed, perceptible or 
meaningful 
Hours on 
Stopwatch 
 
Minutes on 
stopwatch 
 
Seconds on 
stopwatch 
XXXX 
 
XX 
Perceptible/meaningful 
XX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Perceptible pain relief stopwatch refers to the first stop watch and meaningful pain relief, the second stopwatch.
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Statistical Analysis Plan  
 
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Listing 16.2.9.7 
Subjects Global Evaluation of Study Drug  
Safety Population 
 
 
Subject 
Number 
 
 
 
Treatment 
Group 
 
Was Subject 
Global 
Evaluation of 
study drug 
completed 
 
Date/Time of 
evaluation 
Global evaluation 
score 
XXXX 
 
XX 
 
XXXX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                               Note: Patient’s global evaluation of study drug is measured on a scale of 0=poor, 1=fair, 2=good, 3=very good, 4=excellent 
 
 
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Figure 14.4.1.1 
Kaplan-Meier plot of time to first perceptible pain relief 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing first perceptible pain relief 
 
Figure 14.4.1.2 
Kaplan-Meier plot of time to Meaningful Pain Relief  
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing meaningful pain relief  
 
Figure 14.4.1.3 
Kaplan-Meier plot of time to onset of analgesia  
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing analgesia 
 
Figure 14.4.1.4 
Kaplan-Meier plot of time to peak pain relief 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients experiencing peak pain relief 
Figure 14.4.1.5 
Kaplan-Meier plot of time to first use of rescue medication 
ITT Population 
X-Axis- Time (hours) 
Y-Axis- Proportion of patients using rescue medication 
 
Figure 14.4.1.6 
Mean PID Scores versus Time 
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ITT Population 
x-axis Time (hours) 
y-axis- Mean PID score 
Present with error bars of +/- 1 standard error. 
 
Figure 14.4.1.7 
Mean Pain Relief Scores versus Time 
ITT Population 
x-axis Time (hours) 
y-axis- Mean pain relief score 
Present with error bars of +/- 1 standard error. 
 
 
 
Page 315 of 351


trfemlef i
' rm*#mFri: '
Sponsor
Reckitt Benckiser
Protocol Title:
A Randomized, Double-Blind, Double-Duflffiy, Parallel-Group,
Multiple-Dose, Active and Placebo-Controlled Efficacy Study of
Ibuprofen Prolonged-Release Tablets for the Treatment of Pain
after Surgical Removal of Impacted Third Molars
Protocol Number:
5003601
Premier Research PCN:
RECK.177035
Document Version:
Final vl.0
Document Date:
7-Oct-2019
Approvals
Biostatistician
Premier Research
Print Name: Raghu Vishnubhotla
Reckitt Benckiser
Representative
Print Name: Darren Tarsett
{6 - o91-20\\
Sign Name:
Version 1,0
Page 1 of36
16-Oct-2019 | 12:35:58 EDT
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
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Document History 
Not applicable. 
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Version 1.0     
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Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
List of Tables .................................................................................................................................. 5 
List of Figures ................................................................................................................................. 5 
1. 
Overview ............................................................................................................................. 6 
2. 
Study Objectives and Endpoints ......................................................................................... 6 
2.1. 
Study Objectives ........................................................................................................... 6 
2.1.1. Primary Objective ......................................................................................................... 6 
2.1.2. Secondary Objectives.................................................................................................... 6 
2.2. 
Study Endpoints ............................................................................................................ 7 
2.2.1. Safety Endpoints ........................................................................................................... 7 
2.2.2. Efficacy Endpoints ........................................................................................................ 7 
3. 
Overall Study Design and Plan ........................................................................................... 8 
3.1. 
Overall Design .............................................................................................................. 8 
3.2. 
Sample Size and Power ................................................................................................. 8 
3.3. 
Study Population ........................................................................................................... 8 
3.4. 
Treatments Administered .............................................................................................. 8 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................... 8 
3.6. 
Blinding and Unblinding............................................................................................... 8 
3.7. 
Schedule of Events ...................................................................................................... 10 
4. 
Statistical Analysis and Reporting .................................................................................... 13 
4.1. 
Introduction ................................................................................................................. 13 
4.2. 
Interim Analysis .......................................................................................................... 13 
5. 
Analysis Populations ......................................................................................................... 13 
6. 
General Issues for Statistical Analysis .............................................................................. 14 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 14 
6.1.1. Baseline ....................................................................................................................... 14 
6.1.2. Adjustments for Covariates......................................................................................... 14 
6.1.3. Multiple Comparisons ................................................................................................. 14 
6.1.4. Handling of Dropouts or Missing Data ....................................................................... 14 
6.1.5. Analysis Windows ...................................................................................................... 15 
6.1.6. Derived Variables ....................................................................................................... 16 
6.1.7. Data Adjustments/Handling/Conventions .................................................................. 19 
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Version 1.0     
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7. 
Study Patients/Subjects and Demographics ...................................................................... 20 
7.1. 
Disposition of Patients/Subjects and Withdrawals ..................................................... 20 
7.2. 
Protocol Violations and Deviations ............................................................................ 20 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 20 
7.4. 
Exposure and Compliance .......................................................................................... 21 
8. 
Efficacy Analysis .............................................................................................................. 21 
8.1. 
Primary Efficacy Analysis .......................................................................................... 21 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 21 
8.2.1. SPID ............................................................................................................................ 21 
8.2.2. TOTPAR ..................................................................................................................... 22 
8.2.3. SPRID ......................................................................................................................... 22 
8.2.4. Peak Pain Relief .......................................................................................................... 22 
8.2.5. Time to First Perceptible Pain Relief .......................................................................... 22 
8.2.6. Time to Meaningful Pain Relief ................................................................................. 23 
8.2.7. Time to onset of Analgesia ......................................................................................... 23 
8.2.8. Time to Peak Pain Relief ............................................................................................ 23 
8.2.9. Time to first use of Rescue Medication ...................................................................... 24 
8.2.10. Proportion of Responders ........................................................................................... 24 
8.2.11. Numeric rating scale (NRS) pain intensity difference (PID) ...................................... 24 
8.2.12. Pain intensity score at each scheduled time point ....................................................... 24 
8.2.13. Proportion of Subjects Rescue Medication ................................................................. 24 
8.3. 
Exploratory Efficacy Analysis .................................................................................... 25 
8.3.1. Global Evaluation of Study Drug ............................................................................... 25 
9. 
Safety and Tolerability Analysis ....................................................................................... 25 
9.1. 
Adverse Events ........................................................................................................... 25 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 26 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 26 
9.2. 
Clinical Safety Laboratory Data ................................................................................. 26 
9.3. 
Vital Signs ................................................................................................................... 26 
9.4. 
Concomitant Medication ............................................................................................. 26 
10. 
Changes to analysis planned in the protocol ..................................................................... 27 
11. 
References ......................................................................................................................... 27 
12. 
Tables, Listings, and Figures ............................................................................................ 27 
12.1. Planned Table Descriptions ........................................................................................ 28 
12.2. Efficacy Data .............................................................................................................. 28 
12.3. Safety Data .................................................................................................................. 29 
12.4. Planned Listing Descriptions ...................................................................................... 30 
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12.5. Planned Figure Descriptions ....................................................................................... 31 
Appendix 1: Premier Research Library of Abbreviations ............................................................ 32 
 
List of Tables 
Table 1: Schedule of Events ......................................................................................................... 11 
Table 2: Planned Assessment Times............................................................................................. 16 
Table 3: Demographic Data Summary Tables .............................................................................. 28 
Table 4: Efficacy Tables ............................................................................................................... 28 
Table 5: Safety Tables .................................................................................................................. 29 
Table 6: Planned Listings.............................................................................................................. 30 
Table 7: Planned Figures .............................................................................................................. 31 
 
List of Figures 
No table of figures entries found. 
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Statistical   Analysis Plan,  
 
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Protocol Number 5003601  
 
PCN Number RECK.177035 
Version 1.0     
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1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Reckitt 
Benckiser protocol number 5003601 (A Randomized, Double-Blind, Double-Dummy, Parallel-
Group, Multiple-Dose, Active and Placebo-Controlled Efficacy Study of Ibuprofen Prolonged-
Release Tablets for the Treatment of Pain after Surgical Removal of Impacted Third Molars), 
dated 20-Nov-2018, version 1.0. Reference materials for this statistical plan include the protocol 
and the accompanying sample data collection documents. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials1. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to Reckitt Benckiser’s study 
5003601. 
2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is: 
• To evaluate the superiority of 2 x 300 mg ibuprofen PR tablets compared with placebo in 
subjects experiencing acute moderate to severe pain after third molar extraction over 12 
hours post initial dose. 
2.1.2. Secondary Objectives 
The key secondary objectives are: 
• To evaluate the analgesic performance of a total daily dose of 1200 mg of ibuprofen PR 
formulation compared to ibuprofen immediate release (IR) formulation over 24 hours 
post initial dose. 
• To evaluate the safety and tolerability of 2 x 300 mg ibuprofen PR tablets. 
Additional secondary objectives include: 
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• To evaluate the total analgesic effect, peak analgesic effect, onset and duration of action 
and the subject’s overall assessment of the study medications. 
2.2. 
Study Endpoints 
2.2.1. Safety Endpoints 
The safety endpoints of this study include the following: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of changes in vital sign measurements 
2.2.2. Efficacy Endpoints 
2.2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the summed pain intensity difference (SPID) over 
0 to 12 hours (SPID12).  
2.2.2.2. 
Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints of this study include the following:  
• Summed pain intensity difference (SPID) over 0 to 24 hours (SPID24) after Time 0. 
• SPID4, SPID8 and SPID12  
• Sum of total pain relief (TOTPAR) over 0 to 4 hours (TOTPAR4), over 0 to 8 hours 
(TOTPAR8), over 0 to 12 hours (TOTPAR12) and over 0 to 24 hours (TOTPAR24) after 
Time 0. 
• Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over 
0 to 4 hours (SPRID4), over 0 to 8 hours (SPRID8), over 0 to 12 hours (SPRID12) and 
over 0 to 24 hours (SPRID24) after Time 0. 
• Response to study drug 
• Numeric rating scale (NRS) pain intensity difference (PID) at each scheduled timepoint 
after Time 0. NRS ranges from 0=no pain to 10=worst pain ever and pain relief is a 5 
point categorical scale 0=none, 1=a little, 2=some, 3=a lot, 4=complete. PID is the 
difference in NRS pain intensity between each time point and Time 0. 
• Pain intensity score at each scheduled time point after Time 0. 
• Peak pain relief 
• Time to onset of analgesia 
• Time to first perceptible pain relief 
• Time to peak pain relief 
• Proportion of subjects using rescue medication 
• Time to first use of rescue medication 
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2.2.2.3. 
Exploratory Endpoint 
• Patient’s global evaluation of study drug. It is measured on a scale of 0=poor, 1=fair, 
2=good, 3=very good, 4=excellent 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
3.2. 
Sample Size and Power 
The sample size determination is based on the primary efficacy variable, SPID12.  According to 
Farrar 2001, a clinically important improvement in pain is represented by a 2 point reduction on 
an 11-point NRS.  Based on a baseline pain score of 7 this corresponds to an approximate 30% 
reduction in pain.  An average 2 point difference in pain scores between ibuprofen PR and 
placebo across all 14 assessments up to 12 hours will correspond to a difference in SPID12 of 24 
points.  In a previous study, the pooled standard deviation (SD) for SPID12 was 31.65.  
Assuming the same variability in this study, a sample size of 40 subjects per group will have 
>90% power to detect a difference of 24 points in SPID12, between ibuprofen 2x300-mg PR 
tablets and placebo using a 2-sided test with an alpha level of 0.05.  In order to provide a robust 
estimate of treatment effect differences between PR and IR, and to obtain a more precise 
estimate for this comparison, a 3:3:1 allocation ratio will be used, so that 120 subjects are 
randomized into each of the PR and IR groups.  Thus 280 subjects will be enrolled in the study. 
3.3. 
Study Population 
Subjects with moderate to severe pain after extraction of 2 or more third molars will participate 
in this study. 
3.4. 
Treatments Administered 
Treatment A (test product): 2x300 mg ibuprofen PR tablets, BID (total daily dose 1200 mg) 
Treatment B (reference product): 2x200 mg ibuprofen IR tablets, TID (total daily dose 1200 mg) 
Treatment C: matching placebo tablets 
3.5. 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be randomized in a 3:3:1 ratio to receive 2x300 mg ibuprofen PR tablets 
Q12h, 2x200 mg ibuprofen IR Q8h, or placebo using permuted blocks of fixed size.  The 
randomization will be stratified by baseline pain category (moderate or severe) using a 
categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and severe 
(8-10).  The randomization schedule will be prepared by a statistician not otherwise involved in 
the study.  Randomization will be performed using an interactive response system (IRT).   
3.6. 
Blinding and Unblinding 
This is a double-blind, double-dummy study. There will be two placebo tablets designed to be 
comparable to each of the active products (PR and IR) in both shape, size, color and weight. 
All subjects will receive 4 tablets at each dosing timepoint.  All subject packs will be designed 
and labelled to ensure blinding is maintained. 
Access to the unblinding codes will be restricted to personnel not otherwise involved in the study 
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and will be available to the investigator only in the case of a subject requiring unblinding prior to 
database lock.  
Unblinding will only occur after database lock or in the case of emergency unblinding. 
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3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1. 
 
 
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Table 1: Schedule of Events 
 
 
 
 
Page 326 of 351
I 
Screening 
(Day -28 to 
Day -1) 
P,re-
Surgery 
Pre-
dose 
Written informed consent 
X 
Assign a screening number 
X 
In clu siontexclus ion criteria 
X 
X 
Demographics 
X 
Medical llistory 
X 
Xb 
Physical examination° 
X 
Vital signsd 
X 
X 
X 
Height, weighl and BMI 
X 
Clinical laboratory tests (llematology, 
X 
cllemistry, urinalysis) 
Electrocardiogram 
X 
Pregnancy test for female subjects of 
X 
X 
cllildbearing potentiale 
Urine drug screen 
X 
X 
Alcohol breatllalyzer test 
X 
oral radiograp17y1 
X 
Review study restrictions witll subject 
X 
Pain intensity (NRS)9' 
X 
Randomisation 
X 
Dosing with study drug 
Stopwatch assessment" 
Pain relief (5-point categor1ical scale)g 
Surgery (Day 1) 
Post-op 
1, 1.5, 2, 3, 4, 
15, 30 
5, 6, 7, 8, 
0 1'1 
45 min 
10 h 
12 h 
X 
X 
X 
X 
Oh 
8h 
12 h 
X 
X 
X 
X 
Day2 
16 
h 
24h 
X 
X 
X 
16h 
X 
premier' 
research) 
Follow-up 
(Day 8 ±2 days) or 
ETk 
X 
X 


 
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Page 327 of 351
I 
SCireening 
(Day -28 to 
Day -1) 
Pre-
Surge1ry 
Pre-
dose 
Global evaluation of study drug; 
Concomitant medications 
Xb 
X 
Adverse eventsi 
X 
X 
Dispense/prescribe pain medication for use at 
llome, as needed 
Collect unused home pain medications, as 
needed 
Discharge from study site 
Surgery (Day 1) 
Post-op 
1, 1.5, 2, 3, 4, 
15, 30, 
5, 6, 7, 8, 
Oh 
45 min 
10 h 
X 
X 
X 
X 
X 
X 
12 h 
X 
X 
Day 2 
16 
premier' 
research) 
Follow-up 
(Day 8 ±2 days) or 
ETk 
h 
24h 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BMl=body mass index: ET=-early termination: h=hour, min=minute; NRS=numeric rating scale; pre-op=pre--0perative; post-op=post-operative _ 
a Times listed are relative to dosing with study drug. 
b Medical history and concomitant medication use since Screening will be updated on Day 1 before surgery 
c A complete physical examination (excluding the genitourinary examination) will be performed at Screening. An abbreviated confirmatory physical assessment, 
including an examination of tile subject's moutll and neck, will be performed at tile Follow-up Visit (or Eanly Term inalion Visit). 
d Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at tile following times: at screening, before surgery, Wittlin 30 minutes 
before Tiime 0, ·12 ti ours after Time 0, 24 hours after Time 0, and/or immediately before the first dose of rescue medication, and at tile Follow-up Visit (or Early 
Termination Visit). 
e Serum pregnancy test at Screening and urine pregnancy test before surgery on Day 1 (female subjects of childbearing potential only). Test results must be 
negative for the subject to continue in the study. 
f 
Oral radiographs taken within 1 year before Screening will be acceptable and do not need to be repeated. 
g Pain assessments will be conducted (pre-dose, if at one of tile dosing timepoints of O, 8, 12 or 16 hours) at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 
8, 10, 12, 16 and 24 llours after Time o and immediately before eacll dose of rescue medication. Pain intensity will also be assessed pre-dose. At each 
assessment time point, tile pain intensity assessment will be completed first and tile pain relief assessment will be completed second. Subjects will not be 
able to compare their responses with their previous responses. Note for assessments less than 1 hour apart a window of +/-2 min is allowable wll ilst for 
assessments at least 1 llour apart a +l-5 min window is allowable. 
h Two stopwatches will be started immediately after tile subject has swallowed the first dose of study drug with 8 ounces of water (Time 0). Subjects will record 
the time to perceptible and meaningful pain relief, respectively, by stopping the stopwatches. 


 
Statistical   Analysis Plan,  
 
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4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population in each of the treatment arms, unless otherwise specified. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests. In addition to what is detailed in the SAP, other additional 
analyses may be conducted on the data which will only serve as exploratory evidence and the 
unplanned nature of these analyses will be made clear in the Clinical Study Report. 
4.2. 
Interim Analysis 
No interim analyses are planned. 
5. 
Analysis Populations 
The following analysis populations are planned for this study: 
• Safety Population (SAF): The Safety Population includes all subjects who receive any 
amount of planned study medication. Subjects will be assigned to treatment received. 
• Intent-To-Treat Population (ITT): The ITT population includes all subjects who are 
treated with study drug and who have at least 1 pain assessment after Time 0.  The ITT 
population is the primary population for the efficacy analysis. Subjects will be assigned 
to treatment randomized. 
• Per Protocol (PP): The PP Population will consist of all ITT subjects who do not incur a 
major protocol violation that would challenge the validity of their data.  This population 
will be determined at a data review meeting prior to database lock and used to evaluate 
the sensitivity of the primary efficacy analysis. Subjects will be assigned to treatment 
received. 
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6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last observation recorded prior to the first dose of study drug will be used as the baseline 
observation for all calculations of change from baseline.  
6.1.2. Adjustments for Covariates 
For the primary endpoint analysis, the baseline NRS pain score will be included as a covariate. 
For the secondary endpoint analyses, baseline pain will be included as a covariate for SPID, 
SPRID, and TOTPAR variables.   
For the proportion of subjects who are responders and the proportion of subjects using rescue 
medication, logistic regression models will adjust for baseline pain. 
For time to event endpoints, baseline pain will be included as a stratification factor.  
6.1.3. Multiple Comparisons 
No adjustment for multiplicity is required for the primary efficacy analysis – a single comparison 
of SPID12 for placebo versus SPID12 for ibuprofen PR. 
No adjustments will be made for multiple comparisons for other endpoints. 
6.1.4. Handling of Dropouts or Missing Data 
Missing pain assessments for all efficacy analyses will be handled as follows: 
• Missing pain assessments scheduled before the first observed assessment will be imputed 
with the subject’s worst observed pain assessment. 
• Missing intermediate pain assessments will be replaced by linear interpolation. 
• Missing pain assessments at the end of the observation period due to premature 
discontinuation of pain assessments will be imputed by carrying forward the last 
observation prior to that missing. 
All data for assessments other than pain assessments will be analyzed as collected; missing data 
due to premature termination or any other reason will be left as missing. Since this is a short-
term study and subjects remain at the study site throughout the 24-hour pain assessment period, 
the discontinuation rate and the amount of missing data is expected to be minimal.   
In the event that more than 10% of subjects in ibuprofen IR or PR arms take rescue medication 
within the first 12 hours other sensitivity analyses may be performed such as a tipping point 
analysis. These sensitivity analyses will be applicable to assessments taken within 4 hours after 
rescue. The missing pain assessments of subjects who take rescue medication will be assumed to 
be missing at random (MAR).  Standard multiple imputation of the pain assessments under the 
MAR assumption is applied using PROC MI, using treatment group and baseline pain as 
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covariates. The missing pain assessment values after rescue medication are imputed. The 
resulting imputed datasets are analyzed using the ANOVA technique described in Section 8.1. 
The results of these analyses are pooled using PROC MIANALYZE. 
The robustness of the MAR assumption and the impact of the missing data is further investigated 
via a tipping point approach. The tipping points are defined to be the particular setting for the 
missing pain assessment values that would change the study’s conclusions. Multiple imputation 
under the Missing Not At Random (MNAR) assumption is applied by searching for a tipping 
point by using “shift” approaches until the MAR inferences change from significance to non-
significance, or vice-versa. The shifts are applied to the Least Squares mean (LS means from the 
ANOVA analysis) for the subjects who take rescue medication in the Ibuprofen PR treatment 
arm. 
6.1.5. Analysis Windows 
Subjects are required to record their pain assessment (NRS and pain relief) immediately prior to 
each dose of rescue medication. The primary analysis will use windowed worst observation 
carried forward (WOCF) methodology for subjects who use rescue medication.  If a subject 
received rescue medication at time x, for any time point within x + 4 hours, the highest pain 
score from time 0 up until time x will be used. If the pain score for the windowed observation is 
higher than the worst observed score, it will not be replaced.  The same approach will be used for 
pain relief scores. The following sensitivity analyses will also be performed for the primary 
endpoint SPID12: 
1. Analysis using windowed WOCF based on the PP population. 
2. Pain assessments are used regardless of whether rescue medication has been taken, and 
no adjustment is made for use of rescue medication.  In this analysis, the pain assessment 
recorded at the time of rescue medication is disregarded (unless it coincides with a 
planned pain assessment). This analysis will be done on the ITT population. 
3. All pain assessments recorded after the first dose of rescue medication has been taken 
will be disregarded. WOCF and LOCF (Last Observation Carried Forward) imputation 
methods will then be used to impute the disregarded data. 
a. WOCF- The worst (highest) pain assessment until first dose of rescue medication 
will be used to impute all subsequent pain assessments. In other words, this 
method would be treating the subject as if they got no worse than their worst 
observed value prior to rescue medication. This analysis will be done on the ITT 
population. 
b. LOCF-Also, this scenario will be analyzed using LOCF method. In this LOCF 
analysis, the pain assessment taken immediately prior to/at the time of rescue 
medication will be taken as the last observed score, i.e., this method would be 
treating the subject as if they got no worse than their last observed value prior to 
rescue medication. This analysis will be done on the ITT population. 
4. If more than 10% of subjects in either Ibuprofen group use rescue medication in first 12 
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hours, then a tipping point analysis will be implemented for all pain assessments made 
within 4 hrs after rescue medication. This will be done on the ITT population. 
For pain assessments less than 1 hour apart a window of +/- 2 minutes is allowable, while for 
assessments at least 1 hour apart a +/- 5 minute window is allowable. 
6.1.6. Derived Variables 
At each assessment time point, subjects will complete the pain intensity NRS assessment first 
and the pain relief assessment second. 
Planned assessment time points are as follows: 0 (predose), 15, 30, and 45 minutes, and 1, 1.5, 2, 
3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours after Time 0.  Please see Table 2 below. 
 
Table 2: Planned Assessment Times 
i 
Ti (hours) 
0 
0 (predose) 
1 
0.25 
2 
0.5 
3 
0.75 
4 
1 
5 
1.5 
6 
2 
7 
3 
8 
4 
9 
5 
10 
6 
11 
7 
12 
8 
13 
10 
14 
12 
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15 
16 
16 
24 
 
• SPID-12 = summed pain intensity difference (change from Time 0) under the numeric 
rating scale (NRS)-time curve from 15 min through 12 hours calculated using the linear 
trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of 
study drug. Scheduled time points in Table 2 will be used when actual time is missing. 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷12 = ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑆𝑆𝑃𝑃𝐷𝐷𝑖𝑖
14
𝑖𝑖=1
 
 
Where T0 =0, Ti is the actual time, and PIDi is the PID score at time Ti  
PID is defined as  
 
𝑆𝑆𝑃𝑃𝐷𝐷𝑖𝑖= 𝑆𝑆𝑆𝑆𝑖𝑖−𝑆𝑆𝑆𝑆0 
 
Where PI is the pain intensity as measured by the NRS scale. 
• SPID-x = summed pain intensity difference (change from Time 0) under the numeric rating 
scale (NRS)-time curve from 15 min through x hours calculated using the linear trapezoidal 
rule and the actual time points, where Time 0 is the time of the first dose of study drug. 
Scheduled time points in Table 2 will be used when actual time is missing. X = 4, 8, and 
24. 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥= ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑆𝑆𝑃𝑃𝐷𝐷𝑖𝑖
𝑦𝑦
𝑖𝑖=1
 
 
For x=4 y=8; x=8 y=12; x=24 y=16. 
• TOTPAR-x = total pain relief under the Pain Relief Scale (0 – 4) from 15 min through x 
hours calculated using the linear trapezoidal rule and actual time points, where Time 0 is 
the time of the first dose of study drug. Scheduled time points in Table 2 will be used when 
actual time is missing.  x = 4, 8, 12, and 24. 
 
 
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𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑅𝑅𝑥𝑥= ෍
(𝑇𝑇𝑖𝑖−𝑇𝑇𝑖𝑖−1) ∗𝑆𝑆𝑃𝑃𝑅𝑅𝑖𝑖
𝑦𝑦
𝑖𝑖=1
 
For x=4 y=8; x=8 y=12; x=12 y=14; x=24 y=16. PARi is the pain relief score on the Pain Relief 
Scale (0-4) at time Ti  
 
• SPRID-x = summed pain relief (TOTPAR) and intensity difference (SPID) from 15 min 
through x hours calculated using the linear trapezoidal rule and actual time points, where 
Time 0 is the time of the first dose of study drug. Scheduled time points in Table 2 will be 
used when actual time is missing. X = 4, 8, 12, and 24. 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥= 𝑆𝑆𝑆𝑆𝑆𝑆𝐷𝐷𝑥𝑥+ 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑅𝑅𝑥𝑥 
 
• Responder: subject with ≥ 30% improvement in NRS pain intensity from T0 (predose) 
without rescue medication during the first 8 hours. If a subject takes rescue medication 
prior to the 8-hour pain assessment or if the 8-hour assessment is not performed they will 
be considered a non-responder. i.e., 
(𝑆𝑆𝑆𝑆0 −𝑆𝑆𝑆𝑆8)
𝑆𝑆𝑆𝑆0
∗100 ≥30 
Where PI0 and PI8 are the predose and 8-hour NRS pain intensity measurements 
respectively. 
• Time to onset of analgesia = If the subject has had meaningful pain relief (i.e., presses both 
stopwatches) then time to onset of analgesia is date/time of perceptible pain relief – 
date/time of the first dose of study drug. If subjects don’t experience both perceptible pain 
relief and meaningful pain relief during the 8-hour interval after Time 0, time to onset to 
analgesia will be right censored at the time of their last pain assessment in the first 8 hours. 
For subjects who take rescue medication prior to onset of analgesia during the 8-hour 
interval after Time 0, time to onset of analgesia will be right censored at the time rescue 
medication was taken. 
• Time to first perceptible pain relief = date/time of the first reported pain relief (any) as 
assessed by the subject (i.e. subject stops the first stopwatch (irrespective of the second 
stopwatch)) – date/time of the first dose of study drug. If subjects don’t experience 
perceptible pain relief during the 8-hour interval after Time 0, time to first perceptible pain 
relief will be right censored at the time of their last pain assessment in the first 8 hours. If 
the first stopwatch is not stopped but the second stopwatch is stopped, time will be left 
censored at the time that the second stopwatch is stopped. In other words, it is assumed that 
the first stopwatch measurement has already occurred but was missed/not recorded. For 
subjects who take rescue medication prior to first perceptible pain relief during the 8-hour 
interval after Time 0, time to first perceptible pain relief will be right censored at the time 
rescue medication was taken. 
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• Time to meaningful pain relief = date/time of the first reported meaningful (subjective) 
pain relief as assessed by the subject (i.e. the subject stops the second stopwatch) – 
date/time of the first dose of study drug. If subjects don’t experience meaningful pain relief 
during the 8-hour interval after Time 0, time to meaningful pain relief will be right censored 
at the time of their last pain assessment in the first 8 hours. If the subject stops the second 
stopwatch but doesn’t stop the first stopwatch or the first stopwatch assessment is missing, 
then time to meaningful pain relief will be right censored at the time of their last pain 
assessment in the first 8 hours. For subjects who take rescue medication prior to achieving 
meaningful pain relief during the 8-hour interval after Time 0, time to meaningful pain 
relief will be right censored at the time rescue medication was taken. 
• Peak pain relief- Pain relief is measured on a scale from 0 (None) to 4 (Complete). If PRi 
is the pain relief measurement at time Ti , peak pain relief PPR is defined as 
 
𝑆𝑆𝑆𝑆𝑃𝑃= max{𝑆𝑆𝑅𝑅1, 𝑆𝑆𝑅𝑅2, 𝑆𝑆𝑅𝑅3, … , 𝑆𝑆𝑅𝑅16} 
 
• Time to first use of rescue medication = date/time to the first dose of rescue medication – 
date/time of the first dose of study drug. If subjects don’t take rescue medication, subjects 
will be right censored at the time of their last pain assessment. 
• Time to peak pain relief = date/time of peak pain relief– date/time of the first dose of study 
drug. Time of peak pain relief is the time Ti when peak pain relief (PPR) first occurs. If no 
pain relief is observed then the time to peak pain relief will be right censored at the time of 
their last pain assessment. 
• Change from baseline = value at current time point – value at baseline.  
• TEAE = TEAE is defined as any event that started or worsened in intensity or relationship 
to treatment on or after the first dose of study drug. 
6.1.7. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
All P values will be displayed in four decimals and rounded using standard scientific notation (e.g., 
0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as <0.0001. 
Adverse events will be coded using the MedDRA version 21.1 thesaurus. 
A treatment related AE is any AE with a relationship to the study drug with possible, probable or 
certain causality to the study drug as determined by the Investigator. 
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If partial dates occur, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if just day is missing then the day assigned is the first day of the month or 
the date of first dose (if in the same month), whichever is later; if just month is missing then the 
month assigned is the month of the first dose, unless that results in a date prior to the first dose in 
which case the month after the first dose is used; and if both month and day are missing then the 
month assigned is the month of the first dose and the day assigned is either the first day of the 
month or the first dose date, whichever is later. 
If partial times occur, the convention is as follows: if the missing time occurs on the day of the 
first dose and both the hour and minute are missing then the time assigned is the time of the first 
dose, otherwise if both the hour and minute are missing and the date is not the date of first dose 
the time assigned is 12:00; if the date is the same as the date of the first dose and only hour is 
missing the hour assigned is 12 or the hour of first dose, whichever is later, and if the date is the 
same as the date of first dose and only the minute is missing the minute assigned is 30 or the 
minute of first dose, whichever is later. Otherwise the hour assigned is 12 if the hour is missing 
and the date is not the same as the date of first dose and the minute assigned is 30 is the the date 
is not the same as the date of first dose. 
These conventions will be applied only to adverse event onset dates and times with the following 
precaution:  if the missing date and time reflect the date and time of onset of an adverse event, 
the modified date and time will be constructed to match the first documented date/time post drug 
administration while preserving the order in which the AE was reported in the CRF. 
7. 
Study Patients/Subjects and Demographics 
7.1. 
Disposition of Patients/Subjects and Withdrawals 
Disposition will include tabulations of the number of subjects screened, number of subjects 
randomized into each treatment group, the number of subjects who received treatment, tabulated 
reasons for discontinuation from the study, and number of subjects in each analysis population. 
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be listed. 
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, gender, race, ethnicity, height, weight, BMI, baseline pain category 
and baseline pain (continuous) will be presented by treatment groups and overall. For the 
continuous variables, the number of non-missing values and the mean, standard deviation, 
minimum, median and maximum will be tabulated.  
For the categorical variables, the counts and proportions of each value will be tabulated.    
These analyses will be conducted for the ITT, PP, and Safety populations. 
The number and percent of subjects reporting various medical histories, grouped by MedDRA 
system organ class and preferred term (coded using MedDRA v21.1), will be tabulated by 
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treatment group. This analysis will be conducted for the Safety Population. Physical examination 
findings will also be summarized by body system and examination result- Normal, Abnormal – 
Clinically Significant, Abnormal-Not Clinically Significant. 
7.4. 
Exposure and Compliance 
The number of doses taken and treatment duration will be summarized by descriptive statistics. 
All study drug will be administered in clinic. The total number of tablets taken, and the number 
of tablets with active ingredient taken at each time point will be summarized. The dosage (in mg) 
of active ingredient taken and duration of exposure, from first dose to last dose of the study 
treatment will be summarized using descriptive statistics. Any deviations from the planned dose 
should be reported. 
8. 
Efficacy Analysis 
8.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the summed pain intensity difference (SPID) over 0 to 12 hours 
(SPID12).  The primary endpoint will be used to compare the test product (2x300 mg ibuprofen 
PR tablets) against placebo. 
The primary efficacy hypothesis is that SPID12 for placebo is equal to SPID12 for ibuprofen 
2x300 mg PR tablets.  The primary analysis will be an ANCOVA model that includes the main 
effect of treatment and a covariate of the baseline NRS pain score and will use windowed worst 
observation carried forward (WOCF) imputation for subjects who use rescue medication.  The 
primary analysis will be based on a 2-sided test at the significance level of 0.05.  The treatment 
difference will be presented with a 95% confidence interval.   
Normality assumptions will be tested. If the data is considered non-normal, the Wilcoxon rank 
sum test will be used for the comparison between treatments, and the point estimate and 95% 
confidence interval will be calculated using the Hodges-Lehmann estimator. 
The primary efficacy analysis will be based on the ITT population. These analyses will be 
repeated for the PP population.  SPID-12 scores will also be summarized by baseline pain 
category (moderate or severe). 
8.2. 
Secondary Efficacy Analysis 
8.2.1. SPID 
Summed Pain Intensity Difference (SPID) will be calculated for secondary efficacy analysis as 
described in Section 6.1.6 at 4, 8, and 24 hours. Descriptive statistics by treatment regimen will 
be produced. 
ANCOVA models for comparing placebo with other treatment regimens with SPID as the 
dependent variable and treatment group and baseline pain as covariates will be generated. These 
models will be computed for SPID4, SPID8 and SPID12. The least square (LS) mean and 
standard error (SE) for each treatment group will be estimated and the difference in LS means 
and 95% confidence interval (CI) for the comparison of placebo with the IR and PR treatment 
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regimens will be estimated. P-values will be reported but no formal statistical inferences will be 
made on the basis of these tests.  In addition, for the SPID24 endpoint, the difference in LS 
means and 95% CI for the IR versus PR groups will be presented. In the event that normality 
assumptions are violated for a parameter, non-parametric analysis methods will be used. 
8.2.2. TOTPAR 
Total pain relief (TOTPAR) will be calculated as described in Section 6.1.6 at 4, 8, 12 and 24 
hours. Descriptive statistics by treatment regimen will be produced. 
ANCOVA models for comparing placebo with other treatment regimens with TOTPAR as the 
dependent variable and treatment group and baseline pain as covariates will be generated. These 
models will be generated at TOTPAR4, TOTPAR8, TOTPAR12 and TOTPAR24. The LS mean 
and SE for each treatment group will be estimated and the difference in LS means and 95% CI 
for the comparison of placebo with the IR and PR treatment regimens will be estimated. P-values 
will be reported but no formal statistical inferences will be made on the basis of these tests. In 
the event that normality assumptions are violated for a parameter, non-parametric analysis 
methods will be used. 
8.2.3. SPRID 
Summed pain relief and intensity difference is the sum of TOTPAR and SPID and will be 
calculated at 4, 8, and 12 and 24 hours as described in Section 6.1.6. 
Descriptive statistics by treatment regimen will be produced for SPRID at each planned 
assessment time point.  
ANCOVA models for comparing placebo with other treatment regimens with SPRID as the 
dependent variable and treatment group and baseline pain as covariates will be generated. The 
LS mean and SE for each treatment group will be estimated and the difference in LS means and 
95% CI for the comparison of placebo with the IR and PR treatment regimens will be estimated. 
P-values will be reported but no formal statistical inferences will be made on the basis of these 
tests. In the event that normality assumptions are violated for a parameter, non-parametric 
analysis methods will be used. 
8.2.4. Peak Pain Relief  
Peak pain relief will be calculated as described in Section 6.1.6 and will be summarized by 
counts (and percentages) for each pain relief score.  It will be analyzed using a proportional odds 
model (an extension of the logistic regression). This method allows for an ordinal response 
variable with more than two categories. This model will include a factor for treatment and 
baseline pain intensity as a continuous covariate. For each of the PR and IR treatment regimens, 
the odds of being in a higher (better) pain relief category compared to placebo (odds ratio) will 
be presented with a 95% CI and associated p-value.  
8.2.5. Time to First Perceptible Pain Relief 
Time to first perceptible pain relief will be summarized using Kaplan-Meier methods. The 
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definition and censoring rules are described in Section 6.1.6. With baseline pain as a 
stratification factor, treatments will be compared to placebo using a stratified log-rank test or a 
stratified Wilcoxon test as appropriate. Summary tables will provide the number of subjects 
analyzed, the number of subjects censored, estimates for the 25th, 75th percentiles and median 
(including 95% CI), and associated p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated. 
8.2.6. Time to Meaningful Pain Relief  
Time to first meaningful pain relief will be summarized using Kaplan-Meier methods. The 
definition and censoring rules are described in Section 6.1.6. With baseline pain as a 
stratification factor, treatments will be compared to placebo using a stratified log-rank test or a 
stratified Wilcoxon test. Summary tables will provide the number of subjects analyzed, the 
number of subjects censored, estimates for the 25th, 75th percentiles and median (including 95% 
CI), and associated p-value for comparisons versus placebo.   
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated.  
8.2.7. Time to onset of Analgesia 
Time to onset of analgesia will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 6.1.6. With baseline pain as a stratification factor, 
treatments will be compared to placebo and with each other (IR vs PR) using a stratified log-rank 
test or a stratified Wilcoxon test. The summary tables will provide the number of subjects 
analyzed, the number of subjects censored, estimates for the 25th, 75th percentiles and median 
(including 95% CI), and associated p-value for treatment comparisons.   
A measure of the treatment effect comparing each of the active arms with placebo and with each 
other (IR vs PR) will be obtained by calculating a hazard ratio and 95% CI by fitting a Cox 
proportional hazards model with a factor for treatment group and baseline pain as a continuous 
covariate. The assumption of proportional hazards will first be evaluated.  
8.2.8. Time to Peak Pain Relief 
Time to peak pain relief will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 6.1.6. With baseline pain as a stratification factor, 
treatments will be compared to placebo using a stratified log-rank test or a stratified Wilcoxon 
test. The summary tables will provide the number of subjects analyzed, the number of subjects 
censored, estimates for the 25th, 75th percentiles and median (including 95% CI), and associated 
p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
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obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated.  
8.2.9. Time to first use of Rescue Medication 
Time to first use of rescue medication will be summarized using Kaplan-Meier methods. The 
definition of time to first use of rescue medication and censoring rules for subjects who don’t 
take rescue medication are described in Section 6.1.6. With baseline pain as stratification factor, 
treatments will be compared to placebo using a stratified log-rank test or a stratified Wilcoxon 
test. The summary tables will provide the number of subjects analyzed, the number of subjects 
censored, estimates for the 25th, 75th percentiles and median (including 95% CI), and associated 
p-value for comparisons versus placebo.  
A measure of the treatment effect comparing each of the active arms with placebo will be 
obtained by calculating a hazard ratio and 95% CI by fitting a Cox proportional hazards model 
with a factor for treatment group and baseline pain as a continuous covariate. The assumption of 
proportional hazards will first be evaluated. 
8.2.10.  Proportion of Responders 
For the proportion of subjects who are responders, a logistic regression model that adjusts for 
baseline pain (as a continuous covariate) and treatment arm will be used to evaluate the treatment 
effect. As a measure of treatment effect for each of the PR and IR groups versus placebo, odds 
ratios together with a 95% CI and p-values will be presented. 
8.2.11. Numeric rating scale (NRS) pain intensity difference (PID)  
PID at each scheduled time point will be calculated using the formula specified in Section 6.1.6. 
Descriptive summaries (including mean, SD, median, minimum and maximum) will also be 
presented by treatment group. 
8.2.12. Pain intensity score at each scheduled time point  
Pain intensity is measured using NRS at planned assessment time points. Descriptive summaries 
(including mean, SD, median, minimum and maximum) will also be presented by treatment 
group. 
8.2.13. Proportion of Subjects Rescue Medication 
The definition of rescue medication use is presented in Section 6.1.6. The proportion of subjects 
using rescue medication for pain will be analyzed using logistic regression. The logistic 
regression model will include treatment arm and baseline pain (as a continuous covariate) as 
covariates. As a measure of treatment effect for each of the PR and IR groups versus placebo, 
odds ratios together with a 95% CI and p-values will be presented. 
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8.3. 
Exploratory Efficacy Analysis  
8.3.1. Global Evaluation of Study Drug 
Subject’s global evaluation of study drug will be analyzed using a proportional odds model (an 
extension of the logistic regression). This method allows for an ordinal response variable with 
more than two categories. This model will include a factor for treatment group and baseline pain 
intensity as a continuous covariate. For each of the PR and IR treatment regimens, the odds of 
being in a higher (better) evaluation category compared to placebo (odds ratio) will be presented 
with a 95% CI and associated p-value. 
9. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported AEs, and changes in vital signs. 
All safety analyses will be performed on the Safety population. 
9.1. 
Adverse Events 
The number and percent of subjects reporting treatment emergent AEs, grouped by 
MedDRA system organ class and preferred term (coded using MedDRA v21.1), will 
be tabulated by severity and treatment group. In the case of multiple occurrences of the 
same TEAE within the same subject, each subject will only be counted once for each 
preferred term. 
The frequency and percentage of subjects reporting TEAEs, grouped by MedDRA SOC and PT, 
will be tabulated by treatment group for the SAF. Such summaries will be displayed for the 
following: 
• TEAEs by SOC and PT 
• TEAEs by SOC, PT, and severity 
• TEAEs by SOC, PT, and relationship to the study medication 
• TEAEs leading to death by SOC, and PT 
• Serious TEAEs other than deaths by SOC, and PT 
• TEAEs leading to premature discontinuation by SOC, and PT 
• Listing of non-TEAEs 
In the case of multiple occurrences of the same AE within the same subject, each subject will 
only be counted once for each preferred term. In summaries of AE by SOC and PT, along with 
the number (%) of subjects with at least 1 AE in the category, the number of events will be 
displayed. In the summaries showing severity and relationship to study medication the event with 
the maximum severity or strongest relationship will be reported. If a particular event is missing 
the severity and/or relationship, then the strongest possible severity or relationship will be 
assumed for analysis (severity = severe, relationship = certain). 
Missing and partially missing AE start and/or stop dates will be imputed for the purpose of 
statistical analysis, according to the specifications described in Section 6.1.7. 
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In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent will be 
flagged. 
9.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug, by treatment group, SOC, and preferred term will be prepared for the Safety 
Population. No inferential statistical tests will be performed. 
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and also tabulated by system organ class and preferred term 
and presented by treatment. 
9.2. 
Clinical Safety Laboratory Data 
Descriptive statistics for clinical safety laboratory data (laboratory data) recorded at screening 
will be presented overall and by treatment regimen. Summary tables by treatment regimen will 
be presented for each category of data separately. Routine clinical laboratory data will include 
hematology, serum chemistry, and urinalysis. Quantitative laboratory test result summaries will 
include N (population count for each regimen), n (number of subjects with non-missing values), 
mean, SD, median, and range. Qualitative tests (e.g., some urinalysis assessments) will be 
categorized accordingly. The set of laboratory parameters included in each table will correspond 
to those requested in the study protocol. Urine drug screen, alcohol breath analyzer and urine 
pregnancy test results will be presented in listings.  
9.3. 
Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for supine 
systolic blood pressure, supine diastolic blood pressure, heart rate, respiratory rate, and oral body 
temperature, and will be presented by treatment regimen. Summary statistics for 12-lead ECG 
parameters and counts for ECG interpretations at screening will be presented. 
9.4. 
Concomitant Medication 
Prior and concomitant medications will be summarized descriptively by treatment using counts 
and percentages. 
Prior medications will be presented separately from concomitant medications. Medications that 
started prior to the first dose of study drug will be considered prior medications whether or not 
they were stopped prior to the first dose of study drug. Any medications continuing or starting 
post the first dose of study drug will be considered to be concomitant. If a medication starts prior 
to the first dose and continues after the first dose of study drug, it will be considered both prior 
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and concomitant. Medications will be coded using Sept 2018 version of World Health 
Organization Drug Coding ASDFK Dictionary (WHODD). 
10. 
Changes to analysis planned in the protocol 
For the time to event endpoints an additional measure of the treatment effect comparing each of 
the active arms with placebo will be obtained by calculating a hazard ratio and 95% CI by fitting 
a Cox proportional hazards model with a factor for treatment group and baseline pain as a 
continuous covariate. The assumption of proportional hazards will first be evaluated. 
There has been a clarification to the definition of the ITT population to that stated in the 
protocol. The ITT population is defined as all subjects who are treated with study drug and who 
have at least 1 pain assessment after Time 0. In the protocol the ITT population was defined as 
subjects who have at least 1 pain relief assessment. 
11. 
References 
1. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
2. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
3. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
 
12. 
Tables, Listings, and Figures 
All listings, tables, and graphs will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (CRF page or listing number). 
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12.1. Planned Table Descriptions 
The following are planned summary tables for protocol number 5003601. The table numbers and 
page numbers are place holders only and will be determined when the tables are produced. 
Table 3: Demographic Data Summary Tables  
Table Number 
Population 
Table Title/Summary 
14.1 Displays of Demographics and Disposition Data 
Table 14.1.1 
All Subjects 
Subject Disposition 
Table 14.1.2 
Safety Population 
Demographics and Baseline Characteristics 
Table 14.1.2.1 
ITT Population 
Demographics and Baseline Characteristics 
Table 14.1.3 
Safety Population 
Medical History  
Table 14.1.4 
 Safety Population 
Prior Medications  
Table 14.1.5 
 Safety Population 
Concomitant Medications  
Table 14.1.6 
 All Enrolled Subjects 
Summary of Protocol Deviations  
Table 14.1.7 
Safety Population 
Summary of Study Drug Exposure 
12.2. Efficacy Data  
Table 4: Efficacy Tables 
 
 
 
 
 
Table Number 
Population 
Table Title/Summary 
14.2.1  
ITT Population 
Analysis of SPID-12 Scores  
14.2.1.1 
PP Population 
Analysis of SPID-12 Scores  
14.2.1.2 
ITT Population 
Analysis of Imputed SPID-12 Scores  
14.2.1.3 
PP Population 
Analysis of SPID-12 Scores- Sensitivity Analysis 
14.2.1.4 
ITT Population 
Summary of SPID-12 Scores by Baseline Pain 
14.2.2 
ITT Population 
Analysis of Summed Pain Intensity Difference Scores  
14.2.3 
ITT Population 
Analysis of Total Pain Relief Scores  
14.2.4 
ITT Population 
Analysis of Summed Pain Relief and Intensity Difference Scores  
14.2.5 
ITT Population 
Comparison of SPID-24 in Ibuprofen PR and IR arms 
14.2.6 
ITT Population 
Summary of Peak Pain Relief  
14.2.7 
ITT Population 
Time to First Perceptible Pain Relief  
14.2.8 
ITT Population 
Time to Meaningful Pain Relief  
14.2.9 
ITT Population 
Time to Onset of Analgesia  
14.2.10 
ITT Population 
Time to Peak Pain Relief  
14.2.11 
ITT Population 
Time to First use of Rescue Medication  
14.2.12 
ITT Population 
Proportion of Subjects Using Rescue Medication  
14.2.13 
ITT Population 
Proportion of Responders 
14.2.14 
ITT Population 
Summary of NRS Pain Intensity Difference Score  
14.2.15 
ITT Population 
Summary of Pain Intensity Score at each Scheduled Time Point 
14.2.16 
ITT Population 
Summary of Pain Relief at each Scheduled Time Point 
14.2.17 
ITT Population 
Analysis of Patient Global Evaluation of Study Drug 
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12.3. Safety Data 
Table 5: Safety Tables 
Table Number 
Population 
Table Title/Summary 
14.3.1 Summary of Treatment Emergent Adverse Events 
Table 14.3.1.1 
 Safety Population 
Overall Summary of Treatment-Emergent Adverse Events  
Table 14.3.1.2 
Safety Population 
Summary of Treatment-Emergent Adverse Events  
Table 14.3.1.3 
Safety Population 
Summary of Treatment-Emergent Adverse Events by Maximum Severity  
Table 14.3.1.4 
Safety Population 
Summary of Treatment-Emergent Adverse Events by Relationship to 
Study Drug  
Table 14.3.1.5 
Safety Population 
Summary of Non-Serious Treatment-Emergent Adverse Events  
14.3.2 Summary of Deaths, Other Serious and Significant Adverse Events 
Table 14.3.2.1 
 Safety Population 
Summary of Serious Adverse Events  
Table 14.3.2.2 
Safety Population 
Summary of Treatment Emergent Adverse Events Leading to 
Discontinuation  
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 
Table 14.3.3.1 
Safety Population 
Listing of Serious Adverse Events  
Table 14.3.3.2 
Safety Population 
Listing of Treatment Emergent Adverse Events Leading to  
Study Drug Discontinuation 
14.3.4 Abnormal Laboratory Value  
Table 14.3.4.1 
Safety Population  
Listing of  Potentially Clinically Significant Abnormal Laboratory Values   
14.3.5 Laboratory Data Summary Tables 
Table 14.3.5.1 
Safety Population  
Summary of Serum Chemistry Laboratory Results  
14.3.6 Other Safety Data Summary Tables 
Table 14.3.6.1 
 Safety Population 
Summary of Vital Signs  
Table 14.3.6.2 
Safety Population 
Summary of Electrocardiogram (ECG) Interpretations  
Table 14.3.6.3 
Safety Population 
Summary of 12-Lead Electrocardiogram (ECG) Parameters 
Table 14.3.6.4 
Safety Population 
Summary of Physical Examination Findings 
 
 
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12.4. Planned Listing Descriptions 
The following are planned data and patient/subject data listings for protocol number 5003601.  
In general, one listing will be produced per CRF domain. All listings will be sorted by treatment, 
site, and subject number. All calculated variables will be included in the listings. 
In all listings a blank line will be placed between each subject. Within a data listing, if an item 
appears line after line (e.g., repetition of subject number), then only the first occurrence will be 
displayed. 
In data listings, the information for one subject will be kept on one page if at all possible, rather 
than splitting a subject’s information across pages. 
Table 6: Planned Listings 
Data Listing Number 
Population 
Data Listing Title / Summary 
16.2.1 Subject Discontinuations/Completions 
 Listing 16.2.1 
All Subjects 
Subject Disposition 
16.2.2 Protocol Deviations 
Listing 16.2.2.1 
All Subjects  
Eligibility Criteria Not Met 
Listing 16.2.2.2 
All Subjects 
Screen Failures 
Listing 16.2.2.3 
All Subjects 
Protocol Deviations 
16.2.3 Subjects in Analysis Populations 
Listing 16.2.3 
All Subjects 
Analysis Populations 
16.2.4 Demographic Data and Other Baseline Characteristics 
Listing 16.2.4.1 
Safety Population 
Demographics and Baseline Characteristics 
Listing 16.2.4.2 
Safety Population 
Medical History 
Listing 16.2.4.3 
 All Randomized Subjects Listing of Subject Randomization  
Listing 16.2.4.4 
 Safety Population 
Study Drug Administration 
16.2.7 Adverse Event Listings (by Subject) 
Listing 16.2.7.1 
Safety Population 
Adverse Events  
Listing 16.2.7.2 
Safety Population 
Serious Adverse Events 
Listing 16.2.7.3 
Safety Population 
Treatment emergent Adverse Events Related to Study Drug 
Listing 16.2.7.4 
Safety Population 
Deaths 
16.2.8 Laboratory Values by Subject 
Listing 16.2.8.1 
Safety Population 
Clinical Laboratory Data: Serum Chemistry 
Listing 16.2.8.2 
Safety Population 
Clinical Laboratory Data: Hematology 
Listing 16.2.8.3 
Safety Population 
Clinical Laboratory Data: Urine 
Listing 16.2.8.4 
Safety Population 
Clinical Laboratory Data: Coagulation 
Listing 16.2.8.5 
Safety Population 
Serum and Urine Pregnancy Test 
16.2.9 Other Clinical Observations and Measurements (by Subject) 
Listing 16.2.9.1 
Safety Population 
Prior and Concomitant Medications 
Listing 16.2.9.1.1 
Safety Population 
Rescue Medications 
Listing 16.2.9.2 
Safety Population 
Vital Signs Measurements 
Listing 16.2.9.2.1 
Safety Population 
Physical Examination Findings 
Listing 16.2.9.3 
Safety Population 
12-lead Electrocardiogram Measurements  
Listing 16.2.9.3.1 
Safety Population 
Alcohol Breathalyzer Test 
Listing 16.2.9.4 
Safety Population 
NRS Pain Intensity Assessment 
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Data Listing Number 
Population 
Data Listing Title / Summary 
Listing 16.2.9.5 
Safety Population 
Pain Relief Scores  
Listing 16.2.9.6 
Safety Population 
Time to Pain Relief (Stopwatches) 
Listing 16.2.9.7 
Safety Population 
Subjects Global Evaluation of Study Drug 
 
 
 
12.5. Planned Figure Descriptions 
The following are planned summary figures for protocol number 5003601. The figure numbers 
and page numbers are place holders only and will be determined when the figures are produced. 
Table 7: Planned Figures 
Figure 14.4.1.1 
ITT Population 
Kaplan-Meier Plot of Time to First Perceptible Pain Relief 
Figure 14.4.1.2 
ITT Population 
Kaplan-Meier Plot of Time to Meaningful Pain Relief  
Figure 14.4.1.3 
ITT Population 
Kaplan-Meier Plot of Time to Onset Of Analgesia  
Figure 14.4.1.4 
ITT Population 
Kaplan-Meier Plot of Time to Peak Pain Relief 
Figure 14.4.1.5 
ITT Population 
Kaplan-Meier Plot of Time to First Use Of Rescue Medication 
Figure 14.4.1.6 
ITT Population 
Mean Pid Scores versus Time 
Figure 14.4.1.7 
ITT Population 
Mean Pain Relief Scores versus Time 
 
 
 
Figure Number 
Population 
Figure Title / Summary 
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Appendix 1: Premier Research Library of Abbreviations 
 
Abbreviation 
Definition 
aCRF  
annotated case report form 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
BSL 
biostatistician lead 
CCGs 
CRF completion guidelines 
CDISC 
clinical data interchange standards consortium 
CEC 
central ethics committee 
CFR 
code of federal regulations 
CI 
confidence intervals 
CM 
clinical manager 
CMP 
clinical monitoring plan 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CSR 
clinical study report 
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Abbreviation 
Definition 
CTA 
clinical trial administrator 
CTM 
clinical trial manager 
CTMS 
clinical trial management system 
DB 
database 
DBL 
database lock 
DM 
data management 
DMB 
data monitoring board 
DMC 
data monitoring committee 
DMP 
data management plan 
DSMB  
data safety monitoring board 
DSP 
data safety plan 
DSUR 
development safety update report 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eTMF 
electronic trial master file 
EU 
European Union 
FDA 
food and drug administration 
FPI 
first patient in 
GCP 
good clinical practice 
HR 
heart rate 
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Abbreviation 
Definition 
IB 
investigator’s brochure 
IC or ICF 
informed consent or informed consent form 
ICH 
international council for harmonization  
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LLOQ 
lower limit of quantification 
LPI 
last patient in 
LPLV 
last patient last visit 
LPO 
last patient out 
MedDRA 
medical dictionary for regulatory activities 
MHRA 
medicines and healthcare products regulatory agency 
MM 
medical monitor 
MMP 
medical monitoring plan 
MMRM 
mixed effect model repeat measurement 
N 
number 
NA 
not applicable 
NCS 
non-clinically significant 
NF 
non-functional 
PD 
protocol deviation 
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Abbreviation 
Definition 
PDGP 
protocol deviation guidance plan 
PE 
physical examination 
PI 
principal investigator 
PK 
pharmacokinetic 
PKAP 
pharmacokinetic analysis plan 
PM 
project manager 
PMP 
project management plan 
PP 
per-protocol 
PS 
project specialist 
PV 
pharmacovigilance 
PVG 
pharmacovigilance group 
QA 
quality assurance 
QARC 
quality assurance, risk and compliance 
QC 
quality control 
QOL 
quality of life 
SAE 
serious adverse event 
SAF 
Safety Population 
SAP 
statistical analysis plan 
SAS®  
a software system used for data analysis 
SBP 
systolic blood pressure 
SD 
standard deviation 
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Abbreviation 
Definition 
SDS 
study design specifications 
SDTM  
study data tabulation model  
SF 
screen failure 
SFT or SFTP 
secure file transfer or secure file transfer plan 
SIV 
site initiation visit 
SMP 
safety management plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
UAT 
user acceptance testing 
WHO 
world health organization 
WHO-DD 
world health organization drug dictionary 
 
 
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