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
Phase: PHASE3
Conditions: Pain
Sponsor: Reckitt Benckiser Healthcare (UK) Limited

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 
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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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~~ 
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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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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7.6.2 
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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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.
DocuSign Envelope ID: E5C8FB9A-6542-4088-90A8-75E3998F3A16
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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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Investigational Study Protocol Amendment 
Page 3 of 6 
 
 
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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Investigational Study Protocol Amendment 
Page 4 of 6 
 
 
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. 
DocuSign Envelope ID: E5C8FB9A-6542-4088-90A8-75E3998F3A16
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Investigational Study Protocol Amendment 
Page 5 of 6 
 
 
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 
Page 69 of 276

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 
Page 70 of 276

 
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 
DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2D4E7D2BD92D
Page 71 of 276

 
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
Page 72 of 276

 
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 
Page 73 of 276

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 
D8199934 Appendix 1 - lnvestigational Study Protocol Template v5.0 05-Jun-2017 
Page 74 of 276

 
Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 19-Nov-2019, FINAL Version 3.0 
Page 5 of 63 
 
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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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 
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 
DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2D4E7D2BD92D
7.3.1 
7.3.2 
7.3.3 
7.3.4 
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Protocol Version: 19-Nov-2019, FINAL Version 3.0 
Page 7 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
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 
DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2D4E7D2BD92D
7.6.1 
7.6.2 
9.5.1 
9.5.2 
9.6.1 
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Protocol Version: 19-Nov-2019, FINAL Version 3.0 
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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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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 19-Nov-2019, FINAL Version 3.0 
Page 9 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
Figure 3.1 Study Design Schematic ......................................................................................27 
 
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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 19-Nov-2019, FINAL Version 3.0 
Page 10 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
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 
DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2D4E7D2BD92D
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Investigational Study Protocol 
Study No: 5003601 
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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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 
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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7.6.2 
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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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CLINICAL STUDY PROTOCOL 
Study No: 5003601 
Protocol Version: 19-Nov- 2019, FINAL Version 3.0 
Page 61 of 63 
 
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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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CLINICAL STUDY PROTOCOL 
Study No: 5003601 
Protocol Version: 19-Nov- 2019, FINAL Version 3.0 
Page 62 of 63 
 
D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
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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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 
(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 
D8199934 V6.0, Appendix 7 - lnvestigational Study Protocol Amendment 
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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 
D81 99934 V6.0, Appendix 7 - lnvestigational Study Protocol Amendment 
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DocuSign Envelope ID: 086FD250-44B3-4A68-A96E-2D4E7D2BD92D 
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 
Page 138 of 276

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 
D8199934 V6.0, Appendix 7 - lnvestigational Study Protocol Amendment 
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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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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 19 July 2019, FINAL Version 2.0 
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: 94223DB3-7863-400F-8A47-927CF624F1DA
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Investigational Study Protocol 
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Protocol Version: 19 July 2019, FINAL Version 2.0 
Page 3 of 63 
 
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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 
 
DocuSign Envelope ID: 94223DB3-7863-400F-8A47-927CF624F1DA
DocuSign Envelope ID: E3E6664D-BF5F-4B8C-B3C9-631A328A0BEC
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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 
5.5 
Packaging and Labelling and Supply / Resupply ............................................37 
DocuSign Envelope ID: 94223DB3-7863-400F-8A47-927CF624F1DA
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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 
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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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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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D8199934 V6.0, Appendix 7 – Investigational Study Protocol Amendment 
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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 20 November 2018, FINAL 
Version 1.0 
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 
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Investigational Study Protocol 
Study No: 5003601 
Protocol Version: 20 November 2018, FINAL 
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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Investigational Study Protocol 
Study No: 5003601 
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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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 
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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Protocol Version: 20 November 2018, FINAL 
Version 1.0 
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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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D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
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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D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
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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D8199934 Appendix 1 – Investigational Study Protocol Template v5.0 05-Jun-2017 
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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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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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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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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(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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