Clinical trial NCT02689063
Conditions: Post Operative Pain
Keywords: Analgesic
Sponsor: AFT Pharmaceuticals, Ltd.
Start date: 2016-10-26; Completion date: 2017-09-15
Enrollment: 276 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to determine the clinical efficacy and safety of Maxigesic IV, acetaminophen IV, Ibuprofen IV versus placebo IV for the treatment of acute postoperative pain after bunionectomy

Detailed description:
AFT Pharmaceuticals Ltd. has been developing a fixed-dose combination of acetaminophen 1000mg and ibuprofen 300mg/100mL solution for infusion (Maxigesic IV) for the temporary relief of postoperative pain, when administration by intravenous route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration not possible.

A phase 3 efficacy study (AFT-MXIV-07) is proposed to determine the analgesic effects of the fixed dose combination product Maxigesic IV versus its individual components (acetaminophen IV and ibuprofen IV) and placebo in participants with acute post-operative pain after bunionectomy.

The primary efficacy objective is to determine the efficacy of Maxigesic IV, acetaminophen IV, Ibuprofen IV versus placebo IV as measured by the summed pain intensity difference (SPID) (calculated as a time-weighted average) over 0-48 hours (SPID-48) after time 0.

Other secondary efficacy endpoints are:

VAS Pain intensity difference (PID) at each scheduled assessment time point after Time 0 VAS Pain intensity score at each scheduled assessment time point VAS SPID over 0 to 6 hours (SPID-6), over 0 to 12 hours (SPID-12), and over 0 to 24 hours (SPID-24) after Time 0

Summed pain relief (TOTPAR) (calculated as a time-weighted average) over 0 to 6 hours (TOTPAR-6), over 0 to 12 hours (TOTPAR-12), over 0 to 24 hours (TOTPAR-24) after Time 0, and over 0 to 48 hours (TOTPAR-48) after Time 0

Time to onset of analgesia (measured as time to perceptible pain relief confirmed by meaningful pain relief) using the two-stopwatch method Pain relief score on a 5-point categorical scale at each scheduled time point after Time 0

Peak pain relief

Time to peak pain relief

Time to first perceptible pain relief

Time to meaningful pain relief

Proportion of subjects using rescue medication

Time to first use of rescue medication (duration of analgesia)

Total use of rescue analgesia over 0 to 24 hours and over 0 to 48 hours Patient's global evaluation of study drug

Arms: arm 1: intravenous acetaminophen1000 mg + intravenous ibuprofen 300 mg/100 ml solution for infusion, 100 mL, every 6 hours for 48 hours arm 2: IV Acetaminophen 1000 mg/100 mL solution for infusion, 100mL. every 6 hours for 48 hours arm 3: IV Ibuprofen 300 mg/100 mL solution for infusion, 100mL every 6 hours for 48 hours arm 4: Placebo IV- 100 mL saline for infusion, 100mL every 6 hours for 48 hours
Interventions: intervention 1: Maxigesic IV intervention 2: IV Acetaminophen intervention 3: IV Ibuprofen intervention 4: Placebo IV
Intervention descriptions: intervention 1: IV acetaminophen 1000 mg and IV ibuprofen 300 mg /100 mL solution for infusion, 100mL, every 6 hours for 48 hours intervention 2: IV Acetaminophen 1000 mg/100 mL solution for infusion, 100mL, every 6 hours for 48 hours intervention 3: IV Ibuprofen 300 mg/100 mL solution for infusion, 100mL, every 6 hours for 48 hours intervention 4: Placebo IV- 100 mL intravenous saline for infusion, 100mL, every 6 hours for 48 hours

Protocol documents:
Prot_000.pdf: 
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Maxigesic® IV Bunionectomy Study Protocol (AFT-MXIV-07)      Amendment 03,                   4th January   
2017  
Maxigesic® IV (acetaminophen 1000mg + ibuprofen 300mg /100mL intravenous infusion)  
Page 1 of 50 
 
 
STUDY TITLE: 
Maxigesic® IV Bunionectomy Study: A 
Phase 
3, 
Randomized, 
Double-Blind, 
Multiple-Dose, Parallel-Group and Placebo-
Controlled Study of IV Maxigesic®, IV 
acetaminophen and IV ibuprofen for the 
Treatment of Acute Postoperative Pain 
After Bunionectomy 
PROTOCOL NUMBER: 
AFT-MXIV-07 
TRIAL REGISTRATION 
NUMBER: 
NCT02689063 
IND APPLICATION No.  
124213 
STUDY DRUG: 
Maxigesic® IV 
DEVELOPMENT PHASE: 
Phase III 
INDICATION: 
Analgesia for acute postoperative pain. 
SPONSOR: 
AFT Pharmaceuticals Ltd 
Level 1, 129 Hurstmere Rd, Takapuna,  
Auckland, NEW ZEALAND 
CONTRACTORS: 
Optimal Research International LLC 
14808 Physicians Lane, Suite 211 
Rockville 
MD 20850, USA 
Tel: 1-240-238-4917  Fax: 301-309-8610 
INVESTIGATORS: 
Dr. Stephen E Daniels, DO 
SPONSOR 
REPRESENTATIVES: 
Hartley Atkinson, AFT Pharmaceuticals 
Ltd. 
Ioana Stanescu, AFT Pharmaceuticals Ltd.  
AFT PROJECT LEADER 
Ioana Stanescu, AFT Pharmaceuticals Ltd. 
Ph +64-9-4880232, Fax +64-9-4880234 
DRUG SAFETY OFFICER 
Jennifer Zhang, AFT Pharmaceuticals Ltd. 
Ph +64-9-4880232, Fax +64-9-4880234 
AMENDMENT 03 DATE: 
January 4th, 2017 


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Maxigesic® IV Bunionectomy Study Protocol (AFT-MXIV-07)          Amendment 03,                   4th January   
2017 
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Page 2 of 50 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
 
 
INTERNAL APPROVAL FORM 
 
 
CLINICAL RESEARCH PROTOCOL 
 
STUDY DRUG 
Maxigesic® IV:  
Intravenous acetaminophen 1000 mg + intravenous ibuprofen 300 
mg/100 ml solution for infusion 
PROTOCOL TITLE 
Maxigesic® IV Bunionectomy Study: A Phase 3, Randomized, 
Double-Blind, Multiple-Dose, Parallel-Group and Placebo-
Controlled Study of IV Maxigesic®, IV acetaminophen and IV 
ibuprofen for the Treatment of Acute Postoperative Pain After 
Bunionectomy 
PROTOCOL NUMBER 
AFT-MXIV-07 
AMENDMENT 
03 
DOCUMENT DATE  
January 4th, 2017 
                                                                                                                                                                              
 
Preparation 
Prepared by: 
Ioana Stanescu Phil.Lic.., MSc  
Head of Drug Development  
and  
Jennifer ZhangB.Clin Med. MPH  
 SCRA 
Signature: 
 
 
Date: 
January 4th, 2017 
Review 
Reviewed by: 
Dr. Stephen Daniels – Optimal 
Research International LLC 
Signature: 
 
Date: 
January 4th, 2017 
Approval 
Authorised by: 
Hartley Atkinson M.Pharm. PhD.  
CEO 
Signature: 
Date: 
January 4th, 2017 


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Maxigesic® IV Bunionectomy Study Protocol (AFT-MXIV-07)          Amendment 03,                   4th January   
2017 
Maxigesic® IV (acetaminophen 1000mg + ibuprofen 300mg /100mL intravenous infusion  
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PROTOCOL SYNOPSIS 
Name of Sponsor 
AFT Pharmaceuticals Ltd 
Name of Active Ingredient 
Acetaminophen and Ibuprofen 
Title of Study 
A Phase 3, Randomized, Double-Blind, Multiple-Dose, Parallel-Group and
Placebo-Controlled Study of IV Maxigesic®, IV Acetaminophen and IV 
Ibuprofen for the Treatment of Acute Postoperative Pain After Bunionectomy 
Study Centre 
Optimal Research LLC 
3200 Red River, Suite 301. Austin, Texas 78705 
Dr. Stephen Daniels, DO-Principal Investigator 
Phase of Development 
Phase III 
Background and Rationale  
The combination of acetaminophen and ibuprofen in a single tablet 
(Maxigesic®: acetaminophen 500 mg + ibuprofen 150 mg) has been 
shown to be effective in the treatment of postoperative pain (third molar 
extraction) and superior to the same dose of either acetaminophen or 
ibuprofen alone (Merry AF. et al, 2010).  A similar oral combination 
(acetaminophen 325 mg + ibuprofen 97.5 mg given as up to three tablets 
[acetaminophen 975mg + ibuprofen 292.5mg] per dose), developed for 
registration and use in the USA was evaluated in a large Phase 3 clinical 
studies in 408 subjects undergoing dental surgery (IND No. 107,435 
[NCT01420653]. The combination was statistically superior to both 
acetaminophen and ibuprofen monotherapy and placebo, as measured by 
the primary and secondary endpoints. 
 
AFT Pharmaceuticals Ltd. has been developing a fixed-dose combination 
of acetaminophen 1000 mg and ibuprofen 300 mg/100 ml solution for 
infusion (Maxigesic® IV) for the temporary relief of postoperative pain, 
when administration by intravenous route is clinically justified by an 
urgent need to treat pain or hyperthermia and/or when other routes of 
administration are not possible. 
A Phase III efficacy study (AFT-MXIV-02) is proposed to determine the 
analgesic effects of the fixed dose combination product Maxigesic® IV 
versus its individual components (acetaminophen IV and ibuprofen IV) 
and placebo in participants with acute post-operative pain after 
bunionectomy. 
Objectives 
Efficacy Primary Objective: To determine the efficacy of Maxigesic® 
IV, acetaminophen IV, ibuprofen IV versus placebo IV for the treatment 
of acute postoperative pain after bunionectomy as measured by the 
summed pain intensity difference (SPID) (calculated as a time-weighted 
average) over 0 to 48 hours (SPID-48) after Time 0.  
Safety Objectives: To determine the incidence of treatment-emergent 
adverse events (AEs) and changes in vital sign measurements.  
Study Design 
This is a phase 3, multicentre, randomized, double-blind, multiple-dose 
parallel-group, placebo-controlled study to evaluate the safety and 
efficacy of Maxigesic® IV (acetaminophen 1000mg/100ml + ibuprofen 


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Maxigesic® IV Bunionectomy Study Protocol (AFT-MXIV-07)          Amendment 03,                   4th January   
2017 
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300mg/100ml solution for infusion) 4 times daily, IV acetaminophen 
(1000mg/100ml solution for infusion) 4 times daily, IV ibuprofen 
(300mg/100ml solution for infusion) 4 times q6h and placebo ( IV saline 
100ml solution) in subjects with acute postoperative pain after 
bunionectomy.   
Number of Participants 
275 participants (75 in each active group and 50 in placebo) 
Main Inclusion Criteria 
Main Inclusion Criteria: 
 Male or female ≥ 18 and ≤ 65 years of age.  
 Classified as P1 to P2 in the American Society of 
Anesthesiologists (ASA) Physical Status Classification System.  
 Has undergone distal, primary, unilateral, first metatarsal 
bunionectomy (with osteotomy and internal fixation) with no 
additional collateral bony procedures.  
 Experiences a pain intensity rating of ≥ 40 mm on a 100-mm 
Visual Analogue Scale (VAS) during the 9-hour qualification 
period after discontinuation of the anesthetic block.   
Study Drugs & Treatment 
Each participant will be randomly allocated to receive one of the following 
study treatments:  
Treatment A: 
Maxigesic® IV (intravenous acetaminophen1000 
mg + intravenous ibuprofen 300 mg/100 ml 
solution for infusion) 
Treatment B: 
Intravenous 
acetaminophen 
1000 
mg/100mL 
solution for infusion 
Treatment C: 
Intravenous ibuprofen 300 mg/ 100mL solution for 
infusion 
Treatment D: 
Placebo (intravenous saline, 100 mL solution for 
infusion) 
Study Drug Administration 
All study drugs will be administered by injection into a dedicated 
indwelling venous cannula, infused over 15 minutes. The study drugs will 
be administered, every 6 hours (q6h) for 48 hours (a total of 8 doses).  
Duration of Treatment 
The estimated duration of the study for each subject is approximately 40 
days, which includes a screening period up to 28 days,  a 3-day treatment 
period (approximately 72 hours of confinement with 48 hours of treatment), 
and a post treatment follow-up phone call within 5 to 9 days after surgery. 
Rescue Analgesia 
As a primary rescue analgesia oxycodone 5 or 10 mg will be allowed orally 
every 4-6 hours as needed for pain before the anaesthetic infusion is 
discontinued, and as rescue medication after the anaesthetic infusion is 
discontinued.  
If adequate pain relief is not achieved with oxycodone, as a secondary 
rescue analgesia, 2-4 mg intravenous morphine sulphate will be allowed to 
be administered every 4 hours, as needed. 
Evaluation of Efficacy  
Primary Endpoint: 
The primary endpoint is the VAS summed pain intensity difference (VAS 
SPID) (calculated as a time-weighted average) over 0 to 48 hours (VAS 
SPID-48) after Time 0. 
Secondary Endpoints: 
 
VAS Pain intensity difference (PID) at each scheduled assessment 


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Maxigesic® IV Bunionectomy Study Protocol (AFT-MXIV-07)          Amendment 03,                   4th January   
2017 
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time point after Time 0  
 
VAS Pain intensity score at each scheduled assessment time point  
 
VAS SPID over 0 to 6 hours (SPID-6), over 0 to 12 hours (SPID-
12), and over 0 to 24 hours (SPID-24) after Time 0  
 
Summed pain relief (TOTPAR) (calculated as a time-weighted 
average) over 0 to 6 hours (TOTPAR-6), over 0 to 12 hours 
(TOTPAR-12), over 0 to 24 hours (TOTPAR-24) after Time 0, and 
over 0 to 48 hours (TOTPAR-48) after Time 0  
 
Time to onset of analgesia (measured as time to perceptible pain 
relief confirmed by meaningful pain relief) using the two-stopwatch 
method 
 
Pain relief score on a 5-point categorical scale at each scheduled 
time point after Time 0  
 
Peak pain relief  
 
Time to peak pain relief  
 
Time to first perceptible pain relief  
 
Time to meaningful pain relief  
 
Proportion of subjects using rescue medication  
 
Time to first use of rescue medication (duration of analgesia)  
 
Total use of rescue analgesia over 0 to 24 hours and over 0 to 48 
hours  
 
Patient’s global evaluation of study drug 
Evaluation of Safety  
The safety endpoints are the incidence of treatment-emergent adverse 
events (AEs) and changes in vital sign measurements. 
Sample Size Calculation  
In total, 275 participants (75 in each active group and 50 in placebo) will 
be randomised into the study. This sample size will provide 80% power to 
detect as statistically significant (2-sided α=0.05) any difference 
>10.5mm [ES=0.6] in mean time-adjusted SPID between Maxigesic® IV 
and each of the three comparator study groups.  
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................................ 6 
LIST OF TABLES ......................................................................................................................................... 8 
LIST OF ABBREVIATIONS........................................................................................................................... 9 
1. 
INTRODUCTION ............................................................................................................................. 10 
1.1. 
BACKGROUND ................................................................................................................................ 10 
1.2. 
STUDY DRUG RATIONALE ................................................................................................................. 11 
1.3. 
STUDY RATIONALE .......................................................................................................................... 11 
1.3.1. 
Rationale: Study Medication ................................................................................................. 11 
1.3.2. 
Rationale: Comparator ......................................................................................................... 12 
1.3.3. 
Rationale: Treatment Period ................................................................................................. 12 
1.4. 
KNOWN AND POTENTIAL RISKS AND BENEFITS ...................................................................................... 12 
2. 
TRIAL OBJECTIVES AND ENDPOINTS .............................................................................................. 12 
2.1. 
STUDY HYPOTHESIS ......................................................................................................................... 12 
2.2. 
OBJECTIVES AND ENDPOINTS ............................................................................................................ 12 
2.2.1. 
Efficacy Objectives ................................................................................................................ 13 
2.2.1.1. 
Primary Objective/Endpoint....................................................................................................... 13 
2.2.1.2. 
Secondary Objectives/Endpoints ............................................................................................... 13 
2.2.1.3. 
Safety Objectives ........................................................................................................................ 13 
3. 
STUDY DESIGN .............................................................................................................................. 13 
3.1. 
BASIC STUDY DESIGN CHARACTERISTICS .............................................................................................. 13 
3.2. 
SCHEMATIC STUDY DIAGRAM ............................................................................................................ 16 
3.3. 
RANDOMISATION ........................................................................................................................... 17 
3.4. 
BLINDING ...................................................................................................................................... 17 
4. 
STUDY POPULATION ..................................................................................................................... 17 
4.1. 
NUMBER OF PARTICIPANTS ............................................................................................................... 17 
4.2. 
INCLUSION CRITERIA ........................................................................................................................ 17 
4.3. 
EXCLUSION CRITERIA ....................................................................................................................... 18 
4.4. 
WITHDRAWAL CRITERIA ................................................................................................................... 20 
5. 
TREATMENTS ................................................................................................................................ 21 
5.1. 
TREATMENTS TO BE ADMINISTERED.................................................................................................... 21 
5.1.1. 
Identification and Description of Test Agents ....................................................................... 21 
5.2. 
DOSING SCHEDULE AND INSTRUCTIONS ............................................................................................... 21 
5.3. 
STORAGE AND HANDLING OF STUDY DRUGS ........................................................................................ 22 
5.4. 
RESCUE MEDICATION ...................................................................................................................... 22 
6. 
STUDY ASSESSMENTS .................................................................................................................... 22 
6.1. 
EFFICACY ASSESSMENTS ................................................................................................................... 22 
6.1.1. 
Pain Intensity Assessment ..................................................................................................... 23 
6.1.2. 
Pain Relief Assessment –Categorical 5 point Pain Relief Rating ........................................... 23 
6.1.3. 
Time to Perceptible and Meaningful Pain relief (Two-stopwatch method) .......................... 24 
6.1.4. 
Requirement of Rescue Analgesia ......................................................................................... 24 
6.1.5. 
The Global Evaluation of Study Drug .................................................................................... 25 
6.2. 
SAFETY ASSESSMENTS ..................................................................................................................... 25 
7. 
EXPERIMENTAL PROCEDURE ......................................................................................................... 26 


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7.1. 
SEQUENCE OF PROCEDURES .............................................................................................................. 26 
7.1.1. 
Screening Period (Day -28 to Day 0) ..................................................................................... 27 
7.1.2. 
Day of Surgery (Day 0) .......................................................................................................... 28 
7.1.3. 
Randomisation (Day 1 – First postoperative day) ................................................................. 29 
7.1.4. 
Treatment Period (Day 1-3) .................................................................................................. 29 
7.1.5. 
Follow-up ( 5 -9 days after surgery) ...................................................................................... 31 
8. 
ADVERSE EVENTS .......................................................................................................................... 31 
8.1. 
DEFINITIONS .................................................................................................................................. 31 
8.1.1. 
Adverse Event ....................................................................................................................... 31 
8.1.2. 
Serious Adverse Event ........................................................................................................... 32 
8.2. 
PROCEDURE FOR ADVERSE EVENT REPORTING ...................................................................................... 32 
8.3. 
PROCEDURE FOR SERIOUS ADVERSE EVENT REPORTING ......................................................................... 32 
8.3.1. 
Reporting to Sponsor ............................................................................................................ 32 
8.3.2. 
Reporting to Local EC/IRB ..................................................................................................... 33 
8.3.3. 
Reporting to Regulatory Agencies ........................................................................................ 33 
8.4. 
DATA SAFETY MANAGEMENT BOARD (DSMB) REVIEW: ........................................................................ 33 
9. 
PLAN FOR STATISTICAL AND OTHER CALCULATIONS ..................................................................... 33 
9.1. 
ANALYSES POPULATIONS .................................................................................................................. 34 
9.2. 
SAMPLE SIZE .................................................................................................................................. 34 
9.3. 
STATISTICAL ANALYSES .................................................................................................................... 34 
9.3.1. 
Efficacy Analysis .................................................................................................................... 34 
9.3.2. 
Safety Analysis ...................................................................................................................... 36 
9.4. 
DEMOGRAPHIC AND BACKGROUND CHARACTERISTICS ........................................................................... 36 
9.5. 
MISSING DATA ............................................................................................................................... 36 
9.6. 
PROCEDURE FOR AMENDMENTS TO STATISTICAL PLAN ........................................................... 37 
9.7. 
DATA COLLECTION ..................................................................................................................... 37 
10. 
STUDY OR STUDY SITE TERMINATION AND PARTICIPANT DISCONTINUATION .............................. 38 
10.1. 
STUDY OR STUDY SITE TERMINATION ....................................................................................... 38 
10.2. 
PARTICIPANT DISCONTINUATION .............................................................................................. 38 
11. 
PROTOCOL DEVIATIONS ................................................................................................................ 39 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................................. 39 
12.1. 
MONITORING............................................................................................................................. 39 
12.2. 
AUDITING ................................................................................................................................... 39 
13. 
ETHICS AND RESPONSIBILITY ........................................................................................................ 40 
13.1. 
INFORMED CONSENT................................................................................................................. 40 
13.2. 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE .............................................................. 40 
13.3. 
GOVERNANCE OF STUDY AND PUBLICATION POLICY ................................................................ 41 
14. 
CONFIDENTIALITY ......................................................................................................................... 41 
15. 
INVESTIGATOR AGREEMENT ......................................................................................................... 42 
16. 
REFERENCES .................................................................................................................................. 43 
 
 
 
 
 


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LIST OF TABLES 
 
Table 1: Schedule of Assessments .................................................................................... 26 
 
Appendix 1: Grading of Adverse Events .......................................................................... 44 
Appendix 2: Adverse Drug Reactions of the Investigational Product .............................. 45 
Appendix 3: Pain Assessment –100 mm VAS .................................................................. 47 
Appendix 4: Pain Relief Assessment –Categorical 5-Point Pain Relief Rating Scale ...... 48 
Appendix 5:  Patient’s Global Evaluation of Study Drug ................................................. 49 
Appendix 6: Two Stopwatch Pain Relief Assessments .................................................... 50 
 
 


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LIST OF ABBREVIATIONS 
 
AB 
Anesthetic Block  
ADL 
Activity of Daily Living  
AE(s) 
Adverse event(s) 
ANOVA 
Analysis of Variance 
AUC 
Area under the curve 
BOCF 
Baseline Observation Carry Forward  
CRF(s) 
Case Report Form(s) 
CFR  
Code of Federal Regulation  
DSMB  
Data Safety Management Board  
EC 
Ethics Committee 
EP 
Evaluable Portion 
EU 
European Union 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
ICH  
International Conference on Harmonization  
IRB  
Institutional Review Board 
ITT 
Intention to Treat 
IV 
Intravenous  
LOCF  
Last Observation Carry Forward 
Maxigesic® IV 
Intravenous 
acetaminophen 
1000mg 
+ 
intravenous 
ibuprofen 
300mg/100 ml solution for infusion 
NSAID  
Non-steroidal Anti-Inflammatory Drug 
PACU 
Post-anaesthetic Care Unit 
PP 
Per-protocol 
PSB 
Popliteal Sciatic nerve Block 
SAE(s) 
Serious Adverse Event(s) 
SAER 
Serious Adverse Event Report 
SPID  
Summed Pain Intensity Difference 
TOTPAR 
Total Pain Relief 
VAS 
Visual Analogue Scale 
WHO 
World Health Organisation 


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1. 
INTRODUCTION 
This protocol describes a Phase III study designed to examine the analgesic efficacy and 
safety of a combination of intravenous acetaminophen and ibuprofen (Maxigesic® IV). 
Confirmatory clinical trials are necessary to prove analgesic efficacy, preferably using 
parallel group comparisons in which the fixed combination is compared to its individual 
substances in a factorial design, and preferably including a placebo arm (1).  
 
The analgesic efficacy of the combination acetaminophen and ibuprofen has been widely 
reported and the fixed combination Maxigesic® tablets (as two tablets, total dose 
acetaminophen 1000mg + ibuprofen 300mg) have been shown to have superior analgesic 
efficacy than either acetaminophen or ibuprofen alone in acute postoperative pain from third 
molar removal (2) .   
 
In another recently completed phase 3 study, Maxigesic® 325 tablets (acetaminophen 325mg 
+ ibuprofen 97.5mg per tablet, administered as 3 tablets per dose) has clearly demonstrated 
superior analgesic efficacy than either acetaminophen 325 mg alone or ibuprofen 97.5mg 
alone in acute postoperative pain from third molar removal (AFT-MX-6) (3). 
 
However, the use of oral analgesics in the immediate postoperative period may not be 
possible. Maxigesic® IV has been developed to allow a combination analgesic therapy with 
the administration of a single formulation in patients who are unable to take oral analgesics.  
 
In a previous Maxigesic® IV single-dose, open label, 5 period crossover sequence PK study 
in 30 healthy volunteers, it was found that pharmacokinetic parameters for ibuprofen and 
paracetamol were very similar for the combination and monotherapy intravenous 
preparations; ratios of Cmax, AUCt, and AUC0-∞ values fell within the 80-125% acceptable 
bioequivalence range. Precise dose proportionality for both compounds was also determined 
for the half dose of the intravenous formulation compared with the full dose. The relative 
bioavailability of paracetamol (93.78%) and ibuprofen (96.45%) confirmed the 
pharmacokinetic equivalence between the oral and intravenous formulations of the fixed 
dose combination (4).  
 
Clinical safety assessment for all subjects was carried out to evaluate their tolerability to the 
study medications. Study subjects demonstrated good tolerance to the study’s treatments. 
 
Following this, a phase 3 study has been planned to investigate the clinical efficacy and 
safety of Maxigesic® IV in a post-operative pain model.  
 
This study will be conducted in compliance with Good Clinical Practices (GCP) including 
the Declaration of Helsinki and all applicable regulatory requirements. 
 
1.1. Background 
 
Effective treatment of postoperative pain is essential to patient outcome and well-being (5).   
Clinically, inadequate pain relief can have profound implications including cardiovascular, 
respiratory and gastrointestinal (GI) adverse effects, emotional and physical suffering, sleep 


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disturbances, delayed mobilisation (which can promote thromboembolism and delayed 
rehabilitation) and progression to chronic pain syndromes.  Economically, undertreated pain 
can lead to extended hospital stays and/or readmission (6–8). 
 
Opioids are the gold standard for the treatment of postoperative pain but their use is often 
limited by dose dependent adverse events such as nausea and vomiting, constipation, 
sedation and respiratory depression (7).  Sustained opioid use can also lead to tolerance, 
resulting in increased dosing requirements, dependence and a subsequent increase in adverse 
events.   
 
The World Health Organisation (WHO) advocates the use of multimodal analgesia for 
optimal pain control.  Multimodal, or balanced, analgesia acts at different sites within the 
central and peripheral nervous systems to synergistically improve pain control while 
reducing opioid related adverse events (9,10).  The first step on the WHO pain relief ladder 
involves the use of non-opioid analgesics, such as acetaminophen and NSAIDs (9).  Both 
acetaminophen and ibuprofen are effective analgesics that have been used for many years.  
Both are available without a prescription and have well-established safety records (6).   
 
The use of oral analgesics in the postoperative period may not be suitable due to patient 
intubation, sedation, postoperative nausea and vomiting and reduced gastric motility.  Oral 
medications often have a delayed clinical effect due to inconsistent absorption in 
hospitalised patients (11).   
 
A fixed combination of acetaminophen and ibuprofen intravenous formulation may improve 
patient analgesia in the postoperative period, whilst simplifying dosing. 
 
1.2. 
Study Drug Rationale 
 
While there are many analgesic options open to physicians most have limitations. For 
example, fixed dose combinations that include opioids carry the risks of the side effects and 
dependency associated with opioid drugs. Acetaminophen and ibuprofen are well established 
analgesics with excellent safety records in both adults and children.  
 
AFT Pharmaceuticals Ltd. has been developed a fixed-dose combination of acetaminophen 
1000 mg and ibuprofen 300 mg/100 ml solution for infusion (Maxigesic® IV) for the 
temporary relief of postoperative pain, when administration by intravenous route. This is 
clinically justified by an urgent need to treat pain or hyperthermia when other routes of 
administration are not possible or prudent. 
 
1.3. 
Study Rationale 
1.3.1. Rationale: Study Medication 
Acetaminophen and ibuprofen are well established analgesics with excellent safety records 
in both adults and children. Maxigesic® tablets have been previously shown to be effective in 
the relief of postoperative pain but their usefulness in the postoperative period may be 
limited due to medical interventions and patient factors previously described.  An 


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intravenous formulation will allow administration to patients who are in urgent need to treat 
pain or hyperthermia when other routes of administration are not possible or prudent. 
1.3.2. Rationale: Comparator 
This trial design follows the EMA/CHMP/970057/2011 Guideline on the clinical 
development of medicinal products intended for the treatment of pain (12). This guideline 
mandates that confirmatory clinical trials are necessary to prove efficacy, preferably by 
parallel comparisons in which the fixed combination is compared to its individual substances 
and should include a placebo group when feasible.  Maxigesic® IV will therefore be 
compared to intravenous acetaminophen alone, intravenous ibuprofen alone and placebo.  
1.3.3. Rationale: Treatment Period 
To minimize the potential for carryover effects from operative anesthesia medications and to 
allow a uniform administration and evaluation of the study medications, the investigational 
drugs will be administered on the morning of the day after surgery.  
 
1.4. 
Known and Potential Risks and Benefits 
 
All drugs and all clinical studies have risks. However, these are likely to be minimal in the 
present study because both acetaminophen and ibuprofen have been used extensively for 
many years at these dose levels.  The dose ranges in this study fall well within the range that 
has been used worldwide for over 15 years. 
 
The potential benefit of this study lies in its potential to improve the quality of analgesia for 
participants requiring acute pain relief following surgery, and improved safety of 
combination analgesia for this purpose: reducing the amount of ibuprofen offers the potential 
to reduce the rate of known NSAID adverse events while improving efficacy due to the 
addition of acetaminophen. Recently completed preclinical studies Maxigesic® IV was 
considered to have little potential to produce local irritation when administered intravenously 
at the recommended dose level 
 
2. 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1. 
Study Hypothesis 
 
The study hypothesis is that the analgesic effect of Maxigesic® IV (intravenous 
acetaminophen 1000 mg + intravenous ibuprofen 300 mg/ 100 ml solution for infusion) is 
greater than that of intravenous acetaminophen 1000 mg/100 ml solution for infusion given 
individually or placebo. 
 
2.2. 
Objectives and Endpoints 


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2.2.1. Efficacy Objectives 
2.2.1.1. Primary Objective/Endpoint 
To determine the efficacy of Maxigesic® IV, acetaminophen IV, ibuprofen IV versus 
placebo IV for the treatment of acute postoperative pain after bunionectomy as measured by 
summed pain intensity difference (SPID) (calculated as a time-weighted average) over 0 to 
48 hours (SPID-48) after time 0. 
2.2.1.2. Secondary Objectives/Endpoints 
• Pain intensity difference (PID) at each scheduled assessment time point after Time 0 
• Pain intensity score at each scheduled time point 
• SPID over 0 to 6 hours (SPID-6), over 0 to 12 hours (SPID-12), and over 0 to 24 hours 
(SPID-24)  
• Summed pain relief (TOTPAR) (calculated as a time-weighted average) over 0 to 6 
hours (TOTPAR-6), over 0 to 12 hours (TOTPAR-12), over 0 to 24 hours (TOTPAR-24) 
and over 0 to 48 hours (TOTPAR-48)  
• Time to onset of analgesia (measured as time to perceptible pain relief confirmed by 
meaningful pain relief) using the two-stopwatch method) 
• Pain relief score on a 5-point categorical scale at each scheduled time point after Time 0 
• Peak pain relief 
• Time to peak pain relief 
• Time to first perceptible pain relief 
• Time to meaningful pain relief 
• Proportion of subjects using rescue medication 
• Time to first use of rescue medication (duration of analgesia) 
• Total use of rescue analgesia over 0 to 24 hours and over 0 to 48 hours 
• Patient’s global evaluation of study drug 
2.2.1.3. Safety Objectives 
The safety endpoints are the incidence of treatment –emergent adverse events (AEs) and 
changes in vital sign measurements. 
 
3. 
STUDY DESIGN  
3.1. 
Basic Study Design Characteristics 
 
This study is a Phase III, placebo-controlled, randomised, double-blind, parallel-design trial 
to investigate the analgesic efficacy of Maxigesic® IV compared with the individual 
components alone and placebo.  A flow chart providing a schematic representation of the 
study design can be found in Section 3.2. 
  
Eligible subjects will complete all screening procedures within 28 days before the surgery. 
At Screening, subjects will provide written informed consent to participate in the study 


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before any protocol-specified procedures or assessments are completed. 
 
Subjects will be admitted to the study site on the morning of the scheduled surgery (Day 0), 
will remain at the study site until postoperative Day 3 (a total of 3 nights at the study site), 
and will be followed up with a phone call which occurs 5 to 9 days after surgery. 
 
On Day 0, subjects who continue to meet all study entry criteria will undergo standard distal 
first metatarsal bunionectomy procedure using a standardized regimen of regional 
anesthesia. The regional anesthetic technique to be used for this surgery comprises a 
combination of a PSB to establish and maintain surgical field anesthesia (local anesthesia 
using a Mayo block with a short acting anesthetic will be allowed to augment surgical field 
anesthesia at the surgeons discretion) and a continuous sciatic infusion to provide an 
effective method of controlling pain in the immediate postoperative period. 
 
The PSB will be administered using modifications of the Singelyn technique (13).  Subjects 
will receive midazolam and/or propofol for initial sedation at the anesthesiologist’s 
discretion. After adequate sedation is achieved, the anesthesiologist will inject 
approximately 5 mL lidocaine 1% (plain) (or suitable short acting local anesthetic without 
epinephrine) locally to anesthetize the skin, and will determine the location of the sciatic 
nerve for the PSB using a nerve stimulator per standard technique. Once the appropriate 
location is determined, the anesthesiologist will inject 40 mL of ropivacaine 0.5% to 
establish the PSB. Subsequently a catheter will be placed in the proximity of the popliteal 
sciatic nerve for delivery of postoperative anesthesia. If the PSB is not sufficient to provide 
adequate surgical anesthesia, a standard Mayo block (local anesthesia) may be established 
using lidocaine 2% (plain) not to exceed 25 mL. The time, date, dose, and route of all local 
anesthetics will be recorded in the CRF.  
 
The regional anesthesia will be established using a popliteal sciatic nerve block (PSB) after 
which subjects will undergo primary, unilateral, first metatarsal bunionectomy under 
regional anesthesia. The regional anesthesia will be continued postoperatively via a 
continuous anesthetic infusion.  
 
Subjects may receive supplemental analgesia with an opioid product (oxycodone 5 or 10 mg 
every 4-6 hours as needed) after surgery and before randomization to help control 
breakthrough pain if the regional anesthetic infusion fails to provide adequate anesthesia. 
Though sites will be encouraged to use only the oxycodone as supplemental analgesia if 
adequate pain relief is not achieved with oral oxycodone, as a secondary rescue analgesia, 2-
4 mg intravenous morphine sulphate will be allowed to be administered every 4 hours, as 
needed. If the regional anesthetic infusion and supplemental primary and secondary 
analgesia do not effectively control the subject’s postoperative pain, then the subject will be 
discontinued from the study and pain will be managed per standard of care/investigator 
discretion. 
 
On Day 1, the regional anesthetic infusion will be discontinued at approximately 3 AM. 
When subjects request pain medication, they will be asked to rate their pain intensity using 
the 100 mm VAS scale assessment (0-100) (Appendix 3).  


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During the 9-hour qualification period after discontinuation of the anesthetic block, subjects 
who experience a pain intensity rating of ≥ 40 mm on the VAS are eligible to be enrolled 
into the study. If their pain intensity ratings do not meet the minimum entry criteria within 9 
hours of discontinuation of the regional anesthesia, subjects will not be eligible for 
enrollment and will receive routine standard postoperative care at the investigator’s 
discretion. 
 
Once the pain intensity entry criteria are met, subjects will be randomly assigned to one of 
four treatment groups mentioned in section 5.1.1. 
 
A detailed investigational plan can be found in Section 7.1 and Table 1. 
 


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3.2. 
Schematic study diagram 
 
Visit 1 
Visit 2 
Visit 3 
Consent 
Screening  
(within 28 days 
prior to 
randomization) 
Day 0 
Surgery 
Day 1  
Post-surgery 
Qualification 
(within 9 hours discontinuation 
from the anesthetic block) 
Randomisation to 
study drug 
Post-Surgery 
(D1 and D2) 
Discharge 
(D3) 
Follow-up 
Phone Call 
(D5 to 9 after 
surgery) 
Participants 
provided 
with 
information 
about the 
study 
After consent, 
eligibility is 
checked.  
Standard distal 
first metatarsal 
bunionectomy 
procedure using a 
standardized 
regimen of 
regional 
anesthesia. 
Participants must be 
experiencing moderate to 
severe pain (≥ 40 mm on 
VAS) post-operatively to 
be randomized 
Maxigesic® IV 
 
 
Study drugs 
administered 
4 times daily 
(total of 8 
doses in 48 
hours) 
 
Participant 
diaries 
completed 
and safety 
assessment 
 
 
Follow up 
safety data 
Acetaminophen IV 
Ibuprofen IV 
Placebo IV 
 
 
 
 
 
 
 
 
 


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3.3. 
Randomisation 
 
Randomisation will occur at the study site once participant eligibility for the study is confirmed 
postoperatively. Eligibility will be confirmed on the first postoperative morning (Day 1) within 
the 9-hour qualification period after discontinuation of anesthetic block.    
 
Each eligible participant will be assigned a unique study identification number and randomly 
assigned to treatment according to the computer generated randomization schedule.  
 
The randomisation sequence will be computer-generated by the study statistician, in permuted 
blocks prior to any enrolment. The statistician will maintain a confidential schedule of 
participant numbers and drug allocation. The site will receive a set of individual sealed 
randomisation envelopes for each stratum; the envelope for a specific participant can be opened 
only if there is a medical emergency where medical management of the participant requires 
knowing the identity of the study drug the subject was administered. 
 
3.4. 
Blinding 
 
Blinding will be achieved by the use of matching vials prepared by the technical department of 
the sponsor who is not involved in the data collection.  
 
Each vial of study drug will be labelled with the participant’s study identification number. 
 
The participant, investigator and study staff will be blinded to the assigned treatment until all 
participants have completed the protocol (including the follow-up) and after the study database 
has been locked. The participant’s treatment group will be revealed only if there is a medical 
emergency where medical management of the participant requires knowing the identity of the 
study drug the subject was administered. 
 
4. 
STUDY POPULATION 
4.1. 
Number of Participants 
 
In total, 275 subjects (75 subjects in each active and 50 subjects in placebo) who meet all the 
eligibility criteria will be enrolled and randomised into the study. 
 
4.2. 
Inclusion Criteria 
 
All subjects will be eligible for entry into the study if all of the inclusion criteria are met: 
 
1. 
Is male or female ≥ 18 and ≤ 65 years of age. 
 
2. 
Is classified by the anesthesiologist as P1 to P2 in the American Society of 
Anesthesiologists (ASA) Physical Status Classification System. 
 
 


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3. 
Has undergone primary, unilateral, distal, first metatarsal bunionectomy (osteotomy and 
internal fixation) with no additional collateral procedures. 
 
4. 
Experiences a pain intensity rating of ≥ 40 mm on a 100-mm Visual Analogue Scale 
(VAS) during the 9-hour period after discontinuation of the anesthetic block. 
 
5. 
Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 40 kg/m2. 
 
6. 
Female has negative pregnancy test results at screening (urine) and on the day of surgery 
prior to surgery (urine).. 
 
7. 
If female, is either not of childbearing potential (defined as postmenopausal for at least 1 
year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) 
or practicing 1 of the following medically acceptable methods of birth control: 
 
 Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for 
a minimum of 1 full cycle (based on the subject’s usual menstrual cycle period) before 
study drug administration. 
 Total abstinence from sexual intercourse since the last menses before study drug 
administration through completion of final study visit. 
 Intrauterine device (IUD). 
 Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal 
jellies or cream). 
 
8. 
Is able to provide written informed consent to participate in the study and able to 
understand the procedures and study requirements. 
 
9. 
Must voluntarily sign and date an informed consent form (ICF) that is approved by an 
Institutional Review Board (IRB) before the conduct of any study procedure. 
 
10. 
Is willing and able to comply with study requirements (including diet, alcohol, and 
smoking restrictions), complete the pain evaluations, remain at the study site for 
approximately 72 hours, and will be followed up with a phone call at 7 ± 2 days after 
surgery. 
 
4.3. 
Exclusion Criteria 
 
A subject will not be eligible for study entry if any of the following exclusion criteria are met: 
 
1. 
Has a known history of allergic reaction or clinically significant intolerance to 
acetaminophen, aspirin, opioids, or any nonsteroidal anti-inflammatory drugs (NSAIDs, 
including ibuprofen); history of NSAID-induced bronchospasm (subjects with the triad of 
asthma, nasal polyps, and chronic rhinitis are at greater risk for bronchospasm and should 
be considered carefully); or hypersensitivity, allergy, or significant reaction to sulfa 
(including sulfonamide) medicines, ingredients of the study drug, or any other drugs used 


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in the study including anesthetics and antibiotics that may be required on the day of 
surgery.  
 
2. 
Has experienced any surgical complications or other issues that, in the opinion of the 
investigator, could compromise the safety of the subject if he or she continues into 
randomized treatment period or could confound the results of the study.  
 
3. 
Has known or suspected history of alcoholism or drug abuse or misuse within 2 years of 
screening or evidence of tolerance or physical dependence before dosing with study drug. 
  
4. 
Has any clinically significant unstable cardiac, respiratory, neurological, immunological, 
hematological, or renal disease or any other condition that, in the opinion of the 
investigator, could compromise the subject’s welfare, ability to communicate with the 
study staff, or otherwise contraindicate study participation.  
 
5. 
Has any ongoing condition, other than a condition associated with the current primary, 
unilateral, first metatarsal bunionectomy that could generate levels of pain sufficient to 
confound the results of the study (eg, gout, severe osteoarthritis of the target joint or 
extremity).  
 
6. 
Has a history or current diagnosis of a significant psychiatric disorder that, in the opinion 
of the investigator, would affect the subject’s ability to comply with the study 
requirements.  
 
7. 
Has tested positive either on the urine drug screen or on the alcohol breathalyzer test. 
Subjects who test positive at Screening only and can produce a prescription for the 
medication from their physician may be considered for study enrolment at the discretion of 
the investigator.  
 
8. 
Has a history of a clinically significant (investigator opinion) gastrointestinal (GI) event 
within 6 months before Screening or has any history of peptic or gastric ulcers or GI 
bleeding.  
 
9. 
Has a surgical or medical condition of the GI or renal system that might significantly alter 
the absorption, distribution, or excretion of any drug substance.  
 
10. 
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 IV Maxigesic®), to be an unsuitable candidate to receive 
the study drug.  
 
11. 
Is receiving systemic chemotherapy, has an active malignancy of any type, or has been 
diagnosed with cancer within 5 years before Screening (excluding treated squamous or 
basal cell carcinoma of the skin).  
 
12. 
Is currently receiving anticoagulants (eg, heparin or warfarin).  


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13. 
Has received a course of systemic corticosteroids (either oral or parenteral) within 3 
months before Screening (inhaled nasal steroids and regional/limited area application of 
topical corticosteroids (investigator discretion) are allowed).  
 
14. 
Has received or will require any analgesic medication within 5 half-lives (or, if half-life is 
unknown, within 48 hours) before surgery.  
 
15. 
Has a history of chronic use (defined as daily use for > 2 weeks) of NSAIDs, opiates, or 
glucocorticoids (except inhaled nasal steroids and regional/limited topical corticosteroids), 
for any condition within 6 months before study drug administration. Aspirin at a daily dose 
of ≤ 325 mg is allowed for cardiovascular prophylaxis if the subject has been on a stable 
dose regimen for ≥ 30 days before Screening and has not experienced any relevant medical 
problem.  
 
16. 
Has been treated with agents that could affect the analgesic response (such as central alpha 
agents [clonidine and tizanidine], neuroleptic agents, and other antipsychotic agents) 
within 2 weeks before dosing with study drug.  
 
17. 
Has a significant renal or hepatic disease, as indicated by clinical laboratory assessment 
(results ≥ 3 times the upper limit of normal [ULN] for any liver function test, including 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], or creatinine ≥ 1.5 
times the ULN).  
 
18. 
Has any clinically significant laboratory finding at Screening that, in the opinion of the 
investigator, contraindicates study participation.  
 
19. 
Has significant difficulties swallowing capsules or is unable to tolerate oral medication.  
 
20. 
Previously participated in another clinical study of Maxigesic® IV or received any 
investigational drug or device or investigational therapy within 30 days before Screening. 
 
 
4.4. 
Withdrawal Criteria 
 
All participants have the right to withdraw at any point during the study without prejudice.  
Investigators can discontinue any participant at any time.  Whether participant withdrawal is the 
decision of the participant, or an investigator, the following situations may occur: 
 
1. 
The participant is withdrawn from study medication and the participant withdraws consent 
to release follow-up information. 
2. 
The participant is withdrawn from study medication but all follow-up information can still 
be collected. 
3. 
The participant is withdrawn from study medication temporarily, but then recommences, 
and all follow-up information is collected. 
 


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If one of these circumstances should occur, the management of the participant will be at the 
clinical discretion of his or her treating physician. 
 
Because intention-to-treat analysis requires inclusion of all randomised participants in the 
analysis, it is important to obtain complete follow-up safety data for as many participants as 
possible whether or not they receive their assigned treatment or have discontinued the study 
drug.  Every attempt will therefore be made to collect follow-up information except for those 
participants who specifically withdraw consent to release of such information.   
 
The pain intensity, pain relief assessment and the subject’s global evaluation of the study 
medication will be required to be collected by the time of early withdraw.  
 
It will be documented whether or not each participant completed the clinical study.  If for any 
reason the study treatment or observations were discontinued, the reason will be recorded and the 
Sponsor will be notified promptly. 
 
5. 
TREATMENTS 
5.1. 
Treatments to be Administered 
5.1.1. Identification and Description of Test Agents 
Treatment A 
Maxigesic® IV 
IV acetaminophen 1000 mg and IV ibuprofen 300 mg /100 mL 
solution for infusion.   
 
Treatment B  
IV Acetaminophen 1000 mg/100 mL solution for infusion 
  
Treatment C  
IV Ibuprofen 300 mg/100 mL solution for infusion.   
 
Treatment D  
Placebo IV- 100 mL solution for infusion  
 
 
 
All the study drug will be administered 6 hours (q6H) for 48 hours with a maximum of 4 doses 
within a 24 hour period.  
 
 
5.2. 
Dosing Schedule and Instructions 
 
Administration of the study drug will begin on the morning of the first postoperative day (Day 1) 
once the participant’s eligibility has been confirmed by achieving a pain level of ≥ 40 mm VAS 
within the 9-hour qualification period after discontinuation of the continuous anesthetic infusion.  
 
All study drugs will be administered by injection into a dedicated indwelling venous cannula, 
infused over 15 minutes. The study drugs will be administered every 6 hours (q6H) over the 48 
hour treatment period (a total of 8 doses). 
 
 


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5.3. 
Storage and Handling of Study Drugs 
 
All study drugs are manufactured by S.M. Farmaceutici S.R.L. located in Zona Industriale-85050 
TITO (PZ) Italy, at their GMP approved manufacturing facility. 
 
Maxigesic® IV, IV acetaminophen and IV ibuprofen solutions for infusions have been shown to 
be stable for 24 months when stored at 250C (770F). 
 
The study drug supplied for this study is to be prescribed only by the Principal Investigator or 
named co-investigators and may not be used for any purpose other than that outlined in this 
protocol.  Neither the investigators nor any designees may provide study drug to any participant 
not enrolled in this study.  
 
The investigator or pharmacy designee will maintain an inventory record of the study drug 
dispensed to assure regulatory authorities and the Sponsor that the investigational drugs have not 
been dispensed to any person(s) who is not a participant of this study.  
 
At the termination of the study, all unused study drugs (once they have been inventoried and the 
monitor has reviewed their accountability records) will be destroyed, and a destruction certificate 
will be issued by a licensed destruction company. 
 
5.4. 
Rescue Medication 
 
Subjects may receive supplemental analgesia with an opioid product (oxycodone 5 or 10 mg 
every 4-6 hours as needed) after surgery and before randomization to help control breakthrough 
pain if the regional anesthetic infusion fails to provide adequate anesthesia. 
 
Though sites will be encouraged to use only the oxycodone as supplemental analgesia if 
adequate pain relief is not achieved with oral oxycodone, as a secondary rescue analgesia, 2-4 
mg intravenous morphine sulphate will be allowed to be administered every 4 hours, as needed. 
If the regional anesthetic infusion and supplemental primary and secondary analgesia do not 
effectively control the subject’s postoperative pain, then the subject will be discontinued from 
the study and pain will be managed per standard of care/investigator discretion. 
 
After randomization, subjects will be encouraged to wait for at least 1 hour after the first dose of 
study drug before receiving first rescue medication to allow time for the study drug to exert its 
pharmacological effect. Rescue will not be restricted during this period if required.  
 
The study drug will be administered as usual in addition to the rescue medication.   
 
In the event of rescue medication use, a pain intensity assessment and pain relief assessment 
shall be performed prior to the administration of rescue medication and the time-adjusted SPID 
and TOTPAR will be calculated using this pre-rescue assessment.  
 
6. 
STUDY ASSESSMENTS 
6.1. 
Efficacy Assessments 


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6.1.1. Pain Intensity Assessment  
Pain intensity assessment will be obtained by subjects mark on a 100 mm visual analogue scale 
(VAS) with 0 = No pain and 100 = Worst pain imaginable, and will be used to calculate the 
following efficacy assessment endpoints:  
 
 Summed Pain intensity differences (SPID) (calculated as a time-weighted average) over 0 
to 48 hours (SPID-48) after time 0 
 Pain intensity difference (PID) at each scheduled time point after Time 0 
 Pain intensity score at each scheduled time point 
 SPID over 0-4 hours (SPID-4), over 0-8 hours (SPID-8), and over 0-24 hours (SPID-24) 
after Time 0 
Pain intensity assessment on the VAS will be recorded in the inpatient subject diary at scheduled 
time points during the 6-hour period after Time 0 (5, 10, 15, 30 and 45 minutes, then 1, 1.5, 2, 3, 
4, 5 and 6 hours) and then immediately before taking each dose of the study drug and 2 hours 
after each dosing while awake and at the end of 48 hours of double blind treatment period. If 
additional analgesia is required, Pain intensity assessment on the VAS will be recorded 
immediately before taking each dose of the rescue medication (Pre-rescue VAS assessment).  
 
In the event of rescue medication the time-adjusted SPID up to the administration of rescue 
medication will be calculated.  
6.1.2. Pain Relief Assessment –Categorical 5 point Pain Relief Rating  
Pain relief assessment will be obtained by marking on the 5-point categorical rating scale with: 
 0= no pain relief; (the pain is the same, or worse, than the starting pain) 
 1=a little pain relief; (the pain is less than half gone) 
 2= some pain relief; (the pain is about half gone) 
 3= a lot of pain relief; (the pain is more than half gone) 
 4=complete pain relief; (the pain is completely gone) 
 
Pain relief assessment on the 5-point categorical scale will be recorded in the inpatient subject 
diary at scheduled time points during the 6-hour period after Time 0 (5, 10, 15, 30 and 45 
minutes, then 1, 1.5, 2, 3, 4, 5 and 6 hours) then immediately before taking each dose of the 
study drug and 2 hours after each dosing while awake and at the end of 48 hours of double blind 
treatment period. If additional analgesia is required, Pain relief assessment will be recorded 
immediately before taking each dose of the rescue medication (Pre-rescue pain relief 
assessment).  
  
In the event of rescue medication the time-adjusted TOTPAR up to the administration of rescue 
medication will be calculated. 
 


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Pain relief assessment rating will be used to calculate the following endpoints: 
 Summed pain relief (TOTPAR) (calculated as a time-weighted average) over 0-4 hours 
(TOTPAR-4), over 0-8 hours (TOTPAR-8), over 0-24 hours (TOTPAR-24) after Time 0, 
and over 0-48 hours (TOTPAR-48) after Time 0 
 Pain relief sore on a 5-point categorical scale at each scheduled time point after time 0 
 Peak pain relief 
 Time to peak pain relief 
6.1.3. Time to Perceptible and Meaningful Pain relief (Two-stopwatch method)  
Time to onset of pain relief in minutes after the first dose of study drug is defined as (i) 
perceptible pain relief confirmed by (ii) meaningful pain relief as measured by the two-
stopwatch method. 
 
The two stopwatches will be started immediately after the intravenous infusion starts (the first 
dose of study medication. This is Time 0. Each participant will be instructed, “Stop ’Stopwatch 
1’ 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” (i.e. perceptible 
pain relief). The participant will also be instructed, “Stop ’Stopwatch 2’ when you feel the pain 
relief is meaningful to you” (i.e. meaningful pain relief). If the participant does not press/stop the 
stopwatches within 6 hours after Time 0, the use of the stopwatches will be discontinued. 
 
The two-stopwatch procedure will be used to calculate the following efficacy endpoints: 
 
 Time to perceptible pain relief 
 Time to meaningful pain relief 
 
The methodology of two stopwatch procedures is presented in Appendix 6. 
6.1.4. Requirement of Rescue Analgesia 
Subjects may receive supplemental analgesia with an opioid product (oxycodone 5 or 10 mg 
every 4-6 hours as needed) after surgery and before randomization to help control breakthrough 
pain if the regional anesthetic infusion fails to provide adequate anesthesia. 
 
Though sites will be encouraged to use only the oxycodone as supplemental analgesia if 
adequate pain relief is not achieved with oral oxycodone, as a secondary rescue analgesia, 2-4 
mg intravenous morphine sulphate will be allowed to be administered every 4 hours, as needed. 
If the regional anesthetic infusion and supplemental primary and secondary analgesia do not 
effectively control the subject’s postoperative pain, then the subject will be discontinued from 
the study and pain will be managed per standard of care/investigator discretion. 
 
Participants will be encouraged to avoid rescue if their pain is mild in severity (i.e. less than 40 
mm on the VAS pain intensity scale) and to wait up to 60 minutes after study drug 
administration, if possible.  
 


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The use of rescue medication will be documented on the inpatient subject diary and will be used 
to calculate the following efficacy endpoints: 
 
 Proportion of subjects using rescue medication 
 Time to first use of rescue medication (duration of analgesia) 
 Total use of opioid rescue analgesia over 0-24 hours and 0-48 hours  
6.1.5. The Global Evaluation of Study Drug  
Participants will complete a patient’s global evaluation of study drug at the end of treatment 
period (Day 3) before discharge from the study site. 
 
Participants will be asked to “How do you rate the study medication?” on a 5 point categorical 
scale:  
1 = Poor; 
  
2 = Fair;  
 
3 = Good;  
 
4 = Very good;  
 
5 = Excellent.  
 
6.2. 
Safety Assessments 
 
The safety endpoints are the incidence of treatment-emergent adverse events (AEs) and changes 
in vital measurements.  
 
To rigorously evaluate the local tolerance to study medication at the infusion site, no other drug 
will be administered through the cannula dedicated to the infusion of the study drug. 


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7. 
EXPERIMENTAL PROCEDURE 
7.1. 
Sequence of Procedures 
An overview of the sequence of procedures and study assessments are summarised in Table 2, Schedule of Assessments. 
Table 1: Schedule of Assessments 
Measurements/Treatments 
Screening 
Period 
(Days -28 to 0) 
Day 0  
(Day of 
Surgery)  
Day 1-2 (post-surgery 
qualification and 48- hours 
study period) and Day 3 
(discharge) 
Follow –Up 
Phone Call 
( Day 7 ±2 Days) 
Informed Consent 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
Demographic Data 
 
 
 
 
Complete Medical History 
 
 
 
 
Physical Examination  
 
 
 
 
X ray (Foot 2 views)1 
 
 
 
 
Concomitant Medications 
 
 
 
 
Urine Pregnancy Test (females only) 
 
 
 
 
Urinalysis 
 
 
 
 
Biochemistry & Haematology 
 
 
 
 
Vital Signs  
 
 
5 
 
Urine Drug Screening Test 
 
 
 
 
Alcohol Breathalyzer Test  
 
 
 
 
Surgery  
 
 
 
 
Randomisation2 
 
 
 
 
Study Drug Administration3 
 
 
 
 
Pain Intensity Assessment 
 
 
 
 
Pain Relief Assessment 
 
 
 
 
Time to perceptible and meaningful pain relief 
 
 
 
 
Global Evaluation of Study Drug 4 
 
 
 
 
Rescue medication and timing 
 
 
 
 
AE Monitoring 
 
 
 
 
1 Radiographs taken within 6 months before Screening will be acceptable. 
2 Randomisation will occur within the 9 hour period after discontinuation of the anesthetic block which is approximately at 3AM on Day 1, when the pain intensity rating is ≥ 40 mm on the VAS. 
3 The first dose of the study drug will be administered once the participant is randomised and continues 6 hourly for up to 48 hours 
4 Done either at early termination or upon completion of the treatment period, prior to discharge from study centre. 
5. Vital signs will be evaluated at Time 0 and following first dose infusion on Day 1, then each morning prior to the intravenous infusion and at discharge, early termination


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7.1.1. Screening Period (Day -28 to Day 0) 
Screening will occur up to 28 days prior to the day of surgery (Day 0). 
 
Prior to the initiation of the screening assessments, potential participants will be given a 
complete explanation of the study. 
 
Once an individual has agreed to participate and signed a copy of the Informed Consent 
documents the following evaluations will be performed to assess the participant’s eligibility for 
enrolment in the study: 
 
• Demographic data (age, sex, height, weight) 
 
• Complete medical history - including past or present history of cardiac, 
pulmonary, gastrointestinal, hepatic, renal, immunological, haematological, 
neurological, musculoskeletal or psychiatric conditions (if any), allergy to food 
or drugs and medication history for the previous three months. 
 
• Physical examination including the assessments of vital signs (heart rate, blood 
pressure, temperature, respiratory rate)  
 
• Complete X-ray for the foot-2 view (Radiographs taken within 6 months before 
Screening will be acceptable) 
 
• Recording of concomitant medications 
 
• Urine pregnancy tests (females only) 
 
• Urine analysis 
 
• Urine Drug Screening Test (amphetamines, barbiturates, benzodiazepines, 
cocaine, 
methamphetamines, 
opiates, 
phencyclidine 
(PCP), 
and 
tetrahydrocannabinol (THC) 
 
• Blood screening tests including: 
 
Haematology 
 Haemoglobin 
 Haematrocrit 
 Platelet count 
 Red Blood Cell (RBC) count 
 White Blood Cell (WBC) count 
 Differential Leukocyte Count (DLC) 


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 
Biochemistry 
 Sodium 
 Potassium 
 Urea 
 Creatinine 
 Phosphate 
 Glucose 
 Albumin 
 Total protein 
 Alkaline phosphates 
 Gamma-glutamyl transferase 
 Aspartate transaminase 
 Alanine transaminase 
 Bilirubin 
 
7.1.2. Day of Surgery (Day 0) 
Subjects will be admitted to the study site on the morning of the scheduled surgery (Day 0), and 
will remain at the study site until postoperative Day 3 (a total of 3 nights at the study site). 
 
On Day 0, subjects who continue to meet all study entry criteria will undergo standard first 
metatarsal bunionectomy procedure under a standardized regimen of regional anesthesia. The 
local anesthetic technique to be used for this surgery comprises a combination of a PSB to 
establish and maintain surgical field anesthesia and a continuous sciatic infusion to provide an 
effective method of controlling pain in the immediate postoperative period. 
 
The PSB will be administered using modifications of the Singelyn technique (13).  Subjects will 
receive midazolam and/or propofol for initial sedation at the anesthesiologist’s discretion. After 
adequate sedation is achieved, the anesthesiologist will inject approximately 5 mL lidocaine 1% 
(plain) (or suitable short acting local anesthetic without epinephrine) locally to anesthetize the 
skin, and will determine the location of the sciatic nerve for the PSB using a nerve stimulator per 
standard technique. Once the appropriate location is determined, the anesthesiologist will inject 
40 mL of ropivacaine 0.5% to establish the PSB. Subsequently a catheter will be placed in the 
proximity of the popliteal sciatic nerve for delivery of postoperative anesthesia. If the PSB is not 
sufficient to provide adequate intraoperative anesthesia, a standard Mayo block may be 
established using lidocaine 2% (plain) not to exceed 25 mL. The time, date, dose, and route of all 
local anesthetics will be recorded in the CRF.  
 
The regional anesthesia will be continued postoperatively via a continuous anesthetic infusion. 
Subjects may receive supplemental analgesia with an opioid product (see below) after surgery 


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and before randomization to help control breakthrough pain if the regional anesthetic infusion 
appears to be ineffective in the opinion of the investigator.  
 
If the regional anesthetic infusion and supplemental analgesia do not effectively control the 
subject’s postoperative pain, then the subject will be discontinued from the study.  
7.1.3. Randomisation (Day 1 – First postoperative day) 
On Day 1, the regional anesthetic infusion will be discontinued at approximately 3AM. When 
subjects request pain medication, they will be asked to rate their pain intensity using the 100 mm 
Visual Analogue Scale (0-100).  
 
During the 9-qualification hour period after discontinuation of the anesthetic block, subjects who 
experience a pain intensity rating of ≥ 40 mm on the VAS are eligible to be enrolled into the 
study.  
 
If their pain intensity ratings do not meet the minimum entry criteria within 9 hours of 
discontinuation of the regional anesthesia, subjects will not be eligible for enrollment and will 
receive routine postoperative care at the investigator’s discretion.  
 
Once the pain intensity entry criteria are met, subjects will be randomly assigned to one of the 4 
treatment groups:  
 
Treatment A 
Maxigesic® IV 
IV acetaminophen 1000 mg and IV ibuprofen 300 mg/100 mL 
solution for infusion.   
 
Treatment B 
 
IV Acetaminophen 1000 mg/100 mL solution for infusion 
  
Treatment C 
 
IV Ibuprofen 300 mg in 100 mL infusion.   
 
Treatment D 
 
Placebo IV – 100 ml solution for infusion 
 
Study drug will be administered as a blinded medicine. Study drug will be administered by 
injection into a dedicated indwelling venous cannula, infused over 15 minutes every 6 hours (q6h 
regimen) for 48 hours after the first dose, with a maximum of 8 doses. 
7.1.4. Treatment Period (Day 1-3) 
The treatment period will commence at the start of study drug administration and conclude at 
approximately 48 hours after the first dose (with a maximum of 8 doses).  
 
The following participant reported measurements will be taken during the treatment period: 
 
 
Pain Intensity Assessment on the 100 mm VAS will be collected at the following 
times:  


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• 5,10,15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6 hours after the first dose of the study 
drug  
• immediately before taking each dose of the study drug and 2 hours after each 
dosing while awake. 
• At the end of 48 hours of double blind treatment period 
• immediately before taking each dose of the rescue medication if additional 
analgesia is required.  
 
Pain Relief Assessment on a 5-point categorical rating will be collected at the 
following time points: 
• 5, 10, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6 hours after the first dose of the study 
drug  
• immediately before taking each dose of the study drug and 2 hours after each 
dosing while awake. 
• At the end of 48 hours of  double blind treatment period 
• immediately before taking each dose of the rescue medication if extra pain relief 
is required. 
 
Time to onset of perceptible and meaningful pain relief after the first study drug 
administration, using the two-stopwatch method (described in section 6.1.2) during 
the first dosing period 
 
The time of the first dose of rescue medication administered during the 48 hour 
treatment period  
 
The amount of rescue medication administered during the 48 hours treatment period 
 
Patient’s global evaluation of study drug at the end of 48 hours treatment period 
 
Vital signs will be taken at T0, following the first dose infusion, then prior to the 
first infusion each morning, and at discharge/early termination 
 
Subjects may receive supplemental analgesia with an opioid product (oxycodone 5 or 10 mg 
every 4-6 hours as needed) after surgery and before randomization to help control breakthrough 
pain if the regional anesthetic infusion fails to provide adequate anesthesia. 
 
Though sites will be encouraged to use only the oxycodone as supplemental analgesia if 
adequate pain relief is not achieved with oral oxycodone, as a secondary rescue analgesia, 2-4 
mg intravenous morphine sulphate will be allowed to be administered every 4 hours, as needed. 
If the regional anesthetic infusion and supplemental primary and secondary analgesia do not 
effectively control the subject’s postoperative pain, then the subject will be discontinued from 
the study and pain will be managed per standard of care/investigator discretion. 
 
During the treatment period, subjects will be encouraged to wait for at least 1 hour after the first 
dose of study drug before receiving first rescue medication to allow time for the study drug exert 
its pharmacologic effect.  


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During the treatment period, subject whose pain cannot be adequately managed by a combination 
of study drug and rescue medication, or who develop unacceptable side effects during the study, 
will be discontinued from further study participation. Their pain will be managed conventionally 
at investigator’s discretion.  Pain intensity, pain relief assessments and Subject’s global 
evaluation of study medication will be required to be completed prior to premature study 
termination.  
 
Before discharge from the study site on Day 3, study personnel will dispense a prescription for 
pain medication (if not already dispensed). During the follow-up phone call, subjects will also be 
asked about any additional AEs that have occurred since discharge. 
7.1.5. Follow-up ( 5 -9 days after surgery) 
A final follow-up phone call will be conducted within 5-9 days after the surgery. At this follow-
up call any additional adverse event and concomitant medication data will be collected. 
 
8. 
ADVERSE EVENTS 
Participants experiencing adverse events will be followed clinically until their health has 
returned to baseline status or until all abnormal values have returned to normal or have otherwise 
been explained.  The investigators will provide or arrange appropriate supportive care for the 
participant if necessary. 
 
Adverse events common to acetaminophen and ibuprofen are listed in Appendix 2. 
 
8.1. 
Definitions 
8.1.1. Adverse Event 
An adverse event (AE) is defined as any unintended, unfavourable clinical sign or symptom, any 
new illness or disease or deterioration of existing illness or disease, or any clinically relevant 
deterioration in laboratory variables (e.g., haematological, biochemical, hormonal) or other 
clinical tests (e.g., ECG), whether or not considered treatment related. 
 
Note that the definition could include accidents and the reasons for changes in medicine (drug 
and/or dose), medical, nursing and/or pharmacy consultation, and admission to hospital or 
surgical operations. 
 
Normal postoperative sequelae, including pain, itching, bruising, numbness, bleeding, burning,  
tingling, and edema at the surgical site, will not be recorded as AEs unless they are of greater 
severity and/or intensity than would be expected in the surgeon/investigator’s opinion. 
 
Planned hospital admissions and/or surgical operations for an illness or disease which existed 
before the drug was given or the participant was randomised in a clinical study will not be 
considered adverse events. 
 


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The severity of an adverse event and the relationship to study medication will be assessed by the 
investigator (see Appendix 1). 
8.1.2. Serious Adverse Event 
A serious adverse event is an AE (at any dose of study drug) that: 
• results in death; 
• is life-threatening (i.e., the participant was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred; this does not include an event that, 
had it occurred in a more severe form, might have caused death); 
• results in persistent or significant disability/incapacity; 
• requires in-participant hospitalization or prolongs hospitalization; 
• is a congenital anomaly/birth defect; or 
• is another medically significant event that, on the basis of appropriate medical judgment, 
may jeopardise the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed above (e.g. allergic bronchospasm requiring intensive 
treatment in an emergency room or home, blood dyscrasias or convulsions that do not 
result in hospitalization, or the development of drug dependency or drug abuse). 
 
An adverse event fulfilling any one or more of these criteria must be reported as a serious 
adverse event. The circumstances surrounding the occurrence of the event must be gathered, 
however the event itself must be reported, irrespective of the circumstances. 
 
A distinction should be drawn between serious and severe adverse events.  Severity is an 
estimate or measure of the intensity of an adverse event, while the criteria for serious are 
indications of adverse participant outcomes for regulatory reporting purposes.  A severe adverse 
event need not necessarily be considered serious and a serious adverse event need not be 
considered severe.  For example, nausea that persists for several hours may be considered severe 
nausea, but not a serious adverse event.  On the other hand, a myocardial infarction that may be 
considered minor could also be a serious adverse event if it prolonged hospitalization, for 
example. 
 
8.2. 
Procedure for Adverse Event Reporting 
 
All adverse events (non-serious and serious) spontaneously reported by the participant and/or in 
response to an open question from the study personnel or revealed by observation, physical 
examination, or other diagnostic procedures will be recorded.  All adverse events (non-serious 
and serious) must be recorded on the source documents and case report forms provided by the 
Sponsor. 
 
8.3. 
Procedure for Serious Adverse Event Reporting 
8.3.1. Reporting to Sponsor 
In addition to entering each SAE irrespective of causality on the appropriate page of the Case 


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Report Form (CRF), the investigator must complete a Serious Adverse Event Report (SAER) for 
each serious adverse event regardless of causality to study drug.  The SAER must be faxed to the 
Drug Safety Officer at AFT Pharmaceuticals Ltd within 24 hours (from the point in time when 
the SAE is realised) to +64 9 4880234.  The Drug Safety Officer will contact the investigator 
should it be necessary to clarify any of the event information.  The investigator should provide 
any additional follow-up information for the event to AFT Pharmaceuticals Ltd as soon as it 
becomes available and up to the point the event has been resolved.  This reporting requirement is 
applicable to serious adverse events that occur during the designated study period.  If the 
investigator is notified of a serious event post study that he or she determines to be causally 
related to study medication, the event should also be reported through this process. 
8.3.2. Reporting to Local EC/IRB 
All adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited 
reporting to local ethics committee with 72 hours of the study staff being notified (or being made 
aware). The report shall be in compliance with local ethics committee requirements.  
 
Expedited reporting is in appropriate for serious events from clinical investigations that are 
considered not related to study product, whether the event is expected or not. Similarly, non-
serious adverse reactions, whether expected or not, will not be subject to expedited reporting. 
However, these adverse reactions and adverse event will be included in the periodic safety 
reports to local ethics committee.  
 
The sponsor shall take the responsibility to continually monitor the safety of its clinical 
development program and advise local ethics committee in a prompt manner if the updated 
safety information impacts the continued ethical acceptability of the trial which indicates the 
need for a change in the trial protocol or participant information statement. 
8.3.3. Reporting to Regulatory Agencies 
The Principal Investigator shall notify the regulatory agencies (US FDA) by telephone or by 
facsimile transmission of any unexpected fatal or life-threatening experience associated with the 
use of the drug as soon as possible but in no event later than 7 calendar days (21 CFR 312.32) 
after the sponsor’s initial receipt of the information.  Each written notification may be submitted 
on FDA Form 3500A or if preferred on a CIOMS I form (21 CFR 312.32).  
 
The IND safety reporting to Regulatory Agencies will follow the Guidance for Industry and 
Investigators-Safety Reporting Requirements for INDs and BA/BE Studies (US FDA CDER, 
CBER December 2012).  
 
8.4. 
Data Safety Management Board (DSMB) Review: 
 
No DSMB reviews are planned for this study. 
 
9. 
PLAN FOR STATISTICAL AND OTHER CALCULATIONS 
This study is a Phase III, placebo-controlled randomised, double-blind, parallel-design trial of 


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four treatment regimens, to examine the difference in analgesia between Maxigesic® IV, the 
individual constituents and placebo. 
 
9.1. 
Analyses Populations  
 
The analysis populations include the following: 
 
• The Intent-to-treat population (ITT) will consist of all subjects who receive at least 1 
dose of study drug. Subjects will be included in the group to which they were 
randomised irrespective of the treatment actually taken. The ITT population is the 
primary population for the efficacy analysis.   
 
• The Per-protocol (PP) Population will consist of all ITT subjects who remain in the study 
for at least 48 hours of treatment (complete the 48 hour treatment period) and who do not 
incur a major protocol violation that would challenge the validity of their data. This 
population may be utilized to evaluate the sensitivity of the primary efficacy analysis.  
 
• The PP population will be used for secondary analyses of the primary and secondary 
efficacy outcomes, if this population is less than 90% of the ITT population.  
 
• The safety population will include all subjects who are treated with study drug (ITT). 
Subjects will be included in the treatment group according to the treatment actually 
taken. The safety population is the population for all safety assessments.  
 
9.2. 
Sample Size 
 
In total, 275 participants (75 in each active group and 50 in placebo) will be randomised into the 
study. This sample size will provide 80% power to detect as statistically significant (2-sided 
α=0.05) any difference >10.5mm [ES=0.6] in mean time-adjusted SPID between Maxigesic® IV 
and each of the three comparator study groups.  
 
9.3. 
Statistical Analyses 
9.3.1. Efficacy Analysis 
The analysis of the primary efficacy endpoint SPID-48 (calculated as a time-weighted average) 
will be performed using an analysis of covariance (ANCOVA) model, which will include 
treatment effect as the fixed factor and baseline pain intensity as a covariate.  
 
The primary efficacy endpoint will compare IV Maxigesic® with each of the three comparators 
using a sequential testing strategy to preserve the two-sided type I error rate at α=0.05. The 
pairwise comparisons will be conducted in the following sequence with the sequence of tests 
only continuing if the preceding test is statistically significant at p<0.05. The pairwise 
comparisons with IV Maxigesic® will be conducted in the following sequence: 1. Placebo IV, 2. 
IV acetaminophen, and 3. IV ibuprofen.  
 
Other comparisons between the treatment groups will be considered secondary, and no further 


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adjustments for multiple comparisons will be implemented. The least-squares estimates of the 
means for each treatment group from the ANCOVA model will be tabled with standard errors 
and the mean differences between treatments will be summarised with 95% confidence intervals. 
Secondary analyses may explore the consistency of treatment effects across gender, ethnicity and 
surgical trauma rating groups by including these as covariates in addition to baseline pain 
intensity. The primary efficacy variable will also be summarized by site, with no formal 
statistical comparisons between sites. 
 
The continuous secondary endpoints such as SPID-6, SPID-12, SPID-24, pain intensity score 
(VAS) at each scheduled time point, pain intensity difference (PID) at each scheduled time point 
TOTPAR-6, TOTPAR-12, TOTPAR-24 and TOTPAR-48 will be summarised by treatment 
group using means, standard errors medians, minima, and maxima. These endpoints will 
analysed using ANCOVA models with the relevant baseline assessment as a covariate and these 
results summarised as the mean differences between treatments with 95% confidence intervals.  
 
The ordinal secondary endpoints: pain relief score at each scheduled time point, peak pain relief, 
total dose of rescue medication and patient’s global evaluation of study drug will be summarised 
by treatment group using the number and percentage of subjects within each category for each 
treatment group, medians and inter-quartile ranges as appropriate. 
 
Nominal P values from Mann-Whitney U tests and chi-square tests comparing the Maxigesic IV 
group with each treatment group will be provided, but no formal statistical inferences will be 
drawn on the basis of these tests. 
 
The time-to-event endpoints: onset of analgesia, use of rescue medication and time to peak relief 
will be summarised for each treatment group using the Kaplan-Meier method. 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 two-stopwatch method following the first dose of study 
drug. This will be right-censored at 6 hours for subjects who do not experience both perceptible 
pain relief and meaningful pain relief during the 6-hour interval or who require rescue 
medication prior to achieving perceptible or meaningful pain relief.  
 
The time to event results will be summarised by treatment group as the number of subjects 
analyzed, the number of subjects censored, the median times to event (if attained) with 95% 
confidence intervals (CIs). Additionally, the Kaplan-Meier estimates of the percentage with 
effective analgesia at 6 hours with 95% confidence intervals will be calculated. Log-rank tests 
will also be used to compare the Maxigesic IV group with each of the comparators for the time-
to-event outcomes. 
 
The proportion of subjects using rescue medication will be analysed using a logistic regression 
model that includes baseline pain intensity as a covariate. This model will be used to evaluate 
the treatment effect and summarise the odds ratios and 95% confidence intervals comparing 
Maxigesic with the three comparator groups. 
 
Baseline values for all relevant outcomes are defined as the last measurements taken before Time 
0. 


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9.3.2. Safety Analysis  
Data listings will be provided for protocol-specified safety data. The Medical Dictionary for 
Regulatory Activities (MedDRA) (Version 9.1 or higher) will be used to classify all AEs with 
respect to system organ class and preferred term. Adverse event summaries will include only 
treatment-emergent AEs, which will be summarized for each treatment group. Fisher’s 2-sided 
exact test may be used to compare the rates of occurrence of the more common treatment-
emergent AEs (>10% in total group) between the Maxigesic® IV group and the three comparator 
groups. 
 
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. 
 
9.4. 
Demographic and Background Characteristics 
 
Demographic and baseline characteristics (including age, gender, race, weight, height, BMI, 
medical history, surgery duration, and baseline pain intensity) will be summarized for each 
treatment group and for the overall population using descriptive statistics including means, 
medians, standard deviations, ranges and frequencies and percentages as appropriate. No formal 
statistical analyses will be performed. 
 
 
9.5. 
Missing Data 
 
Pain intensity or relief assessments with sporadic missing data points not due to early withdrawal 
will have these intermediate points interpolated and be time-adjusted if necessary to allow 
analysis of the efficacy endpoints. 
 
As the full study is conducted within the trial clinics it is anticipated that there will be very few 
individuals who do not complete the full 48 hour efficacy assessments even if some withdraw 
from study medication. For pain intensity and relief measures, any subjects who withdraw from 
the study early e.g. due to lack of efficacy, an AE or intolerance to study drug, but have post 
withdrawal assessments, all their scheduled assessments after the time of withdrawal will be 
included in the ITT population for the primary efficacy endpoint analysis. The data from those 
who withdraw consent to participant in the study and therefore provide incomplete efficacy data 
will be imputed as detailed below.  
 
It is expected that these early withdrawals will have higher pain intensity and lower relief 
measures therefore these poor outcomes will be manifest in the efficacy measures. Diligent 
monitoring and data review will be implemented before database lock to ensure that the reasons 
for withdrawal are correctly identified. 
 
For participants who withdraw from all study procedures (e.g. following an AE) and therefore 
provide no additional efficacy data beyond the point of withdrawal the relevant efficacy data will 


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be imputed using a multiple imputation process. The imputation model will include the baseline 
measures age, gender and the baseline efficacy measure additionally the post randomisation 
measures of the appropriate efficacy outcome, randomised group and the interaction between the 
post-randomisation efficacy outcome and randomised group. 
 
For subjects who take any dose of rescue medication, a 6 hour window of subsequent measures 
after the dose of rescue medication will be imputed using the assessment which is taken 
immediately prior to the use of rescue medication. It is expected that the assessment immediately 
prior to the use of rescue will reflect the high pain intensity level and poor relief necessitating the 
use of rescue medication therefore, these poor outcomes will be manifest in the efficacy 
measures. 
 
Sensitivity analyses will be undertaken on all pain intensity and pain relief outcomes which only 
include measured data without any imputation. The results from these analyses will be used to 
show the sensitivity of the results to the imputation process. 
 
9.6. 
PROCEDURE FOR AMENDMENTS TO STATISTICAL PLAN 
 
It is intended that all statistical analyses specified in this protocol will be performed.  However, it 
is conceivable that some scheduled analyses may not be performed.  In addition, study 
observations or analysis results may suggest the need for additional statistical analyses of the 
collected study data.  In either case, deviations (subtractions or additions) from the planned 
statistical analysis will be fully described in the final clinical study report. 
 
9.7. 
DATA COLLECTION 
 
The CRF will be used to collect all participant data assessments that will be used for evaluation 
of specified analyses.  The CRF should be completed in a timely fashion. 
 
As this study will be conducted under International Conference on Harmonization (ICH) GCP 
guidelines, these guidelines require all investigators participating in clinical drug trials to 
maintain detailed clinical data for one of the following periods: 
 
• A period of at least 2 years following the date after the last approval of a marketing 
application in an ICH region and until there are not any pending or contemplated 
marketing applications in an ICH region. 
• 
A period of at least 2 years after the formal discontinuation of clinical development of the 
investigational product. 
 
Should countries participating in this study have other guidelines for record retention, the period 
of record retention should follow the strictest guidelines, for example, New Zealand guidelines 
require documents to be retained for 10 years and Australian guidelines for 15 years. 
 
It is agreed that the investigator and the Sponsor will share in the responsibility to maintain these 
records. Each will maintain a complete set. Neither the investigator not the Sponsor will dispose 
of any records relevant to this study without either written permission from the other and from 
the relevant authorities.  The investigator and Sponsor shall both be responsible for maintaining 
adequate and accurate hard copy source documents of all observations and data generated during 


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this study, including any data clarification forms (DCFs) received from the Sponsor.  Such 
documentation is subject to inspection by the Sponsor or its agents, and/or regulatory agencies.  
The investigator may work with the sponsor to ensure that archiving facilities are provided 
during the archiving period. 
 
10. 
STUDY OR STUDY SITE TERMINATION AND PARTICIPANT 
DISCONTINUATION 
10.1. STUDY OR STUDY SITE TERMINATION 
 
If the Sponsor, Investigator, Study Monitor or appropriate regulatory officials discover 
conditions arising during the study that indicate that the study should be halted or that the study 
centre should be terminated, this action may be taken after appropriate consultation among the 
Sponsor, Investigator and Study Monitor.  Conditions that may warrant termination of the study 
include, but are not limited to, the following:  
 
 The discovery of an unexpected, serious, or unacceptable risk to the participants enrolled 
in the study. 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product. 
 
A study conducted at a single study site or a single study site in a multi-center study may also 
warrant termination under the following conditions: 
 
 Failure of the Investigator to enrol participants into the study at an acceptable rate. 
 Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities. 
 Submission of knowingly false information from the research facility to the Sponsor, 
Study Monitor or appropriate regulatory authority. 
 Insufficient adherence to protocol requirements. 
 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the International Conference of Harmonisation (ICH) sixth efficacy publication (E6) on Good 
Clinical Practice, Section 4.12, ICH E6 4.13, ICH E6 5.20 and ICH E6 5.21. 
 
10.2. PARTICIPANT DISCONTINUATION 
 
Participants will be encouraged to complete the study; however, they may voluntarily withdraw 
at any time.  The Investigator will provide a written report on the appropriate CRF page 
describing the reason for discontinuation.   If a participant withdraws before completion this will 
be dealt with as described in Section 4.4.    
 
A participant may be removed from the study for the following medical or alternative reasons: 
 Adverse event 
 If a participant suffers an adverse event that, in the judgement of the Investigator or the 
Sponsor, presents an unacceptable consequence or risk to the participant, the participant 
may be discontinued from further participation in the study.  


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 Intercurrent illness 
 A participant may also be discontinued from the study if, in the judgement of the 
Investigator, he or she develops an intercurrent illness or complication that is not 
consistent with the protocol requirements or that, in any way, justifies his or her 
withdrawal from the study. 
 Failure of subject to comply fully with protocol required safety and/or efficacy 
assessments or general protocol non-compliance (in the opinion of the investigator at 
his/her discretion) 
 
11. 
PROTOCOL DEVIATIONS 
This study will be conducted, within reasonable limits, as described in this protocol, except for 
emergency situations in which the protection, safety, and well-being of the participant requires 
immediate intervention, based on the judgment of the investigator (or a responsible, 
appropriately trained professional designated by the investigator).  In the event of a significant 
deviation from the protocol due to an emergency, accident, or mistake, the investigator or 
designee must contact the Sponsor, or the Sponsor’s agent, at the earliest possible time by 
telephone.  This will allow an early joint decision regarding the best way to proceed with the 
study (note the ITT protocol – it is expected that all consenting participants will at least continue 
to be followed up for adverse events). The investigator and the Sponsor will document this 
decision. The Institutional Review Board (IRB) or Ethics Committee (EC) will be informed of 
all protocol changes by the investigator in accordance with the IRB or EC established procedure.  
No significant planned or deliberate deviations from the protocol of any type will be made 
without the Sponsor’s agreement and complying with all the IRB or EC established procedures. 
 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. MONITORING 
 
The Sponsor has ethical, legal, and scientific obligations to carefully follow this study in a 
detailed and orderly manner in accordance with established research principles and applicable 
regulations.  As part of a concerted effort to fulfil these obligations the Sponsor's monitor will 
visit the centre(s) during the study in accordance with the Monitoring Plan set forth for this trial 
as well as maintain frequent telephone and written communication. The investigator expects that 
the Sponsor will fulfil this obligation, and provide early opportunity for the investigator to 
correct any deficiencies identified in the data. 
 
12.2. AUDITING 
 
The Sponsor can conduct audits at the study centre(s).  Audits can include, but not be limited to: 
drug supply, presence of required documents, the informed consent process, and comparison of 
case report forms with source documents.  The investigator agrees to participate with audits 
conducted at a reasonable time in a reasonable manner. 
 
Regulatory authorities worldwide may also audit the investigator during or after the study.  The 
investigator should contact the Sponsor immediately if this occurs, and must fully cooperate with 
regulatory authority audits conducted at a reasonable time in a reasonable manner.  


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The sponsor agrees to meet all reasonable costs that arise out of such audits, including reasonable 
remuneration of staff involved in complying with the requirements of such audits. 
 
13. 
ETHICS AND RESPONSIBILITY 
This study will be conducted in compliance with the protocol, with the Sponsor’s standard 
operating procedures and/or guidelines, the ICH GCP guidelines, the Declaration of Helsinki, 
and with any local country GCP guidelines, whichever are the strictest. 
 
13.1. INFORMED CONSENT 
 
Written informed consent will be obtained from the participant before any study-related 
procedures (including any pre-treatment procedures) are performed.  The investigator(s) has both 
ethical and legal responsibility to ensure that each participant being considered for inclusion in 
this study, is given a full explanation of the protocol.  This shall be documented on a written 
informed consent form, which shall be approved by the same IRB or EC responsible for approval 
of this protocol.  Each informed consent form shall include the elements required by ICH GCP 
guidelines.  The investigator agrees to obtain approval from the Sponsor of any written informed 
consent form used in the study, preferably prior to submission to the IRB or EC. 
 
Once the appropriate essential information has been provided to the participant and fully 
explained by the investigators (or a qualified designee) and it is felt that the participant 
understands the implications of participating, the participant and the investigator (or a medically 
qualified designee) shall sign the IRB- or EC-approved written informed consent form.  The 
participants shall be given a copy of the signed informed consent form, and the original shall be 
kept in the site’s regulatory file.  A second copy may be filed in the participant's medical record, 
if allowed by the institution. 
 
13.2. INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE 
 
This protocol and the written informed consent form shall be submitted to the IRB or EC 
identified with this responsibility at the research facility.  Notification in writing of approval 
must come from the IRB or EC chairman or secretary, to the investigator, either as a letter or as a 
copy of the appropriate section of the IRB or EC meeting minutes where this protocol and 
associated informed consent form were discussed.  The investigator will not participate in the 
decision.  If the investigator is an IRB or EC member, the written approval must indicate such 
non-participation.  The investigator will submit status reports to the IRB or EC at least annually 
(when applicable).  The IRB or EC must be notified by the investigator in writing of the 
interruption and/or completion of the study; the investigator must promptly report to the IRB or 
EC all changes in research (protocol amendments) and will not make such changes without IRB 
or EC approval except where necessary to eliminate apparent immediate hazards to human 
participants.  In these cases, the IRB or EC must be notified within 5 days of the change.  The 
investigator will promptly report to the IRB or EC all unanticipated problems involving risk to 
participants or others.  The investigator is required to maintain an accurate and complete record 
of all written correspondence to and received from the IRB or EC and must agree to share all 
such documents and reports with the Sponsor. 


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13.3. GOVERNANCE OF STUDY AND PUBLICATION POLICY 
 
The Governance of the study will be the joint responsibility of the Principal Investigators and the 
Sponsor.   
 
The sponsor agrees that no restriction will be placed on publication of the data. The investigator 
agrees that the sponsor has the right to review and comment on any manuscript prior to 
submission for either publication or presentation at a scientific conference. Thirty days will be 
allowed for this review and comment. 
 
The study will be registered by the Sponsor on the appropriate Clinical Trial Register. 
 
14. 
CONFIDENTIALITY 
All information generated in this study must be considered highly confidential and must not be 
disclosed by either the investigator or the Sponsor to any persons not directly concerned with the 
study without written prior permission from the Sponsor and Investigator (as the case may be).  
However, authorised regulatory officials, the Investigator personnel and Sponsor personnel will 
be allowed full access to the records.  All medications provided and participant bodily fluids 
and/or other materials collected shall be used solely in accordance with this protocol, unless 
otherwise agreed to in writing by the Sponsor and the Investigator, and in compliance with all 
relevant regulations. 
 
Only initials and unique participant numbers in case report forms will identify participants.  
Their full names may, however, be made known to a regulatory agency or other authorised 
official if necessary and approved by the IRB or EC. 


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15. 
INVESTIGATOR AGREEMENT 
Certain responsibilities devolve to the Principal Investigator (notably those of signing the 
Statutory Declarations related to the Ethics Committee, the requirement to retain records, and 
oversight and governance of the study). Other responsibilities apply to all named co-
investigators. 
 
I have read and understand the protocol (including the Investigator’s Brochure) and agree that it 
contains all the ethical, legal, and scientific information necessary to conduct this study.  I will 
personally conduct the study as described, with the assistance of co-investigators and study 
personnel. 
 
I will provide copies of the protocol to all physicians, nurses, and other professional personnel 
responsible to me who will participate in the study.  Together with the Sponsor, I will arrange 
briefing sessions and will discuss the protocol with them, to assure myself that they are 
appropriately informed regarding the investigational new drug Maxigesic® IV, the concurrent 
medications, the efficacy and safety parameters and the conduct of the study in general.  I agree 
to make all reasonable efforts to adhere to the attached protocol.  I understand that this EC 
approved protocol will be submitted to the regulatory authorities by the Sponsor’s Contractor, as 
appropriate.  I agree to allow Sponsor monitors and auditors full access to all medical records at 
the research facility for participants screened or randomised in the study. In return the Sponsor 
agrees to undertake audits regularly and assist me in identifying any deficiencies in the conduct 
of the study as early as possible, and in instituting appropriate measures to address these. 
 
I agree to provide all participants with informed consent forms, as required by government and 
ICH regulations.  I further agree to report to the Sponsor any adverse experiences in accordance 
with the terms of this protocol and FDA regulation, 21 CFR 312.64. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator ‘s Name (printed) Signature  
Date 


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16. 
REFERENCES 
1.  EMEA/CHMP/EWP/240/95 Rev.1. Guideline on clinical development of fixed combination 
medicinal products [Internet]. European Medicines Agency, London; 2009. Available from: 
www.ema.europa.eu/docs/en_GB/document.../WC500003686.pdf 
2.  Merry AF, Gibbs RD, Edwards J, Ting GS, Frampton C, Davies E, et al. Combined acetaminophen 
and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial. 
2010;104(1):80-8. Br J Anaesth.; 2010.  
3.  Clinical Study Report Maxigesic 325 Acute Dental Pain Study (AFT-MX-6), April 2015. AFT 
Pharmaceuticals Ltd.;  
4.  Clinical Study Report Maxigesic IV PK Study (AFT-MXIV-01), Mar 2015,. AFT Pharmaceuticals 
Ltd.;  
5.  Brennan, F, Carr, DB, Cousins, M. Pain Management: a fundamental human right. Anesth Analg. 
2007;105(1):205–21.  
6.  Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national 
survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97(2):534–40.  
7.  Oderda GM, Said Q, Evans RS. Opiod-related adverse drug events in surgical hospitalization: impact 
on costs and length of stay. Ann Pharmacother. 2007;41(3):400–6.  
8.  Elvir-Lazo OL, White PF. The role of multimodal analgesia in pain management after ambulatory 
surgery. Curr Opin Anaesthesiol. 2010;23(6):697–703.  
9.  American Society of Anesthesioloists Task Force on Acute Pain Management. Practice guidelines for 
acute pain management in the perioperative setting: an updated report by the American Society of 
Anaesthesiologists Task Force on Acute Pain Management. Anaesthesilogy; 2012.  
10.  Harding J. Is there a role for intravenous paracetamol in postoperative pain relief? Pharm Pract. 
2009;19(2):67–71.  
11.  Power BM P, Forbes AM, Van Heerden PV. Pharmacokinetics of drugs used in critically ill adults. 
Clin Pharmacokinet. 1998;34(1):25–6.  
12.  EMEA/CPMP/970057/2011-Draft guideline on the clinical development of medicinal products 
intended for the treatement of pain  
13. Singelyn FJ, Gouverneur JM, Gribomont BF.  Popliteal sciatic nerve block aided by a nerve 
stimulator: a reliable technique for foot and ankle surgery. Reg Anesth. 1991 Sep-
Oct;16(5):278-81 
 
 
 
 
 


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Appendix 1: Grading of Adverse Events 
Severity: 
 
Mild  
Discomfort noticed but no disruption of normal daily activity 
 
Moderate 
Discomfort sufficient to reduce or affect daily activity 
 
Severe 
Inability to work or perform daily activity 
 
 
Relationship: 
 
Not related 
A temporal (timely) relationship of the onset of the event, relative 
to the administration of the product is unlikely or not reasonable. 
Or where another cause can explain the occurrence of the event by 
itself 
 
Unlikely  
A temporal (timely) relationship of the onset of the event, relative 
to the administration of the product is unlikely but cannot be ruled 
out.  
 
Possibly related 
A temporal (timely) relationship of the onset of the event, relative 
to the administration of the product is reasonable, but the event 
could have been due to an equally likely cause. 
 
Probably related 
A temporal (timely) relationship of the onset of the event, relative 
to the administration of the product is reasonable and the event is 
more likely to be explained by the medicinal product than by 
another cause.  
 
Definitely related  
A temporal (timely) relationship of the onset of the event, relative 
to the administration of the product is reasonable and there is no 
other cause to explain the event. Cause to explain the event, or a 
re-challenge is positive. 
  
 


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Appendix 2: Adverse Drug Reactions of the Investigational Product 
 
Known adverse drug reactions of acetaminophen alone: 
 
Impaired liver function or a history of liver disease:  
Acetaminophen should be administered with caution to participants with impaired hepatic function because of 
the possibility of delayed elimination or increased serum concentrations. 
 
Impaired Renal Function: 
Acetaminophen should be administered with caution to participants with impaired renal function because of the 
possibility of delayed elimination or increased serum concentrations. 
 
Known adverse drug reactions of Ibuprofen alone: 
 
Asthma: 
Caution is required if ibuprofen is administered to participants suffering from, or with a previous history of, 
bronchial asthma since ibuprofen has been reported to cause bronchospasm in such participants. 
 
Ophthalmological Monitoring: 
Adverse ophthalmological effects have been observed with NSAIDs; accordingly, participants who develop 
visual disturbances during treatment with ibuprofen should have an ophthalmological examination. 
 
Impaired Liver Function or a History of Liver Disease: 
Participants with impaired liver function or a history of liver disease who are on long term ibuprofen therapy 
should have hepatic function monitored at regular intervals. Ibuprofen has been reported to have a minor and 
transient effect on liver enzymes. 
Severe hepatic reactions, including jaundice and cases of fatal hepatitis, though rare, have been reported with 
ibuprofen as with other NSAIDs. If abnormal liver tests persist or worsen, or if clinical signs and symptoms 
consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), ibuprofen 
should be discontinued. 
 
Impaired Renal Function: 
Caution should be used when initiating treatment with ibuprofen in participants with considerable dehydration.  
The two major metabolites of ibuprofen are excreted mainly in the urine and impairment of renal function may 
result in their accumulation. The significance of this is unknown. NSAIDs have been reported to cause 
nephrotoxicity in various forms; interstitial nephritis, nephrotic syndrome and renal failure. In participants with 
renal, cardiac or hepatic impairment, those taking diuretics and ACE inhibitors and the elderly, caution is 
required since the use of NSAIDs may result in deterioration of renal function. The dose should be kept as low as 
possible and renal function should be monitored in these participants. 
 
Cardiovascular Effects: 
Fluid retention and oedema have been reported in association with ibuprofen, therefore, the drug should be used 
with caution in participants with a history of heart failure or hypertension. 
 
Aseptic Meningitis: 
Aseptic meningitis has been reported only rarely, usually but not always in participants with systemic lupus 
erythematosus (SLE) or other connective tissue disorders. 
 
Haematological Monitoring: 
Blood dyscrasias have been rarely reported. Participants on long-term therapy with ibuprofen should have regular 
haematological monitoring. 


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Coagulation Defects: 
Like other NSAIDs, ibuprofen can inhibit platelet aggregation. Ibuprofen has been shown to prolong bleeding 
time (but within the normal range), in normal participants. Because this prolonged bleeding effect may be 
exaggerated in participants with underlying haemostatic defects, ibuprofen should be used with caution in 
persons with intrinsic coagulation defects and those on anti-coagulation therapy. 
 
Masking Signs of Infection: 
As with other drugs of the NSAID class, ibuprofen may mask the usual signs of infection. 
 
Special Precautions: 
In order to avoid exacerbation of disease or adrenal insufficiency, participants who have been on prolonged 
corticosteroid therapy should have their therapy tapered slowly rather than discontinued abruptly when ibuprofen 
is added to the treatment program. 
 
 
 
 
 


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Appendix 3: Pain Assessment –100 mm VAS 
100 mm Visual Analogue Scale 
Mild Pain 
 
Mild pain is annoying; it hurts, but might not really bother you and doesn’t prevent you from 
doing things you might want to do.  You would still be able to read a book or the newspaper and 
you would not automatically want to take medication.   
 
If you have mild pain you would mark in the shaded area below. 
 
No pain  
0 
 
       
 
 
Worst pain 
imaginable  
100 
 
 
 
 
 
Moderate Pain 
 
Moderate pain is uncomfortable and might make it hard to concentrate i.e. it is hard to ignore and 
it would be difficult to concentrate on reading a book or newspaper.  It bothers you significantly 
and you want to relieve it by taking medication or doing something.   
 
Moderate pain is represented on the pain scale by the shaded area below. 
 
No pain  
0 
 
       
 
 
Worst pain 
imaginable  
100 
 
 
 
 
 
Severe Pain  
 
Severe pain means your pain is intense and overwhelming.  You would not be able to 
concentrate and can’t think of anything other than your pain. You will definitely want and need 
medication to relieve it.  
 
No pain  
0 
 
 
 
 
Worst pain 
imaginable  
100 
 
 
  
 


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Appendix 4: Pain Relief Assessment –Categorical 5-Point Pain Relief Rating Scale 
 
 
Please rate your pain relief: 
 
 0= no pain relief; (the pain is the same, or worse, than the starting pain) 
 1=a little pain relief; (the pain is less than half gone) 
 2= some pain relief; (the pain is about half gone) 
 3= a lot of pain relief; (the pain is more than half gone) 
 4=complete pain relief; (the pain is completely gone) 
 
 
 
 


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Appendix 5:  Patient’s Global Evaluation of Study Drug 
 
 
How do you rate the study medication?  
 
 1= Poor;  
 2=Fair;  
 3=Good;  
 4=very Good;  
 5= Excellent 
 
The assessment will be conducted at the end of 48 hours. 
 
 


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Appendix 6: Two Stopwatch Pain Relief Assessments 
 
1. Start the two stopwatches immediately after the intravenous infusion starts (the first dose of 
study medication). This is Time 0. 
2. Check both stopwatches have started, then supply “Stopwatch A” to the participant.  Instruct 
the participant to “stop ‘Stopwatch A’ 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). 
3. If/when the participant stops ‘Stopwatch A’ record time on stopwatch below: 
 
 
 
 
 
 
4. Ask the participant “Do you consider the pain relief you experienced meaningful”. Record 
answer below: 
 
Is pain relief meaningful to the participant? 
   
 Yes     /    
 No 
 
5. If the participant answers “yes”, the two stopwatch method is complete. Remove both 
Stopwatch A and B. 
6. If the participant answers “no”, instruct the participant to “stop ‘Stopwatch B’ when you feel 
the pain relief is meaningful to you”. 
7. If/when the participant stops ‘Stopwatch B’ record the time on the stopwatch below: 
 
 
 
 
 
 
NOTE:  
1. If the subject never experiences “Perceptible Pain Relief”, they will retain ‘Stopwatch A’ for the entire 6 hour 
evaluation period.   If the subject experiences “Perceptible Pain Relief” but not “Meaningful Pain Relief”, they 
will retain ‘Stopwatch B’ for the remainder of the evaluation period.  Unless “Meaningful Pain Relief” is 
achieved, either by answering “yes” to the question or stopping ‘Stopwatch B”, the participant will always have 
an active stopwatch with them. 
2. The two stopwatches will be discontinued if rescue medication is required.  
 
Time of stopping the Stopwatch A (hh:mm:ss) 
(Perceptible Pain Relief) 
|____|____| : |____|____|: |____|____| 
Time of stopping the Stopwatch B (hh:mm:ss) 
(Meaningful Pain Relief) 
|____|____| : |____|____|: |____|____| 

SAP_001.pdf: 
AFT-MXIV-07: Maxigesic® IV Bunionectomy Study 
 
AFT Pharmaceuticals Ltd.                        
Statistical Analysis Plan 
 
 
Version: 1 
Date: 22nd November 2017 
 
Page 1 
 
 
 
 
Maxigesic® IV Bunionectomy Study: 
A Phase 3, Randomized, Double-Blind, Multiple-Dose, Parallel-Group 
and Placebo-Controlled Study of IV Maxigesic®, IV acetaminophen 
and IV ibuprofen for the Treatment of Acute Postoperative Pain after 
Bunionectomy 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
Protocol Number AFT-MXIV-07 
Amendment 03 
Document Date  4th January 2017 
Version 1 
Document Date 22nd November 2017 


AFT-MXIV-07: Maxigesic® IV Bunionectomy Study 
 
AFT Pharmaceuticals Ltd.                        
Statistical Analysis Plan 
 
 
Version: 1 
Date: 22nd November 2017 
 
Page 2 
22nd November 2017 
22nd November 2017 
22nd November 2017 
 
 
 
Approval Form 
 
Prepared  by: 
Charles Beasley 
R&D Project Manager 
AFT Pharmaceuticals Ltd. 
____________________ 
Signature 
________________ 
Date 
 
Chris Frampton 
Consulting Biostatistician 
____________________ 
Signature 
________________ 
Date 
Reviewed & 
Approved by: 
Ioana Stanescu 
Head of Drug 
Development 
AFT Pharmaceuticals Ltd. 
____________________ 
Signature 
________________ 
Date 
 
 


AFT-MXIV-07: Maxigesic® IV Bunionectomy Study 
 
AFT Pharmaceuticals Ltd.                        
Statistical Analysis Plan 
 
 
Version: 1 
Date: 22nd November 2017 
 
Page 3 
1 
TITLE 
A Phase 3, Randomized, Double-Blind, Multiple-Dose, Parallel-Group and Placebo controlled 
Study of Maxigesic® IV, IV Acetaminophen, and IV Ibuprofen for the treatment of acute 
postoperative pain after bunionectomy.  
 
2 
RATIONALE  
While there are many analgesic options open to physicians most have limitations. For example, 
fixed dose combinations that include opioids carry the risks of the side effects and dependency 
associated with opioid drugs. Acetaminophen and ibuprofen are well established analgesics 
with excellent safety records in both adults and children.  
AFT Pharmaceuticals Ltd. has been developed a fixed-dose combination of acetaminophen 
1000 mg and ibuprofen 300 mg/100 ml solution for infusion (Maxigesic® IV) for the temporary 
relief of postoperative pain, when administration by intravenous route. This is clinically 
justified by an urgent need to treat pain or hyperthermia when other routes of administration 
are not possible or prudent. 
 
3 
STUDY DESIGN AND OBJECTIVES 
3.1 
Design 
This study is a Phase III, placebo-controlled, randomised, double-blind, parallel-design trial to 
investigate the analgesic efficacy of Maxigesic® IV compared with the individual components 
alone and placebo.   
Eligible subjects will complete all screening procedures within 28 days before the surgery. At 
Screening, subjects will provide written informed consent to participate in the study before any 
protocol-specified procedures or assessments are completed. 
Subjects will be admitted to the study site on the morning of the scheduled surgery (Day 0), 
will remain at the study site until postoperative Day 3 (a total of 3 nights at the study site), and 
will be followed up with a phone call Day 7 (±2 days). 
On Day 0, subjects who continue to meet all study entry criteria will undergo standard distal 
first metatarsal bunionectomy procedure using a standardized regimen of regional anaesthesia. 
The regional anaesthetic technique to be used for this surgery comprises a combination of a 
PSB to establish and maintain surgical field anaesthesia (local anaesthesia using a Mayo block 
with a short acting anaesthetic will be allowed to augment surgical field anaesthesia at the 
surgeons discretion) and a continuous sciatic infusion to provide an effective method of 
controlling pain in the immediate postoperative period. 
The PSB will be administered using modifications of the Singelyn technique.  Subjects will 
receive midazolam and/or propofol for initial sedation at the anaesthesiologist’s discretion. 
After adequate sedation is achieved, the anaesthesiologist will inject approximately 5 mL 
lidocaine 1% (plain) (or suitable short acting local anaesthetic without epinephrine) locally to 
anesthetize the skin, and will determine the location of the sciatic nerve for the PSB using a 
nerve stimulator per standard technique. Once the appropriate location is determined, the 
anaesthesiologist will inject 40 mL of ropivacaine 0.5% to establish the PSB. Subsequently a 


AFT-MXIV-07: Maxigesic® IV Bunionectomy Study 
 
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Statistical Analysis Plan 
 
 
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catheter will be placed in the proximity of the popliteal sciatic nerve for delivery of 
postoperative anaesthesia. If the PSB is not sufficient to provide adequate surgical anaesthesia, 
a standard Mayo block (local anaesthesia) may be established using lidocaine 2% (plain) not 
to exceed 25 mL. The time, date, dose, and route of all local anaesthetics will be recorded in 
the CRF.  
The regional anaesthesia will be established using a popliteal sciatic nerve block (PSB) after 
which subjects will undergo primary, unilateral, first metatarsal bunionectomy under regional 
anaesthesia. The regional anaesthesia will be continued postoperatively via a continuous 
anaesthetic infusion.  
Subjects may receive supplemental analgesia with an opioid product (oxycodone 5 or 10 mg 
every 4-6 hours as needed) after surgery and before randomization to help control breakthrough 
pain if the regional anaesthetic infusion fails to provide adequate anaesthesia. 
Though sites will be encouraged to use only the oxycodone as supplemental analgesia if 
adequate pain relief is not achieved with oral oxycodone, as a secondary rescue analgesia, 2-4 
mg intravenous morphine sulphate will be allowed to be administered every 4 hours, as needed. 
If the regional anaesthetic infusion and supplemental primary and secondary analgesia do not 
effectively control the subject’s postoperative pain, then the subject will be discontinued from 
the study and pain will be managed per standard of care/investigator discretion. 
On Day 1, the regional anaesthetic infusion will be discontinued at approximately 3 AM. When 
subjects request pain medication, they will be asked to rate their pain intensity using the 100 
mm VAS scale assessment (0-100).  
During the 9-hour qualification period after discontinuation of the anaesthetic block, subjects 
who experience a pain intensity rating of ≥ 40 mm on the VAS are eligible to be enrolled into 
the study. If their pain intensity ratings do not meet the minimum entry criteria within 9 hours 
of discontinuation of the regional anaesthesia, subjects will not be eligible for enrolment and 
will receive routine standard postoperative care at the investigator’s discretion. 
Once the pain intensity entry criteria are met, subjects will be randomly assigned to one of four 
treatment groups: 
• Maxigesic® IV (acetaminophen 10 mg/1 mL + ibuprofen 3 mg/mL solution for 
infusion) 
• Acetaminophen IV (acetaminophen 10 mg/1 mL solution for infusion) 
• Ibuprofen IV (ibuprofen 3 mg/mL solution for infusion) 
• Placebo solution for infusion 
 
During the treatment period (Day 1-3) study drugs will be administered q6h for a total of 8 
doses over 48 hours, and the following participant reported measurements will be made: 
• Pain Intensity Assessment on the 100 mm VAS will be collected at the following times:  
o 5,10,15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6 hours after the first dose of the study 
drug  
o Immediately before and 2 hours after each subsequent dose (doses 2-8) of the 
study drug while awake 
o At the end of 48 hours of double-blind treatment period 


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o Immediately before taking each dose of the rescue medication if additional 
analgesia is required 
• Pain Relief Assessment on a 5-point categorical rating will be collected at the following 
time points: 
o 5, 10, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6 hours after the first dose of the 
study drug 
o Immediately before and 2 hours after each subsequent dose (doses 2-8) of the 
study drug while awake 
o At the end of 48 hours of double-blind treatment period 
o Immediately before taking each dose of the rescue medication if additional 
analgesia is required 
• Time to onset of perceptible and meaningful pain relief after the first study drug 
administration, using the two-stopwatch method during the first dosing period 
• Patient’s global evaluation of study drug at the end of the 48 hours treatment period 
 
Patients will be discharged on Day 3 after 48 hours and a final follow-up phone call will be 
conducted on Day 7 (±2 days). 
3.2 
Efficacy Objective 
To determine the efficacy of Maxigesic® IV, acetaminophen IV, ibuprofen IV and placebo IV 
for the treatment of acute postoperative pain after bunionectomy.   
The Efficacy Objective of this study will be addressed by analysis on the following efficacy 
endpoints. 
Primary Efficacy Endpoint 
• Time-adjusted Summed Pain Intensity Difference (SPID) from baseline over 48 hours 
(Time-adjusted SPID48) 
 
Secondary Efficacy Endpoints 
• Time-adjusted Summed Pain Intensity Difference (SPID) from baseline over 6, 12 and 
24 hours (Time-adjusted SPID6, Time-adjusted SPID12, and Time-adjusted SPID24, 
respectively) 
• Total Pain Relief (TOTPAR) over 6, 12, 24 and 48 hours after the first dose of study 
drug (TOTPAR6, TOTPAR12, TOTPAR24, and TOTPAR48, respectively) 
• VAS Pain intensity scores (mm) at each scheduled assessment time point after the first 
dose of study drug 
• Pain Intensity Difference (PID) at each scheduled VAS assessment time point after the 
first dose of study drug 
• Pain Relief Score at each scheduled assessment time point after the first dose of study 
drug  
• Peak Pain Relief 
• Time to Peak Pain Relief 
• Response Rate 
• Time to Response 
• Time to onset of analgesia (perceptible and meaningful pain relief using two stopwatch 
method) 


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Statistical Analysis Plan 
 
 
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• Time to first use of rescue medication 
• Proportion of patients using rescue medication 
• Total use of rescue medication over 24 and 48 hours after first dose of study drug 
• Patients’ global evaluation of study drug  
 
3.3 
Safety Objective 
To determine the incidence of treatment-emergent adverse events (AEs) and changes in vital 
sign measurements.  
 
4 
GENERAL ANALYSIS DEFINITIONS 
4.1 
Treatment Allocation 
Randomisation will occur at the study site once participant eligibility for the study is confirmed 
postoperatively. Eligibility will be confirmed on the first postoperative morning (Day 1) within 
the 9-hour qualification period after discontinuation of anaesthetic block.    
The randomisation sequence will be computer-generated by the study statistician, in permuted 
blocks prior to any enrolment. The statistician will maintain a confidential schedule of 
participant numbers and drug allocation. The site will receive a set of individual sealed 
randomisation envelopes for each stratum; the envelope for a specific participant can be opened 
only if there is a medical emergency where medical management of the participant requires 
knowing the identity of the study drug the subject was administered. 
Each eligible participant will be assigned a unique study identification number and randomly 
assigned to treatment according to the randomization schedule, computer-generated by the 
study statistician, in permuted blocks prior to any enrolment. The statistician will maintain a 
confidential schedule of participant numbers and drug allocation.  
Blinding will be achieved by the use of matching vials prepared by the technical department of 
the sponsor who is not involved in the data collection.  
Each vial of study drug will be labelled with the participant’s study identification number. The 
participant, investigator and study staff will be blinded to the assigned treatment until all 
participants have completed the protocol (including the follow-up) and after the study database 
has been locked. The site will receive a set of individual sealed randomisation envelopes for 
each stratum; the envelope for a specific participant can be opened only if there is a medical 
emergency where medical management of the participant requires knowing the identity of the 
study drug the subject was administered. 
 
4.2 
Sample size calculation 
In total, 275 participants (75 in each active group and 50 in placebo) will be randomised into 
the study. This sample size will provide 80% power to detect as statistically significant (2-sided 
α=0.05) any difference >10.5mm [SE=0.6] in mean time-adjusted SPID between Maxigesic® 
IV and each of the three comparator study groups.  


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Statistical Analysis Plan 
 
 
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4.3 
Participant Populations 
4.3.1 Intention-to-treat (ITT) Population  
The Intent-To-Treat (ITT) population will consist of all subjects who receive at least 1 dose of 
study drug. Subjects will be included in the group to which they were randomised irrespective 
of the treatment actually taken. The ITT population is the primary population for the efficacy 
analysis.   
4.3.2 Per Protocol (PP) Population  
The Per-protocol (PP) Population will consist of all ITT subjects who remain in the study for 
at least 48 hours of treatment (complete the 48 hour treatment period) and who do not incur a 
major protocol violation that would challenge the validity of their data. Additional Analyses of 
efficacy measures using the Per Protocol (PP) population may be performed as a sensitivity 
analysis of the above ITT analyses if the PP population is <90% of the ITT population. 
4.3.3 Safety Population 
The safety population is the population for all safety assessments. The safety population will 
include all subjects who are treated with study drug (ITT). Subjects will be included in the 
treatment group according to the treatment actually taken.  
4.4 
Observational Period 
The observational period for the study will be from the first dose of study medicine (post-
operatively) up to 48 hours after the first dose. 
For safety data, adverse events will be assessed following participant’s randomization during 
the hospital stay, and during a follow-up phone call on Day 7 (±2 days). 
5 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics (including age, gender, race, weight, height, BMI, 
medical history, surgery duration, and baseline vitals and pain intensity) will be summarized 
for each treatment group and for the overall population using descriptive statistics including 
means, medians, standard deviations, ranges and frequencies and percentages as appropriate.  
These data will be examined for any profound imbalances between randomised treatments, and 
these imbalances reported. If potentially confounding influences are thus identified, 
appropriate statistical means will be used to mitigate these, and they will be reported and 
discussed in any reports or publications arising from the study. No formal hypothesis testing 
will be conducted on these baseline variables. 
6 
PARTICIPANT DISPOSITION 
A flowchart will be produced showing the flow of participants throughout the study. The 
numbers of participants consented, screened, randomized, dosed and completed the study will 
be summarized. 
The time intervals between consent & randomisation and randomisation & the start of study 
drug administration will be summarised for each randomised group. Any participants who were 
randomised but did not receive at least one dose of study medication will be individually listed 
with explanation, by randomised group. 


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Statistical Analysis Plan 
 
 
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Any patients inappropriately randomised (e.g. subsequent to randomisation are found to violate 
inclusion/exclusion criteria) will also be individually listed with their inclusion or exclusion 
violations. Participants who use prohibited concomitant medications during the study will be 
individually listed with the study medication, dosage, start and finish dates.  
Total participant numbers for the ITT and PP populations will be summarised by randomised 
group and total participant numbers in the Safety Population will be summarised by treatment 
actually received (should be in accordance with randomized allocation).  
7 
STUDY MEDICATION AND CONCOMITANT THERAPY 
7.1 
Compliance 
To evaluate the degree of treatment compliance during the trial, tabular summaries of study 
drug usage per 24 hour interval will be presented for each randomised group.  
Participants whose study drug usage, or dose rate exceeded the limitations provided by the 
study protocol will be included in a list of protocol deviations. The potential effect of such 
deviations on the resulting clinical evaluations will be discussed in the study report. 
7.2 
Concomitant Medications  
Concomitant medications commenced during the study will be coded and summarised as 
frequencies and percentages by randomised group. The timing of the start of these new 
medications relative to the start of study medication will also be summarised. Medications will 
be grouped into drug classes for these summarises. 
 
 


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Statistical Analysis Plan 
 
 
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8 
 EFFICACY ANALYSES 
8.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the time-adjusted Sum of Pain Intensity Differences over 48 
hours after the first dose of study medication (time-adjusted SPID48).  
A Pain Intensity Difference is the difference between the Visual Analogue Scale (VAS) pain 
score recorded at baseline and a score recorded at any time after the first dose of study 
medication. Taken together, a patient’s PID scores capture the pain relief profile attributable to 
the assigned study medication (an example from 6 hours’ worth of data from study AFT-MX-
6 is presented in Figure 1). The extent of pain relief can then be calculated by the Area Under 
the Curve the PID scores (also referred to as the Sum of Pain Intensity Differences [SPID]).  
 
For the calculation of the SPID, intermittent missing VAS scores will be imputed by linear 
interpolation of adjacent values immediately preceding and following the missing value. 
Additionally, in the event that a patient required rescue medication, the SPID will be calculated 
up until the first Pre-Rescue VAS pain assessment (inclusive): 
1. Example 1: Patient X recorded VAS pain up until 48 hours, but consumed their first 
dose of rescue medication 2.5 hours after the first dose of study medication. The Time-
adjusted SPID will be calculated using the scheduled and pre-rescue VAS pain intensity 
assessments made up to 2.5 hours after the first dose.  
2. Example 2: Patient Y recorded VAS pain intensity scores up until 44 hours after the 
first dose of study medication and did not require any rescue medication. The Time-
adjusted SPID will be calculated using the scheduled VAS pain intensity assessments 
made over 44 hours. 
 
Figure 1: Example PID curves obtained from AFT-MX-6 for the first 6 hours after baseline. FDC 
975/292.5 = 3 tablets of a Fixed Dose Combination of Acetaminophen 325 mg & ibuprofen 97.5 mg 


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Statistical Analysis Plan 
 
 
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Date: 22nd November 2017 
 
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Subsequently, SPID48 scores will be adjusted by the time interval from baseline to the final 
VAS score used in the SPID, using the following formula: 
Time-adjusted SPID48 (mm) = SPID (mm*hr) / Time (hr) 
The analysis of Time-adjusted SPID48 will be performed on the Intention to Treat (ITT) 
population using an analysis of covariance (ANCOVA) model, which will include treatment 
effect as the fixed factor and baseline pain intensity as a covariate. The primary efficacy 
endpoint will compare Maxigesic® IV with each of the three comparators using a sequential 
testing strategy to preserve the two-sided type I error rate at α=0.05. The pairwise comparisons 
will be conducted in the following sequence with the sequence of tests only continuing if the 
preceding test is statistically significant at p<0.05. The pairwise comparisons with Maxigesic® 
IV will be conducted in the following sequence: 1. Placebo IV, 2. Acetaminophen IV, and 3. 
Ibuprofen IV. 
Other comparisons between the treatment groups will be considered secondary, and no further 
adjustments for multiple comparisons will be implemented. The least-squares estimates of the 
means for each treatment group from the ANCOVA model will be tabled with standard errors 
and the mean differences between treatments will be summarised with 95% confidence 
intervals.  
The primary efficacy variable will also be summarized by site, with no formal statistical 
comparisons between sites.  
8.2 
Secondary Efficacy Analyses 
Continuous Secondary Efficacy Endpoints will be summarized by treatment group using 
means, standard errors, medians, minima and maxima. These endpoints will be analysed 
using ANCOVA model with the baseline pain intensity as a covariate and these results 
summarized as the mean differences between treatments with 95% CIs. Continuous 
Secondary Efficacy Endpoints include the following: 
• Time-adjusted SPID6  
• Time-adjusted SPID12 
• Time-adjusted SPID24 
• VAS pain intensity score (mm) at each scheduled time point 
• PID (mm) at each scheduled time point 
• Total Pain Relief over 6 hours (TOTPAR6) 
• TOTPAR12 
• TOTPAR24 
• TOTPAR48 
 
Time-adjusted SPID6 through to SPID24 will be derived in a similar manner to the Time-
adjusted SPID48 (i.e. up until the first Pre-Rescue VAS inclusive).  
Total Pain Relief (TOTPAR) is a measure of total Area Under the Curve of Pain Relief 
scores, weighted by time. For all TOTPARs, in the event that a patient required rescue 
medication (either IR oxycodone 5-10 mg or morphine 2-4 mg), the Area Under the Pain 
Relief curve will be calculated up until the first Pre-Rescue Pain Relief score (inclusive).  


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Statistical Analysis Plan 
 
 
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The Ordinal Secondary Efficacy Endpoints will be summarised by treatment group using the 
number and percentage of subjects within each category for each treatment group, medians 
and inter-quartile ranges as appropriate. Nominal P values from Mann-Whitney U tests and 
chi-square tests comparing the Maxigesic® IV group with each treatment group will be 
provided, but no formal statistical inferences will be drawn on the basis of these tests. Ordinal 
Secondary Efficacy Endpoints include the following: 
• Pain Relief score at each scheduled time point 
• Peak Pain Relief  
• Total Dose (mg) of primary (oxycodone) and secondary (morphine) rescue 
medication over first 24 hours and the full 48 hour study period 
• Total oral Morphine Milligram Equivalent (MME) dose of all rescue medication over 
the first 24 hours and the full 48 hour study period 
• Global Evaluation of Study Drug 
   
A patient’s Peak Pain Relief will be determined from all pain relief ratings recorded prior to 
the first dose of rescue medication (if taken), or up until the end of participation in the 
double-blind treatment period (if no rescue taken). 
The oral Morphine Milligram Equivalent (MME) of PO oxycodone is obtained by 
multiplying the dose of Oxycodone by 1.5 (1). The oral MME of IV morphine is obtained by 
multiplying the dose of IV morphine by 3.0 (2). The MME is a useful tool for comparing to 
doses with other oral opioid drugs such as hydrocodone, hydromorphone, oxymorphone, 
fentanyl, and codeine, etc.  
Time to Event Secondary Efficacy Endpoints will be summarized for each treatment group 
using the Kaplan-Meier Method. For these time-to-event analyses any participants who do 
not experience the event, will be censored at the end of the relevant observation period. The 
time to event results will be summarised by treatment group as the number of subjects 
analyzed, the number of subjects censored, the median times to event (if attained) with 95% 
confidence intervals (CIs). Additionally, the Kaplan-Meier estimates of the percentage with 
effective analgesia at 6 hours with 95% confidence intervals will be calculated.  
Time to onset of analgesia (measured as time to perceptible pain relief and confirmed by 
meaningful pain relief) will be based on data collected using the two-stopwatch method 
following the first dose of study drug. This will be right-censored at 6 hours for subjects who 
do not experience both perceptible pain relief and meaningful pain relief during the 6-hour 
interval or who require rescue medication prior to achieving perceptible or meaningful pain 
relief. 
Log-rank tests will also be used to compare the Maxigesic IV group with each of the 
comparators for the time-to-event outcomes. Time to Event Secondary Efficacy Endpoints 
include the following: 
• Time to Perceptible and Meaningful Pain Relief (Two Stopwatch Assessment) 
• Time to Peak Pain Relief 
• Time to Response 
• Time to first dose of Rescue Medication 
 


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Statistical Analysis Plan 
 
 
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The Response Rate, defined as the percentage of patients that obtain at least a 50% reduction 
in baseline VAS pain, will be analysed using a Chi-square test. An individual patient’s 
response to treatment will be determined from their VAS scores recorded prior to the first 
dose of rescue medication (if taken), or up until the end of their participation in the double-
blind treatment period (if no rescue taken). 
Additionally, the proportion of subjects using rescue medication will be analysed using a 
logistic regression model that includes baseline pain intensity as a covariate. This model will 
be used to evaluate the treatment effect and summarise the odds ratios and 95% confidence 
intervals comparing Maxigesic® IV with the three comparator groups. 
All secondary endpoints will be analysed using all participants in the ITT population that 
have the appropriate assessment of the endpoint or an estimate. There will be no correction 
for multiple comparisons for the analyses of the secondary endpoints. A two-tailed p-value 
<0.05 will be taken to indicate statistical significance for all analyses of secondary efficacy 
endpoints.  
 
8.3 
Additional analyses  
8.3.1 Subgroup Analyses 
Analysis of the primary efficacy endpoint will also be presented by gender, age, ethnicity and 
baseline severity subgroups. A consistency of treatment effect among subgroups will be tested 
for each of the subgroups.  
Secondary analyses may explore the consistency of treatment effects across gender, ethnicity 
and baseline severity subgroups. These factors would be included as covariates in the analyses 
and the interaction between the sub-group factor and randomised treatment would be tested.  
8.3.2 Sensitivity Analyses 
Additional Analyses of efficacy measures using the Per Protocol (PP) population may be 
performed as a sensitivity analysis of the above ITT analyses if the PP population is <90% of 
the ITT population.  
Sensitivity analyses will be undertaken on the Primary Efficacy endpoint (Time-adjusted 
SPID48) for the ITT population to determine the impact of calculating the Time-adjusted SPID48 
using all VAS pain assessments recorded up until the first Pre-Rescue VAS (inclusive. This 
will include the following approaches: 
1. Calculate the Time-adjusted SPID48 using all VAS pain assessments recorded up until 
the first Pre-Rescue VAS score (inclusive), and by carrying forward the first Pre-
Rescue VAS score until the end of participation in the study 
2. Calculate the Time-adjusted SPID48 using the full complement of VAS pain 
assessments (includes both Scheduled AND Pre-Rescue VAS scores recorded by each 
patient). 
3. Calculate the Time-adjusted SPID48 by carrying forward the Pre-Rescue VAS score 
up to 4 hours after each rescue treatment. 4 hours is consistent with the duration of 
action of both rescue medications (oxycodone and morphine). In the event that a 
patient requires two or more doses of rescue medication within a 4 hour interval, a 
subsequent Pre-Rescue VAS score will override the previous one (i.e. Pre-Rescue 
VAS scores will not supplant subsequent Pre-Rescue VAS scores).  


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Additionally, sensitivity analyses will be undertaken on all pain intensity and pain relief 
outcomes where multiple imputation was used for early withdrawals (see Section 11 Missing 
Data). Theses analyses will only include the recorded data (i.e. no imputation) and the outcome 
will be used to show the sensitivity of the main results to the imputation process. 
Statistical significance is not required from all these sensitivity analyses but the analyses will 
be presented and inconsistencies with the primary efficacy endpoint analysis will be discussed.  
9 
SAFETY ANALYSES 
Safety analyses will be performed using the safety population, defined as all subjects who are 
treated with study drug (ITT) with group allocation according to the treatment they actually 
received.  Treatment-emergent Adverse events coded to MedDRA v 20.0 Preferred Term and 
System Organ Class Code will be tabulated as frequencies and percentages by treatment group, 
and by treatment group and severity class and treatment group and relatedness to study drug. 
Fisher’s 2-sided exact test may be used to compare the rates of occurrence of the more common 
treatment-emergent AEs (>10% in total group) between the Maxigesic® IV group and the three 
comparator groups. 
The frequencies and proportions of participants discontinuing as a result of adverse events will 
also be listed and summarised. Serious adverse events will be individually listed by randomised 
group.  
Changes in vital signs from baseline at the following points will compared between treatment 
groups: 
• End of Infusion of first dose 
• Prior to 5th Dose of study drug 
• At discharge on Day 3/early termination 
 
 
 


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Statistical Analysis Plan 
 
 
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10 PROTOCOL VIOLATIONS 
All protocol violations and deviations will be individually listed by randomised group. 
11 MISSING DATA 
Intermittent missing VAS scores will be imputed by linear interpolation of adjacent values 
immediately preceding and following the missing value.  
For the time to response (50% reduction in baseline VAS pain) and the time to first dose of 
Rescue Medication, patients that do not experience the event within the 48 hour study period 
will be censored at the end of the period (48.0 hours) and presumed not to have had the 
appropriate event.  
For the Time to Perceptible and Meaningful Pain Relief, a value of 6 hrs indicates that the 
patient did not experience the event.  
As the full study is conducted within the trial clinics it is anticipated that there will be very 
few individuals who do not complete the full 48 hour efficacy assessments even if some 
withdraw from study medication. For pain intensity and relief measures, any subjects who 
withdraw from the study early but have post withdrawal assessments, all their scheduled 
assessments after the time of withdrawal will be included in the ITT population for the 
primary efficacy endpoint analysis.  
For participants who withdraw from all study procedures and therefore provide no additional 
efficacy data beyond the point of withdrawal the primary efficacy endpoint will be imputed 
using a multiple imputation process. The imputation model will include age, gender and the 
baseline efficacy measure as well as the post-randomisation measures of the appropriate 
efficacy outcome, randomised group and the interaction between the post-randomisation 
efficacy outcome and randomised group. 
12 PROCEDURE FOR AMENDMENTS TO STATISTICAL PLAN 
It is intended that all statistical analyses specified in this protocol will be performed.  However, 
it is conceivable that some scheduled analyses may not be performed.  In addition, study 
observations or analysis results may suggest the need for additional statistical analyses of the 
collected study data.  
Any revisions to this document prior to database lock will be made in the form of an 
amendment to the Statistical Analysis Plan. Any deviations or additional analyses that are 
performed will be summarised in the form of an addendum to the Statistical Analysis Plan. In 
either case, deviations (subtractions or additions) from the planned statistical analysis will be 
fully described in the final Clinical Study Report. 
 
 
 


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Statistical Analysis Plan 
 
 
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13 SUMMARY TABLES, TO INCLUDE BUT IS NOT LIMITED TO 
These tables will produce variable summaries within each treatment group and for the total 
participant population. The summaries will include means, medians, geometric means, 
frequencies, percentages, ranges, standard deviations and standard errors as appropriate. For 
the efficacy variables, differences between Maxigesic® IV and the comparator groups will be 
tabulated along with p-values as applicable. 
If efficacy analysis are undertaken on the PP population, these analyses will be summarized in 
separate table using the same format as outline below.  
Baseline Demographic Information 
• 
Age 
• 
Gender 
• 
Weight 
• 
Height 
• 
BMI 
• 
Race/ethnicity 
Baseline Clinical Characteristics 
• 
Medical History 
• 
Surgery duration 
• 
Baseline VAS pain level  
• 
Vital Signs (Systolic Blood Pressure, Diastolic Blood Pressure, Heart Rate, Respiratory Rate and 
Temperature)  
Study Drug Admin & Concomitant Therapy 
• 
Summary of withdrawals (if applicable) 
• 
Summary of compliance (study drug usage) 
• 
Summary of protocol deviations 
• 
Summary of concomitant medications 
Primary Endpoint 
• 
Summary of Time-adjusted SPID up to 48 hours (mm) 
Secondary Endpoints 
• 
VAS Pain intensity score (mm) at baseline and each scheduled assessment time point after the first 
dose of study drug 
• 
VAS Pain intensity difference (PID) at each scheduled assessment time point after the first dose of 
study drug  
• 
Time-adjusted SPID6, SPID12 and SPID24 
• 
Total Pain Relief (TOTPAR) including TOTPAR6, TOTPAR12¸ TOTPAR24 and TOTPAR48 
• 
Response Rate 
• 
Time to Response 
• 
Time to onset of analgesia using the two-stopwatch method (measured as time to perceptible pain relief 
confirmed by meaningful pain relief) 
• 
Pain relief score on a 5-point categorical scale at each scheduled time point after the first dose of study 
drug 
• 
Peak pain relief 
• 
Time to peak pain relief  
• 
Proportion of subjects using rescue medication  
• 
Time to first use of rescue medication (duration of analgesia)  
• 
Total Dose (mg) of primary (oxycodone) and secondary (morphine) rescue medication over first 24 
hours, and the full 48 hour study period 
• 
Total oral Morphine Milligram Equivalent (MME) dose of all rescue medication over the first 24 hours 
and the full 48 hour study period 
• 
Patient’s global evaluation of study drug 
Sensitivity Analyses 
• 
Sensitivity Analysis of the primary endpoint (Time-adjusted SPID48) 
• 
Sensitivity Analyses of imputation of VAS and PR scores  


AFT-MXIV-07: Maxigesic® IV Bunionectomy Study 
 
AFT Pharmaceuticals Ltd.                        
Statistical Analysis Plan 
 
 
Version: 1 
Date: 22nd November 2017 
 
Page 16 
 
Adverse Events (AEs) 
• 
Frequency/incidence of AEs coded to MedDRA Preferred Term or System Organ Class Code, by study 
drug and/or relationship, and/or  severity 
• 
Listings of SAEs 
• 
Changes from baseline in Vital Sign measurements (Systolic Blood Pressure, Diastolic Blood Pressure, 
Heart Rate, Respiratory Rate and Temperature) at the following time points:  
• 
End of infusion of first dose 
• 
Prior to 5th dose  
• 
At discharge on Day 3/early termination 
 
14 REFERENCES 
1.  Centers for Disease Control and Prevention. Calculating Total Daily Dose of Opioids For 
Safer Dosage [Internet]. [cited 2017 Jul 7]. Available from: 
https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf 
2.  Open Anaesthesia. IV to PO opioids – Equivalency [Internet]. [cited 2017 Jul 7]. 
Available from: https://www.openanesthesia.org/aba_iv_to_po_opioids_-_equivalency/