Conditions: Postoperative Pain
Keywords: Analgesic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 232
Healthy volunteers: no

Brief summary:
The study aims to determine the tolerability of repeated doses of Maxigesic® IV over an extended period of exposure.

Detailed description:
Combined administration of acetaminophen and ibuprofen has been shown to provide superior analgesia over administration of comparable doses of either component alone or placebo, when given as an intravenous formulation or as a solid oral tablet in the postoperative setting.

The superior efficacy of the combination does not appear to come at the expense of tolerability. A previous study of Maxigesic® IV in bunionectomy patients found that there were no differences between patients treated with repeated doses of Maxigesic® IV and those treated with intravenous acetaminophen, ibuprofen or placebo in the rate of discontinuations due to adverse events (AEs), the overall incidence of treatment-emergent AEs (TEAEs) or the severity of TEAEs. The incidence of common TEAEs (affecting ≥ 10% of the study population), including gastrointestinal disorders, nervous system disorders, general disorders and administration site conditions, and skin and subcutaneous tissue disorders, was not changed due to combined administration of acetaminophen and ibuprofen in Maxigesic® IV.

This study aims to determine the tolerability of repeated doses of Maxigesic® IV over an extended period of exposure (≥ 48 hours).

Arms:
arm 1: Acetaminophen 10 mg/ml + ibuprofen 3 mg/ml in 100 ml solution for infusion. The study drug will be administered by injection into a dedicated indwelling venous cannula, infused over 15 minutes. The study drug will be administered every 6 hours (q6h) for a minimum of 48 hours up to at least 5 days, with a maximum of 4 doses within a 24 hour period.

Interventions: intervention 1: Maxigesic® IV
Intervention descriptions: intervention 1: acetaminophen 1000 mg + ibuprofen 300 mg, 100 ml solution for infusion

Protocol document:
Prot_000.pdf: 
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Maxigesic® IV Exposure Study Protocol (AFT-MXIV-11) 
Version3, 21st Aug 2019 
Page 1 of 37 
 
STUDY TITLE: 
A Phase 3, Open-Label, Multiple-Dose, Single-
Arm Exposure Study of Maxigesic® IV in 
Patients with Acute Pain Following Orthopedic, 
General or Plastic Surgery 
PROTOCOL IDENTIFICATION: 
AFT-MXIV-11 
NAME OF STUDY DRUG: 
Maxigesic® IV 
INDICATION STUDIED 
Analgesia for acute postoperative pain 
DEVELOPMENT PHASE: 
Phase 3 
IND APPLICATION NUMBER 
124213 
TRIAL REGISTRATION NUMBER:  
ACTRN12619000587101p 
SPONSOR: 
AFT Pharmaceuticals Limited,  
Level 1, 129 Hurstmere Road, Takapuna,  
Auckland, New Zealand  
Ph: + 64 9 488 0232 Fax: + 64 9 488 0234 
 
INVESTIGATORS: 
Dr. Ira J. Gottlieb (Chesapeake Research Group) 
Dr. Gregory L. Ruff (Chapel Hill Research 
Group) 
Dr. Simon Carson (Southern Clinical Trials Ltd) 
Dr. Nigel Gilchrist (Canterbury Geriatric Medical 
Research Trust) 
 
RESEARCH SITES: 
Chesapeake Research Group 
8030B Ritchie Highway 
Pasadena, MD 21122  
United States of America 
Ph: +1 410 761 0118, Fax: +1 410 761 5118 
 
Chapel Hill Research Group 
110 Timberhill Place 
Chapel Hill, NC 27514 
United States of America 
Ph: +1 919 888 4088, Fax: +1 443 577 4297 
 
Southern Clinical Trials Ltd 
Forte 2, Level 2, 132 Peterborough Street 
Christchurch Central, Christchurch 8013 
New Zealand 
Ph: +64 3 337 1979 
 
Canterbury Geriatric Medical Research Trust 
Burwood Hospital, 300 Burwood Road, 


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Christchurch, 8083, 
New Zealand 
Ph: + 64 3 337 7821 
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 
DATE: 
21 Aug 2019 
 
 
 


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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:  
A Phase 3, Open-Label, Multiple-Dose, Single-Arm Exposure 
Study of Maxigesic® IV in Patients with Acute Pain Following 
Orthopedic, General or Plastic Surgery 
PROTOCOL NUMBER: 
AFT-MXIV-11 
DOCUMENT DATE: 
21st Aug 2019 
 
Prepared by  
Phillip Aitken 
Clinical Scientist 
Signature: 
 
Date: 
21st Aug 2019 
Reviewed by  
Ioana Stanescu 
Head of Drug Development  
Signature: 
 
Date: 
21st Aug 2019 
Approved by  
Hartley Atkinson 
Managing Director 
 
Signature: 
 
Date: 
21st Aug 2019 
 
 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor 
AFT Pharmaceuticals Ltd 
Name of Active Ingredient(s) 
Acetaminophen and Ibuprofen 
Title of Study 
A Phase 3, Open-Label, Multiple-Dose, Single-Arm Exposure Study of 
Maxigesic® IV in Patients with Acute Pain Following Orthopedic, General 
or Plastic Surgery 
Study Centers 
Chesapeake Research Group 
8030B Ritchie Highway 
Pasadena, MD 21122  
United States of America 
Ph: +1 410 761 0118, Fax: +1 410 761 5118 
 
Chapel Hill Research Group 
110 Timberhill Place 
Chapel Hill, NC 27514 
United States of America 
Ph: +1 919 888 4088, Fax: +1 443 577 4297 
 
Southern Clinical Trials Ltd 
Forte 2, Level 2, 132 Peterborough Street 
Christchurch Central, Christchurch 8013 
New Zealand 
Ph: +64 3 337 1979 
 
Canterbury Geriatric Medical Research Trust 
Burwood Hospital, 300 Burwood Road, Christchurch, 8083, 
New Zealand 
Ph: + 64 3 337 7821 
Phase of Development 
Phase 3 
Background and Rationale 
Combined administration of acetaminophen and ibuprofen has been shown 
to provide superior analgesia over administration of comparable doses of 
either component alone or placebo, when given as an intravenous 
formulation or as a solid oral tablet in the postoperative setting. This has 
been demonstrated in three Phase 2/3 clinical trials in patients following 
third molar removal or arthroscopic knee surgery using oral tablets of 
Maxigesic® (acetaminophen 500 mg + ibuprofen 150 mg), in one Phase 3 
clinical study in dental surgery patients with Combogesic® (acetaminophen 
325 mg + ibuprofen 97.5 mg) and in one Phase 3 trial in bunionectomy 
patients using Maxigesic® IV (acetaminophen 10 mg/ml + ibuprofen 3 
mg/ml in 100 ml solution for infusion).  
 
The superior efficacy of the combination does not appear to come at the 
expense of tolerability. In the Phase 3 study of Maxigesic® IV in 
bunionectomy patients, there were no differences between patients treated 
with Maxigesic® IV and those treated with intravenous acetaminophen, 
ibuprofen or placebo in the rate of discontinuations due to adverse events 
(AEs), the overall incidence of treatment-emergent AEs (TEAEs) or the 
severity of TEAEs. The incidence of most common TEAEs (affecting ≥ 10% 
of the study population), including gastrointestinal disorders, nervous 
system disorders, general disorders and administration site conditions, and 
skin and subcutaneous tissue disorders was not significantly different 
between treatment groups. Some differences were observed between 


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treatment groups in the incidence of specific AEs, such as vomiting and 
administration site pain, however these were attributable to the individual 
components, acetaminophen and ibuprofen respectively.  
 
All safety data obtained for Maxigesic® IV to date has come from patients 
exposed to single doses of the study drug (n=60) or six hourly doses for up 
to 48 hours (n=75). This study aims to determine the tolerability of repeated 
doses of Maxigesic® IV over an extended period of exposure.  
Objectives 
To determine the incidence of treatment-emergent adverse events, and 
changes in vital signs or clinical laboratory values associated with prolonged 
exposure to Maxigesic® IV  
Study Design 
Phase 3, multicenter, open-label, single arm, multiple dose study to evaluate 
the safety of Maxigesic® IV (acetaminophen 10 mg/ml + ibuprofen 3 mg/ml 
in 100 ml solution for infusion)  
Number of Participants 
225 (including 50 participants with at least 5 days exposure) 
Main Inclusion Criteria 
- 
Male or female ≥ 18 years of age 
- 
Requirement of multiple doses of parenterally administered 
nonopioid analgesics over multiple days as a result of surgery (non-
laparoscopic general, plastic or orthopedic surgery) 
- 
Expected stay in facility ≥ 48 hours 
Study Drugs & Treatment 
Maxigesic® IV (acetaminophen 10 mg/ml + ibuprofen 3 mg/ml in 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 a minimum of 48 hours (8 doses).  
Duration of Treatment 
The estimated duration of the study for each subject is approximately 42 
days, which includes a screening period of up to 30 days, a treatment period 
of at least 2 days (with up to 50 participants treated for at least 5 days), and 
a post treatment follow-up visit 7 ± 2 days after the last dose. The first dose 
is to be administered in the immediate postoperative period, as soon as the 
patient is stable following surgery. 
Study Endpoints 
- 
Incidence of TEAEs at any time during the treatment period 
- 
The time course of TEAEs 
- 
Incidence of treatment-related adverse events 
- 
Incidence of TEAEs of interest: 
- 
cardiovascular thrombotic events 
- 
gastrointestinal events 
- 
renal conditions 
- 
hepatic conditions 
- 
administration site conditions 
- 
bleeding related to surgical procedures 
- 
Changes in vital sign measurements  
- 
Changes in clinical laboratory values 
- 
Patient’s global evaluation of study drug 
Statistical Methods Summary 
All subjects who receive at least one dose of the study drug will be included 
in the safety population. The safety population will be used for all summaries 
of study endpoints. Early withdrawals for any reason will be tabulated. 
 
The demographic and clinical characteristics of the study population at study 
entry, including age, gender, race, ethnicity, indication (type of surgery), use 


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of concomitant medications (e.g. opioids), vitals and laboratory results will 
be summarized as means, medians, standard deviations, ranges and 
frequencies and percentages as appropriate. 
 
Treatment-emergent adverse events are defined as events first occurring or 
worsening during the course of the study, regardless of their relationship to 
the study drug. Treatment-emergent adverse events will be coded to 
MedDRA System Organ Class Code and Preferred Term and tabulated as 
frequencies and percentages in the following time periods: At any timepoint 
during the observational period; at any timepoint during the treatment 
period; on Day 1; Day 2; Day 3; Day 4; Day 5; Day 6+; and during follow-
up. Clinically significant changes from baseline in vital sign measurements 
or laboratory test results will be classified as adverse events. 
  
The proportion of TEAEs that are considered by the Investigator to be 
“probably” or “definitely” related to study medication (treatment-related 
AEs, TRAEs) will be summarized.  
 
All cardiovascular, gastrointestinal, renal, hepatic, administration site 
conditions and bleeding-related AEs will be summarized and the proportion 
of these that are considered treatment-related will be tabulated. 
 
The incidence of TEAEs will be summarized by gender, race, age (<65, 65-
75, >75 years), duration of exposure (≤ 48 hours, 48 hours – 4 days, ≥ 5 
days) and indication (surgery type). This analysis is subject to recruitment 
of sufficient participants within each subgroup. 
 
Vital sign measurements and clinical laboratory values at each scheduled 
timepoint will be summarized with standard descriptive statistics, including 
means, standard deviations and ranges. Summary shift tables will be 
produced overall and by duration of treatment (≤ 48 hours, 48 hours – 4 days, 
≥ 5 days) of the number of cases with normal baseline laboratory tests 
changed to abnormal at the end of the treatment period, and abnormal 
baseline laboratory tests worsened at the end of the treatment period, with 
the severity of changes summarized as proportional effects. 
 
The use of concomitant medications following study drug administration 
will be summarized as frequencies and percentages within ATC-coded drug 
groups.   
 
The frequency and percentage of subjects rating the study drug as ‘poor’, 
‘fair’, ‘good’, ‘very good’ and ‘excellent’ will be summarized.  
Sample Size Calculation 
In total, 225 participants will be enrolled in this study, with at least 50 
participants exposed to the study drug for at least 5 days. The sample size 
for this safety study is not based on formal statistical power calculations but 
will ensure with 95% probability that any TEAEs present in approximately 
2% or more of the target population will be identified in this study. 


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Schedule 
of 
Assessments 
Schedule of Assessments  
Study Assessments 
Screening Period 
(within 
30 
days 
before surgery) 
Day 1 - ≥5 (Treatment period) 
Follow-Up Visit 
(7 ± 2 days after 
last dose) 
Day 1 
(Prior 
to 
Surgery) 
Day 1 
(Immediately Post 
Surgery) 
Day 
2 
- 
≥5 
(Treatment period) 
After last dose, prior 
to discharge 
Informed Consent 
✓ 
 
 
 
 
 
Demographic Data 
✓ 
 
 
 
 
 
Complete Medical 
History 
✓ 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
✓ 
✓ 
 
 
 
 
Physical Examination  
✓ 
✓* 
 
 
✓ 
✓ 
Concomitant Medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Urine Pregnancy Test1 
✓ 
✓* 
 
 
 
 
Vital Signs (including 
HR, BP)2 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
ECG3 
 
✓ 
 
✓ 
✓ 
 
Urinalysis 
✓ 
✓* 
 
 
✓ 
 
Biochemistry & 
Hematology 
✓ 
✓* 
 
 
✓ 
 
Urine Drug Screening 
Test 
✓ 
✓* 
 
 
 
 
Alcohol Breathalyzer 
Test  
 
✓ 
 
 
 
 
Study Drug 
Administration4 
 
 
✓ 
✓ 
 
 
Global Evaluation of 
Study Drug 
 
 
 
 
✓ 
 
Adverse Event 
Monitoring 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
* Not required if screening done within 7 days of surgery 
1 Females of childbearing potential only 
2 Vital signs will be evaluated at Time 0, prior to and following first dose infusion on Day 1, then each morning prior to the intravenous infusion and after the last dose/prior to discharge/early 
termination 
3 ECGs will be conducted prior to surgery, at 48 hours after the first dose and after the last dose/prior to discharge 
4 The first dose of the study drug will be administered in the immediate postoperative period, as soon as the patient is stable following surgery 


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TABLE OF CONTENTS 
 
Protocol Synopsis .............................................................................................................................................. 4 
Table of Contents .............................................................................................................................................. 8 
Index of Tables .................................................................................................................................................. 9 
Index of Figures ................................................................................................................................................. 9 
List of Abbreviations ....................................................................................................................................... 10 
1 
Introduction ............................................................................................................................................. 11 
1.1 
Background ...................................................................................................................................... 11 
1.2 
Drug Name ...................................................................................................................................... 11 
2 
Trial Objectives ....................................................................................................................................... 13 
2.1 
Study Hypothesis ............................................................................................................................. 13 
2.2 
Obejectives and Endpoints .............................................................................................................. 13 
3 
Investigational Plan ................................................................................................................................. 13 
3.1 
Overall Study Design and Plan: Description ................................................................................... 13 
3.2 
Discussion of Study Design ............................................................................................................. 14 
4 
Patient Population .................................................................................................................................... 15 
4.1 
Number of Patients .......................................................................................................................... 15 
4.2 
Inclusion Criteria ............................................................................................................................. 15 
4.3 
Exclusion Criteria ............................................................................................................................ 16 
4.4 
Withdrawal Criteria ......................................................................................................................... 17 
5 
Treatments ............................................................................................................................................... 17 
5.1 
Treatments to be Administered ........................................................................................................ 17 
5.2 
Identity of Investigational Products ................................................................................................. 18 
5.3 
Randomization ................................................................................................................................. 18 
5.4 
Blinding ........................................................................................................................................... 18 
5.5 
Prohibited Concomitant Medications .............................................................................................. 18 
5.6 
Treatment Compliance .................................................................................................................... 19 
6 
Efficacy, Pharmacokinetic and Safety Variables ..................................................................................... 19 
6.1 
Efficacy and Safety Measures Assessed .......................................................................................... 19 
7 
Sequence of Procedures ........................................................................................................................... 19 
7.1 
Pretreatment Period ......................................................................................................................... 21 
7.2 
Treatment Period ............................................................................................................................. 22 
7.3 
Follow-Up ........................................................................................................................................ 23 
8 
Adverse Events ........................................................................................................................................ 23 
8.1 
Definitions ....................................................................................................................................... 23 
8.2 
Adverse Event Reporting Period ..................................................................................................... 24 
8.3 
Procedure for Adverse Event Reporting .......................................................................................... 24 
8.4 
Procedure for Serious Adverse Event Reporting to the Sponsor ..................................................... 24 


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8.5 
The Data Safety Monitoring Board ................................................................................................. 25 
9 
Protocol Deviations ................................................................................................................................. 25 
10 
Statistical Plan ..................................................................................................................................... 26 
10.1 
Sample Size ..................................................................................................................................... 26 
10.2 
Definitions ....................................................................................................................................... 26 
10.3 
Statistical Analyses .......................................................................................................................... 26 
10.4 
Missing Data .................................................................................................................................... 29 
10.5 
Procedure for Amendments to Statistical Plan ................................................................................ 29 
10.6 
Data Collection ................................................................................................................................ 29 
11 
Records Retention ............................................................................................................................... 29 
12 
Quality Control and Quality Assurance ............................................................................................... 30 
12.1 
Monitoring ....................................................................................................................................... 30 
12.2 
Auditing ........................................................................................................................................... 30 
13 
Ethics and Responsibility .................................................................................................................... 30 
13.1 
Informed Consent ............................................................................................................................ 30 
13.2 
Institutional Review Board/Ethics Committee ................................................................................ 31 
13.3 
Governance of the Study and Publication Policy ............................................................................ 31 
14 
Confidentiality ..................................................................................................................................... 31 
15 
Investigator Agreement ....................................................................................................................... 32 
16 
Reference List ...................................................................................................................................... 33 
Appendix 1: Grading of Adverse Events ......................................................................................................... 34 
Appendix 2: Adverse Drug Reactions of the Investigational Product ............................................................. 35 
Appendix 3: Patient’s Global Evaluation of the Study Drug .......................................................................... 37 
 
 
INDEX OF TABLES 
 
Table 1: Schedule of Assessments................................................................................................................... 20 
 
 
INDEX OF FIGURES 
 
Figure 1: Schematic of Trial Design ................................................................................................................ 14 
 
 


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LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE(s) 
Adverse Event(s) 
BP 
Blood Pressure 
CI  
Confidence Interval  
CRF(s) 
Case Report Form(s) 
DBP 
Diastolic Blood Pressure 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EPP 
Evaluable Participant Portion 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GI 
Gastrointestinal 
hr 
Hour(s) 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
IUD 
Intrauterine Device 
kg 
Kilogram(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mL 
Milliliter(s) 
mmHg 
Millimeters of Mercury 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NZ 
New Zealand 
OTC 
Over-the-counter 
PI 
Principal Investigator 
PP 
Per-protocol Population  
SAE(s) 
Serious Adverse Event(s) 
SAER 
Serious Adverse Event Report 
SAP  
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure  
SD 
Standard Deviation 
SDV 
Source Data Verification 
SE  
Standard Error  
sec 
Second(s) 
TEAE 
Treatment-Emergent Adverse Event 
TRAE 
Treatment-Related Adverse Event 
WHO  
World Health Organization  
 
 
 


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1 
INTRODUCTION 
This protocol describes a Phase 3 safety study designed to examine the safety of a combination of intravenous 
acetaminophen and ibuprofen (Maxigesic® IV). 
1.1 
BACKGROUND 
Multimodal analgesia with a variety of analgesics (systemic pharmacological therapies with local, regional 
and neuraxial anesthetics) is strongly recommended for the treatment of postoperative pain (1). In terms of 
systemic treatments, nonopioid oral or parenteral acetaminophen and/or nonsteroidal anti-inflammatory drugs 
(NSAIDs) generally form the basis of treatment, in conjunction with opioids of increasing strength as required. 
Combined treatment with acetaminophen and ibuprofen has been shown to provide superior analgesia over 
administration of comparable doses of either component alone or placebo, when administered as an intravenous 
formulation or as a solid oral tablet in the postoperative setting.  
AFT Pharmaceuticals Ltd. has sponsored several Phase 2/3 studies which have demonstrated that Maxigesic® 
tablets (acetaminophen 500 mg + ibuprofen 150 mg, 2 tablets per dose) and Combogesic® tablets 
(acetaminophen 325 mg + ibuprofen 97.5 mg, 3 tablets per dose) provide superior pain following third molar 
removal or arthroscopic knee surgery than either drug alone or placebo (2–4).   
1.2 
DRUG NAME 
To extend the therapeutic advantage of Maxigesic®/Combogesic® to patients who may not be able to take oral 
analgesics, due to patient intubation, sedation, postoperative nausea and vomiting and reduced gastric motility, 
AFT Pharmaceuticals Ltd. has developed a fixed-dose combination containing acetaminophen 10 mg/ml + 
ibuprofen 3 mg/ml in 100 ml solution for infusion (Maxigesic® IV). Maxigesic® IV is intended for the relief 
of mild to moderate pain and the reduction of fever, 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. 
1.2.1 Clinical Studies 
Maxigesic® IV has been evaluated in two Phase 1 pharmacokinetic studies and one Phase 3 efficacy and safety 
study.  
The first study, AFT-MXIV-01, was a single-dose, open-label, 5-period crossover pharmacokinetic study in 
30 healthy volunteers. This study found that pharmacokinetic parameters for acetaminophen and ibuprofen 
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 acetaminophen (93.78%) and ibuprofen (96.45%) confirmed the 
pharmacokinetic equivalence between the oral (Maxigesic®) and intravenous formulations of the fixed dose 
combination (5). 
A second pharmacokinetic study, AFT-MXIV-06, was conducted to compare Maxigesic® IV with brands of 


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intravenous acetaminophen and ibuprofen that have been approved in the United States, as well as 
Combogesic® tablets (acetaminophen 325 mg + ibuprofen 97.5 mg, 3 tablets per dose). The study was a single-
dose, open-label, 4-period crossover pharmacokinetic study in 30 healthy volunteers. Similar to AFT-MXIV-
01, ratios of Cmax, AUCt, and AUC0-∞ for Maxigesic® IV to OfirmevTM and CaldolorTM fell within the 80-125% 
acceptable bioequivalence range. The relative bioavailability of acetaminophen (83%) and ibuprofen (85%) 
re-confirmed the pharmacokinetic equivalence between the oral (Combogesic®) and intravenous formulations. 
A Phase 3 efficacy and safety study demonstrated the superior analgesic effect of Maxigesic® IV in 276 
participants reporting moderate to severe postoperative pain following distal, first metatarsal bunionectomy 
(6). Patients were treated with six hourly doses of Maxigesic® IV, acetaminophen IV (1000 mg), ibuprofen IV 
(300 mg) or placebo for 48 hours. The study found that Maxigesic® IV provided superior pain relief to 
comparable doses of either monocomponent or placebo and reduced the requirement for opioid rescue 
medication. 
Importantly, the superior efficacy of the combination does not appear to come at the expense of tolerability. In 
the Phase 3 study of Maxigesic® IV in bunionectomy patients, there were no differences between patients 
treated with Maxigesic® IV and those treated with acetaminophen IV, ibuprofen IV or placebo in the rate of 
discontinuations due to adverse events (AEs), the overall incidence of treatment-emergent AEs (TEAEs) or 
the severity of TEAEs. The incidence of most common TEAEs (affecting ≥ 10% of the study population), 
including gastrointestinal disorders, nervous system disorders, general disorders and administration site 
conditions, and skin and subcutaneous tissue disorders was not significantly different between treatment 
groups. Some differences were observed between treatment groups in the incidence of specific AEs, such as 
vomiting and administration site pain, however these were attributable to the individual components, 
acetaminophen and ibuprofen respectively.  
All safety data obtained for Maxigesic® IV to date has come from patients exposed to single doses of the study 
drug (n=60) or six hourly doses for up to 48 hours (n=75). The present study aims to determine the tolerability 
of repeated doses of Maxigesic® IV over an extended period of exposure in a larger population. 
1.2.2 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. 
Previous studies have indicated that there is no change in the safety profile of either drug when administered 
as a fixed-dose combination. The potential benefit of this study lies in its potential to provide superior analgesia 
to participants requiring acute pain relief following surgery.  
 
 


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2 
TRIAL OBJECTIVES  
2.1 
STUDY HYPOTHESIS 
The study hypothesis is that Maxigesic® IV (intravenous acetaminophen 1000 mg + intravenous ibuprofen 300 
mg/ 100 ml solution for infusion) is well tolerated over a treatment period of 5 days, and that the safety profile 
does not markedly change with extended exposure of 5 days. 
2.2 
OBEJECTIVES AND ENDPOINTS 
2.2.1 Primary Objective and Endpoint  
The primary objective is to summarize the safety profile of Maxigesic® IV in patients exposed for ≥ 48 hours. 
The primary endpoint is the incidence of treatment-emergent adverse events associated with exposure to 
Maxigesic® IV.  
2.2.2 Secondary Objectives and Endpoints 
The following secondary endpoints will be assessed: 
- 
The time course of treatment-emergent adverse events 
- 
Treatment-related adverse events 
- 
Treatment-emergent adverse events of interest (cardiovascular, gastrointestinal, renal, hepatic, 
administration site conditions and bleeding-related events) 
- 
Changes in vital sign measurements  
- 
Changes in clinical laboratory values 
- 
Patient’s global evaluation of the study drug 
3 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION 
This study is a Phase 3, multicenter, open-label, single arm, multiple dose study to evaluate the safety of 
Maxigesic® IV (acetaminophen 10 mg/mL + ibuprofen 3 mg/mL in 100 mL solution for infusion). A flow 
chart providing a schematic representation of the study design is provided in Figure 1. 


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Figure 1: Schematic of Trial Design 
 
The study drug, Maxigesic® IV (acetaminophen 10 mg/ml + ibuprofen 3 mg/ml in 100 ml solution for 
infusion), will be administered by injection into a dedicated indwelling venous cannula, infused over 15 
minutes. The study drug will be administered every 6 hours (q6h) for a minimum of 48 hours (8 doses), with 
some patients treated for at least 5 days (≥ 20 doses). 
The study is open-label and single arm. All eligible participants will be assigned to the same study drug, and 
all patients and study staff will know the treatment being administered.  
3.2 
DISCUSSION OF STUDY DESIGN 
The study is designed to investigate the safety and tolerability of Maxigesic® IV in a larger study population 
over an extended period of time. As Maxigesic® IV may be used for longer than 48 hours in clinical practice, 
the study aims to determine if prolonged exposure to Maxigesic® IV results in any changes to the safety profile.  
The study is designed as a descriptive investigation of the safety profile of Maxigesic® IV in a larger sample 
size than has previously been evaluated. The study aims is to determine the safety profile and the temporal 
nature of the safety profile after extended exposure to Maxigesic® IV for ≥ 48 hours.  


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4 
PATIENT POPULATION 
4.1 
NUMBER OF PATIENTS 
In total, 225 participants who meet all the eligibility criteria will be enrolled into the study, including at least 
50 participants with an anticipated period of exposure of ≥ 5 days. The gender distribution of enrolled patients 
should be approximately evenly divided amongst males and females, with no more than 60% of participants 
being of either gender. 
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 years of age. 
2. Is classified by the anesthesiologist as P1 to P2 in the American Society of Anesthesiologists (ASA) 
Physical Status Classification System. 
3. Requires multiple doses of parenterally administered nonopioid analgesics over multiple days as a result 
of surgery (non-laparoscopic general, plastic or orthopedic surgery). 
4. Has an expected stay in facility ≥ 48 hours. 
5. Has a body weight ≥ 45 kg. 
6. If female and of childbearing potential, is nonlactating and nonpregnant (has negative urine pregnancy test 
results at Screening and on the day of surgery prior to surgery, if greater than 7 days between Screening 
and surgery). 
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: 
i) 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. 
ii) Total abstinence from sexual intercourse since the last menses before study drug administration 
through completion of final study visit. 
iii) Intrauterine device (IUD). 
iv) 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 remain at the study site for at least 48 hours and to attend a follow-up visit at 7 ± 2 


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days after the last dose of study drug. 
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 
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 participates in the study or could confound the results of 
the study.  
3. Has a 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 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.  
6. Has tested positive either on the urine drug screen or on the alcohol breathalyzer test. Subjects who test 
positive and can produce a prescription for the medication from their physician may be considered for 
study enrolment at the discretion of the Investigator.  
7. 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.  
8. 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.  
9. Is considered by the Investigator, for any reason to be an unsuitable candidate to receive the study drug.  
10. 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).  
11. Is currently receiving anticoagulants (e.g. heparin or warfarin).  
12. 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).  
13. Has a history of chronic use (defined as daily use for > 2 weeks) of NSAIDs, opiates, or glucocorticoids 


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(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.  
14. 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).  
15. Has any clinically significant laboratory finding at screening that, in the opinion of the Investigator, 
contraindicates study participation.  
16. 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. 
If one of these circumstances should occur, the management of the participant will be at the clinical discretion 
of his or her treating physician. 
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 from those participants who specifically withdraw consent to 
release of such information.   
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 
Maxigesic® IV: acetaminophen 10 mg/ml + ibuprofen 3 mg/ml in 100 ml solution for infusion.  
The first dose of the study drug is to be administered in the immediate postoperative period, as soon as the 
patient is stable following surgery.  


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The study drug will be administered by injection into a dedicated indwelling venous cannula, infused over 15 
minutes. The study drug will be administered every 6 hours (q6h) for a minimum of 48 hours up to at least 5 
days, with a maximum of 4 doses within a 24 hour period. The maximum duration of exposure will be at the 
discretion of the Investigator. 
5.2 
IDENTITY OF INVESTIGATIONAL PRODUCTS 
The active ingredients of Maxigesic® IV are acetaminophen and ibuprofen. AFT Pharmaceuticals will supply 
the study drug. The study drug is manufactured by S.M. Farmaceutici S.R.L. located in Zona Industriale-85050 
TITO (PZ) Italy, at their GMP approved manufacturing facility. The study drug is provided as a sterile solution 
in 100 ml glass vials closed with a stopper and sealed with aluminum caps. Maxigesic® IV has been shown to 
be stable for 24 months when stored at 25°C (77°F). 
The study drug supplied for use in 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 patient not participating in this study. 
The Investigator or pharmacy designee will maintain an inventory record of study drug dispensed to assure 
regulatory authorities and the Sponsor that the investigational new drug has not been dispensed to any person 
who is not a participant under the terms and conditions set forth in this protocol. At the termination of the 
study, all unused study drug (once it has been inventoried and the monitor has reviewed the accountability 
records and any retesting procedures completed) will be destroyed, and a destruction certificate will be issued 
by a licensed destruction company.  
5.3 
RANDOMIZATION 
As the study is designed as a single arm study, no randomization will occur. All participants who meet the 
eligibility criteria will be enrolled and administered the study drug. 
5.4 
BLINDING  
The study is open-label; all patients and study staff will know the treatment being administered. 
5.5 
PROHIBITED CONCOMITANT MEDICATIONS 
The following concomitant medications are prohibited during the study period:  
1. Any medication containing acetaminophen  
2. Any nonsteroidal anti-inflammatory drugs, including ibuprofen 
3. Any other medications which might, in the Investigators’ opinion, pose a potential threat to patient safety 
At the discretion of the Investigator, opioids are permitted to be used as supplementary analgesia if pain is not 
sufficiently controlled by the investigational product. The use of any supplementary analgesia shall be 
documented in the Case Report Form.  


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5.6 
TREATMENT COMPLIANCE 
Compliance will be assessed by recording the volume and timing of each dose administered in the Case Report 
Form (CRF). All participants who receive at least one dose of the study drug will be included in the analysis. 
6 
EFFICACY, PHARMACOKINETIC AND SAFETY VARIABLES 
6.1 
EFFICACY AND SAFETY MEASURES ASSESSED 
6.1.1 Safety Variables 
The safety variables to be recorded are treatment-emergent adverse events (TEAEs), vital signs, ECGs, and 
clinical laboratory values.  
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. 
Participants will complete a global evaluation of the study drug (Appendix 3) at the end of the treatment period 
or upon early withdrawal from the study, before discharge from the study site.  
7 
SEQUENCE OF PROCEDURES 
 
An overview of the sequence of procedures and study assessments is summarized in Table 1.


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Table 1: Schedule of Assessments 
Study Assessments 
Screening Period 
(within 30 days before 
surgery) 
Day 1 - ≥5 (Treatment period) 
Follow-Up Visit 
(7 ± 2 days after 
last dose) 
Day 1 
(Prior to 
Surgery) 
Day 1 
(Immediately Post 
Surgery) 
Day 2 - ≥5 (Treatment 
period) 
After last dose, prior to 
discharge 
Informed Consent 
✓ 
 
 
 
 
 
Demographic Data 
✓ 
 
 
 
 
 
Complete Medical History 
✓ 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
✓ 
✓ 
 
 
 
 
Physical Examination  
✓ 
✓* 
 
 
✓ 
✓ 
Concomitant Medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Urine Pregnancy Test1 
✓ 
✓* 
 
 
 
 
Vital Signs (including HR, 
BP)2 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
ECG3 
 
✓ 
 
✓ 
✓ 
 
Urinalysis 
✓ 
✓* 
 
 
✓ 
 
Biochemistry & 
Hematology 
✓ 
✓* 
 
 
✓ 
 
Urine Drug Screening Test 
✓ 
✓* 
 
 
 
 
Alcohol Breathalyzer Test  
 
✓ 
 
 
 
 
Study Drug 
Administration4 
 
 
✓ 
✓ 
 
 
Global Evaluation of Study 
Drug 
 
 
 
 
✓ 
 
Adverse Event Monitoring 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
* Not required if screening done within 7 days of surgery 
1 Females of childbearing potential only 
2 Vital signs will be evaluated at Time 0, prior to and following first dose infusion on Day 1, then each morning prior to the intravenous infusion and at discharge, early termination 
3 ECGs will be conducted prior to surgery, at 48 hours after the first dose and after the last dose/prior to discharge 
4 The first dose of the study drug will be administered in the immediate postoperative period, as soon as the patient is stable following surgery 
 
 
 


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7.1 
PRETREATMENT PERIOD 
Screening will occur up to 30 days prior to the day of surgery (Day 1). 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, hematological, neurological, musculoskeletal or psychiatric conditions 
(if any), allergy to food or drugs and medication history for the previous three months. 
- 
Physical examination including an assessment of vital signs (heart rate, blood pressure, temperature, 
respiratory rate)  
- 
Recording of concomitant medications 
- 
Urine pregnancy tests (females of childbearing potential only) 
- 
Urine analysis 
- 
Urine drug screening test (amphetamines, barbiturates, benzodiazepines, cocaine, methamphetamines, 
opiates, phencyclidine (PCP), and tetrahydrocannabinol (THC)) 
- 
Blood screening tests including: 
o Hematology: 
▪ 
Hemoglobin 
▪ 
Hematocrit 
▪ 
Platelet count 
▪ 
Red Blood Cell (RBC) count 
▪ 
White Blood Cell (WBC) count 
▪ 
Differential Leukocyte Count (DLC) 
o Biochemistry: 
▪ 
Sodium 
▪ 
Potassium 
▪ 
Urea 
▪ 
Creatinine 
▪ 
Phosphate 
▪ 
Glucose 
▪ 
Albumin 
▪ 
Total protein 
▪ 
Alkaline phosphates 
▪ 
Gamma-glutamyl transferase 
▪ 
Aspartate transaminase 
▪ 
Alanine transaminase 
▪ 
Bilirubin 


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If screening is conducted more than 7 days prior to surgery, the following evaluations will be performed on 
Day 1, prior to surgery: 
- 
Physical examination 
- 
Urine pregnancy tests (females of childbearing potential only) 
- 
Urine analysis  
- 
Blood screening tests as described above  
- 
Urine drug screening test as described above 
The following evaluations will be performed on Day 1 prior to surgery, regardless of whether screening was 
conducted within 7 days of the surgery: 
- 
Recording of concomitant medications 
- 
Assessments of vital signs (heart rate, blood pressure, temperature, respiratory rate) 
- 
Electrocardiogram  
- 
Alcohol breathalyzer test 
Adverse events and concomitant medications will be recorded from the time of enrollment.  
7.2 
TREATMENT PERIOD 
The first dose is to be administered in the immediate postoperative period, as soon as the patient is stable 
following surgery.  
The treatment period will commence at the start of administration of the first dose of study drug administration 
and will conclude at the clinician’s discretion. The minimum exposure is anticipated to be 48 hours (8 doses), 
with at least 50 patients treated for at least 5 days (≥ 20 doses). Assessments to be conducted at the end of the 
treatment period should be done after the last dose (if possible, approximately 6 hours after the last dose) and 
prior to discharge.  
The following participant reported measurement will be taken during the treatment period: 
- 
Patient’s global evaluation of study drug at the end of the treatment period or at early withdrawal 
In addition, the following evaluations will be completed: 
- 
Vital signs will be evaluated before and following the first dose infusion on Day 1, then each morning 
prior to the intravenous infusion and at the end of the treatment period or early withdrawal 
- 
Electrocardiogram at 48 hours after the first dose and at the end of the treatment period 
- 
A physical examination will be conducted at the end of the treatment period or at early withdrawal 
- 
Blood tests as described above will be conducted at the end of the treatment period or at early withdrawal 
- 
Urine analysis will be conducted at the end of the treatment period or at early withdrawal 
Adverse events and concomitant medications will be recorded throughout the treatment period. All doses of 
the study drug will be recorded, including volume and timing. 


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7.3 
FOLLOW-UP 
A follow-up visit will be conducted 7 ± 2 days after the last dose of study drug. At this follow-up, any additional 
adverse event and concomitant medication data will be collected. Additionally, a physical examination 
including an assessment of vital signs (heart rate, blood pressure, temperature, respiratory rate) will be 
conducted. 
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, unfavorable 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., hematological, biochemical, hormonal) or other clinical tests (e.g., ECG), whether or not 
considered treatment related. 
Treatment-emergent adverse events (TEAEs) are defined as events that emerge during treatment, having been 
absent pre-treatment, or that worsen relative to the pre-treatment status (ICH E9). 
Treatment-emergent adverse events that are considered by the Investigator to be “probably” or “definitely” are 
treatment-related adverse events (TRAEs). 
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 enrolled in the clinical study will not be considered adverse events. 
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, 


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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 jeopardize 
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 
ADVERSE EVENT REPORTING PERIOD 
Adverse event data will be collected from the time of enrollment through to the follow-up visit, 7 ± 2 days 
after administration of the last dose.  
8.3 
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. 
8.4 
PROCEDURE FOR SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
8.4.1 Reporting to the Sponsor 
In addition to entering each serious adverse event irrespective of causality on the appropriate page of the 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 (+64 9 488 0234) within 24 hours from the point in time when the SAE is realized. 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 regarding the event to AFT 


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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 after the study period that he or she determines to be causally 
related to study medication, the event should also be reported through this process. 
8.4.2 Reporting to Local Ethics Committee/Institutional Review Board 
All adverse drug reactions (ADRs) reporting shall be compliant to applicable local IRB/IEC requirements. 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. 
8.4.3 Reporting to Regulatory Agencies 
8.4.3.1 
Fatal or Life-Threatening Unexpected Adverse Drug Reactions 
An ADR is considered “fatal or life threatening” if, in the review of either the Investigator or Sponsor, its 
occurrence places the participants at immediate risk of death. It does not include an adverse event or adverse 
drug reaction that, had it occurred in a more severe form, might have caused death.  
Fatal or life-threatening, unexpected ADRs occurring in clinical investigations is subject to expedited 
reporting. Regulatory agencies should be notified (e.g., by telephone, facsimile transmission, or in writing) as 
soon as possible but no later than 7 calendar days after first knowledge by the Sponsor that a case qualifies, 
followed by as complete a report as possible within 8 additional calendar days. This report must include an 
assessment of the importance and implication of the findings, including relevant previous experience with the 
same or similar medicinal products (CPMP/ICH/377/95). 
8.4.3.2 
All Other Serious, Unexpected Adverse Drug Reactions 
Serious, unexpected ADRs that are not fatal or life-threatening must be filed as soon as possible but no later 
than 15 calendar days after first knowledge by the Sponsor that the case meets the minimum criteria for 
expedited reporting (CPMP/ICH/377/95). 
It is recommended to use the CIOMS form, which contains the information as listed in the attachment 1 of 
ICH E2A Clinical Safety Data Management Guideline.  
Adverse events which are not subject to expedited reporting shall be summarized in a periodic safety reporting 
according to applicable local regulatory requirements (e.g. Medsafe 6 month’s progress report / US FDA IND 
annual report). 
8.5 
 THE DATA SAFETY MONITORING BOARD 
No Data Safety Monitoring Board reviews are planned for this study. 
9 
PROTOCOL DEVIATIONS 
This study will be conducted, within reasonable limits, as described in this protocol, except for emergency 


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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 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. 
10 STATISTICAL PLAN 
This is a Phase 3, multicenter, open-label, single arm, multiple dose study to evaluate the safety of Maxigesic® 
IV. As a single arm study, the study is descriptive in nature, however summaries of safety endpoints will be 
generated within specific time intervals and by pre-specified subgroups. 
10.1 SAMPLE SIZE 
In total, 225 participants will be enrolled in this study, with at least 50 participants exposed to the study drug 
for at least 5 days. The sample size for this safety study is not based on formal statistical power calculations 
but will ensure with 95% probability that any TEAEs present in approximately 2% or more of the target 
population will be identified in this study. 
10.2 DEFINITIONS 
10.2.1 Patient Population 
The safety analysis will be on all participants who are administered at least one dose of study medication with 
treatment allocation for analysis based on the actual treatment the participant received. 
10.2.2 Observational Period 
The observational period is from administration of the first dose of the study drug to the follow-up visit, 7 ± 2 
days after administration of the last dose. The treatment period is from administration of the first dose of the 
study drug to approximately 6 hours after the last dose, and prior to discharge.  
10.3 STATISTICAL ANALYSES 
10.3.1 Demographic and Baseline Characteristics 
The demographic and baseline clinical characteristics of the study population including age, gender, race, 
ethnicity, indication (type of surgery), vitals, laboratory values and concomitant medications, will be 
summarized as means, medians, standard deviations, ranges and frequencies and percentages as appropriate. 


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10.3.2 Treatment Compliance 
Participants whose study drug usage, or dose rate exceeds 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. 
10.3.3 Exposure 
To evaluate the extent of drug exposure during the trial, tabular summaries of study drug usage (number of 
doses, duration of exposure, mean interval between doses) will be presented. Early withdrawals for any reason 
will be tabulated. 
10.3.4 Primary Analyses 
The primary endpoint is the incidence of TEAEs associated with exposure to Maxigesic® IV. TEAEs occurring 
at any timepoint during the treatment period will be coded to MedDRA System Organ Class Code and 
Preferred Term and tabulated as frequencies and percentages. 
10.3.5 Secondary Analyses 
10.3.5.1 Time Course of Treatment-Emergent Adverse Events 
TEAEs will be tabulated as frequencies and percentages during the following time periods: 
- 
At any time during the observational period 
- 
On each day during the treatment period: 
o Day 1 
o Day 2 
o Day 3 
o Day 4 
o Day 5 
o Day 6+ 
- 
During follow-up 
Days will be defined as 24-hour intervals after the first dose of study drug. 
10.3.5.2 Treatment-Related Adverse Events 
TEAEs considered by the investigator to be “probably” or “definitely” are treatment-related AEs; TRAEs. 
TRAEs will be summarized in the same manner as TEAEs.  
10.3.5.3 Treatment-Emergent Adverse Events of Interest 
All cardiovascular, gastrointestinal, renal, hepatic, administration site conditions and bleeding-related TEAEs 
will be summarized as frequencies and percentages, and the proportion of these that are considered treatment-
related will be tabulated. 
10.3.5.4 Changes in Vital Signs 
Clinically significant changes from baseline in vital sign measurements will be classified as adverse events 


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and included in all analyses of adverse events.  
Vital sign measurements at each scheduled timepoint will be summarized with standard descriptive statistics. 
10.3.5.5 Changes in Clinical Laboratory Values 
Clinically significant changes from baseline in laboratory test results will be classified as adverse events and 
included in all analyses of adverse events.  
Clinical laboratory values at each scheduled timepoint will be summarized with standard descriptive statistics. 
Summary shift tables will be produced overall and by duration of treatment (≤ 48 hours, 48 hours – 4 days, ≥ 
5 days), of the number of cases with normal baseline laboratory tests changed to abnormal at the end of the 
treatment period, and abnormal baseline laboratory tests worsened at the end of the treatment period, with the 
severity of changes summarized as proportional effects.  
10.3.5.6 Patient’s Global Evaluation of the Study Drug 
The patient’s global evaluation of the study drug will be summarized by the number and percentage of subjects 
within each category. 
10.3.6 Subgroup Analyses 
The incidence of TEAEs will be summarized within the following subgroups as sample sizes permit: 
- 
gender 
- 
race 
- 
age (patients aged <65 years, 65-75 years, >75 years)  
- 
duration of exposure (dosed for ≤ 48 hours, dosed for 48 hours – 4 days, dosed for ≥ 5 days) 
- 
indication (type of surgery) 
Subgroup analyses are subject to recruitment of sufficient participants in each group. 
10.3.7 Other Safety Analyses 
10.3.7.1 Severity and Relationship of Treatment Emergent Adverse Events to the Study Drug 
In addition to the primary and secondary analyses of the incidence of TEAEs, TEAEs occurring at any 
timepoint during the treatment period will be coded to MedDRA System Organ Class Code and Preferred 
Term and tabulated as frequencies and percentages by severity class and relationship to the study drug. 
10.3.7.2 Concomitant medication 
The use of concomitant medications following study drug administration will be summarized as frequencies 
and percentages within ATC-coded drug groups.   
10.3.7.3 Electrocardiograms 
Clinically significant changes from baseline in ECG results will be classified as adverse events and included 
in all analyses of adverse events.  
Summary shift tables will be produced overall and by duration of treatment (≤ 48 hours, 48 hours – 4 days, ≥ 


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5 days), of the number of cases with normal baseline ECGs changed to abnormal at 48 hours and/or the end of 
the treatment period, and abnormal baseline ECGs worsened at 48 hours and/or the end of the treatment period.  
10.4 MISSING DATA 
As the study is focused on safety and tolerability, and is conducted within the trial clinics, it is expected that 
all adverse event data will be collected, even if some participants withdraw from the study medication.  
10.5 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. 
10.6 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. 
11 RECORDS RETENTION 
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 nor 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 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. 


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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 center(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 center(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.  
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 


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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. 
13.3 GOVERNANCE OF THE 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, authorized regulatory 
officials, 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 authorized 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 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 randomized 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 local EC and ICH GCP 
requirements.  I further agree to report to the Sponsor any adverse experiences in accordance with the terms of 
this protocol, local regulatory (Medsafe) requirements and FDA regulation, 21 CFR 312.64. 
 
 
 
 
 
 
 
 
 
 
 
______________________________ 
______________________________ 
_________________ 
Principal Investigator’s Name (printed) 
Signature 
Date 


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16 REFERENCE LIST 
1.  Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, et al. Management of 
Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society 
of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee 
on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016 Feb;17(2):131–
57.  
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. Br J Anaesth. 2010 Jan 
1;104(1):80–8.  
3.  Atkinson HC, Currie J, Moodie J, Carson S, Evans S, Worthington JP, et al. Combination paracetamol 
and ibuprofen for pain relief after oral surgery: a dose ranging study. Eur J Clin Pharmacol. 2015 
May;71(5):579–87.  
4.  Daniels SE, Atkinson HC, Stanescu I, Frampton C. Analgesic Efficacy of an Acetaminophen/Ibuprofen 
Fixed-dose Combination in Moderate to Severe Postoperative Dental Pain: A Randomized, Double-blind, 
Parallel-group, Placebo-controlled Trial. Clin Ther. 2018 Oct;40(10):1765-1776.e5.  
5.  Atkinson HC, Stanescu I, Frampton C, Salem II, Beasley CPH, Robson R. Pharmacokinetics and 
Bioavailability of a Fixed-Dose Combination of Ibuprofen and Paracetamol after Intravenous and Oral 
Administration. Clin Drug Investig. 2015 Oct;35(10):625–32.  
6.  AFT Pharmaceuticals Ltd. 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. 2018 May. Report No.: 
CSR/MXIV-07/03.  
 
 


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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 edema 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. 
 
Hematological Monitoring: 
Blood dyscrasias have been rarely reported. Participants on long-term therapy with ibuprofen should have 
regular hematological monitoring. 
 
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 


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exaggerated in participants with underlying hemostatic 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: PATIENT’S GLOBAL EVALUATION OF THE 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 the treatment period/early withdrawal. 
 

SAP_001.pdf: 
AFT Document Number: CSR/MXIV-11  
Confidential Information 
 
 
Clinical Study Report 
 
 
Appendix 1.9 
Maxigesic® IV Exposure Study (AFT-MXIV-11) 
Page 1 of 1 
 
APPENDIX 1.9 
 
Documentation of Statistical Methods 
 
The Statistical Analysis Plan is enclosed overleaf. Further information may be provided in the form of a 
Study Data Reviewer’s Guide and an Analysis Data Reviewer's Guide, upon request. 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 1 
 
 
 
 
A Phase 3, Open-Label, Multiple-Dose, Single-
Arm Exposure Study of Maxigesic® IV in 
Patients 
with 
Acute 
Pain 
Following 
Orthopedic, General or Plastic Surgery 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
Protocol Number 
AFT-MXIV-11 
Amendment 
03 
Document Date  
21st August 2019 
Version 
Final 
Document Date 
7th October 2020 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 2 
 
 
 
Approval Form 
 
Prepared by: 
Phillip Aitken 
Clinical Scientist 
AFT Pharmaceuticals 
Ltd. 
____________________ 
Signature 
7th October 2020 
Date 
Reviewed 
by: 
Rebecca Playne 
Clinical Scientist 
AFT Pharmaceuticals 
Ltd. 
____________________ 
Signature 
  7th October 2020_ 
Date 
Reviewed & 
Approved 
by: 
Ioana Stanescu 
Head of Drug 
Development 
AFT Pharmaceuticals 
Ltd. 
____________________ 
Signature 
7th October 2020 
Date 
 
 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 3 
1 
TITLE 
A Phase 3, Open-Label, Multiple-Dose, Single-Arm Exposure Study of Maxigesic® IV in 
Patients with Acute Pain Following Orthopedic, General or Plastic Surgery 
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 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 the intravenous route is clinically justified by an 
urgent need to treat pain or hyperthermia, and/or when other routes of administration are not 
possible or prudent. 
All safety data obtained for Maxigesic® IV to date has come from patients exposed to single 
doses of the study drug (n=60) or six hourly doses for up to 48 hours (n=75). This study aims 
to determine the tolerability of repeated doses of Maxigesic® IV over an extended period of 
exposure. 
 
3 
STUDY DESIGN AND OBJECTIVES 
3.1 
Design 
This study is a Phase III, multicentre, open-label, single arm, multiple dose study to evaluate 
the safety of Maxigesic® IV (acetaminophen 10 mg/ml + ibuprofen 3 mg/ml in 100 ml solution 
for infusion). 
Eligible subjects will complete all screening procedures within 30 days prior to the surgery. At 
screening, subjects will provide written informed consent to participate in the study before any 
protocol-specified procedures or assessments are completed. At screening, 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  
- 
Physical examination including an assessment of vital signs (heart rate, blood pressure, 
temperature, respiratory rate)  
- 
Recording of concomitant medications 
- 
Urine pregnancy tests (females of childbearing potential only) 
- 
Urine analysis 
- 
Urine drug screening test (amphetamines, barbiturates, benzodiazepines, cocaine, 
methamphetamines, opiates, phencyclidine (PCP), and tetrahydrocannabinol (THC)) 
- 
Blood screening tests including: 
o Hematology: 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 4 
 Hemoglobin 
 Hematocrit 
 Platelet count 
 Red Blood Cell (RBC) count 
 White Blood Cell (WBC) count 
 Differential Leukocyte Count (DLC) 
o Biochemistry: 
 Sodium 
 Potassium 
 Urea 
 Creatinine 
 Phosphate 
 Glucose 
 Albumin 
 Total protein 
 Alkaline phosphates 
 Gamma-glutamyl transferase 
 Aspartate transaminase 
 Alanine transaminase 
 Bilirubin 
 
If screening is conducted more than 7 days prior to surgery, the following evaluations will be 
performed on Day 1, prior to surgery: 
- 
Physical examination 
- 
Urine pregnancy tests (females of childbearing potential only) 
- 
Urine analysis  
- 
Blood screening tests as described above  
- 
Urine drug screening test as described above 
 
The following evaluations will be performed on Day 1 prior to surgery, regardless of whether 
screening was conducted within 7 days of the surgery: 
- 
Recording of concomitant medications 
- 
Assessments of vital signs (heart rate, blood pressure, temperature, respiratory rate) 
- 
Electrocardiogram  
- 
Alcohol breathalyzer test 
 
Patients will undergo either non-laparoscopic general, plastic or orthopedic surgery. 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 5 
The first dose of Maxigesic® IV (acetaminophen 10 mg/ml + ibuprofen 3 mg/ml in 100 ml 
solution) will be administered in the immediate postoperative period, as soon as the patient is 
stable following surgery. 
The treatment period will commence at the start of administration of the first dose of study 
drug administration and will conclude 6 hours after the final dose of study drug. The number 
of doses of study drug, and therefore the length of the treatment period, will be determined at 
the clinician’s discretion. The minimum exposure is anticipated to be 48 hours (8 doses), with 
at least 50 patients treated for at least 5 days (≥ 20 doses). Assessments to be conducted at the 
end of the treatment period should be done after the last dose (if possible, 6 hours after the last 
dose) and prior to discharge. 
Subjects may receive supplemental analgesia with an opioid product if pain is not sufficiently 
controlled by the investigational product. 
The following participant reported measurement will be taken during the treatment period: 
- 
Patient’s global evaluation of study drug at the end of the treatment period or at early 
withdrawal 
 
In addition, the following evaluations will be completed: 
- 
Vital signs will be evaluated before and following the first dose infusion on Day 1, then 
each morning prior to the intravenous infusion and at the end of the treatment period or 
early withdrawal 
- 
Electrocardiogram at 48 hours after the first dose and at the end of the treatment period 
- 
A physical examination will be conducted at the end of the treatment period or at early 
withdrawal 
- 
Blood tests as described above will be conducted at the end of the treatment period or 
at early withdrawal 
- 
Urine analysis will be conducted at the end of the treatment period or at early 
withdrawal 
 
Adverse events and concomitant medications will be recorded throughout the treatment period. 
All doses of the study drug will be recorded, including volume and timing. 
A follow-up visit will be conducted 7 ± 2 days after the last dose of study drug. At this follow-
up, any additional adverse event and concomitant medication data will be collected. 
Additionally, a physical examination including an assessment of vital signs (heart rate, blood 
pressure, temperature, respiratory rate) will be conducted. 
 
3.2 
Primary Objective 
The primary objective is to summarize the safety profile of Maxigesic® IV in patients exposed 
for ≥ 48 hours. 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 6 
The primary endpoint is the incidence of treatment-emergent adverse events associated with 
exposure to Maxigesic® IV. 
3.3 
Secondary Objectives and Endpoints 
The following secondary endpoints will be assessed: 
- 
The time course of treatment-emergent adverse events 
- 
Treatment-related adverse events 
- 
Treatment-emergent adverse events of interest (cardiovascular, gastrointestinal, renal, 
hepatic, administration site conditions and bleeding-related events) 
- 
Changes in vital sign measurements 
- 
Changes in clinical laboratory values 
- 
Patient’s global evaluation of the study drug 
4 
GENERAL ANALYSIS DEFINITIONS 
 
4.1 
Sample size calculation 
In total, 225 participants will be enrolled in this study, with at least 50 participants exposed to 
the study drug for at least 5 days. The sample size for this safety study is not based on formal 
statistical power calculations but will ensure with 95% probability that any TEAEs present in 
approximately 2% or more of the target population will be identified in this study. 
4.2 
Participant Populations 
4.2.1 Patient Population  
The safety analysis will be on all participants who are administered at least one dose of study 
medication with treatment allocation for analysis based on the actual treatment the participant 
received.  
4.3 
Observational Period 
The observational period is from administration of the first dose of the study drug to the follow-
up visit, 7 ± 2 days after administration of the last dose. The treatment period is from 
administration of the first dose of the study drug to 6 hours after the last dose, and prior to 
discharge. 
5 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
The demographic and baseline clinical characteristics of the study population including age, 
gender, race, ethnicity, indication (type of surgery), surgery duration, vitals and laboratory 
values, will be summarized as means, medians, standard deviations, ranges and frequencies 
and percentages as appropriate. Medical history will be displayed by System Organ Class and 
Preferred Term. 
6 
PARTICIPANT DISPOSITION 
To evaluate the extent of drug exposure during the trial, tabular summaries of study drug usage 
(number of doses, duration of exposure, mean interval between doses) will be presented. 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 7 
Exposure will also be presented by age group, race, sex and study site. Early withdrawals for 
any reason will be tabulated. 
7 
STUDY MEDICATION AND CONCOMITANT THERAPY 
7.1 
Compliance 
Participants whose study drug usage, or dose rate exceeds the limitations provided by the study 
protocol will be included in a summary 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 at baseline that continue through the study period and those that 
commenced during the study will be coded and summarised as frequencies and percentages 
within ATC-coded drug groups. Baseline and study concomitant medications will be presented 
in separate tables. 
 
8 
SAFETY ANALYSES 
8.1 
Primary Analyses 
The primary endpoint is the incidence of TEAEs associated with exposure to Maxigesic® IV. 
A TEAE is any AE that starts or worsens during the treatment period. AEs occurring at any 
timepoint during the treatment period will be coded to MedDRA System Organ Class Code 
and Preferred Term and tabulated as frequencies and percentages. 
 
8.2 
Secondary Analyses 
8.2.1 Time Course of Treatment-Emergent Adverse Events 
TEAEs will be tabulated as frequencies and percentages of subjects receiving at least one dose 
of the study drug during the following time periods: 
- 
On each day during the treatment period: 
o Day 1 
o Day 2 
o Day 3 
o Day 4 
o Day 5 
o Day 6+ 
- 
In addition, AEs during follow-up will be tabulated as frequencies and percentages. 
 
Days will be defined as 24-hour intervals after the first dose of study drug. 
If an AE cannot be precisely assigned to a day, for instance because of a missing start time, it 
will be assigned to the earliest possible day. 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 8 
 
8.2.2 Treatment-Related Adverse Events 
TEAEs considered by the investigator to be “probably” or “definitely” are treatment-related 
AEs; TRAEs. TRAEs will be summarized in the same manner as TEAEs.  
 
8.2.3 Treatment-Emergent Adverse Events of Interest 
All cardiovascular, gastrointestinal, renal, hepatic, administration site conditions and bleeding-
related TEAEs will be summarized as frequencies and percentages, and the proportion of these 
that are considered treatment-related will be tabulated. 
 
8.2.4 Changes in Vital Signs 
Clinically significant changes from baseline in vital sign measurements will be classified as 
adverse events and included in all analyses of adverse events.  
Vital sign measurements at each scheduled timepoint will be summarized with standard 
descriptive statistics. 
8.2.5 Changes in Clinical Laboratory Values 
Clinically significant changes from baseline in laboratory test results will be classified as 
adverse events and included in all analyses of adverse events.  
Clinical laboratory values at each scheduled timepoint will be summarized with standard 
descriptive statistics. Summary shift tables will be produced overall and by duration of 
treatment (≤ 48 hours, 48 hours – 4 days, ≥ 5 days), of the number of cases with normal baseline 
laboratory tests changed to abnormal at the end of the treatment period, and abnormal baseline 
laboratory tests worsened at the end of the treatment period, with the severity of changes 
summarized as proportional effects.  
Shift tables will also present the number of subjects with low, normal, high or missing 
laboratory values at baseline along with their shifts at the end of treatment. The number of 
important shifts (normal to low, normal to high, high to low, low to high) will also be tabulated, 
along with the number of these which resulted in abnormal values considered clinically 
significant by the investigator.  
 
8.2.6 Patient’s Global Evaluation of the Study Drug 
The patient’s global evaluation of the study drug will be summarized by the number and 
percentage of subjects within each category. 
 
8.3 
Subgroup Analyses 
The incidence of TEAEs will be summarized within the following subgroups as sample sizes 
permit: 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 9 
- 
gender 
- 
race 
- 
age (patients aged <65 years, 65-75 years, >75 years)  
- 
duration of exposure (dosed for ≤ 48 hours, dosed for 48 hours – 4 days, dosed for ≥ 5 days) 
- 
indication (type of surgery) 
- 
study site 
 
Subgroup analyses are subject to recruitment of sufficient participants in each subgroup. 
 
8.4 
Other Safety Analyses 
8.4.1 Severity and Relationship of Treatment Emergent Adverse Events to the Study Drug 
In addition to the primary and secondary analyses of the incidence of TEAEs, TEAEs occurring 
at any timepoint during the treatment period will be coded to MedDRA System Organ Class 
Code and Preferred Term and tabulated as frequencies and percentages by severity class and 
relationship to the study drug. 
 
8.4.2 Electrocardiograms 
Clinically significant changes from baseline in ECG results will be classified as adverse events 
and included in all analyses of adverse events.  
Summary shift tables will be produced overall and by duration of treatment (≤ 48 hours, 48 
hours – 4 days, ≥ 5 days), of the number of cases with normal baseline ECGs changed to 
abnormal at 48 hours and/or the end of the treatment period, and abnormal baseline ECGs 
worsened at 48 hours and/or the end of the treatment period.  
 
8.5 
Meta-analysis with MXIV-07 data 
Data from the previous study MXIV-07 will be combined with MXIV-11 data, increasing the 
number of patients in the Maxigesic IV exposure group and allowing comparisons with 
placebo, ibuprofen and acetaminophen monotherapy treatment. The following endpoints will 
be repeated with the new combined dataset. Only the first 48 hour period of MXIV-11 will be 
used in the metanalysis to match the MXIV-07 treatment period. 
8.5.1 Demographic and Baseline Characteristics 
The demographic and baseline clinical characteristics of the combined population including 
age, gender, race, ethnicity, indication (type of surgery), surgery duration and vitals, will be 
summarized as means, medians, standard deviations, ranges and frequencies and percentages 
as appropriate. 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 10 
8.5.2 Participant disposition 
To evaluate the extent of drug exposure, tabular summaries of study drug usage (number of 
doses, duration of exposure, mean interval between doses) will be presented. Early withdrawals 
for any reason will be tabulated. 
8.5.3 Concomitant Medications  
Concomitant medications at baseline that continue through the study period and those 
commenced during the study will be coded and summarised as frequencies and percentages 
within ATC-coded drug groups. Baseline and study concomitant medications will be presented 
in separate tables. 
8.5.4 Incidence of TEAEs 
The incidence of TEAEs associated with exposure to any study drug occurring at any timepoint 
during the treatment period will be coded to MedDRA System Organ Class Code and Preferred 
Term and tabulated as frequencies and percentages. 
8.5.5 Time Course of Treatment-Emergent Adverse Events 
TEAEs will be tabulated as frequencies and percentages of subjects receiving at least one dose 
of the study drug during the following time periods: 
- 
On each day during the first 48 hour treatment period: 
o Day 1 
o Day 2 
- 
In addition, AEs during follow-up will be tabulated as frequencies and percentages. 
 
Days will be defined as 24-hour intervals after the first dose of study drug. 
 
8.5.6 Treatment-Related Adverse Events 
TEAEs considered by the investigator to be “probably” or “definitely” are treatment-related 
AEs; TRAEs. TRAEs will be summarized in the same manner as TEAEs.  
 
8.5.7 Treatment-Emergent Adverse Events of Interest 
All cardiovascular, gastrointestinal, renal, hepatic, administration site conditions and bleeding-
related TEAEs will be summarized as frequencies and percentages, and the proportion of these 
that are considered treatment-related will be tabulated. 
 
8.5.8 Changes in Vital Signs 
Clinically significant changes from baseline in vital sign measurements will be classified as 
adverse events and included in all analyses of adverse events.  
Vital sign measurements at each scheduled timepoint will be summarized with standard 
descriptive statistics. 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 11 
 
8.5.9 Patient’s Global Evaluation of the Study Drug 
The patient’s global evaluation of the study drug will be summarized by the number and 
percentage of subjects within each category. 
 
8.5.10 Subgroup Analyses 
The incidence of TEAEs will be summarized within the following subgroups as sample sizes 
permit: 
- 
gender 
- 
race 
- 
age (patients aged <65 years, 65-75 years, >75 years)  
- 
indication (type of surgery) 
 
Subgroup analyses are subject to recruitment of sufficient participants in each subgroup. 
8.5.11 Severity and Relationship of Treatment Emergent Adverse Events to the Study Drug 
TEAEs occurring at any timepoint during the treatment period will be coded to MedDRA 
System Organ Class Code and Preferred Term and tabulated as frequencies and percentages by 
severity class and relationship to the study drug. 
 
8.6 
Missing Data 
As the study is focused on safety and tolerability, and is conducted within the trial clinics, it is 
expected that all adverse event data will be collected, even if some participants withdraw from 
the study medication.  
 
8.7 
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. 
 
9 
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. 
 
 
 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 12 
10 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.  
Baseline Demographic Information 
• 
Age 
• 
Gender 
• 
Weight 
• 
Height 
• 
BMI 
• 
Race/ethnicity 
Baseline Clinical Characteristics 
• 
Medical History by SOC and PT 
• 
Surgery duration 
• 
Vital Signs (Systolic Blood Pressure, Diastolic Blood Pressure, Heart Rate, Respiratory Rate and 
Temperature)  
• 
Laboratory values (hematology/chemistry) 
• 
Concomitant medications 
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 
• 
Treatment-Emergent Adverse Events Occurring during the Treatment Period 
Secondary Endpoints 
• 
Time Course of Treatment-Emergent Adverse Events - Day 1 
• 
Time Course of Treatment-Emergent Adverse Events - Day 2 
• 
Time Course of Treatment-Emergent Adverse Events - Day 3 
• 
Time Course of Treatment-Emergent Adverse Events - Day 4 
• 
Time Course of Treatment-Emergent Adverse Events - Day 5 
• 
Time Course of Treatment-Emergent Adverse Events - Day 6+ 
• 
Time Course of Adverse Events - During Follow-up 
• 
Treatment-Related Adverse Events 
• 
Treatment-Emergent Adverse Events of Interest 
• 
Treatment-Related Adverse Events of Interest 
• 
Changes in Vital Signs 
• 
Changes in Hematology/Chemistry Values 
• 
Hematology/Chemistry Summary shift tables - Overall 
• 
Hematology/Chemistry Summary shift tables - duration of treatment ≤ 48 hours 
• 
Hematology/Chemistry Summary shift tables - duration of treatment between 48 hours and 4 
days 
• 
Hematology/Chemistry Summary shift tables - duration of treatment ≥ 5 days 
• 
Patient’s Global Evaluation of the Study Drug 
Subgroup Analyses 
• 
TEAEs by Gender 
• 
TEAEs by Race 
• 
TEAEs by Age 
• 
TEAEs by Duration of Exposure 
• 
TEAEs by Indication (Type of Surgery) 
• 
TEAEs by Study Site 
Other Safety Analyses 
• 
TEAEs by Severity 


AFT-MXIV-11: Maxigesic® IV Exposure Study 
AFT Pharmaceuticals Ltd.                        
 
Statistical Analysis Plan 
 
 
Version: Final 
Date: 7th October 2020 
 
Page 13 
• 
TEAEs by Relationship to the Study Drug  
• 
Summary ECG shift tables - overall 
• 
Summary ECG shift tables - duration of treatment ≤ 48 hours 
• 
Summary ECG shift tables - duration of treatment between 48 hours and 4 days 
• 
Summary ECG shift tables - duration of treatment  ≥ 5 days 
Meta-analysis tables (MXIV-07 + MXIV-11) 
• 
Age 
• 
Gender 
• 
Weight 
• 
Height 
• 
BMI 
• 
Race/ethnicity 
• 
Surgery duration 
• 
Vital Signs (Systolic Blood Pressure, Diastolic Blood Pressure, Heart Rate, Respiratory Rate and 
Temperature)  
• 
Baseline Concomitant medications 
• 
Summary of withdrawals (if applicable) 
• 
Summary of compliance (study drug usage) 
• 
Summary of concomitant medications 
• 
Treatment-Emergent Adverse Events Occurring during the Treatment Period 
• 
Time Course of Treatment-Emergent Adverse Events - Day 1 
• 
Time Course of Treatment-Emergent Adverse Events - Day 2 
• 
Time Course of Adverse Events - During Follow-up 
• 
Treatment-Related Adverse Events 
• 
Treatment-Emergent Adverse Events of Interest 
• 
Treatment-Related Adverse Events of Interest 
• 
Changes in Vital Signs 
• 
Patient’s Global Evaluation of the Study Drug 
• 
TEAEs by Gender 
• 
TEAEs by Race 
• 
TEAEs by Age 
• 
TEAEs by Indication (Type of Surgery) 
• 
TEAEs by Severity 
• 
TEAEs by Relationship to the Study Drug