Single Site, Randomized, Double Blind, Placebo-Controlled Study to Assess the Long-Term Safety of Tafenoquine
Phase: PHASE2
Conditions: Healthy Volunteers
Sponsor: 60 Degrees Pharmaceuticals LLC

 
 
 
60PH04 Long Term Safety Protocol 
 
NCT03320174 
29Nov2018 
 

Clinical Study Protocol 
CONFIDENTIAL AND 
PROPRIETARY 
60PH04 
 
 
 
 
Protocol Version 7.0 
Dated 29Nov2018 
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Multisite, Randomized, Double Blind, Placebo-Controlled Study to Assess the Long-Term 
Safety of Tafenoquine 
 
Protocol Number: 60PH04 
 
 
 
Sponsor: 
60° Pharmaceuticals LLC 
Version number: 
Version 7.0 
Date: 
29Nov2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
 
The information contained in this document is confidential and proprietary to 60° 
Pharmaceuticals LLC and the US Army Medical Research and Materiel Command 
(USAMRMC). The information may only be used by the entities to which it was disclosed for 
the purpose it was disclosed and is therefore provided to you in confidence for review. To the 
maximum extent permissible by law, the information must not be disclosed to any third parties 
without the prior written consent of 60° Pharmaceuticals LLC and USAMRMC. 
 
 
This study is being funded by USAMRMC.  
Contract Number/Task Order: S4501151-1076-TQ. 

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Investigator Signature Page 
 
 
 
 
Multisite, Randomized, Double Blind, Placebo-Controlled Study to Assess the Long-Term 
Safety of Tafenoquine  
 
(Version 7.0, 29Nov2018) 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study 
as described. I will conduct this protocol as outlined herein and will make a reasonable effort to 
complete the study within the time designated. 
I agree to personally conduct or supervise the study. 
The study will be conducted in accordance with the principles set out in the following documents: 
• The most recent version of the World Medical Association Declaration of Helsinki – 
Ethical Principles for Medical Research Involving Human Participants; 
• National Statement on Ethical Conduct in Human Research (NHMRC 2007a, updated 
May 2015); 
• Notes for Guidance on Good Clinical Practice – Annotated with Comments 
(CPMP/ICH/135/95), as adopted by the Australian Therapeutic Goods Administration 
(TGA) (July 2000); and 
• The current Clinical Trial Protocol as approved by the local Human Research Ethics 
Committee (HREC), Institutional Review Board (IRB) and the USAMRMC Human 
Research Protection Office (HRPO). 
I agree to inform all participants that the study drug is being used for investigational purposes and 
I will ensure that the requirements related to obtaining informed consent are in accordance with 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Guidelines for Good Clinical Practice (GCP) Section 4.8 (CPMP/ICH/135/95) 
and local requirements. 
I agree to report adverse events (AEs) that occur in the course of the study to the sponsor in 
accordance with ICH GCP Section 4.11 and local requirements. 
I have read and understand the information in the 60P Investigator’s Brochure (IB), including the 
potential risks and side effects of the study drug. 
I agree to promptly report to the HREC any changes in the research activity and all unanticipated 
problems involving risk to the participants. I will not make any changes to the conduct of the 
study without the HREC, IRB, HRPO and sponsor approval, except when necessary to eliminate 
apparent, immediate harm to participants. 
I agree to maintain adequate and accurate records and make those records available in accordance 
with ICH GCP Section 4.9 and local requirements. 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 

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I understand that the study may be terminated or enrollment suspended at any time by the 
sponsor, with or without cause, or by me if it becomes necessary to protect the best interest of the 
participants. 
 
Site Principal Investigator 
 
 
________________________________   
Date: ________________________ 
Dr Fred Chen 
Lions Eye Institute 
 
Site Principal Investigator 
 
 
________________________________   
Date: ________________________ 
Dr Mark Chittum 
Retina Consultants of Southern Colorado 
 
Site Principal Investigator 
 
 
_________________________________________ 
Dr. Victor Gonzalez 
Valley Retina Institute 
 
________________________________   
Date: ________________________ 
Signature 
 
Sponsor’s Representative: 
 
 
________________________________   
Date: ________________________ 
Dr Geoff Dow 
CEO, 60° Pharmaceuticals LLC 
 

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Responsibilities 
Site Principal Investigator: 
Dr Fred Chen MBBS (Hons), PhD, FRANZCO 
The Lions Eye Institute 
2 Verdun Street 
Nedlands, WA, 6009, Australia 
Tel: +61 (0)8 9381 0777 
Mobile: +61(0)466 590 737 
Email: fredchen@lei.org.au 
Site Principal Investigator: 
Mark E. Chittum, MD 
Retina Consultants of Southern Colorado 
2770 North Union Blvd Suite 140  
Colorado Springs, CO, 80909 
Tel: 719-473-9595 
Email: mchittum@coloradoretina.com 
Site Principal Investigator: 
Victor Gonzalez, MD 
Valley Retina Institute 
1309 East Ridge Road, Suite 1 
McAllen, TX, 78503 
Tel: 956-631-8875 
Email: vgonzalez@vritx.com 
Pharmaceutical Sponsor: 
60° Pharmaceuticals LLC  
1025 Connecticut Avenue NW 
Suite 1000 
Washington DC, 20036, USA 
Sponsor’s Representative: 
Dr Geoffrey Dow, PhD, MBA 
CEO 
1025 Connecticut Avenue NW 
Suite 1000 
Washington DC, 20036, USA 
Tel: +1 (240) 351-1167 
Email: geoffdow@60degreespharma.com 
Local Australian Sponsor: 
Clinical Network Services (CNS) Pty Ltd 
Level 4, 88 Jephson Street 
Toowong, QLD, 4066, Australia 
Tel: +61 7 3719 6000 
Email: cns@clinical.net.au 
Australian Clinical Study 
Centers: 
Linear Clinical Research  
QEII Medical Centre 
First Floor, B Block Hospital Avenue 
Nedlands, WA, 6009, Australia 
Tel: +61 (0)8 6382 5100 
 

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The Lions Eye Institute 
2 Verdun Street 
Nedlands, WA, 6009, Australia 
Tel: +61 (0)8 9381 0777 
Australian Local Medical 
Monitor (LMM):  
Dr John Gillies, MBChB, FRACP, FRCPSC, FAAP 
Clinical Network Services (CNS) Ltd 
PO Box 78312 
Grey Lynn, Auckland 1245, New Zealand 
Tel: +64 21 664 484 
Email: john.gillies@clinical.net.au 
US Local Medical 
Monitor: 
Timothy Baxter, MD 
Baxter Healthcare Consulting 
Richmond, VA, USA 
Tel: +1 (804) 291-7037 
Email: timbaxter@bhccllc.com 
Sponsor Chief Medical 
Officer 
Dr Bryan Smith, MD, FAAFP 
Chief Medical Officer  
60° Pharmaceuticals LLC 
1025 Connecticut Ave NW 
Suite 1000 
Washington DC, 20036, USA 
Tel: +1 (301) 807-8548 
Email: bryansmith@60degreespharma.com 
Australian Regulatory and, 
Site Monitoring: 
Clinical Network Services (CNS) Pty Ltd 
Level 4, 88 Jephson Street 
Toowong, QLD, 4066, Australia 
Tel: +61 (0)7 3719 6000 
Email: cns@clinical.net.au   
United States Clinical 
Sites: 
Listed above under Site Principal Investigator 
Data Management Center 
Katrina Riggs, CCRA 
Fast-Track Drugs & Biologics, LLC  
5 Paramus Ct,  
North Potomac, Maryland, 20878, USA 
Tel: +1 (301) 762 2609 
Email: kriggs@fasttrackresearch.com 
Australian Bioanalytical 
Laboratory (PK Samples): 
Dr Alistair Draffan, PhD 
360biolabs Pty Ltd 
85 Commercial Road 
Melbourne, VIC, 3004, Australia 
Tel: +61 (0)3 8506 2453 
Email: a.draffan@360biolabs.com 

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USA Bionalytical 
Laboratory (PK Samples): 
Worldwide Clinical Trials Early Phase Services/Bioanalytical 
Sciences, Inc. 
8609 Cross Park Dr. 
Austin, TX 78754 
Phone: (512) 834-7766 
Fax: (512) 834-1165 
Second Blinded Reading 
Site 
Fundus Photograph Reading Center  
Department of Ophthalmology and Visual Sciences,  
University of Wisconsin School of Medicine and Public Health 
2828 Marshall Court, Ste 200 
Madison, WI, 53705, USA 
Tel: +1 (608) 262 1334 
Biostatistician 
Charles Scott, Ph.D. 
Fast-Track Drugs & Biologics, LLC 
5 Paramus Ct. 
North Potomac, MD, 20178, USA 
Tel: +1(240) 421-7826 
Email: cscott@fasttrackresearch.com 
Serious Adverse Event 
(SAE) Reporting to 
FDA/TGA: 
Clinical Network Services (CNS) Pty Ltd 
Level 4, 88 Jephson Street 
Toowong, QLD, 4066, Australia 
Tel: +61 (0)7 3719 6000 
Fax: +61 (0)7 3719 6011  
Email: safety@clinical.net.au 
 
Fast-Track Drugs & Biologics, LLC  
5 Paramus Ct,  
North Potomac, Maryland, 20878, USA 
Tel: +1 (301) 762-5787 
Fax: +1 (301) 762-5730 
Email: jransom@fasttrackreseach.com 
Australian Human 
Research Ethics 
Committee: 
Bellberry Ltd 
129 Glen Osmond Road 
Eastwood, SA, 5063, Australia 
Tel: +61 (0)8 8361 3222 
Email: bellberry@bellberry.com.au 
US Central Institutional 
Research Board: 
IntegReview IRB 
3815 S. Capital of Texas Highway, Suite 320 
Telephone: 512-326-3001 
Fax: 512-697-0085 
Website: www.integreview.com 

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Funding Party and 
Collaborator 
Pharmaceutical Systems Project Management Office (PSPMO) 
US Army Medical Materiel Development Activity 
1430 Veterans Drive 
Fort Detrick, MD ,21702, USA 
Tel: +1 301 619 7871  
Email: victor.e.zottig.mil@mail.mil 
USAMRMC Office of 
Research Protections 
Human Research Protection Office 
US Army Medical Research and Materiel Command 
ATTN: MCMR-RPH 
504 Scott Street 
Fort Detrick, MD, 21702-5012, USA 
Fax: +1 (301) 619-7803 
Tel: +1 (301) 619-2165 
Email: usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil 

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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE......................................................................................... 2 
RESPONSIBILITIES ...................................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................ 8 
LIST OF NON-STANDARD ABBREVIATIONS AND DEFINITIONS ................................... 13 
STUDY SYNOPSIS ...................................................................................................................... 19 
1. 
STUDY SCHEDULE OF EVENTS .......................................................................... 31 
2. 
INTRODUCTION...................................................................................................... 34 
2.1. 
Background ................................................................................................................ 34 
2.1.1. 
Ophthalmic Background ............................................................................................ 35 
2.1.1.1. 
Corneal Deposits ........................................................................................................ 37 
2.1.1.2. 
Retinal Effects ............................................................................................................ 38 
2.1.1.3. 
Effects of Chloroquine/Hydroxychloroquine on the Retina ...................................... 40 
2.1.2. 
Psychiatric and Neurologic Effects ............................................................................ 40 
2.2. 
Nonclinical Studies .................................................................................................... 45 
2.2.1. 
Nonclinical Pharmacology ......................................................................................... 45 
2.2.2. 
Pharmacokinetics and Product Metabolism in Animals ............................................ 47 
2.2.3. 
Nonclinical Toxicology .............................................................................................. 48 
2.3. 
Clinical Studies .......................................................................................................... 49 
2.3.1. 
Efficacy ...................................................................................................................... 49 
2.3.2. 
Human Safety Data .................................................................................................... 50 
2.3.3. 
Human Pharmacokinetic Data .................................................................................... 51 
3. 
STUDY RATIONALE............................................................................................... 53 
4. 
STUDY OBJECTIVES .............................................................................................. 54 
4.1. 
Primary Objective ...................................................................................................... 54 
4.2. 
Secondary Objectives ................................................................................................. 54 
5. 
STUDY DESIGN ....................................................................................................... 55 
5.1. 
Overview .................................................................................................................... 55 
5.2. 
Study Endpoints ......................................................................................................... 56 
5.2.1. 
Primary Endpoint ....................................................................................................... 56 
5.2.2. 
Secondary Endpoints .................................................................................................. 56 
5.3. 
Rationale of Dose Selection and Dosing Regimen .................................................... 57 
5.4. 
Individual Subject Withdrawal .................................................................................. 57 
5.5. 
Risk Benefit Evaluation for this Study ....................................................................... 58 

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5.5.1. 
Risks/Discomfort to Participants and Precautions to Minimize Risk ........................ 58 
5.5.1.1. 
Local Reactions .......................................................................................................... 58 
5.5.1.2. 
Systemic Reactions .................................................................................................... 58 
5.5.1.3. 
Pregnancy ................................................................................................................... 59 
5.5.1.4. 
Lactation ..................................................................................................................... 59 
5.5.1.5. 
Venipuncture .............................................................................................................. 59 
5.5.1.6. 
Ocular Examination and Investigation ....................................................................... 59 
5.5.1.7. 
Allergic Reaction ....................................................................................................... 59 
5.5.1.8. 
Unknown Risks .......................................................................................................... 59 
5.5.2. 
Alternatives to this IMP Product or Study ................................................................. 59 
5.5.3. 
Intended Benefit for Participants ............................................................................... 60 
5.5.4. 
Risks to the Study Personnel and the Environment ................................................... 60 
5.6. 
Route of Administration, Dosage Regimen, Treatment Period, and 
Justification ................................................................................................................ 60 
5.7. 
Compliance Statement ............................................................................................... 61 
5.8. 
Study Sites .................................................................................................................. 61 
6. 
STUDY POPULATION ............................................................................................ 62 
6.1. 
Inclusion Criteria ........................................................................................................ 62 
6.2. 
Exclusion Criteria ....................................................................................................... 63 
6.2.1. 
Justification of the Inclusion and Exclusion Criteria ................................................. 65 
6.3. 
Subject Identification ................................................................................................. 66 
6.4. 
Specific Dietary, Fluid and Other Restrictions .......................................................... 66 
6.4.1. 
General ....................................................................................................................... 66 
6.4.2. 
Concomitant Treatment .............................................................................................. 66 
7. 
INVESTIGATIONAL PRODUCTS .......................................................................... 67 
7.1. 
Description of Products .............................................................................................. 67 
7.1.1. 
Investigational Medicinal Product (IMP) - Tafenoquine ........................................... 67 
7.2. 
Packaging, Labeling and Storage ............................................................................... 67 
7.2.1. 
IMP – Tafenoquine and Placebo Tablets ................................................................... 67 
7.3. 
Investigational Medicinal Product Accountability ..................................................... 68 
7.3.1. 
Medication Adherence and Reminder System ........................................................... 68 
7.3.2. 
Participant Risk .......................................................................................................... 69 
7.3.3. 
Patient Confidentiality ............................................................................................... 69 
7.4. 
Method of Assigning Participants to Treatment Groups ............................................ 69 
7.5. 
Investigational Product Administration ..................................................................... 70 

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7.5.1. 
Tafenoquine/Placebo .................................................................................................. 70 
7.6. 
Treatment Blinding .................................................................................................... 70 
7.7. 
Unblinding.................................................................................................................. 70 
7.8. 
Returns and Destruction ............................................................................................. 71 
8. 
VISIT SCHEDULE .................................................................................................... 72 
8.1. 
Screening: Week -6 to Day -1 (Visit 1a and 1b) ........................................................ 72 
8.2. 
IMP Loading Dose: Starting Day 1 of Week 1 (Visit 2) ............................................ 74 
8.3. 
Treatment Period: Week 4, 12, 24, and 52 (Visits 3, 4, 5 and 6) ............................... 75 
8.4. 
Early Termination/EOS assessments, Weeks 64 (Visit 7a and 7b) ........................... 76 
8.5. 
Part 3 Follow-up for Ongoing AEs Weeks 76, 89, and 104 (Visits 8, 9, and 
10): ............................................................................................................................. 77 
8.6. 
Assessment and Visit Windows ................................................................................. 78 
8.7. 
Unscheduled Visits..................................................................................................... 79 
9. 
ASSESSMENTS ........................................................................................................ 80 
9.1. 
Screening and pre-IMP dosing Assessments ............................................................. 80 
9.1.1. 
Demographics ............................................................................................................ 80 
9.1.2. 
Height and Weight ..................................................................................................... 80 
9.1.3. 
Medical, Surgical and Current Medical Conditions ................................................... 80 
9.2. 
Safety .......................................................................................................................... 80 
9.2.1. 
Physical Examination ................................................................................................. 80 
9.2.2. 
Vital Signs .................................................................................................................. 81 
9.2.3. 
12-lead ECG ............................................................................................................... 81 
9.2.4. 
Laboratory Evaluations .............................................................................................. 81 
9.2.5. 
Pharmacokinetics for Compliance ............................................................................. 83 
9.2.6. 
Ophthalmic Assessments ........................................................................................... 83 
9.2.7. 
Psychiatric Assessment (M.I.N.I. 7.0.2) .................................................................... 84 
9.2.8. 
Leeds Sleep Evaluation Questionnaire (LSEQ) ......................................................... 85 
9.2.9. 
Dizziness Handicap Inventory (DHI) ......................................................................... 85 
9.2.10. 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................. 85 
10. 
SAFETY MONITORING .......................................................................................... 86 
10.1. 
Responsibilities for Ensuring the Safety of Study Participants ................................. 86 
10.2. 
Principal Investigator ................................................................................................. 86 
10.3. 
Study Pharmaceutical Sponsor ................................................................................... 87 
10.4. 
Responsibilities of the Local Australian Sponsor ...................................................... 89 
10.5. 
Local Medical Monitors ............................................................................................. 90 

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10.6. 
Responsibilities of the Institution............................................................................... 91 
10.7. 
Responsibilities of the HREC/IRB............................................................................. 91 
10.8. 
Responsibilities of the TGA and FDA ....................................................................... 91 
10.9. 
Data and Safety Monitoring Board ............................................................................ 91 
10.10. 
Safety Surveillance During the Study ........................................................................ 92 
10.11. 
Adverse Events ........................................................................................................... 92 
10.11.1. 
Definitions .................................................................................................................. 92 
10.11.2. 
Assessment and Recording of Adverse Events .......................................................... 95 
10.11.3. 
Action taken and follow-up of events ........................................................................ 97 
10.11.4. 
Reporting of SAEs ..................................................................................................... 98 
10.11.5. 
Reporting of AESIs .................................................................................................. 100 
10.11.6. 
Reporting of Pregnancy ............................................................................................ 100 
11. 
DATA MANAGEMENT ......................................................................................... 101 
11.1. 
Data Collection ......................................................................................................... 101 
11.2. 
Site Monitoring ........................................................................................................ 101 
11.3. 
Database Management and Quality Control ............................................................ 101 
12. 
STATISTICAL METHODS .................................................................................... 103 
12.1. 
Sample Size Calculation .......................................................................................... 103 
12.2. 
Analysis and Presentation of Data ........................................................................... 104 
12.2.1. 
General ..................................................................................................................... 104 
12.2.2. 
Subject Demographics and Baseline Characteristics ............................................... 104 
12.2.3. 
Safety Data ............................................................................................................... 104 
12.2.3.1. 
Primary Endpoint ..................................................................................................... 105 
12.2.3.2. 
Secondary Endpoints ................................................................................................ 106 
13. 
ETHICAL CONSIDERATIONS ............................................................................. 110 
13.1. 
Ethical Principles ..................................................................................................... 110 
13.2. 
Ethical Review ......................................................................................................... 110 
13.3. 
Informed Consent Procedures .................................................................................. 110 
13.4. 
Subject Data Protection ............................................................................................ 111 
14. 
ADMINISTRATIVE CONSIDERATIONS ............................................................ 112 
14.1. 
Liability/Indemnity/Insurance .................................................................................. 112 
14.2. 
Changes to the Final Study Protocol ........................................................................ 112 
14.2.1. 
Non-Substantial Amendment ................................................................................... 112 
14.2.2. 
Substantial Amendment ........................................................................................... 112 
14.2.3. 
Urgent Amendment .................................................................................................. 113 

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14.2.4. 
Clinical Data Recording ........................................................................................... 113 
14.3. 
Record Retention ...................................................................................................... 113 
14.4. 
Biological Samples................................................................................................... 113 
14.5. 
Shipment Procedures ................................................................................................ 113 
14.6. 
Monitoring................................................................................................................ 114 
14.7. 
Reporting and Communication of Results ............................................................... 114 
14.8. 
Discontinuation of the Study .................................................................................... 115 
14.9. 
Study Audit .............................................................................................................. 115 
15. 
REFERENCES ......................................................................................................... 116 
APPENDIX 1. SD-OCT FINDING .......................................................................................... 123 
APPENDIX 2. QFAF FINDINGS ............................................................................................ 124 
APPENDIX 3. ESTIMATE OF TOTAL BLOOD VOLUME COLLECTED DURING 
THE STUDY PERIOD ............................................................................................ 125 
APPENDIX 4. CENTRAL FOVEAL THICKNESS (CENTRAL 1 MM CIRCLE) ON 
SPECTRALIS DEVICE........................................................................................... 126 
APPENDIX 5. LEEDS SLEEP EVALUATION QUESTIONNAIRE .................................... 127 
APPENDIX 6. DIZZINESS HANDICAP INVENTORY ....................................................... 128 
APPENDIX 7: COLUMBIA-SUICIDE SEVERITY RATING SCALE.................................... 130 
APPENDIX 8: PROTOCOL AMENDMENTS .......................................................................... 132 
 
LIST OF TABLES 
Table 1: 
Summary of Ophthalmologic AEs: Tafenoquine Recommended Regimen 
Group vs Placebo and Mefloquine ............................................................................. 36 
Table 2: 
Summary of Psychiatric Adverse Events: Tafenoquine Recommended 
Regimen Group vs Placebo and Mefloquine ............................................................. 43 
Table 3: 
Adverse Events occurring in ≥1% of Subjects in the Tafenoquine ACR Group 
and with an Incidence Numerically Greater than in the Placebo Group .................... 50 
Table 4: 
Sponsor Reporting of SSIs ......................................................................................... 89 
Table 5: 
Primary Endpoint Evaluation Criteria ...................................................................... 106 
 
LIST OF FIGURES 
Figure 1: 
Structures of Primaquine and Tafenoquine ................................................................ 35 
Figure 2: 
Subjects with Specific Categories of Adverse Events. Tafenoquine 
Recommended Regimen groups in ADF population versus non-ADF 
population versus placebo .......................................................................................... 44 
 

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List of Non-Standard Abbreviations and Definitions 
Abbreviation 
Definition 
β-HCG 
Beta-human chorionic gonadotropin 
14C 
Carbon-14 
60P 
60° Pharmaceuticals LLC 
Ab 
Antibody 
ABN 
Australian business number 
Recommended Regimen 
Anticipated clinical regimen 
ADF 
Australian Defence Force 
ADL 
Activity of daily living 
ADR 
Adverse drug reactions 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AFS 
Awake following sleep 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AM 
Ante meridiem- before noon 
ANZCTR 
Australia New Zealand Clinical Trials Registry 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BCVA 
Best corrected visual acuity 
BDC 
Bile duct cannulated 
BFW 
Behavior following wakening 
BUN 
Blood urea nitrogen 
CAD 
Color assessment and diagnosis 
CBC 
Complete blood count 
CD 
Curative dose 
CD50 
The dose of a therapeutic agent that radically cures 50% of the 
target pathogen 
CDC 
Centers for Disease Control and Prevention 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of federal regulations 
CI 
Confidence interval 
CIDI 
Composite international diagnostic interview 
CIOMS 
Council for International Organizations of Medical Sciences 

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Abbreviation 
Definition 
CL/f 
The apparent systemic clearance from plasma following 
extravascular administration 
Cmax 
The observed maximum plasma concentration following drug 
administration 
CNS 
Central Nervous System or 
Clinical Network Services (CNS) Pty Ltd 
CPMP 
Committee for Proprietary Medicinal Products 
CQ 
Chloroquine 
CRO 
Clinical research organization 
CSF 
Central sub field 
C-SSRS 
Columbia - Suicide Severity Rating Scale 
CTCAE 
Common terminology criteria for adverse events  
CTN 
Clinical trial notification 
CYP 
A member of the cytochrome P450 gene family 
DDE 
Drug dictionary enhanced 
DHI 
Dizziness handicap inventory 
DICOM 
Digital imagery and communications in medicine 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSMB 
Data and safety monitoring board 
DSUR 
Drug safety update report 
DVC 
DynPort Vaccine Corporation 
EC 
European Commission 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ED50 
The dose of a therapeutic agent that eradicates 50% of the target 
pathogen 
EDMS 
Electronic data management system 
EDTA 
Ethylene diamine tetra-acetic acid 
EMA 
European Medicines Agency 
EOS 
End of study  
ERG 
Electroretinography 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAF 
Fundus auto fluorescence 
FBC 
Full blood count (as known as complete blood count [CBC]) 
FCSR 
Final clinical study report 
FDA 
US Food and Drug Administration 

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Abbreviation 
Definition 
FEV1 
Forced expiry volume in 1 second 
FFA 
Fundus fluorescein angiogram 
FLS 
Forward light scatter 
FM 
Farnsworth-Munsell 
FSH 
Follicle stimulating hormone 
G6PD 
Glucose-6-phosphate dehydrogenase  
GCP 
Good clinical practice 
GGT 
Gamma glutamyl transpeptidase 
GI 
Gastrointestinal 
GMP 
Good manufacturing practice 
GP 
General practitioner 
GTS 
Getting to sleep 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCQ 
Hydroxychloroquine 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
HCVA 
High contrast visual acuity 
hERG 
Human ether-a-go-go related gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRA 
Heidelberg retina angiograph 
HREC 
Human research ethics committee 
HRPO 
Human research protection office 
IAW 
In accordance with 
IB 
Investigator’s Brochure 
IC50 
The half maximal inhibitory concentration of a particular drug or 
substance 
ICD 
International classification of diseases 
ICH 
International Council for Harmonization of Technical Requirements 
for Pharmaceuticals for Human Use 
IDMC 
Independent data monitoring committee 
ILM 
Internal limiting membrane 
IMP 
Investigational medicinal product 
IND 
Investigational new drug 

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Abbreviation 
Definition 
IOP 
Intraocular pressure 
IRB 
Institutional review board 
ISCEV 
International Society for Clinical Electrophysiology of Vision 
ISS 
Integrated safety summary 
ITT 
Intention-to-treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
ka 
First order absorption rate constant 
LCVA 
Low contrast visual acuity 
LLN 
Lower limit of normal 
LMM 
Local medical monitor 
logCS 
Logarithm of contrast sensitivity 
logMAR 
Logarithm of minimum angle of resolution 
LSEQ 
Leeds sleep evaluation questionnaire  
M.I.N.I 
Mini international neuropsychiatric interview 
MAIA 
Macular integrity assessment 
MATE1 
Multidrug and toxin extrusion 1 transporter 
MATE2-K 
Multidrug and toxin extrusion 2-K transporter 
MCH 
Mean corpuscular hemoglobin 
MCT 
Mesopic contrast threshold 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
MetHb 
Methemoglobin 
ms 
Millisecond 
N or n 
Number 
NHMRC 
National Health and Medical Research Council 
NI 
Non-inferiority 
OCT 
Optical coherence tomography 
OCT2 
Human organic cation transporter 2 
P. berghei 
Plasmodium berghei 
P. cynomolgi 
Plasmodium cynomolgi 
P. cynomolgi bastianelli 
Plasmodium cynomolgi bastianelli 
P. falciparum 
Plasmodium falciparum 
P. fragile 
Plasmodium fragile 

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Abbreviation 
Definition 
P. vivax 
Plasmodium vivax 
PCFR 
Patient clinical/fetus report 
pH 
Power of hydrogen 
PI 
Principal investigator 
PIICF 
Participant information and informed consent form 
PIC/S 
Pharmaceutical inspection cooperation scheme 
PK 
Pharmacokinetic 
Plt 
Platelet count 
PM 
Post meridiem – after noon 
PP 
Per protocol 
PSPMO 
Pharmaceutical Systems Project Management Office 
PT 
Preferred term 
PXR 
Pregnane-X-receptor 
QD 
quaque die (once per day) 
qFAF 
Quantitative fundus auto fluorescence  
Also termed quantitative auto fluorescence 
QOS 
Quality of sleep 
QT 
Interval measured from the start of the Q wave to the end of the T 
wave (time taken for ventricular depolarization and repolarization) 
QTc 
Corrected QT interval 
RBC 
Red blood cell 
RPE 
Retinal pigment epithelium 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SCID-P 
Structured clinical interview for diagnostic and statistical manual of 
mental disorders 
SCT 
Scotopic contrast threshold 
SD 
Standard deviation 
SD-OCT 
Spectral domain optical coherence tomography 
SDTM 
Study data tabulation model 
SOC 
System organ class 
SOP 
Standard operating procedure 
SOSE 
Serious ophthalmic safety event 
SSI 
Significant safety issue 

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Abbreviation 
Definition 
SUSAR 
Suspected unexpected serious adverse reaction 
t½  
The terminal elimination half-life 
TD 
Time domain 
TBS 
TGA business services 
TEAE 
Treatment emergent adverse event 
TGA 
Australian Therapeutic Goods Administration 
TNFα 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
UPIRTSO 
Unanticipated problems involving risks to participants or others 
USAMMDA 
US Army Medical Materiel Development Activity 
USAMRMC 
US Army Medical Research and Materiel Command 
USM 
Urgent safety measure 
UV 
Ultraviolet 
V/f 
Volume of distribution 
VA 
Visual acuity 
WBC 
White blood cell 
WHO 
World Health Organization 
WHO-DDE 
WHO Drug dictionary enhanced 
WOCBP 
Women of child bearing potential 
 

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Study Synopsis 
Name of Sponsor: 
60° Pharmaceuticals LLC  
Name of 
Investigational 
Product: 
Tafenoquine succinate 
Study Title: 
Multisite, Randomized, Double-Blind, Placebo-Controlled Study to Assess 
the Long-term Safety of Tafenoquine 
Protocol Number: 
60PH04 
Local CRO 
Australia: 
Clinical Network Services (CNS) Pty Ltd 
Level 4, 88 Jephson Street 
Toowong, QLD, 4066, Australia 
Tel: +61 7 3719 6000 
Email: cns@clinical.net.au  
Local CRO United 
States: 
Fast-Track Drugs & Biologics, LLC 
5 Paramus Ct. 
North Potomac, MD 20878 
Tel: 301-762-5787 
Email:jransom@fasttrackresearch.com 
Study Centers: 
Linear Clinical Research, Australia; Lions Eye Institute, Australia 
Retina Consultants of Southern Colorado, Colorado Springs, CO, USA 
Valley Retina Institute, McAllen, TX, USA 
Site Principal 
Investigators: 
Dr Fred Chen, Lions Eye Institute 
Dr. Mark Chittum, Retina Consultants of Southern Colorado 
Dr. Victor Gonzalez, Valley Retina Institute 
Study Period:  
August 2017 to August 2020 
Purpose and 
Objectives: 
Primary objective: 
• 
To assess the ophthalmic safety of tafenoquine after 12 months of 
exposure versus placebo using Spectral Domain Optical Coherence 
Tomography (SD-OCT) and Quantitative Fundus Auto Fluorescence 
(qFAF). 
Secondary objective: 
• 
To assess the long-term safety and tolerability of tafenoquine versus 
placebo as assessed by clinical monitoring of vital signs, ECG, 
laboratory data, and reporting of Adverse Events (AEs) after 
12 months of exposure. 
• 
To assess the long term safety and tolerability of tafenoquine after 12 
months of exposure to tafenoquine versus placebo by measuring 
ophthalmic and psychiatric changes from baseline to end of study. 
Study Design: 
This randomized, double-blind, placebo controlled study will involve 600 
healthy (Glucose-6-Phospate Dehydrogenase [G6PD] normal) volunteers and 

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will run over two phases.  
Part 1 – Treatment Phase (52 weeks, Week 1, 4, 12, 24, and 52) 
Participants who meet the eligibility criteria will be randomized (ratio 1:1) 
using clinical site as a randomization variable to receive a loading dose of 
either tafenoquine 200 mg (2 x 100 mg tablets) or placebo daily for three 
consecutive days, followed by study treatment (tafenoquine 200 mg or 
placebo) once per week for 51 weeks, with safety follow-up visits at Weeks 4, 
12, 24, and 52. A Columbia Suicidality Rating Scale (C-SSRS) Interview will 
be conducted at the Day 1 visit and every 4 weeks ± 1 week thereafter. All 
efforts will be made to retain participants through to study completion. 
Reasons for withdrawal may include 1) withdrawal of consent, 2) lost to 
follow-up, 3) evidence of substance abuse that may affect the participant’s 
capacity to complete the study in the investigator’s opinion and 4) 
development of a new or worsening psychiatric disease (including suicidal 
ideation) at a non-scheduled visit or during routine M.I.N.I. evaluation that 
would jeopardize the safety of the participant if they continued in the study 
(see Section 9.2.7).  If a participant stops taking their study drug, they should 
still continue to have all follow-up safety visits. If the subject wants to 
withdraw, they should have an end of study (EOS) visit (preferably 65-75 
days after cessation of study treatment). The reasons for any treatment 
discontinuation (temporarily or permanently) will be documented on the 
electronic Case Report Form (eCRF).  
Part 2 – Follow-up Phase (Week 64) 
Due to the long t1/2 of tafenoquine (13-15 days with an expected 65-75-day 
washout period), all participants will return to the clinic at Week 64 for their 
EOS visits. If the participant has an ongoing AE, they will continue in Part 3 
of the study, otherwise this is the final visit. 
Part 3 – Follow-up Phase (Weeks 76, 89, and 104).  
Participants who meet the criteria for continuation for additional safety 
assessments at the Week 64 visit will continue to be assessed for up to 3 more 
times at approximately 12-week intervals or until resolution or stabilization of 
the AE whichever is earlier.  
Endpoints: 
Primary endpoint: 
• 
Proportion of participants with protocol-defined serious ophthalmic 
safety event (SOSE). SOSE is assessed by significant retinal changes 
from baseline using SD-OCT and qFAF. The details of significant 
protocol defined retinal changes using SD-OCT and qFAF are 
defined in Table 5. 
Secondary endpoints:  
• 
The incidence, severity and relationship to the investigational 
medicinal product (IMP) of AEs (including unexpected toxicities, 
AEs encountered during or after IMP administration), safety 
laboratory parameters, vital signs, and ECG, up to and including 
Week 64. 
• 
Mean change from baseline in key SD-OCT parameters including 
central subfield thickness (CST), total macular volume (TMV), and 
parafoveal (inner ring of Early Treatment Diabetic Retinopathy Study 
[ETDRS] grid), retinal thickness and the proportion of participants 
with ellipsoid or interdigitating zone disruption (as per Table 5). 
• 
Proportion of participants with abnormal changes from baseline 

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observed on qFAF using the Spectralis Heidelberg Retina Angiograph 
(HRA)+OCT device with grey scale values extracted from these 
images for statistical analysis using qFAF software (Heidelberg 
Engineering). 
• 
Mean change from baseline in Best Corrected Visual Acuity (BCVA). 
• 
Proportion of participants with corneal deposits from slit lamp 
examination of the corneal epithelium. 
• 
Time to onset of corneal deposits and overall time duration to 
resolution post treatment start. 
• 
Time duration to resolution of corneal deposits after treatment 
cessation. 
• 
Proportion of participants with new abnormalities compared with 
baseline observed with color retinal digital photography 
(conventional and wide field). 
• 
Proportion of participants with new abnormalities compared with 
baseline observed with microperimetry. 
• 
Proportion of participants with any new anomaly on the backlit 
ETDRS chart. 
• 
Proportion of participants with any clinically significant change in 
ETDRS BCVA (defined as >15 letter change [≥ 3 lines] of change in 
ETDRS BCVA at 4 meters) 
• 
Proportion of participants who develop a color deficiency using the 
Farnsworth-Munsell 100 (FM-100) hue test. 
• 
Proportion of participants who develop a loss of 0.12 or greater 
logarithm of contrast sensitivity (logCS) on the Mars letter contrast 
sensitivity test. 
• 
Proportion of participants who develop a psychiatric disorder in 
accordance with the Diagnostic and Statistical Manual of Mental 
Disorders Version 5 (DSM-5) as assessed with the Mini International 
Neuropsychiatric Interview (M.I.N.I.) 7.0.2 assessment questionnaire 
and suicidal ideation or suicide attempt by C-SSRS interview. 
• 
Proportion of participants with an AE of dizziness or vertigo and 
severity as assessed by the Dizziness Handicap Inventory (DHI). 
• 
Mean change from baseline scores in Getting to Sleep (GTS), Quality 
of Sleep (QOS), Awake Following Sleep (AFS), and Behavior 
Following Wakening (BFW) as assessed by the Leeds Sleep 
Evaluation Questionnaire (LSEQ). 
Sample Size 
(planned): 
The study will involve 600 healthy (G6PD normal) volunteers (300 on 
tafenoquine and 300 on Placebo) and will run over three parts.  
The primary endpoint is the proportion of participants with protocol-defined 
SOSE. SOSE is assessed by significant retinal changes from baseline using 
SD-OCT and qFAF at any follow-up visit. The details of significant protocol 
defined retinal changes using SD-OCT and qFAF are defined in Table 5. 
Sample size estimation is based on the primary endpoint.  
Based on the binomial distribution, if the true SOSE rate is assumed to be 1% 
in the tafenoquine group, there is a 95% probability to observe at least one 
SOSE with 300 participants.  
This study could therefore also be considered a non-inferiority (NI) safety 

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study. The incidence of SOSE was conservatively assumed to be 1% (i.e., 
99% without SOSE) for both the placebo and tafenoquine group. A non-
inferiority margin of 2.5% (treatment-placebo, in terms of SOSE rates) was 
considered to be clinically relevant, and therefore used to compare the non-
inferiority between tafenoquine and placebo. The 2.5% NI margin is 
estimated from literature. On an Australian population scale, the prevalence of 
maculopathy is 1.3% in age cohorts 49-54 years with increasing prevalence in 
cohorts aged 55-64 (2.6%), 65-74 (8.5%), 75-84 (15.5%), and 85+ (28.0%) 
years (Mitchell 1995). The 2.5% NI margin sets a lenient threshold to 
determine if tafenoquine causes retinal deficits beyond what is expected even 
in a high-risk group at the upper age range of 55 years for the study 
population. That is, if the SOSE rate for tafenoquine group is not more than 
2.5% higher than the placebo, the safety for tafenoquine will be regarded as 
no worse than placebo. For a two-sided significance level of 5% (α=0.025 
one-sided) with 600 randomized subjects, the power is 86% (β=0.14) to test 
the non-inferiority margin. 
Study duration: 
Each participant will participate for up to 25 months: 
Screening period – 6 weeks; 
Exposure period – 12 months; and 
Follow-up period – 3 months or until AE resolution (up to 12 months). 
Investigational 
Medicinal 
Products: 
Investigational Medicinal Products: 
Tafenoquine and matched placebo, manufactured under contract by the US 
Army Medical Research and Materiel Command (USAMRMC), will be 
supplied by 60° Pharmaceuticals LLC in tablet form for oral administration. 
Each tablet will contain 100 mg tafenoquine. The dose to be administered is 
200 mg (two tablets) per day for three consecutive days (loading doses), 
followed by another 200 mg dose once per week for the following 51 weeks 
(beginning post-loading dose Day 10).  
Control participants will receive identically matched double-blind placebo 
tablets under the same schedule.  
Main Inclusion 
Criteria: 
Participants eligible for inclusion in this study must fulfill all of the following 
criteria: 
1. Completion of the written informed consent process (signed). 
2. Male or female age 18 to 55 years inclusive, in good health as 
assessed by the investigator. 
3. Normal G6PD enzyme activity levels as defined by the parameters of 
the specific G6PD test employed at the local laboratory. 
4. Negative Hepatitis B surface antigen (HBsAg) and Hepatitis C virus 
(HCV), Human Immunodeficiency Virus (HIV)-1, HIV-2 antibody 
screen at the screening visit. 
5. Negative serum pregnancy test. 
6. Women of Child Bearing Potential (WOCBP) agree to use an 
acceptable method of contraception from the time of the first 
administration of the IMP until 12 weeks following last 
administration of the IMP or have undergone a sterilization procedure 
or are post menopausal. Acceptable birth control methods include: 
a. Oral contraceptives (combination estrogen/progesterone pills), 
injectable progesterone or sub dermal implants (commenced at 
least 14 days prior to IMP administration to the female 
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b. A medically prescribed topically applied transdermal 
contraceptive patch (commenced at least 14 days prior to IMP 
administration to the female participant); 
c. Intrauterine device or intrauterine system; 
d. Partner uses condom with spermicide; 
e. Male partner has had a vasectomy (more than 3 months 
previously) 
f. True abstinence: when this is in line with the preferred and usual 
lifestyle of the participant. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
Abstinent participants (in consultation with their partners) have to 
agree to use one of the above-mentioned contraceptive methods, 
if they start sexual relationships during the study and for up to 90 
days after the last dose of study drug. 
Acceptable sterilization procedures include: 
g. Essure® sterilization;  
h. Bilateral tubal ligation; 
i. 
Hysterectomy; 
j. 
Bilateral oophorectomy; or, 
k. Be postmenopausal with amenorrhea for at least 1 year prior to 
screening and confirmed by a serum Follicle Stimulating 
Hormone (FSH) test at screening. 
7. Willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 
8. Agree to stay in contact with the study site for the duration of the 
study and up to 2 weeks following the EOS visit, provide updated 
contact information as necessary, and have no current plans to move 
away from the study area for the duration of the study. 
Safety, Tolerability, 
Ophthalmic, 
Neurologic and 
Psychiatric 
Assessments: 
Safety evaluations will include the following: AE evaluation, physical 
examination, vital signs, ECG, laboratory parameters (hematology, 
biochemistry, and urinalysis). These will be performed at various time points 
throughout the study to assess baseline function and any changes from 
baseline after administration of IMP during the Treatment Phase.  
Screening, -6 Weeks to Day -1 (Visit 1a/1b) 
• 
Informed consent. 
• 
Inclusion and exclusion criteria. 
• 
Demographics. 
• 
Body height and weight. 
• 
Medical, surgical and social histories. 
• 
Prior medications. 
• 
Full physical examination as defined in the protocol. 
• 
Vital signs (sublingual body temperature, respiratory rate, pulse rate, 
systolic and diastolic blood pressure). 
• 
12-lead electrocardiogram (ECG). 
• 
Blood sampling for determination of the following parameters: 
o Complete blood count (CBC) (Hematology [platelet count 
{Plt}, red blood cell {RBC} count, hemoglobin (Hb), 
hematocrit {Hct}, mean corpuscular volume {MCV}, mean 
corpuscular hemoglobin {MCH}, white blood cell {WBC} 
count with differential [neutrophils, lymphocytes, monocytes, 
eosinophils and basophils]); 

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o Biochemistry (blood urea nitrogen [BUN], creatinine, 
potassium, sodium, aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase [ALP], gamma 
glutamyl transpeptidase [GGT], total and direct bilirubin); 
o G6PD activity; 
o Methemoglobin (MetHb)%; 
o Serology: HIV-1 and HIV-2, HCV, HBsAg; 
o Serum pregnancy test (females): (serum beta-human 
chorionic gonadotropin) [β-HCG]) or FSH test (for 
post-menopausal females). 
• 
Alcohol breath test. 
• 
Urine sampling for determination of the following parameters: 
o Urinalysis (specific gravity, power of hydrogen [pH], 
glucose, protein, blood, ketones, leukocyte esterase, and 
nitrites). Microscopic examination (if blood, leukocyte 
esterase or nitrites are positive). 
o Urine drug screen (amphetamines, methamphetamines, 
barbiturates, benzodiazepines, cocaine, methadone, opiates, 
phencyclidine, tetrahydrocannabinols, tricyclic 
antidepressants); 
• 
Psychiatric Assessments: 
o M.I.N.I. English Version 7.0.2. 
Screening, -6 Weeks to Day -1 (Visit 1b). Note that 1a and 1 b visits can be 
split over two or more days, but the ophthalmologic assessments can be 
conducted at the 1a visit after other screening procedures are completed at the 
discretion of the clinical site in the order most convenient to the site and study 
subject: 
• 
Ophthalmic assessments (before pupil dilation): 
o BCVA (ETDRS letter score); 
o Color vision assessment with FM-100 hue test;  
o Mars letter contrast sensitivity test; 
o M-chart distortion test; and 
o Slit lamp examination. 
• 
After pupil dilation: 
o Macular Integrity Assessment (MAIA) microperimetry. 
Conducted twice with the first result discarded to minimize 
learning effect; 
o Heidelberg Spectralis SD-OCT (including wide field macular 
scan); 
o Heidelberg Spectralis qFAF (set of 3 images to ensure 
consistency in measurement); 
o Digital photograph of corneal surface (conventional and wide 
field); 
o Digital photograph of retina (conventional and wide field); 
and, 
o Slit lamp retinal examination (pupils dilated) and intraocular 
pressure (IOP) measurement. 
IMP Loading Dose: Week 1, Day 1 (Visit 2) 
• 
Confirmation of consent/signed informed consent. 
• 
Update information regarding any new medical conditions, medicines 
(including herbal products and nutritional supplements), surgery or 
illnesses since screening. 
• 
C-SSRS to update suicidal ideation since screening MINI. 

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• 
Update information on social history since screening. 
• 
Abbreviated physical examination (pre-dose).  
• 
Vital signs. 
• 
Blood sampling for determination of the following parameters: 
o CBC and biochemistry; 
o MetHb%; and 
o PK analysis for tafenoquine. 
• 
Urine sampling for determination of the following parameters: 
o Urine pregnancy test (β-HCG) (pre-dose, WOCBP 
participants only); 
o Urinalysis (specific gravity, power of hydrogen [pH], 
glucose, protein, blood, ketones, leukocyte esterase, and 
nitrites). Microscopic examination (if blood, leukocyte 
esterase or nitrites are positive); and 
o Urine drug screen (amphetamines, methamphetamines, 
barbiturates, benzodiazepines, cocaine, methadone, opiates, 
phencyclidine, tetrahydrocannabinols, and tricyclic 
antidepressants). 
• 
Alcohol breath test. 
• 
Psychiatric Assessments 
o DHI (only collected if participant reports AE of dizziness or 
vertigo); and 
o LSEQ assessment. 
• 
Recording AEs and any concomitant medications;  
• 
Inclusion/exclusion criteria confirmed, 
• 
Randomize subject using IWRS using clinical site as a randomization 
variable; and 
• 
Dispense IMP and provide instructions on use of diary card and 
training on electronic compliance system. 
Part 1 - Treatment Phase, Week 4 to Week 52 (Visits 3, 4, 5, and 6): 
• 
Abbreviated physical examination for Weeks 4, 12 and 24  
• 
Vital signs. 
• 
12-lead ECG (Weeks 4 and 52 [Visits 3 and 6]). 
• 
Blood sampling for determination of the following parameters: 
o CBC and biochemistry;  
o MetHb %; and 
o PK blood collection for tafenoquine. 
• 
Urine sampling for determination of the following parameters: 
o β-HCG urine screen (WOCBP only); 
o Urinalysis (specific gravity, pH, glucose, protein, blood, 
ketones, leukocyte esterase, and nitrites). Microscopic 
examination (if blood, leukocyte esterase or nitrites are 
positive); and 
o Urine drug screen (amphetamines, methamphetamines, 
barbiturates, benzodiazepines, cocaine, methadone, opiates, 
phencyclidine, tetrahydrocannabinols, and tricyclic 
antidepressants). 
• 
Ophthalmic Assessments (before pupil dilation): 
o BCVA (ETDRS letter score); 
o Color vision assessment with FM-100 hue test;  
o Mars letter contrast sensitivity test; 
o M-chart distortion test; and 

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o Slit lamp examination and corneal deposit grading (the 
Orlando system).  
• 
After pupil dilation: 
o MAIA microperimetry; (only Weeks 24 and 52);  
o Heidelberg Spectralis SD-OCT (including wide field macula 
scan);  
o Heidelberg Spectralis qFAF (set of 3 images to ensure 
consistency in measurement); 
o Digital photograph of corneal surface (conventional and wide 
field); 
o Digital photograph of retina (conventional and wide field); 
• 
Slit lamp retinal examination and IOP measurement.  
• 
Psychiatric Assessments: 
o M.I.N.I. English Version 7.0.2 at Weeks 12, 24 and 52;  
o DHI (only collected if participant reports AE of dizziness or 
vertigo); and 
o LSEQ. 
• 
AEs. 
• 
Concomitant medications. 
• 
Electronic compliance system, diary cards and used blister packs 
checked. Diary cards and final used blister packs collected at Week 
52. 
Part 1 – Treatment Phase – Every 4 Weeks 
• C-SSRS interview will be conducted every 4 weeks ± 1 week. 
The interview can either be conducted by telephone or in person at a 
clinic visit.  
Part 2 – EOS Follow-up Phase, Week 64 (Visit 7a and 7b) Note 
assessments can be distributed over one or more days at the convenience 
of the site and subject: 
• 
Full physical examination as defined in the protocol.  
• 
Vital signs (sublingual body temperature, respiratory rate, pulse rate, 
systolic and diastolic blood pressure). 
• 
12-lead ECG. 
• 
Blood sampling for determination of the following parameters: 
o CBC and biochemistry. 
o MetHb%. 
o Serum pregnancy test (β-HCG) (WOCBP participants only). 
• 
Urine sampling for determination of the following parameters: 
o Urinalysis (specific gravity, pH, glucose, protein, blood, 
ketones, leukocyte esterase, and nitrites). Microscopic 
examination (if blood, leukocyte esterase or nitrites are 
positive). 
o Urine drug screen (amphetamines, methamphetamines, 
barbiturates, benzodiazepines, cocaine, methadone, opiates, 
phencyclidine, tetrahydrocannabinols, tricyclic 
antidepressants); 
• 
Ophthalmic Assessments (before pupil dilation): 
o BCVA (ETDRS letter score); 
o Color vision assessment with FM-100 hue test;  
o Mars letter contrast sensitivity test; 
o M-chart distortion test; and 
o Slit lamp examination and corneal deposit grading (the 

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Orlando system).  
• 
After pupil dilation: 
o MAIA microperimetry;  
o Heidelberg Spectralis SD-OCT (including wide field macula 
scan);  
o Heidelberg Spectralis qFAF (set of 3 images to ensure 
consistency in measurement); 
o Digital photograph of corneal surface (conventional and wide 
field); 
o Digital photograph of retina (conventional and wide field); 
o Slit lamp retinal examination and IOP measurement; and 
• 
Psychiatric Assessments: 
o M.I.N.I. English Version 7.0.2 at Weeks 12, 24 and 52; 
o DHI (only collected if participant reports AE of dizziness or 
vertigo);  
o LSEQ; and, 
o C-SSRS – every 4 weeks ± 1 week after the Week 52 Visit  
• 
AEs. 
Part 3 - Follow-up Ongoing AEs Weeks 76, 89, and 104 (Visits 8, 9 and 
10) every 3 months until resolution (out to 12 months post final study 
drug dose – visits will only be scheduled if an AE was ongoing at a prior 
visit): 
• 
12-lead ECG 
• 
Blood sampling. 
• 
CBC and biochemistry; and 
• 
MetHb%. 
• 
Urinalysis (specific gravity, pH, glucose, protein, blood, ketones, 
leukocyte esterase, and nitrites). Microscopic examination (if blood, 
leukocyte esterase or nitrites are positive). 
• 
Ophthalmic assessments, including selected ophthalmic examination, 
microperimetry, BCVA (EDTRS), FM-100 hue testing, Mars letter 
contrast sensitivity test, M-chart and qFAF to follow only specific, 
abnormal results. 
• 
Psychiatric assessments: 
o M.I.N.I. English Version 7.0.2. (If required to follow-up an 
AE or disorder). 
o DHI (if AE reported by participant); and 
• 
Any other AE.  
For compliance confirmation during the dosage phase – plasma samples will 
be taken at Weeks 1, 4, 12, 24, and 52. There is no specific timing for 
obtaining the pharmacokinetic (PK) sample during each scheduled visit. The 
date and time of the PK sample is to be recorded in the eCRF. Date, time, and 
number of tablets recorded in participant diary cards and/or electronic 
compliance management system will also be transferred to the eCRF. 
Drawing of blood samples is estimated to be 135 mL/participant within the 
trial prescribed procedures and will not exceed 275 mL for the entire study 
period (Appendix 3). 
Statistical analysis: 
Safety population: All participants who received study treatment at least once 
will be included in the safety population. This is the primary population for 
safety and tolerability analysis. 
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participants as they are randomized to the study. Primary and secondary 
ophthalmic endpoints will be analyzed by ITT population. In this non-
inferiority setting, analysis based on ITT population provides supportive 
evidence to analyses based on Per Protocol population.  
Per Protocol (PP) population: All participants who received at least 25% of 
the total planned dose for IMP, had at least one valid baseline and post 
baseline evaluation by SD-OCT and qFAF, and had no major protocol 
deviations will be included in the PP population. This is the primary 
population for the primary safety endpoint analysis and other secondary 
ophthalmic endpoints.  
Though this is a safety study, all subjects will be analyzed in the treatment 
group to which they were randomized. Detailed aspects of the analysis will be 
presented in the statistical analysis plan (SAP), which will be finalized prior 
to breaking of the study blind and database lock. 
In general, for safety analyses, descriptive statistics will be tabulated by 
treatment group for all participants. Unless otherwise stated, all safety 
analyses will use the Safety population. The analysis of AEs will consider 
only AEs occurring for the first time, or worsening, during or after the first 
administration of study medication. The analysis will focus on incidence of 
AEs in the treatment groups, although for AEs of special interest, the number 
of events will also be provided (i.e. ophthalmic assessments). Tables 
summarizing AEs will be displayed by preferred term and system organ class 
(SOC). Analysis of Serious Adverse Events (SAEs) and the categorization of 
AEs by severity and relationship to study medication will also be included. 
AEs leading to study withdrawal or deaths on-study will also be presented in 
tables and/or listings.  
Treatment-emergent changes in vital signs and laboratory parameters will be 
presented using tabulations by group. Descriptive statistics for each parameter 
and/or the change from baseline at each time point will be provided. For 
endpoints measured on a categorical scale the number of participants and 
percentages will be provided.  
Primary Endpoint Measures  
The primary endpoint for the safety of tafenoquine versus placebo is 
measured by SOSE rate, as assessed by SD-OCT and qFAF parameters. A 
detailed list of SD-OCT and qFAF parameters assessed in this study is 
presented in Appendix 1 and Appendix 2. Clinically significant changes for 
quantitative measures will be defined as a change from baseline by a 
threshold taken from previously published coefficient of repeatability 
(Table 5). For qualitative assessments, new findings or worsening of findings 
from baseline exams regarded to be of clinical importance will be considered 
a change from baseline. If either of the automated reading (CST or TMV) is 
missing or deemed unreliable; the pericentral (inner ring) retinal thickness 
will be used to impute the missing data. 
Descriptive summary tables will be produced showing the results by each eye 
and across both eyes, for each assessment (including follow-up). Data from 
repeated tests carried out due to abnormal values will not be tabulated. All 
data, including those from repeat tests, will be provided in a listing.  
For this primary endpoint, a participant will be considered to have a clinically 
significant SOSE if any of the five parameters listed in Table 5 indicates a 
change from baseline in either eye at any time point during treatment. The 
95% confidence intervals (CI) of SOSE rate will be calculated by treatment 
group, using the Clopper Pearson Exact methodology for the proportion of 

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participants who did experience a clinically significant deterioration. The risk 
difference of the SOSE rates between tafenoquine and placebo will be 
estimated. The upper limit of two-sided 95% CI for the risk difference will be 
compared against the protocol pre-specified NI margin.  
Secondary Endpoint Measures 
• 
The incidence, severity and relationship to the IMP of AEs will be 
summarized at ≥1% (common) and ≥10% (very common) level. 
Safety laboratory parameters and vital signs up to and including the 
EOS visit (Week 64) will be summarized descriptively. 
• 
Mean change from baseline in key SD-OCT parameters including 
CST, TMV, and parafoveal (inner ring of ETDRS grid) retinal 
thickness and the proportion of participants with ellipsoid or 
interdigitating zone disruption (Table 5). The difference in the 
proportion of participants with clinically significant ophthalmologic 
changes (as defined in the primary endpoint) between treatment group 
and the placebo group in each of SD-OCT parameters will be 
calculated. In addition, the change from baseline in individual SD-
OCT and qFAF parameters listed in Appendix 1 and Appendix 2 will 
be tabulated and compared between tafenoquine and placebo-treated 
groups.  
• 
Proportion of participants with abnormal changes from baseline 
observed on qFAF using the Spectralis HRA+OCT device with grey 
scale values extracted from these images for statistical analysis using 
qFAF software (Heidelberg Engineering). 
• 
Mean change from baseline in BCVA. Changes from baseline in 
BCVA results by the ETDRS chart will be tabulated and compared 
between the two groups. A clinically significant deterioration is 
defined as a reduction of more than 4 letters from baseline (Week 1, 
Day 1 [Visit 2]) of 0.08 logMAR. The M-chart will be used to 
quantify the severity of the distortion (if detected). An additional 
analysis of BCVA changes will include the proportion of participants 
experiencing a 1-4 letter change (less than one line of ETDRS visual 
acuity change), a 5-9 letter change (1 line, but less than 2-line 
change), 10-14 letter change (2 lines, less than 3 lines) or 15 or more 
letter change (3 lines or more) in BCVA from baseline. A three line 
or more change in ETDRS BCVA at 4 meters is considered clinically 
significant.  
• 
Proportion of participants with corneal deposits from slit lamp 
examination of the corneal epithelium. Severity of corneal deposits by 
impairment of vision: The proportion of participants with grades I to 
IV corneal deposits and with impairment on any of the vision tests 
will be tabulated for each time point for each eye and overall. For 
participants with corneal deposits identified from slit lamp 
examination, the time to first onset and time to resolution after 
treatment cessation will be tabulated. Corneal structural changes are 
defined as changes from Baseline (Week 1, Visit 2) of two or more 
grades of corneal changes. These data will also be provided in a 
listing. 
• 
Time to onset and resolution of corneal deposits after treatment 
cessation. 
 

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• 
Proportion of participants with new abnormal changes from baseline 
observed with color retinal digital photography (conventional and 
wide field). 
• 
Proportion of participants with new abnormal changes from baseline 
observed with microperimetry. 
• 
Proportion of participants who develop a loss of 0.12 or greater logCS 
on the Mars letter contrast sensitivity test. 
• 
Proportion of participants with any new anomaly on the backlit 
ETDRS chart. 
• 
Proportion of participants who develop a new color deficiency using 
the FM-100 hue test. 
• 
Retinal changes (structural) and the impact on macular function 
(functional) will be tabulated for each time point for each eye. The 
macular function tests include BCVA (EDTRS), FM-100 hue test, 
M-chart, and microperimetry. Clinically significant changes in any of 
the results of all five tests will be counted as having an impact on 
macular function. Retinal abnormalities on fundoscopy, digital fundus 
photography (conventional and wide field), SD-OCT and qFAF at 
Screening are considered to be structural changes but may not affect 
macular function with 12 months of treatment with tafenoquine.  
• 
The proportion of participants with retinal abnormalities identified 
from digital photographs (conventional and wide field) will be 
tabulated for each time point and overall. These data will also be 
provided in a listing. 
• 
Proportion of participants who develop a new psychiatric disorder in 
accordance with the DSM-5 as assessed with the M.I.N.I. 7.0.2 
assessment questionnaire and suicidal ideation or suicide attempt by 
C-SSRS interview. 
• 
Proportion of participants with an AE of dizziness or vertigo and 
severity as assessed by the DHI. 
• 
Mean change from baseline in GTS, QOS, AFS, and BFW as 
assessed by the LSEQ. 
For the above secondary safety endpoints, the proportion of participants with 
a type of abnormal change or new abnormal change will be compared by a 
Fisher’s exact test between tafenoquine and placebo. The 95% CI of the 
abnormality rate will be summarized by Clopper Pearson Exact methodology. 
A logistic regression will be used to compare the risk of having the 
abnormality (odds ratio and 95% CI) between tafenoquine and placebo. For 
time to event safety endpoint, a log-rank test will be used to compare the time 
to onset/resolution of the event between tafenoquine and placebo. Cox 
regression will be used to compare the risk of having the safety endpoint 
(hazard ratio and 95% CI) between tafenoquine and placebo. Change from 
baseline in BCVA, key SD-OCT continuous parameters (Table 5) and LSEQ 
component scores will be analyzed by a random intercept mixed model to 
account for correlation between repeated measures. Treatment effect 
(difference and 95% CI) on the change from baseline variables will be 
estimated across study visits. 

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1. 
STUDY SCHEDULE OF EVENTS 
Study Phase 
Screening 
Treatment (Week 1 to Week 52) 
Phase 2 
Follow-up 
Phase 3 follow-up (ongoing AEs 
at end of Phase 2) 
Week 
-6 Weeks to  
Day -1 
Week 1, 
Day 1 
Week 4 
+3 days 
Week 12 
+2 weeks 
Week 24 
+2 weeks 
Week 52 
+ 2 weeks 
 
Week 64  
+2 weeks 
(EOS) 
Week 76  
+ 2 
weeks 
Week 
89 + 2 
weeks 
Week 104  
+ 2 weeks 
Visit Number 
1a/ 1ba 
2 
3 
4 
5 
6 
7a/7bb 
8 
9 
10 
Written informed consent 
X 
 
Xc 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
X 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion  
X 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Body height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical, surgical & social history 
X 
 
Update 
 
 
 
 
 
 
 
 
 
Prior medicationsd 
X 
 
Update 
 
 
 
 
 
 
 
 
 
Physical examinatione 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vital signsf 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
12-lead ECG 
X 
 
 
X 
 
 
X 
X 
 
Repeat if needed to follow AE 
Hematology/ biochemistryg 
X 
 
X 
X 
X 
X 
X 
X 
 
Repeat if needed to follow AE 
G6PD testing 
X 
 
 
 
 
 
 
 
 
 
 
 
Methemoglobin (MetHb%) 
X 
 
X 
X 
X 
X 
X 
X 
 
Repeat as needed to follow AE 
Serologyh 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testi 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
PK blood collection for tafenoquinej 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 

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Study Phase 
Screening 
Treatment (Week 1 to Week 52) 
Phase 2 
Follow-up 
Phase 3 follow-up (ongoing AEs 
at end of Phase 2) 
Week 
-6 Weeks to  
Day -1 
Week 1, 
Day 1 
Week 4 
+3 days 
Week 12 
+2 weeks 
Week 24 
+2 weeks 
Week 52 
+ 2 weeks 
 
Week 64  
+2 weeks 
(EOS) 
Week 76  
+ 2 
weeks 
Week 
89 + 2 
weeks 
Week 104  
+ 2 weeks 
Visit Number 
1a/ 1ba 
2 
3 
4 
5 
6 
7a/7bb 
8 
9 
10 
Alcohol breath test 
X 
 
X 
 
 
 
 
 
 
 
Urinalysis (dipstick) and urine drug 
screenk 
X 
 
X 
X 
X 
X 
X 
X 
 
Repeat urinalysis only if needed to 
follow AE 
Ophthalmic assessments (before 
dilation: BCVA (ETDRS letter 
score FM-100 hue test, MARS letter 
contrast sensitivity test, M-Chart 
and slit lamp examination/grading 
of deposits after Screening. 
(After dilation: SD-OCT, qFAF, 
digital photograph of cornea, retina 
(conventional and wide field), slit 
lamp retinal exam and IOP 
measurement 
 
X 
 
 
X 
X 
X 
 
X 
Repeat if needed to follow AE 
Microperimetryl 
 
X 
 
 
 
X 
X 
 
X 
Repeat if needed to follow AE 
MINI 7.0.2 
X 
 
 
 
X 
X 
X 
X 
 
Repeat if needed to follow AE 
DHI 
 
 
Only collected if participant reports AE of dizziness or vertigo 
Repeat if needed to follow AE 
LSEQ 
 
 
X 
X 
X 
X 
X 
X 
 
 
C-SSRS 
 
 
X 
 Every 4 weeks ± 1 week 
 
 
AE collection 
 
 
X 
X 
X 
X 
X 
X 
 
Repeat if needed to follow AE 
Concomitant medication 
 
 
X 
X 
X 
X 
X 
X 
 
 
IMP administration 
 
 
200 mg daily x 3 days Week 1, then 200 mg once/week through 
to Week 52 
 
 
 
 
 

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Study Phase 
Screening 
Treatment (Week 1 to Week 52) 
Phase 2 
Follow-up 
Phase 3 follow-up (ongoing AEs 
at end of Phase 2) 
Week 
-6 Weeks to  
Day -1 
Week 1, 
Day 1 
Week 4 
+3 days 
Week 12 
+2 weeks 
Week 24 
+2 weeks 
Week 52 
+ 2 weeks 
 
Week 64  
+2 weeks 
(EOS) 
Week 76  
+ 2 
weeks 
Week 
89 + 2 
weeks 
Week 104  
+ 2 weeks 
Visit Number 
1a/ 1ba 
2 
3 
4 
5 
6 
7a/7bb 
8 
9 
10 
Diary cards and blister packs issued/ 
checked/ collected 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
a Note that 1a and 1 b visits can be split over two or more days, but the ophthalmologic assessments can be conducted at the 1a visit after other screening procedures are 
completed at the discretion of the clinical site in the order most convenient to the site and study subject 
b Note that the 7a and 7b visits can be conducted over multiple days and arranged at the convenience of the site and subject within the visit window. 
c Review prior to dosing with IMP. 
d 28-days before date of first IMP including herbal supplements and nutritional supplements. 
e Full physical exam at Screening (Visit 1a) and at Week 64 (Visit 7a). Abbreviated physical exam to be conducted for the remainder of the study visits. 
f Blood pressure, pulse rate, respiratory rate and sublingual body temperature after the participant has been sitting for 5 minutes. 
g Hematology and biochemistry include tests listed in Section 9.2.4 Laboratory evaluations. 
h Including HBsAg antigens and HCV, HIV-1 and HIV-2 antibodies. 
i Serum pregnancy test (ß-HCG) will be done in all WOCBP at Screening (Visit 1a) and Week 64 (Visit 7a). Urine pregnancy tests will be performed prior to the first dose of 
IMP and all other time points. FSH test may be substituted for a ß-HCG test to confirm menopausal status (females only). 
j PK samples may be taken at any time during the visit. 
k Urinalysis (specific gravity, pH, glucose, protein, blood, ketones, leukocyte esterase, and nitrites). Microscopic examination (if blood, leukocyte esterase or nitrites are 
positive). Urine drug screen (amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, phencyclidine, tetrahydrocannabinols, tricyclic 
antidepressants). 
l Microperimetry will be conducted at Screening (Visit 1b) twice (first result discarded to minimize learning effects) then repeated at Week 24 and 64 (Visits 5 and 7b).  
 
 

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2. 
INTRODUCTION 
2.1. 
Background 
Five species of the malaria Plasmodium parasite infect humans, with P. falciparum and 
P. vivax being the most common and deadly. Plasmodium has a complex lifecycle with 
different forms in both the mosquito and humans (CDC 2016a). The pathogenesis of malaria 
has been well described (Kim 2013). When an individual is bitten by an infected mosquito, 
unicellular Plasmodium sporozoites enter the blood and are rapidly transported to the liver. 
There the sporozoites enter hepatocytes, where they develop into schizonts, each containing 
~30,000 merozoites per hepatocyte. After 6 to 16 days, the schizonts burst and the daughter 
merozoites are released into the bloodstream and infect susceptible red blood cells (RBCs). 
These parasitized RBCs (approximately 1-20 RBCs per µL of blood) become sticky and 
clump, blocking capillaries in various parts of the body, including vital organs (WHO 2015). 
Also, within the RBCs, merozoites develop rapidly into schizonts, and after 48 to 72 hours 
they release a new wave of merozoites into the circulation, accompanied by lysis of RBCs. 
The release of tumor necrosis factor alpha (TNFα) and inflammatory cytokines produces high 
fever and the direct destruction of RBCs results in anemia. In severe cases, potentially fatal 
neurological manifestations of cerebral malaria, renal, hepatic, pulmonary and circulatory 
failure occur (Wattavidanage 1999). Worldwide, over 1 million deaths occur each year due 
predominantly to falciparum malaria. In Africa alone, almost 3,000 children die from malaria 
each day (Johns Hopkins 2016). 
In malaria due to P. vivax or P. ovale, dormant parasitic forms termed “hypnozoites” can 
remain in hepatocytes for weeks to years, ultimately giving rise to a distinct disease episode 
after the primary attack (“relapsing” malaria) (Kim 2013). Consequently, malaria due to P. 
vivax or P. ovale can produce significant morbidity during these relapses. P. vivax malaria is 
a neglected disease that is an important public health issue in many parts of the world. This 
form of malaria caused an estimated 13.8 million cases globally in 2015, and accounted for 
about half of all malaria cases outside of Africa (WHO 2015). 
In the non-immune population, those without previous exposure to and recovery from 
malaria, infection with P. falciparum or P. vivax is a medical emergency since it can lead to 
severe complications and death. The US Centers for Disease Control and Prevention (CDC) 
recommends malaria chemoprophylaxis for US persons travelling to malaria endemic regions 
when there is sufficient risk of contracting Plasmodium infection (CDC 2016b). As of 2015, 
the CDC-recommended malaria chemoprophylactic regimens for regions where 
chloroquine-resistant P. falciparum exists included the following drugs: atovaquone-
proguanil, doxycycline, mefloquine (CDC 2016b). Additionally, primaquine has also been 
used in prophylaxis of malaria, but is not US Food and Drug Administration (FDA)-approved 
for this indication (CDC 2016b). None of these regimens is optimal on the basis of efficacy, 
tolerance, and convenience/compliance (Castelli 2010). For malaria chemoprophylaxis, the 
unmet medical need is for an effective drug that can be administered weekly and does not 
have the adverse side effects of other antimalarials (Dow 2015).  
Tafenoquine [2, 6-methoxy-4-methyl-5-(3-trifluoromethylphenoxy) primaquine, succinate] is 
a primaquine analog, with a long half-life of approximately 13-15 days (Figure 1) (Brueckner 
1998). Tafenoquine under the trade name of ARAKODA™ was approved by the US FDA for 
the prophylaxis of malaria in adults in August 2018. Tafenoquine under the tradename of 

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KODATEF™ was approved by the Australian Therapeutic Goods Administration in 
September 2018. Tafenoquine under the trade name KRINTAFEL also received approval 
from the US FDA for the radical cure (prevention of relapse) of P. vivax malaria in July 
2018. The dosing regimen utilized in this study, 200 mg per day of tafenoquine for 3 days 
then weekly thereafter starting 7 days after the last loading dose is the same as that in the US 
FDA Prescribing Information. 
Tafenoquine has been shown to be well tolerated and efficacious in the prevention of 
Plasmodium infections in nonclinical models and during Phase 1, 2 and 3 clinical studies in 
> 4,000 participants. 
Figure 1: 
Structures of Primaquine and Tafenoquine 
 
 
Primaquine 
Tafenoquine 
 
From (Brueckner 1998) 
2.1.1. 
Ophthalmic Background 
Ophthalmologic AEs reported during clinical trials of the tafenoquine Recommended 
Regimen are summarized in Table 1. Ophthalmologic AEs leading to study discontinuation 
were night blindness and reduced visual acuity, both of which affected the same participant 
(incidence 0.1%) in the tafenoquine Recommended Regimen group during a 6-month 
ophthalmic and renal safety study (Study 057). Keratopathy (corneal deposits) was reported 
as an SAE in 0.6% of participants in the tafenoquine Recommended Regimen group during 
the 6 month pivotal Phase III study in East Timor (Study 033, Nasveld 2010). The 
“keratopathy” (a term used by the initial reports) was presented in the analysis of the 
phospholipidosis safety subgroup as an SAE, as it was a significant new finding. These SAEs 
were subject to a 15-day Investigational New Drug (IND) safety report filed with the US 
FDA. No further cases of corneal deposits in Study 033 were reported as SAEs. Structurally, 
tafenoquine has cationic amphiphilic characteristics, and accordingly it has potential to cause 
phospholipid accumulation (60P IB). The corneal deposits were not associated with any 
effect on visual acuity and were fully resolved in all participants by 1 year (Nasveld 2010). In 
addition, the SAE of “retinal disorders” occurred in 0.2% of participants who received the 
tafenoquine Recommended Regimen, a slightly lower incidence than was seen in the 
mefloquine group (0.3%). Eye disorders that occurred at incidences ≥ 1% in the tafenoquine 
Recommended Regimen group were conjunctivitis and keratopathy (corneal deposits), of 
which only keratopathy (corneal deposits) occurred at a higher incidence (8.2%) than in the 

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placebo population (0%). An expert panel reviewed the findings in Study 033 and concluded 
that the “keratopathy” was in fact benign and reversible. Study 057 did not track corneal 
changes as “keratopathy” but as eye test abnormalities. Therefore, corneal changes were not 
captured in Study 057 as AEs. In this protocol, the term “corneal deposits” will be used in 
preference to “keratopathy”. 
Ocular tissue imaging by means of OCT has become essential for the evaluation of retinal 
diseases and treatment decisions (Wenner 2011). SD-OCT, also known as Fourier-domain 
OCT has resulted in improved resolution of the B-scan images (Grover 2009). These newer 
high-resolution instruments can show localized thinning of the retinal layers in the parafoveal 
region and confirm drug toxicity. Loss of the inner/outer segment line (now known as the 
ellipsoid zone) may be an early objective sign of parafoveal damage (Marmor 2016). Normal 
reference values for macular thickness have been previously established by Time Domain 
(TD) Stratus OCT and this study will use a normative range value of 222-318 μm for study 
participants (Appendix 4) using SD-OCT. TD-OCT is no longer recommended 
(Section 2.1.1.3). A literature search showed that macular thickness can be different between 
different racial or ethnic groups and can be further affected by age, gender, refractive error 
and axial length. It is important to note that changes in foveal thickness are expected to be 
found in eyes with symptomatic macular pathology (Wenner 2011). However, toxic 
maculopathy tends to start in the parafoveal region without acuity loss. Therefore, total 
macular volume and parafoveal (inner ring of ETDRS grid) thickness are also examined as 
one of the secondary endpoints in this study. 
Table 1: 
Summary of Ophthalmologic AEs: Tafenoquine Recommended Regimen 
Group vs Placebo and Mefloquine 
 
Number (%) of Subjects 
 
Tafenoquine 200 mg 
daily x 3 days, then 
200 mg weekly 
(Recommended 
Regimen) (n=825) 
Placebo 
(n=396) 
Mefloquine 250 mg 
daily x 3 days, then 
250 mg weekly 
(n=309) 
Included Studies  
030, 033, 043, 045, 057 
030, 043, 044, 045, 057 
030, 033, 045 
AEs leading to Discontinuation  
Metamorphopsia 
0 
1 (0.3%) 
0 
Night blindness 
1 (0.1%) 
0 
0 
Visual acuity reduced 
1 (0.1%) 
0 
0 
Ophthalmologic SAEs 
Keratopathy 
5 (0.6%) 
0 
0 
Retinal disorder 
2 (0.2%) 
0 
1 (0.3%) 
Metamorphopsia 
0 
1 (0.3%) 
0 

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Table 1: 
Summary of Ophthalmologic AEs: Tafenoquine Recommended Regimen 
Group vs Placebo and Mefloquine (Continued) 
 
Number (%) of Subjects 
 
Tafenoquine 200 mg 
daily x 3 days, then 
200 mg weekly 
(Recommended 
Regimen) (n=825) 
Placebo 
(n=396) 
Mefloquine 250 mg 
daily x 3 days, then 
250 mg weekly 
(n=309) 
Ophthalmologic AEs Occurring in ≥1% of Study Subjects 
Conjunctivitis 
24 (2.9%) 
18 (4.5%) 
13 (4.2%) 
Keratopathy 
68 (8.2%)a 
0 
0 
a Reported as an AE only in a small cohort of Study 033 that was targeted for specialized eye tests 
(phospholipidosis safety subgroup). After the initial 5 cases were reported as SAEs (a significant new safety 
finding), the remainder of the keratopathy reports in the phospholipidosis safety subgroup were reported as AEs 
only.  
2.1.1.1. 
Corneal Deposits 
Corneal deposits are thought to be a manifestation of systemic phospholipidosis. This 
metabolic effect of tafenoquine was observed during 3-6 month repeat dose toxicity studies in 
mice, rats and dogs. In addition to corneal deposits, findings indicative of systemic 
phospholipidosis included foamy macrophage accumulation and lamellar inclusion bodies in 
alveolar macrophages and type II pneumocytes, and eosinophilic material in alveoli of the 
lung. Generally, these effects were similar between species and were both time- and 
dose-dependent. Phospholipidosis is a well-documented effect resulting from an 
accumulation of intracellular phospholipids, which is known to occur with cationic 
amphiphilic drugs such as tafenoquine and many other antimalarials (Halliwell 1997). The 
lesion is characterized by excessive accumulation of foamy alveolar macrophage, 
mononuclear cells and amorphous material in alveolar spaces (Halliwell 1997). This response 
is considered an adaptive response to the presence of the drug and is not necessarily a toxic 
response nor is it predictive of similar findings clinically. There appeared to be no linked 
functional consequence to the phospholipidosis effects in animals, except for one dog 
receiving 4.0 mg/kg/day in the 12-month study showing increased respiratory rate and the 
largest lung weight compared to control males. Foamy macrophages have also been reported 
following 2-years administration of chloroquine to rats (Nelson 1948) and the FDA review of 
phospholipidosis indicated that over 50 marketed and experimental drugs of a cationic 
amphiphilic structure from a wide variety of pharmacological classes induce this effect 
(Sadrieh 2010). 
Signs of phospholipidosis in man were monitored for during Study 033. A subset of 95 
participants was assessed for the possible effects/signs of phospholipidosis on the eye 
(ophthalmic assessments), lung function by measurement of the diffusion capacity of the 
lungs to carbon monoxide (indicator of disease) and forced expiratory volume (FEV1), and by 
electron microscopy examination of white blood cells (WBCs) prior to and after 6 months’ 
treatment. Of the phospholipidosis safety subgroup, 74 participants had been randomized to 
receive the tafenoquine Recommended Regimen. 
No significant effects were noted for the lung or electron microscopy examination of WBCs. 
However, at the end of the study’s prophylactic period (6-month visit), 69 (93.2%) of the 

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74 participants randomized to tafenoquine among the phospholipidosis safety subgroup had 
developed corneal deposits initially categorized as “keratopathy”. There were no changes in 
tests of visual fields, visual acuity, or color vision in these participants. The majority of 
participants with corneal changes (42 of 69) had resolution at 3 months after the end of the 
prophylactic period, while the remainder had complete resolution of their corneal deposits 
within 1 year after the end of tafenoquine dosing. An expert ophthalmology advisory board 
reviewed the ophthalmologic findings from Study 033 and concluded that the observed 
corneal changes were benign and fully reversible. 
As a follow-up to Study 033, the aim of Study 057 was to provide further evidence of the 
ophthalmic safety of tafenoquine for its use as an antimalarial agent (Leary 2009). Although 
the corneal deposits observed in Study 033 had resulted in no evident effects on vision, their 
possible effect on night vision had not been evaluated. Since impairment of night vision 
would prevent active duty soldiers from fully performing their duties, the possibility of 
tafenoquine adversely affecting night vision was investigated in Study 057. The visual impact 
of corneal deposits was assessed using multiple tests, including measurement of forward light 
scatter (FLS), low contrast visual acuity (LCVA), mesopic contrast threshold (MCT), and 
scotopic contrast threshold (SCT). The primary ophthalmic safety endpoint was the number 
of participants with impaired night vision due to corneal deposits, as measured by the FLS 
test. Overall, there were no FLS test failures in either treatment group. The results of the 
primary ophthalmic safety analysis clearly showed that night vision was unimpaired in the 
tafenoquine-treated group. The secondary ophthalmic safety endpoints that assessed 
deterioration in night vision via LCVA, MCT, and SCT testing showed similar findings for 
tafenoquine Recommended Regimen participants and placebo participants. In summary, there 
was no evidence in Study 057 that exposure to tafenoquine had an adverse effect on the 
quality of vision.  
In Study 057, 10 (14.3%) participants in the tafenoquine Recommended Regimen group and 
7 (21.9%) participants in the placebo group had evidence of corneal deposits in either eye at 
screening. After the screening visit, 15 (2l.4%) participants receiving tafenoquine and 4 
(12.5%) participants receiving placebo developed new-onset corneal deposits in one or both 
eyes during the study. Approximately 60% of the corneal deposit cases among participants 
receiving tafenoquine and 100% of the cases among participants receiving placebo emerged 
by Week 12 of the study. No trends were apparent with respect to the time to onset of these 
new corneal deposits in participants who did not have corneal abnormalities at screening. 
New-onset corneal deposits in all four participants in the placebo group resolved within 
6 weeks of onset, while in the tafenoquine Recommended Regimen group, corneal deposits 
resolved within 12 weeks of onset in all but one participant. Corneal deposits in the 
remaining tafenoquine-treated participant resolved by Week 48. 
In summary, benign, reversible corneal deposits have been noted in some participants treated 
with the tafenoquine Recommended Regimen. Participants are unaware of the development 
of these corneal deposits; it does not impact vision, and resolves within 1 year in all cases.  
2.1.1.2. 
Retinal Effects 
Retinopathy and night vision decline may also be a manifestation of systemic 
phospholipidosis. As previously described, selected participants in Study 033 underwent 
more detailed ophthalmic assessments (phospholipidosis safety subgroup). These included 
fundoscopy, which was performed at baseline (before tafenoquine dosing) and at 6 month’s 
post-prophylaxis in 69 participants in the tafenoquine Recommended Regimen group and 

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17 participants in the mefloquine group. Examiners who performed the fundoscopy were 
aware of the participants’ corneal deposits (if present) and were therefore unblinded in that 
respect. Fundoscopic examinations revealed abnormalities (e.g., granularity/pigmentation of 
retinal pigment epithelium [RPE], hard drusen) in 27 of 69 (39.1%) tafenoquine 
Recommended Regimen participants and in 4 of 17 (23.5%) mefloquine participants at the 
end of dosing. Vision was not affected in any of these individuals. Among the participants 
with retinal findings, fundus fluorescein angiograms (FFA) were performed in 15 of the 
31 cases and were considered abnormal in 4 of 14 (28.6%) of the tafenoquine Recommended 
Regimen participants and in 1 of 1 (100%) mefloquine participants. When an expert 
ophthalmology board was asked to review this data, relevance of the retinal findings (based 
on fundoscopy and FFA) could not be ascertained because no baseline retinal photography 
data was available. The ophthalmology board noted that the results observed could reflect 
normal variability and the participative nature of the examinations. They did not consider that 
the FFA results provided evidence of a drug effect.  
In Study 058, adult participants with confirmed P. vivax malaria received either tafenoquine 
400 mg/day for 3 days (Days 1-3), or combination treatment with chloroquine and 
primaquine (chloroquine 100 mg on Days 1 and 2, chloroquine 500 mg on Day 3, and 
primaquine 15 mg on Days 3 through 16). Retinal safety assessments were performed at 
baseline (before dosing with IMP) and on Study Days 28 and Day 90. Retinal pigmentation 
was documented at the Day 28 assessment in 9 (19.6%) of patients with P. vivax malaria who 
received tafenoquine 400 mg/day x 3 days, and this pigmentation was still present in eight of 
the nine tafenoquine-treated malaria participants at Day 90. In comparison, 1 (4.2%) of the 
P. vivax participants who received chloroquine with primaquine developed retinal findings 
(described as mild mottling of the RPE or pigmentary changes). All of these AEs were mild 
and did not impact the vision of the participants. Of the nine retinal AEs reported at the Day 
28 ophthalmic assessment, one had resolved by the Day 90 ophthalmic assessment and eight 
were reported as ongoing. These eight ongoing retinal AEs and the one first reported at the 
Day 90 assessment did not require further follow-up as they were all mild and did not affect 
the vision of the participants. 
As in Study 033, the presence of retinal findings was not associated with any change in 
vision. An Independent Data Monitoring Committee (IDMC), which included two 
ophthalmic experts, reviewed all of the ophthalmologic safety data for all participants 
through the Day 28 assessment. Both ophthalmic experts concurred that there was no 
difference in visual function tests between the tafenoquine 400 mg group and the chloroquine 
with primaquine group. They also had no major concerns regarding findings in the digital 
photographs of the corneas or retinas, and they agreed that the eye findings did not raise 
undue concern, since visual function did not change. In addition, a blinded review of the 
retinal digital photographs conducted at the Fundus Photograph Reading Site, University of 
Wisconsin, found no evidence of anatomical changes consistent with retinal toxicity. The 
findings of the IDMC and blinded review of the digital retinal photographs were confirmed 
by an ophthalmology advisory board, which reviewed all of the ophthalmology safety data 
from the study and were in unanimous agreement that there was no evidence from the data 
presented of any impact on vision in participants taking tafenoquine. The IDMC also 
concluded that there was no evidence from assessment of the digital fundus images for any 
retinal toxicity. 
During Study 057, retinal examinations were performed at baseline (before dosing with 
tafenoquine); during the 6-month dosing phase of the study (at 3 weeks, 6 weeks, 12 weeks, 

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18 weeks, and 24 weeks); and at the follow-up safety visit (at 12 weeks after tafenoquine 
dosing was completed). Retinal changes and impact on macular function were documented at 
each time point for each eye of every participant. Macular function tests included Amsler 
Grid, Humphrey Perimetry Test, high contrast visual acuity (HCVA), and color vision “color 
assessment and diagnosis” (CAD) test. There was no evidence that exposure to tafenoquine 
had any adverse effect on the retina. Assessment of macular function via the Amsler Grid 
Test, demonstrated no abnormalities in either eye for any participant in the tafenoquine 
group. Sporadic abnormalities across both treatment groups with the Humphrey Perimetry 
Test revealed no trends with respect to study treatment. Failures with the HCVA test were 
more frequent among tafenoquine participants at the Week 6 and Week 12 time points; 
however, at Follow-up (Week 12 and Week 24 after cessation of treatment), the incidence of 
failures was higher in the placebo group. A retinal abnormality (described as an area of 
retinal pigmentation that was not near the fovea) was identified by digital photography in the 
right eye of one participant (1.8% of the population) who received the tafenoquine 
Recommended Regimen. In that participant, the retinal changes were seen only at the follow-
up visit. There were no retinal abnormalities in any participant in the tafenoquine 
Recommended Regimen group during the dosing phase of the study. In the placebo group, 
one participant (3.7% of the population) also had a retinal abnormality, which was similarly 
detected at the Follow-up visit. This study confirmed that administration of the tafenoquine 
Recommended Regimen for 6 months did not cause retinal toxicity in healthy participants. 
2.1.1.3. 
Effects of Chloroquine/Hydroxychloroquine on the Retina 
The exact mechanism of chloroquine (CQ) and hydroxychloroquine (HCQ) toxicity is not 
well understood. The classic clinical picture of a bilateral bull’s-eye maculopathy caused by a 
ring of parafoveal RPE depigmentation that spares a foveal island should no longer be seen 
because screening tests will detect HCQ toxicity long before RPE damage is visible by 
imaging or fundus examination (Marmor 2016). In addition to being cationic amphiphilic 
drugs and thereby sharing potential issues of general toxicity concern with other 
phospholipidosis causing drugs (Nonoyama 2008), it is known that the highest concentrations 
of CQ and HCQ are found in melanin-containing tissues of the choroid and ciliary body of 
the eye (Mackenzie 1983) and that this binding to melanin in the RPE may serve to 
concentrate the drugs and contribute to, or prolong, their toxic effects (Marmor 2016). In 
practice the primary damage is to the photoreceptors, and as the outer nuclear layer 
degenerates, there is secondary disruption of the RPE. Additionally, CQ and less frequently 
HCQ can cause whorl-like intraepithelial deposits in the cornea. These are not associated 
with visual loss, and in contrast to retinopathy are usually reversible (Marmor 2016).  
The most critical risk factor for the development of CQ or HCQ toxicity is excessive daily 
dose by weight of >5 mg/kg which dramatically increases both population risk and annual 
incremental risk (Marmor 2016). Duration of use is also linked to dosage as a critical factor. 
Some other preexisting medical conditions such as renal disease, tamoxifen use, and other 
retinal or macular diseases increase the risk further still. SD-OCT has become the 
recommended primary screening tool because it is objective, highly specific, and generally 
sensitive for levels of damage and thinning of the outer nuclear layer that might be visually 
significant (Marmor 2016).  
2.1.2. 
Psychiatric and Neurologic Effects 
Psychiatric AEs reported during clinical trials of the tafenoquine Recommended Regimen are 
summarized in Table 2. Psychiatric AEs leading to study discontinuation in the tafenoquine 

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Recommended Regimen group included depression and a suicide attempt, each of which 
occurred in one (0.1%) participant as follows: 
• In Study 043, Subject 1166 (a 24-year-old Kenyan male) was withdrawn due to 
the SAE of alcohol intoxication/intentional self-injury (coded as a “suicide 
attempt”) that occurred on Study Day 7 (total of 3 loading doses and 1 weekly 
dose of tafenoquine 200 mg). While acutely intoxicated with ethanol, the 
participant’s self-destructive actions (“taking poison”) had been reportedly 
prompted by marital problems. Subject 1166 was hospitalized, tafenoquine was 
discontinued, and the SAE was considered resolved in two days. The suicide 
attempt was considered to be a “severe” AE, which was “not related” to 
tafenoquine. 
• In Study 033, Subject 26048, a 28-year-old white Australian Defence Force 
(ADF) soldier with a history of intracranial head injury, reported moderate 
depression beginning on Study Day 24. He was withdrawn from the study and 
treated with paroxetine, and his depression resolved after 87 days. The 
participant’s depression was considered “suspected” related to tafenoquine. 
In comparison, there were no psychiatric discontinuations in the placebo group, while in the 
mefloquine group; one participant was discontinued due to anxiety.  
Insomnia as a psychiatric AE occurred at an incidence ≥1.2 % in the tafenoquine 
Recommended Regimen group (Table 2). In comparison, less than 1% of participants 
experienced insomnia in the placebo and mefloquine groups.  
Because the comparator drug mefloquine carried a risk for psychiatric side effects (Barrett 
1996; Croft 1996; Hennequin 1994; Lench 1995; Shlagenhauf 2003), the AE profile of 
tafenoquine was examined in greater depth for relatively rare AEs that occurred at extremely 
low incidences <1% (Table 2). Overall, participants in the tafenoquine Recommended 
Regimen group and the mefloquine group had comparable incidences of these rare 
psychiatric AEs, but both of these groups had higher incidences of psychiatric AEs than did 
placebo participants. Psychiatric AEs that occurred in tafenoquine Recommended Regimen 
participants but not in the placebo group included: abnormal dreams, sleep disorder, 
nightmare, depression, agitation, anxiety disorder, euphoric mood, bipolar disorder, 
depressed mood, neurosis, panic attack, stress, and suicide attempt. Of these, the majority 
affected only 1 to 2 participants each of the 825 participants in this group.  
Five psychiatric AEs were observed in both the tafenoquine Recommended Regimen group 
and in the mefloquine group: insomnia, abnormal dreams, sleep disorder, nightmare, and 
depression. The incidences of these AEs were comparable between the two groups with the 
exception of insomnia, which occurred in a higher percentage of participants in the 
tafenoquine Recommended Regimen group (1.2%) than in the mefloquine group (0.3%). 
Notably, both the tafenoquine Recommended Regimen group and the mefloquine group 
included military populations exposed to war-like conditions in Study 033, which is likely to 
have increased their risk for psychiatric AEs compared to participants taking placebo in a 
non-war like environment (Novitt-Moreno 2017).  
A sub analysis of the AEs in the tafenoquine Recommended Regimen population (n=825) for 
the Integrated Safety Summary (ISS), showed that the percentage of AEs was markedly 
higher in the deployed ADF subgroup (n=492) (94.9%) compared with non-ADF participants 
(n=333) (67.6%). In addition, a much higher percentage of AEs in the ADF participants were 

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considered to be “not related” to treatment (86.7%) than in the non-ADF subgroup (53.0%). 
This suggests that the ADF subgroup had been exposed to extrinsic factors associated with 
their deployment in a hostile environment that influenced the safety findings in Study 033. 
Compared to non-ADF participants, deployed ADF participants had higher incidences of ear 
and labyrinth disorders, eye disorders, gastrointestinal (GI) disorders, immune system 
disorders, infections and infestations, injuries, poisonings, and procedural complications, 
musculoskeletal and connective tissue disorders, psychiatric disorders and skin and 
subcutaneous tissue disorders associated with military operations (Figure 2a). Conversely, 
non-ADF participants taking the tafenoquine Recommended Regimen had higher incidences 
of general disorders and administration site conditions, hepatobiliary disorders, investigation 
AEs, metabolism and nutrition disorders, nervous system disorders, renal and urinary 
disorders, reproductive system and breast disorders, and respiratory, thoracic, and mediastinal 
disorders (Figure 2b) consistent with a more mundane home-centered lifestyle with its 
associated risk of typical nasopharyngeal infections, coughs, constipation, and headaches. In 
some cases, (primarily in African studies) there was also a risk for endemic concurrent 
infections (e.g., amebiasis and helminthic infections) and for suboptimal nutrition.  
Notably, for many of the AE categories, the profile of the non-ADF subgroup on tafenoquine 
was similar to that of placebo (n=295). This included ear and labyrinth disorders, eye 
disorders, GI disorders, infections and infestations, investigation AEs, musculoskeletal and 
connective tissue disorders, nervous system disorders, reproductive system and breast 
disorders, and skin and subcutaneous tissue disorders (Figure 2c).  
To examine further, whether specific extrinsic factors could be identified in participants who 
reported psychiatric AEs in the ADF subgroup versus the non-ADF subgroup, medical 
histories and non-psychiatric AEs were reviewed for participants who reported insomnia or 
sleep disorder in these two subgroups. Concurrent GI illnesses, active pain, or upper 
respiratory illnesses affected eight out of 10 participants with insomnia or sleep disorders in 
the ADF subgroup and two of three participants in the non-ADF subgroup. When these 
confounding illnesses and events were eliminated, comparable percentages (0.3%-0.4%) of 
the two subgroups experienced insomnia or sleep disorders. In terms of the tafenoquine 
Recommended Regimen overall population, although insomnia (1.2%) or sleep disorder 
(0.4%) was reported in 1.6% of this population, only 3 of 825 participants (0.4% of the 
tafenoquine Recommended Regimen overall population) did not have an identifiable 
concurrent illness or injury that might have contributed to their insomnia or other reported 
sleep disorders. The LSEQ will be used to measure difficulty of getting to sleep, quality of 
sleep, awakening, and participants behavior following wakening (Appendix 4). The DHI will 
be added to assess dizziness and vertigo severity with respect to normal functioning if this 
AE is reported (Appendix 5). Although the suicide attempt of a subject in Study 043 was 
considered unrelated to tafenoquine, the C-SSRS interview will be used in this study to 
document subjects’ suicidal ideation or any suicide attempt. 
 

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Table 2: 
Summary of Psychiatric Adverse Events: Tafenoquine Recommended 
Regimen Group vs Placebo and Mefloquine 
 
Number (%) of Subjects 
 
Tafenoquine 200 mg 
daily x 3 days, then 
200 mg weekly 
(Recommended 
Regimen) (n=825) 
Placebo 
(n=396) 
Mefloquine 250 mg 
daily x 3 days, then 
250 mg weekly 
(n=309) 
Included Studies  
030, 033, 043, 045, 057 
030, 043, 044, 045, 057 
030, 033, 045 
AEs leading to Discontinuation  
Anxiety 
0 
0 
1 (0.3%) 
Depression 
1 (0.1%) 
0 
0 
Suicide attempt 
1 (0.1%) 
0 
0 
Psychiatric SAEs 
 
 
 
Anxiety 
0 
0 
1 (0.3%)a 
Suicide attempt 
1 (0.1%)a 
0 
0 
AEs Occurring in ≥1% of Study Subjects 
  Insomnia 
10 (1.2%) 
3 (0.8%) 
1(0.3%) 
AEs Occurring in ≤1% of Study Subjects 
  Abnormal dreams 
5 (0.6%) 
0 
2 (0.6%) 
  Sleep disorder 
3 (0.4%) 
0 
2 (0.6%) 
  Nightmare 
3 (0.4%) 
0 
1 (0.3%) 
  Depression 
2 (0.2%) 
0 
1 (0.3%) 
  Agitation 
2 (0.2%) 
0 
0 
  Anxiety Disorder 
2 (0.2%) 
0 
2 (0.6%) 
  Euphoric mood 
2 (0.2%) 
0 
0 
  Bipolar disorder 
1(0.1%) 
0 
0 
  Depressed mood 
1(0.1%) 
0 
0 
  Neurosis 
1(0.1%) 
0 
0 
  Panic attack 
1(0.1%) 
0 
0 
  Stress 
1(0.1%) 
0 
0 
  Suicide attempt 
1(0.1%) 
0 
0 
  Somnambulism 
0 
0 
1 (0.3%) 
  Loss of libido 
0 
0 
1 (0.3%) 
a SAE led to discontinuation 

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Figure 2: 
Subjects with Specific Categories of Adverse Events. Tafenoquine 
Recommended Regimen groups in ADF population versus non-ADF 
population versus placebo 
 
 

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2.2. 
Nonclinical Studies 
2.2.1. 
Nonclinical Pharmacology 
The intrinsic prophylactic effect of tafenoquine has been evaluated against various patient 
isolates and parasite clones in vitro from diverse geographic regions where P. falciparum is 
prevalent. Tafenoquine was proven more active than primaquine against P. falciparum 
isolates from Gabon (Central Africa), Senegal (West Africa), and Djibouti (East Africa) 
(Pradines 2006). In sponsor’s studies, tafenoquine was 1.3- to 18-fold more active than 
primaquine on an equimolar basis in vitro. Furthermore, there are no obvious patterns of 
cross-resistance between tafenoquine and other antimalarial drugs (Vennerstrom 1999). 
Multi-drug resistant strains of P falciparum were susceptible to tafenoquine in vitro 
(Ramharter 2002). Tafenoquine exhibited equivalent activity to primaquine against 
chloroquine-susceptible strains; however, chloroquine-resistant and other multi-drug 
(mefloquine, pyrimethamine) resistant parasite strains were more susceptible to tafenoquine. 
In vivo, tafenoquine demonstrated curative and prophylactic effects in mice and monkeys 
following subcutaneous and/or oral administration. In primate models, blood stages of 
chloroquine-resistant P. vivax were successfully treated with tafenoquine. Tafenoquine also 
showed blood schizonticidal activity against two simian malaria infections, P. cynomolgi 
bastianelli and P. fragile, in rhesus monkeys (Puri 2003). 
Unlike blood schizonticides such as mefloquine, which are only active against asexual blood 
forms, 8-aminoquiniolines such as tafenoquine and primaquine are effective against both 
initial liver forms and subsequent blood asexual forms. Prophylactic activity against the 
initial liver or blood forms are termed “causal” or “suppressive” activity, respectively, since 

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liver activity treats the underlying “cause” of subsequent blood infection and blood activity 
“suppresses” parasites that emerge from the liver but does not attack the cause. It is difficult 
to precisely determine the ratio of causal activity to suppressive activity for the 
8-aminoquiniolines, since this determination requires separate quantification of parasite 
elimination in the liver versus elimination in the blood. This experiment has only been 
performed once, in the luciferase-tagged P. berghei infected mouse model (Li 2014).  
Because this parasite is luciferase-tagged, parasite luminescence in the liver can be measured 
separately from luminescence of the rest of the body. In the P. berghei infected mouse, 
parasites emerge from the liver to infect the blood at 48 hours (2 days) after sporozoite 
challenge, and tafenoquine has a t½ in the blood of 66 hours (3 days). After a single dose of 
5 mg/kg tafenoquine on Day (-1), the day prior to sporozoite dosing, 10 of 10 (100%) 
tafenoquine-treated animals were protected. Elimination of liver parasites was not quite 
complete (98.6% were eliminated) at 48 hours. Since 100% of parasites were eliminated at 
72 hours, 1.4% of parasites escaped being killed in the liver but were then killed in the blood 
by tafenoquine that is present three days after dosing (Li 2014).  
In a causal prophylactic experiment, rhesus monkeys were dosed orally with 0.1, 0.316, 1.0 
or 1.78 mg/kg/day of tafenoquine for three days. A later phase of the experiment dosed 
monkeys orally at lower doses of 0.0316, 0.1 or 0.316 mg/kg/day for 3 days to validate 
results seen in the initial phase. Monkeys were dosed with P. cynomolgi sporozoites on Day 
0. A vehicle control and a positive control (primaquine) were dosed in each group of 
inoculated monkeys. Blood smears were examined from Day 7 to 70 to observe patency. 
Tafenoquine doses of 0.316, 1 or 1.78 mg/kg/day given orally for three days were found to be 
protective in all monkeys dosed while one of two monkeys dosed at 0.1 mg/kg/day became 
patent (showed infection). These data were further validated at doses of 0.0316, 0.1 and 0.316 
mg/kg/day given orally for three days where doses of 0.316 mg/kg/day was protective in 5 
out of 5 (100%) of monkeys while the lower doses were ineffective. The calculated effective 
dose to eradicate 50% of the target pathogen (ED50) for tafenoquine was 0.124 mg/kg for 
3 days. In this study, it was concluded that tafenoquine was effective at preventing sporozoite 
induced infections of P. cynomolgi when oral doses of ≥0.3 mg/kg/day were given for 3 days. 
The calculated causal prophylactic ED50 was 0.124 mg/kg/day for 3 days. This represents 
activity 10.5 times more potent than primaquine against pre-erythrocytic stages of P. 
cynomolgi (Milhous 1998). A single dose of 5.68 mg/kg tafenoquine was fully protective 
when given 3 days prior to challenge. A dose of 5.34 mg/kg primaquine was protective when 
administered on the day of infection (DiTusa 2014, Milhous 1998). 
In a test designed to evaluate the tissue schizonticidal (radical curative) activity of 
tafenoquine in Indian rhesus monkeys infected with P. cynomolgi sporozoites, following 
infection, tafenoquine dosing (0.0316, 0.1, 0.3161 and 1.0 mg/kg/day) was given once a day 
for 7 consecutive days after parasite count exceeded 5000/mm3 and following a completely 
suppressive blood schizonticidal regimen of chloroquine. It was concluded that tafenoquine 
given orally for seven days at doses ≥0.1 mg/kg/day in combination with chloroquine 
(3.1 mg/kg/day) was effective in curing an established tissue infection of P. cynomolgi in 
rhesus monkeys. The calculated 50% curative dose (CD50) for tafenoquine was 
0.172 mg/kg/day given over seven days making it 7.4 times more active than primaquine 
(Study SEATO 338).  
Similarly, the total minimum curative dose of tafenoquine monotherapy for radical cure of 
P. cynomolgi bastianelli infected Indian rhesus monkeys (Macaca mulatta) is 18 mg/kg 
(6 mg/kg/day over three days) and the minimum total dose required to clear blood stage 

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parasites is 6 mg/kg (2 mg/kg/day over three days). In this relapsing malaria model, animals 
were infected with 1 million sporozoites intravenously (IV) and microscopy was conducted 
daily from Days 6-21 post-inoculation until the animals became patent (Day 8). Tafenoquine 
was administered once the parasitemia reached 5000/µL resulting in cure within 3.5 days. 
The minimum blood stage clearance dose (2 mg/kg/day) in Indian rhesus monkeys is 
equivalent to a dose of 38.7 mg/kg/day in humans (271 mg total dose) based on standard 
bodyweight conversion and a human body weight of 60 kg (FDA 2005). At this curative 
dose, parasitemia continued to rise in the Indian rhesus monkeys from Day -1 to Day 1 before 
rapidly declining from Day 2-3 (Dow 2011). 
In the in vitro human ether-a-go-go related gene (hERG) channel electrophysiology assay, the 
50% maximal inhibitory concentration (IC50) value for inhibition of hERG tail current was 
1.1 μM (equivalent to 0.510 μg/mL), a relatively low micromolar value and approximately 
equivalent to the predicted plasma concentration at the maximum proposed dose in humans. 
However, there were no adverse effects observed in the ECG evaluations (including QTc 
interval) conducted in in vivo oral and IV cardiovascular and pulmonary safety pharmacology 
studies in dogs, and in repeat dose oral toxicity studies in dogs of up to 52 weeks in duration, 
in which plasma tafenoquine concentrations of ~18.4 μg/mL and greater were achieved. In 
addition, there were no remarkable effects on action potential parameters in an in vitro dog 
isolated Purkinje fiber assay at concentrations up to 10 μM. Therefore, tafenoquine has a low 
potential for QTc prolongation, which is supported by thorough QT/QTc clinical 
investigations (Green 2014). 
2.2.2. 
Pharmacokinetics and Product Metabolism in Animals 
In nonclinical species, the absorption of tafenoquine appeared to be slow (highest plasma 
concentrations generally >3 hours after dosing) and was incomplete in rats, but high in dogs, 
with a long elimination t1/2 (40 hours or greater). In the primary toxicology species (rat and 
dog) systemic exposure increased proportionally with dose and there was substantial 
accumulation of tafenoquine following repeat oral administration, consistent with its long 
half-life. No sex differences in systemic exposure were observed in the mouse, rat or dog 
(Study 6, Study SBF/232, Study 8740-87-5 and Study 802/589). 
In vitro, plasma protein binding in the mouse, rat, dog and human was very high (≥99.5%) 
(Study DI00292 and Study DI99078). Tafenoquine association with blood cells was 77%, 
54% and 57%, in rat, dog and human, respectively. Incubation with rat, dog and human 
plasma in the light resulted in irreversible binding of some tafenoquine-related material to 
plasma protein (22% to 34%, compared with 1% for samples stored in the dark), and light-
induced degradation of tafenoquine to a quinoneimine structure was postulated as a possible 
mechanism.  
Following a single oral dose of [14C]tafenoquine to rats, radioactivity was widely distributed 
by two hours post dose and most tissues contained concentrations of radioactivity greater 
than those in blood with the exception of the brain and the spinal cord (Study 
SB-252263/RSD-101HHL/1). Tissue concentrations of radioactivity declined slowly with 
time and at 10 days after dosing, most tissues still contained quantifiable amounts of 
radioactivity. This was consistent with slow elimination of radioactivity from intact and bile 
duct cannulated (BDC) rats and dogs, which occurred primarily via the bile/feces (accounting 
for ~75% and 40% of the dose in rats and dogs, respectively). Fecal elimination also 
predominated in intact monkeys (~56% of the dose) (Study 9). 

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In rats, dogs and humans, the only notable drug-related material detected in the plasma was 
unchanged parent compound. The primary metabolites detected in rat and/or dog bile 
included the products of O-demethylation; oxidation to alcohols, ketones and carboxylic 
acids; deamination and N-dealkylation. Desaryl metabolites were present as imino/keto and 
di-imino compounds or tautomers of these structures. Tafenoquine was the major identifiable 
component of fecal extracts from both intact and BDC rats and dogs (Study DI99224). In 
humans, metabolites detected in the urine were largely those previously seen in rats and/or 
dogs. 
Despite tafenoquine inhibiting a variety of cytochrome P450 (CYP) enzymes in vitro 
(including CYP1A2, 2C9, 2D6 and 3A4/5) (Study 040), subsequent clinical studies have 
shown a low risk of meaningful drug-drug interactions via these enzymes. Furthermore, 
tafenoquine did not activate the human pregnane-X-receptor (PXR), using an in vitro reporter 
gene assay, suggesting that tafenoquine is unlikely to perpetrate a drug-drug interaction as a 
result of induction of CYP3A4 (60P IB). 
Tafenoquine inhibited the in vitro transport of [14C] metformin via human organic cation 
transporter 2 (OCT2), multidrug and toxin extrusion 1 transporter (MATE1), and multidrug 
and toxin extrusion 2K transporter (MATE-2K) with calculated IC50 values of 0.28, 2.0 and 
0.63 μM, respectively. Based on unbound systemic concentrations at therapeutic doses, and 
the IC50 derived, there is a potential, but low risk of drug interactions with OCT/MATE 
substrates (60P IB). 
2.2.3. 
Nonclinical Toxicology 
The key target tissue effects in repeat dose toxicology studies of tafenoquine of up to 26 and 
52 weeks duration in rats and dogs, respectively, were oxidative changes in red cell elements 
of blood (methemoglobinemia, Heinz bodies, decreased hemoglobin concentration) and 
findings indicative of phospholipidosis (foamy macrophage accumulation, lamellar inclusion 
bodies in alveolar macrophages and type II pneumocytes, and eosinophilic material in 
alveoli), which were manifested principally in the lung. Hemosiderin deposition in various 
tissues, increased spleen weight and bone marrow hyperplasia were associated with the RBC 
effects. A renal tubular lesion in mice and rats may have been a consequence of hemoglobin 
reabsorption and breakdown. There were no significant renal changes observed in the dog, 
with only slight pigment deposition noted. Hepatic findings (including increased weight, 
small increases in plasma enzyme markers, subacute inflammation and fatty changes) may 
reflect pathophysiological responses to either or both anemia or altered phospholipid 
accumulation. All of the principal pathological changes were fully reversible, or showed 
partial reversibility, following a 13-week drug-free recovery period in the 13-week studies.  
Based on the phospholipidosis-related changes in the lungs, the approximate overall no effect 
dose was 0.5 mg/kg/day (26 weeks) in rats and 0.1 mg/kg/day (52 weeks) in dogs. Findings 
increased in severity with both dose and duration of tafenoquine administration, thereby 
reducing the no effect dose to lower doses in the repeat dose toxicity studies conducted for 
shorter periods of time than 26 weeks in rats and 52 weeks in dogs. In separate 8-week 
toxicokinetic studies using the same doses as the repeat dose studies, the no effect dose was 
shown to be associated with plasma area under the concentration-time curve from 0 to one 
week (AUC0-1 week) values of 6.66 μg·h/mL in rats and 6.84 μg·h/mL in dogs (sexes 
combined). 
No ophthalmological changes have been observed in any of the nonclinical animal toxicity 
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In a neurobehavioral, histopathologic and toxicokinetic study performed using single 
super-therapeutic doses of tafenoquine (125, 250 or 500 mg/kg) in rats, tafenoquine appeared 
to be free of neurologic toxicity (Dow 2017). There were no drug-related findings in the brain 
sections of rats dosed with 500 mg/kg tafenoquine (the minimum lethal dose) compared to 
controls. There was no evidence of neurodegeneration or other morphological abnormalities; 
axon morphology was comparable between tafenoquine-treated and control animals; and the 
gracile nucleus, thought to be a potential target for toxicity, showed no abnormalities. 
No adverse effects on fertility or embryofetal development (including at maternally toxic 
doses), or on post-natal survival, were observed in a complete battery of developmental and 
reproductive toxicology studies as well as a juvenile toxicity study. 
Standard in vitro and in vivo genotoxicity studies for tafenoquine led to the conclusion that 
tafenoquine itself does not present a genotoxic risk to humans. 
When compared to the area under the curve (AUC) in humans consequent to the 
Recommended Regimen of tafenoquine (200 mg x 3 days followed by 200 mg/week), 
systemic exposures at the no effect doses in both rat and dog were assessed as representing 
relatively small fractions (~12%) of the AUC in humans, further confirming the observed 
heightened sensitivity of the two animal species to the treatment-related phospholipidosis and 
hematological effects seen with tafenoquine (60P IB). 
2.3. 
Clinical Studies 
The clinical development program for tafenoquine has spanned decades and consists of 
16 Phase 1, nine Phase 2 and two Phase 3 clinical studies in more than 4,000 participants. 
The studies have included single and multiple oral dose studies, single dose rising studies in 
fasted and non-fasted participants, bioavailability studies for different tafenoquine 
formulations, drug-interaction and safety studies and malaria challenge studies. Field studies 
to assess tafenoquine efficacy have been conducted in Africa and Asia (60P IB).  
2.3.1. 
Efficacy 
Phase 1 malaria challenge studies and Phase 2 and 3 clinical studies with tafenoquine have 
shown the potential utility of tafenoquine in the chemoprophylaxis of P. falciparum and 
P. vivax malaria (reflecting activity against initial liver forms and blood asexual forms) and in 
the radical cure/relapse prevention in P. vivax infection (reflecting activity against liver 
hypnozoites). Tafenoquine also has anti-gametocidal activity (Study 058).  
Tafenoquine has been assessed for its ability to treat existing infection with P. vivax. 
Parasitemia (parasites/µL) was recorded on Day 0 (the day treatment was started) as well as 
on Days 1 and 2 after treatment was started. In 43 patients, mean (highest) parasitemia values 
were: 8000 (44000) and 8000 (49000) for AM and PM on Day 0; 6000 (2000) and 5000 
(16000) for AM and PM on Day 1; 3000 (12000) and 2000 (10000) for AM and PM on 
Day 2. For a randomized group of 22 patients administered standard therapy with 
chloroquine/primaquine, values were: 6000 (30000) and 8000 (40000) for AM and PM on 
Day 0; 2000 (4000) and 1000 (12000) for AM and PM on Day 1; 100 (500) and 100 (100) for 
AM and PM on Day 2. These data indicate that for treatment of P. vivax, the decline of 
parasitemia with time is slower for tafenoquine than for a standard blood schizonticide such 
as chloroquine, but this observation is of little consequence for chemoprophylactic use of the 
drug as a monotherapy (Study 058). 

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Pivotal trials in Oceania and in Africa have shown tafenoquine to have the same prophylactic 
efficacy as mefloquine. For non-immunes in Oceania where the incidence of P. falciparum 
and P. vivax malaria in non-chemoprophylaxed persons was estimated to be 1% and 7% 
respectively, the prophylactic efficacies of weekly tafenoquine and mefloquine were both 
100% (Dow 2014). For semi-immunes in Africa where the incidence of P. falciparum 
infection in placebos was measured as 32%; the number of persons infected in the weekly 
tafenoquine and mefloquine groups were each 2% (Dow 2015).  
2.3.2. 
Human Safety Data 
Tafenoquine has been evaluated in over 4,000 healthy volunteers and patients with malaria in 
Phase 1, Phase 2, and Phase 3 clinical studies including single and multiple oral dose studies, 
dose rising studies in fasted and non-fasted participants, bioavailability studies for different 
tafenoquine formulations, drug-interaction studies, malaria challenge studies, malaria 
prophylaxis and P. vivax malaria treatment studies. In the studies conducted to date, a capsule 
formulation containing dosage strengths of 4 mg, 14 mg, 25 mg, 50 mg, 100 mg, 200 mg and 
250 mg of tafenoquine (as tafenoquine succinate) was studied. Undesirable effects in this 
large sample of participants and patients administered multiple doses can be summarized as 
the following and are presented in Table 3:  
• Blood and lymphatic system disorders, including hemolytic anemia (in patients 
with G6PD deficiency) and methemoglobinemia. 
• Corneal deposits that are fully reversible (within 1 year). Notably, no treatment-
related retinal findings were observed following extended treatment (200 mg x 
3 days loading dose followed by 200 mg/week for 23 weeks) in a Phase 1 clinical 
safety study (Leary 2009; Study 057).  
• GI disorders: nausea, vomiting, abdominal pain and diarrhea. 
• Immune system disorders: hypersensitivity reactions including urticaria. 
Table 3: 
Adverse Events occurring in ≥1% of Subjects in the Tafenoquine ACR 
Group and with an Incidence Numerically Greater than in the Placebo 
Group 
Adverse Reaction 
All Tafenoquine 
Subjects (N=825) 
Non-Deployed 
Tafenoquine Subjects 
(N=333) 
Placebo (N=396) 
Gastroenteritis 
209 (25.3%) 
26 (7.8%) 
17 (4.3%) 
Back pain 
116 (14.1%) 
47 (14.1%) 
26 (6.6%) 
Nasopharyngitis 
108 (13.1%) 
11 (3.3%) 
9 (2.3%) 
Diarrhea 
105 (12.7%) 
16 (4.8%) 
23 (5.8%) 
Keratopathy* 
68 (8.2%) 
0 
0 
Soft tissue injury 
62 (7.5%) 
2 (0.6%) 
0 
Arthralgia 
61 (7.4%) 
14 (4.2%) 
15 (3.8%) 
Heat rash 
53 (6.4%) 
0 
0 
Viral infection 
48 (5.8%) 
8 (2.4%) 
6 (1.5%) 
Laceration 
37 (4.5%) 
8 (2.4%) 
6 (1.5%) 

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Table 3: 
Adverse Events occurring in ≥1% of Subjects in the Tafenoquine ACR 
Group and with an Incidence Numerically Greater than in the Placebo 
Group (Continued) 
Adverse Reaction 
All Tafenoquine 
Subjects (N=825) 
Non-Deployed 
Tafenoquine Subjects 
(N=333) 
Placebo (N=396) 
Vomiting 
31 (3.8%) 
7 (2.1%) 
6 (1.5%) 
Oropharyngeal pain 
30 (3.6%) 
18 (5.4%) 
12 (3.0%) 
Tonsillitis 
27 (3.3%) 
11 (3.3%) 
2 (0.5%) 
Rash 
25 (3.0%) 
5 (1.5%) 
2 (0.5%) 
Tinea pedis 
24 (2.9%) 
0 
0 
Lethargy 
24 (2.9%) 
1 (0.3%) 
0 
Motion sickness 
21 (2.5%) 
0 
0 
Joint injury 
21 (2.5%) 
3 (0.9%) 
0 
Seasonal allergy 
20 (2.4%) 
1 (0.3%) 
0 
Chest pain 
18 (2.2%) 
17 (5.1%) 
5 (1.3%) 
Body tinea 
17 (2.1%) 
5 (1.5%) 
4 (1.0%) 
Sinusitis 
17 (2.1%) 
5 (1.5%) 
2 (0.5%) 
Muscle strain 
17 (2.1%) 
3 (0.9%) 
2 (0.5%) 
Neck pain 
17 (2.1%) 
5 (1.5%) 
4 (1.0%) 
GERD 
14 (1.7%) 
1 (0.3%) 
1 (0.3%) 
Arthropod bite 
14 (1.7%) 
2 (0.6%) 
2 (0.5%) 
Ingrowing nail 
12 (1.5%) 
0 
0 
Ear pain 
11 (1.3%) 
5 (1.5%) 
4 (1.0%) 
Otitis externa 
11 (1.3%) 
2 (0.6%) 
4 (1.0%) 
Heat illness 
11 (1.3%) 
0 
0 
Ligament sprain 
10 (1.2%) 
4 (1.2%) 
0 
Thermal burn 
10 (1.2%) 
1 (0.3%) 
0 
Insomnia 
10 (1.2%) 
2 (0.6%) 
3 (0.8%) 
Impetigo 
8 (1.0%) 
0 
0 
Tinea infection 
9 (1.1%) 
2 (0.6%) 
0 
*Early reports of corneal deposits thought to be secondary to phospholipidosis were initially reported as 
keratopathy and reported as SAEs. Once these were determined to be benign and reversible, later reports of 
keratopathy were not reported as SAEs. 
2.3.3. 
Human Pharmacokinetic Data 
In PK studies in humans, AUC and maximum concentration (Cmax) of tafenoquine increased 
in a dose proportional fashion, and the mean terminal half-life (t1/2) of tafenoquine ranged 
from 13 to 15 days. Food can increase the absorption of tafenoquine, as AUC and Cmax 
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compared with dosing in the fasted state. However, tafenoquine can be taken with or without 
food at the recommended dose to produce therapeutic blood levels, so there are no dietary 
restrictions. 
Population PK analysis showed that tafenoquine typical values of the first-order absorption 
rate constant (ka), clearance (CL/f) and volume of distribution (V/f) were 0.243 h-1, 
0.056 L/h/kg and 23.7 L/kg, respectively, and the mean elimination t½ was 12.7 days. Only 
body weight had a significant effect on V/f and CL/f, both increasing with increasing weight 
(60P IB).  

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3. 
STUDY RATIONALE 
Previous studies in over 4,000 healthy volunteers and patients suggests tafenoquine is safe 
and efficacious when given over a period of 6 months.  
This study will evaluate the overall safety and tolerability of tafenoquine for long-term use 
(12-months). Participation in the study will be approximately 80 weeks, including a screening 
period of up to 4 weeks, a 52 week dosing period (including the loading dose in Week 1), and 
a 24-week follow-up period. 
This study aims to expand the safety database for tafenoquine for a 12-month period of 
exposure by examining general tolerance and detailed assessments of ophthalmologic 
parameters, clinical laboratory tests, and psychiatric evaluation to support the use of 
tafenoquine as a potential antimalarial prophylactic drug to prevent malaria in adults for 
longer term use. Specifically, ophthalmologic changes will be assessed from Screening using 
SD-OCT (including wide field macular scan) and qFAF at Weeks 12, 24,  52, and 64 (Visits 4, 
5, 6, and 7), and if required also at Weeks 76, 89 and 104 (Visits 8, 9 and 10) in healthy 
(G6PD normal) adult participants, dosed with tafenoquine 200 mg once a day (QD) for 3 
days and then 200 mg every week up to 51 weeks. Additional ophthalmic assessments will 
include BCVA using the ETDRS chart, FM-100 hue test, Mars letter contrast sensitivity test, 
M-chart, slit lamp evaluations of the corneal epithelium, microperimetry and retinal digital 
photography (conventional and wide field, to enable detection of subtle peripheral toxicity). 
The incidence, severity and relationship to tafenoquine of AEs (unexpected toxicities, AEs 
encountered during or after tafenoquine administration), safety laboratory parameters, and 
vital signs and ECG up to and including Week 64 (Visit 7) at a ≥ 1% (common) or ≥10% 
very common frequency. A placebo control group will be used to compare the results in the 
tafenoquine group. 
While neurologic and psychiatric events are rare, neurologic and psychiatric AEs have been 
reported in clinical trials conducted with tafenoquine and mefloquine. The AEs reported in 
the treatment group were: abnormal dreams, sleep disorders, nightmares, depression, 
agitation, anxiety disorder, euphoric mood, bipolar disorder, depressed mood, neurosis, panic 
attack, stress, and suicide attempt.  
This study will continue the characterization of the exposure-response relationship for these 
AEs including sleep disturbances assessed using the LSEQ and the development of 
psychiatric disorders in accordance with DSM-5 criteria using the M.I.N.I. English Version 
7.0.2 and suicidality using the C-SSRS. The DHI will be used to assess severity of dizziness 
as it relates particularly to effects on functioning, if dizziness or vertigo is reported as an AE.  

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4. 
STUDY OBJECTIVES 
4.1. 
Primary Objective 
To assess the long-term ophthalmic safety of tafenoquine Recommended Regimen after 
12 months of exposure versus placebo using SD-OCT and qFAF. 
4.2. 
Secondary Objectives 
To assess the long-term safety and tolerability of tafenoquine versus placebo as assessed by 
clinical monitoring of vital signs, ECG, laboratory data, and reporting of AEs after 12 months 
of exposure. 
To assess the long term safety and tolerability of tafenoquine after 12 months of exposure to 
tafenoquine versus placebo by measuring ophthalmic and psychiatric changes from baseline 
to end of study. 
 

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5. 
STUDY DESIGN 
5.1. 
Overview 
This randomized, double-blind, placebo controlled study will involve 600 healthy (G6PD 
normal) volunteers and will run in three parts. The Study Site may stagger enrollment of 
participants into weekly groups to accommodate the screening period.  
Part 1 – Treatment phase (52 weeks) 
Participants who meet the eligibility criteria will be randomized (ratio 1:1) using clinical site 
as a randomization variable to receive a loading dose of either tafenoquine 200 mg (2 x 100 
mg tablets) or placebo daily for 3 consecutive days starting at Day 1, Week 1 (Visit 2), 
followed by study treatment (tafenoquine 200 mg or placebo) once per week for 51 weeks 
with safety follow-up visits at Weeks 4, 12, 24 and 52 (Visits 3, 4, 5, and 6). All efforts will 
be made to retain participants through to study completion. The reasons for withdrawal may 
include: 1) withdrawal of consent, 2) lost to follow-up, 3) evidence of substance abuse that 
may affect the participant’s capacity to complete the study in the investigator’s opinion, and 
4) development of a new or worsening psychiatric disease (including suicidal ideation) at a 
non-scheduled visit or during routine M.I.N.I. evaluation that would jeopardize the safety of 
the participant if they continued in the study (see Section 9.2.7).  If a participant stops taking 
their study drug, they should continue to have all follow-up safety visits. If the subject wants 
to withdraw, they should have an EOS visit (preferably 65-75 days after cessation of study 
treatment that includes all of the Week 64 assessments). The reasons for any treatment 
discontinuation (temporarily or permanently) will be documented on the eCRF. 
Part 2 – Follow-up phase (12 weeks) 
Due to the long t1/2 of tafenoquine (13-15 days with an expected 65-75-day washout period), 
all participants will return to the clinic at the Week 64 (Visit 7a and 7b) for their EOS visit. If 
the participant has an ongoing AE, they will continue in Part 3 of the study, otherwise this is the final 
visit. 
Part 3 – Follow-up Phase (every 12 weeks, up to 12 months) 
Participants who meet the criteria for continuation for additional safety assessments at 
Week 64 (Visit 7a and 7b) will continue to be assessed for up to 3 more times at 
approximately 12-week intervals or until resolution or stabilization of the AE whichever is 
earlier. 
The duration of subject’s participation in the study will be up to 110 weeks, including a 
screening period of up to 6 weeks, a 52-week dosing period, and a 12-week follow-up period. 
If abnormalities are detected at the 12-week follow-up visit (Week 64 EOS) the subject will 
continue quarterly follow-up out to 12 months post last dose of IMP. For example, if corneal 
deposit was the only abnormality found during Week 64, then there is no need to repeat any 
of the ocular examinations except for corneal photography and corneal slit lamp examination 
at Weeks 76, 89 or 104 (Visits 8, 9 or 10). 
The study will consist of the following for each participant: 
• A screening period of up to 6 weeks prior to the first IMP dose. At the first screening 
visit (Visit 1a), subjects will be screened for eligibility with the exception of the 

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ophthalmologic assessments. If still eligible after the first visit, the subject will be 
scheduled for screening and baseline ophthalmic testing (Visit 1b).  
• Randomization to receive tafenoquine or placebo in a 1:1 ratio using clinical site as a 
randomization variable; 
• One 200 mg dose of tafenoquine per day for three consecutive days (loading doses; 
Days 1, 2 and 3) (Week 1, Visit 2) or equivalent dose of matched placebo; 
• Once weekly 200 mg doses of tafenoquine or equivalent placebo on Week 2 through 
Week 52; Follow-up visits on Weeks 4, 12, 24, 52 and 64, and if applicable, Weeks 
76, 89, and 104 to follow any ongoing AEs from the prior visit.  
5.2. 
Study Endpoints 
5.2.1. 
Primary Endpoint 
Proportion of subjects with protocol-defined SOSE. SOSE is assessed by significant retinal 
changes from baseline using SD-OCT and qFAF. The details of significant protocol defined 
retinal changes using SD-OCT and qFAF are defined in Table 5. 
5.2.2. 
Secondary Endpoints 
• The incidence, severity and relationship to the IMP of AEs (including unexpected 
toxicities, AEs encountered during or after IMP administration), safety laboratory 
parameters, vital signs, and ECG up to and including the end of treatment period 
Week 52 (Visit 6). 
• Mean change from baseline in key SD-OCT parameters including CST, TMV, 
parafoveal (inner ring of ETDRS grid) retinal thickness and the proportion of 
participants ellipsoid and interdigitating zone disruption (as per Table 5). 
• Proportion of participants with abnormal changes from baseline observed on qFAF 
using the Spectralis HRA+OCT device with grey scale values extracted from these 
images for statistical analysis using qFAF software (Heidelberg Engineering). 
• Mean change from baseline in BCVA.  
• Proportion of participants with corneal deposits from slit lamp examination of the 
corneal epithelium. 
• Time to onset of corneal deposits and overall time duration to resolution post 
treatment start. 
• Time duration to resolution of corneal deposits after treatment cessation. 
• Proportion of participants with new abnormalities compared with baseline observed 
with color retinal digital photography (conventional and wide field). 
• Proportion of participants with new abnormalities compared with baseline observed 
with microperimetry. 
• Proportion of participants with any new anomaly on the backlit ETDRS chart. 
• Proportion of participants with any clinically significant change in ETDRS BCVA 
(defined as >15 letter change [≥ 3 lines] of change in ETDRS BCVA at 4 meters) 
• Proportion of participants who develop a color deficiency using the FM-100 hue test. 
• Proportion of participants who develop a loss of 0.12 or greater logCS on the Mars 
letter contrast sensitivity test. 

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• Proportion of participants who develop a psychiatric disorder in accordance with the 
DSM-5 as assessed with the M.I.N.I. 7.0.2 assessment questionnaire and suicidal 
ideation or suicide attempt by C-SSRS interview. 
• Proportion of participants with an AE of dizziness or vertigo and severity as assessed 
by the DHI. 
• Mean change from baseline in GTS, QOS, AFS, and BFW as assessed by the LSEQ. 
5.3. 
Rationale of Dose Selection and Dosing Regimen 
Previous clinical studies support a Recommended Regimen for malaria prophylaxis of a 
loading dose of 200 mg once daily for 3 days before travel to a malarious area, followed by 
weekly 200 mg maintenance doses while in the malarious area and an additional dose of 
200 mg at one week of return from travel.  
The tafenoquine dose regimen chosen for this study is based on safety and tolerability data, 
PK data from Phase 1 and 2 studies and efficacy data from dose-ranging chemoprophylaxis 
studies. The tafenoquine 200 mg dose is regarded as the highest, well-tolerated dose that 
achieves a protective tafenoquine concentration of 80 ng/mL in 95% of the sample 
population. Moreover, this is the tafenoquine recommended regimen for malaria prophylaxis 
approved by the FDA. Results from the placebo arm will be used as a comparator for 
spontaneous occurrence of ophthalmic and psychiatric effects. 
5.4. 
Individual Subject Withdrawal 
All efforts will be made to retain participants through to study completion. Participants may 
be withdrawn from the study for any of the following reasons: 1) withdrawal of consent, 2) 
lost to follow-up, 3) evidence of substance abuse that may affect the participant’s capacity to 
complete the study in the investigator’s opinion and 4) development of a new or worsening 
psychiatric disease (including suicidal ideation) at a non-scheduled visit or during routine 
M.I.N.I. evaluation or reported at an unscheduled visit that would jeopardize the safety of the 
participant if they continued in the study (see Section 9.2.7).   
Participants will be considered withdrawn if they state an intention to withdraw, fail to return 
for visits, or are lost to follow-up for any other reason. The investigator will make every 
effort to determine the primary reason for a participant’s withdrawal from the study and 
record this information in the eCRF. For participants who are lost to follow-up, the 
investigator will demonstrate "due diligence" by documenting all steps taken to contact the 
participant (e.g., dates of telephone calls) in the source documents.  
Unless lost to follow-up, withdrawn participants will be asked to participate in a safety visit 
as soon as possible after the time that withdrawal has been requested or determined to be in 
the best interest of the subject and return for a final safety visit  65-75 days after the last dose 
of tafenoquine (after 5 half-lives tafenoquine clearance). The date of withdrawal in the case 
of lost to follow-up is the date of the last contact with the subject either in the clinic or by 
telephone. The date of withdrawal for a subject who withdraws consent is to be reported on 
the Disposition eCRF as the date of withdrawal; however, if the subject agrees to safety 
follow-ups, the date of last contact with the subject, as described above, will also be recorded 
on the eCRF. See section 8.4 for a list of procedures to be conducted at this visit.  The reason 
for treatment discontinuation will be documented on the Drug Compliance eCRF. 

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5.5. 
Risk Benefit Evaluation for this Study 
The administration of tafenoquine may be associated with unforeseen and serious risks. 
Full discussions of the potential risks associated with the administration of tafenoquine are 
detailed in the Investigator’s Brochure (60P IB). 
No benefit is expected for individual participants participating in this study. Benefits of the 
study are society-based and related to possible future antimalarial therapies. 
Risks to healthy (G6PD normal), participants in this study will be minimized in the following 
ways: 
• Strict adherence to eligibility criteria will be maintained to ensure that only 
participants who are not at any perceived risk are enrolled in the study; 
• The doses have been demonstrated previously to be safe and tolerable in healthy 
human participants and within predefined exposure limits; 
• Close clinical monitoring to ensure the safety and well-being of the study participants 
including the following: 
− Exclusion of participants with clinically significant abnormalities from 
participation in the study at screening; 
− Regular measurements of participants’ vital signs (blood pressure, pulse rate, 
sublingual temperature, respiratory rate); 
− Regular assessment of biochemistry and hematological blood parameters 
(including liver function tests) will be performed at scheduled time points and 
repeated, if necessary, to ensure appropriate follow-up of any clinically relevant 
abnormality. 
• The total volume of blood drawn from each participant will not exceed 275 mL during 
the study (Appendix 3). This volume includes allowance for unscheduled safety 
laboratory assessments that may be required at the discretion of the PI to ensure 
participant safety. 
5.5.1. 
Risks/Discomfort to Participants and Precautions to Minimize Risk 
Outlined below are anticipated AEs, and a brief description of procedures to ameliorate risks 
and symptoms. All known risks and precautions described here are explained in detail in the 
participant information and informed consent form (PIICF). 
5.5.1.1. 
Local Reactions 
As the drug is being administered orally, no local reactions are anticipated. 
5.5.1.2. 
Systemic Reactions 
Undesirable side effects that have been observed during tafenoquine clinical trials have 
included the following: 
• Blood and lymphatic system disorders, including hemolytic anemia (in patients with 
G6PD deficiency) and methemoglobinemia. 
• Corneal deposits that are fully reversible (within one year). Notably, no treatment-
related retinal findings were observed following extended treatment (200 mg x 3 days 

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loading dose followed by 200 mg/week for 23 weeks) in a Phase 1 clinical safety 
study (Leary 2009; Study 057).  
• GI disorders: nausea, vomiting, abdominal pain and diarrhea. 
• Serious hypersensitivity reactions (e.g., angioedema and urticaria) (See also Section 
5.5.1.7). 
5.5.1.3. 
Pregnancy 
Risks to unborn babies are unknown at this time; pregnant females will be excluded from this 
study. Female participants should not become pregnant for at least 3 months (5.8 half-lives) 
after the last dose of IMP. Women of child bearing potential must agree to use an acceptable 
method of birth control until 90 days following the last dose of IMP. 
5.5.1.4. 
Lactation 
Risks to nursing infants are unknown at this time; breastfeeding females will be excluded 
from this study. 
5.5.1.5. 
Venipuncture 
Blood sampling carries a minimal risk of minor discomfort and the possibility of minor 
bruising at the site of the needle puncture and, rarely, the possibility of infection and radial 
nerve palsy at the needle puncture site. 
5.5.1.6. 
Ocular Examination and Investigation 
Eye examination required administration of topical anesthetic eye drops which stings on 
initial application. Pupil dilation is required during retinal investigations. This also requires 
phenylephrine and tropicamide eye drops. All these eye drops are administered during a 
standard comprehensive eye examination. Blurry vision occurs for up to 4 hours following 
pupillary dilation. Participants are advised to wear sun glasses and refrain from driving for 
this period. The risk of angle closure glaucoma is extremely low from pupil dilation. This is 
further minimized by study procedure that ensures intraocular pressure measurements are 
taken during ocular examination. 
5.5.1.7. 
Allergic Reaction 
As with any IMP administration, no matter what precautions are taken, there is always the 
risk of serious, or even life-threatening, allergic reaction. Medical emergency equipment is 
located at the Study Sites. This is available to handle emergencies, such as anaphylaxis, 
angioedema, bronchospasm, and laryngospasm. 
5.5.1.8. 
Unknown Risks 
As with all research, there is the remote possibility of risks that are unknown or that cannot 
be foreseen based on current information. 
5.5.2. 
Alternatives to this IMP Product or Study 
An alternative is not to participate in this study. 

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5.5.3. 
Intended Benefit for Participants 
This is a study in healthy (G6PD normal) volunteers, thus there is no benefit to the individual 
or community except the knowledge that the individual’s participation has furthered the 
development of an antimalarial drug. 
5.5.4. 
Risks to the Study Personnel and the Environment 
The principal risk in the clinical setting lies in the handling of needles that may be 
contaminated, the attendant exposure to human pathogens (hepatitis viruses, HIV, and other 
human pathogens). Adherence to standard operating procedures (SOP) for working with 
infectious agents and universal precautions will reduce the risk of exposure. 
There are no known risks to the environment, other than those associated with the generation 
of biohazardous waste attendant to drawing blood from humans. All biohazardous waste will 
be disposed of as stipulated by local, state, and federal regulations and in accordance with 
study site SOPs. 
5.6. 
Route of Administration, Dosage Regimen, Treatment Period, and 
Justification 
The 600 study participants will be randomized to the tafenoquine or the placebo group in a 
1:1 ratio using clinical site as a randomization variable; two groups of 300 participants each 
will be enrolled in each group.  
Each active IMP tablet will contain 100 mg tafenoquine. The dose to be administered orally 
is 200 mg tafenoquine (2 x 100 mg tablets) per day for three consecutive days (loading 
doses), followed by another 200 mg dose once per week for the following 51 weeks 
(beginning post-loading dose Day 10). The placebo group will receive identically-matched 
double-blind placebo tablets. The IMP tablets will be taken with 180 mL of water but there is 
no restriction on whether the tablets are taken with or without food.  
Safety evaluations will include the following assessments: AE evaluation, physical 
examination, vital signs, laboratory parameters (hematology, biochemistry, and urinalysis). 
These will be performed at various time points throughout the study to assess baseline 
function and any changes from baseline after administration of IMP. Hematology, including 
methemoglobin assessment, biochemistry and urinalysis will be conducted at Screening, 
Weeks 4, 12, 24, 52, and 64. Clinical laboratory values indicative of an AE at EOS Week 64 
will be repeated during the Follow-up Phase at Weeks 76, 89, 104 until resolution or 
stabilization. 
Previous clinical studies support a recommended dosage tafenoquine regimen for malaria 
prophylaxis of a loading dose of 200 mg once daily for 3 days before travel to a malarious 
area, followed by weekly 200 mg maintenance doses while in the malarious area, for a period 
not exceeding 6 months, and an additional dose of 200 mg at one week of return from travel 
(60P IB).  
In this study tafenoquine will be administered for 12 months to confirm the long term safety 
of tafenoquine past the 6-month safety window for travelers or military personnel who may 
be in a malarious area for prolonged periods of time.  

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5.7. 
Compliance Statement 
The study will be conducted according to the protocol and in compliance with International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) (CPMP/ICH/135/95), and 
Belmont Principles (Office for Human Research Protections 1979). All identified study 
personnel will be trained to perform their roles and will carry out their responsibilities in 
accordance with ICH GCP guideline and Study Site SOPs.  
5.8. 
Study Sites 
This is a multisite study that will be conducted at three sites: 
• Linear Clinical Research, Perth, Australia with selected ophthalmologic 
assessments performed at the Lions Eye Institute, Perth, Australia. 
• Retina Consultants of Southern Colorado, Colorado Springs, Colorado, USA 
• Valley Retina Institute, McAllen, Texas, USA 
  

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6. 
STUDY POPULATION 
Up to 600 healthy (G6PD normal), adult men and women aged 18 to 55 years (age matched 
to the Study 033 ADF population) will be enrolled in the study.  
Participants will be recruited from the Study Site’s approved database of healthy participants, 
or in response to a general or study specific advertisement to students of local universities or 
the general community, as approved by the local HREC, IRB and HRPO. All racial groups 
will be included. 
After an initial telephone interview conducted by clinical trial staff has occurred to review 
background information, screening visits will be scheduled over two days. Potential 
participants will be invited to come to the Study Site. During this initial screening visit, the 
potential participant will read the participant information sheet and will be encouraged to ask 
questions regarding the information detailed therein. Participants willing to be considered for 
inclusion may sign the consent form during the screening visit, or return to the Study Site at a 
later stage after further consideration. The participant will be given a signed copy of the 
consent form for their records. The signed and dated originals will be held on file by the 
Study Site. 
After providing written consent to participate, the participant will be examined by the PI or 
sub-investigator. A detailed medical history will be obtained and a physical examination 
(including measurements of vital signs and basic ophthalmic testing) will be performed. 
Blood and urine samples will be collected for safety and eligibility assessments. The 
participants will be fully informed of the nature of the study at this time, and advised of the 
requirement to repeat some screening tests as indicated (e.g. see Section 1 Study Schedule of 
Events) prior to IMP administration.  
Eligibility for enrollment will be based on the inclusion and exclusion criteria described 
below. Participants that fail to meet all eligibility criteria will be excluded from enrollment 
into the study. The PI or designee will review the screening data and document if a subject 
meets all of the criteria for enrollment. The PI may also discuss eligibility of a participant 
with the Local Medical Monitor (LMM). 
6.1. 
Inclusion Criteria 
Participants eligible for inclusion in this study must fulfill all of the following criteria: 
1. Completion of the written informed consent process (signed). 
2. Male or female age 18 to 55 years inclusive, in good health as assessed by the 
investigator. 
3. Normal G6PD enzyme activity levels as defined by the parameters of the specific 
G6PD test employed at the local laboratory. 
4. Negative HBsAg and HCV, HIV-1, HIV-2 antibody screen at the screening visit. 
5. Negative serum pregnancy test. 
6. Women of child bearing potential must agree to use an acceptable method of 
contraception from the time of the first administration of the IMP until 12 weeks 
following administration of the IMP or have undergone a sterilization procedure or are 
post menopausal. Acceptable birth control methods include: 

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a. Oral contraceptives (combination estrogen/progesterone pills), injectable 
progesterone or subdermal implants (commenced at least 14 days prior to IMP 
administration to the female participant)  
b. A medically prescribed topically applied transdermal contraceptive patch 
(commenced at least 14 days prior to IMP administration to the female 
participant); 
c. Intrauterine device or intrauterine system; 
d. Partner uses condom with spermicide; 
e. Male partner has had a vasectomy (more than 3 months previously) 
f. True abstinence: when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Abstinent participants (in consultation with their partners) have to agree to use one 
of the above-mentioned contraceptive methods, if they start sexual relationships 
during the study and for up to 90 days after the last dose of study drug. 
Acceptable sterilization procedures include: 
g. Essure® sterilization;  
h. Bilateral tubal ligation; 
i. Hysterectomy; 
j. Bilateral oophorectomy; or, 
k. Be postmenopausal with amenorrhea for at least one year prior to screening and 
confirmed by a serum FSH test at screening. 
7. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
8. Agree to stay in contact with the study site for the duration of the study and up to 
2 weeks following the EOS visit (Week 64), provide updated contact information as 
necessary, and have no current plans to move away from the study area for the 
duration of the study. 
6.2. 
Exclusion Criteria 
Participants fulfilling any of the following criteria are not eligible for inclusion in this study: 
1. History of allergy or intolerance to tafenoquine, primaquine or any excipients. 
2. History of thalassemia or current or past history of methemoglobinemia,   
methemoglobin >2% at screening, or hemolytic anemia. 
3. Participants with a history of previous eye surgery, is currently using prescription eye 
drops or has evidence of corneal or retinal abnormalities identified in Screening 
ophthalmological examination, or by the investigator following review of examination 
including but not limited to: 
a. BCVA (bilateral) at Screening of <72 letters in either eye; 
b. Eye disease that could compromise assessment of BCVA or imaging of the 
posterior pole by fundus photography, or SD-OCT, qFAF or is likely to require 
intervention during the study period (e.g., cataract, glaucoma with documented 
visual field loss, ischemic optic neuropathy, any inherited retinal disease, 
nystagmus and any other retinal abnormality or ocular motor disturbance); 
c. History of retinal vascular disease, retinal detachment, diabetic retinopathy, 
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(up to 5% of male population), amblyopia or other retinal disease that may affect 
posterior retinal function or architecture; 
d. Vitreoretinal interface disorders (e.g. epiretinal membrane, vitreomacular traction) 
that may affect posterior retinal function or architecture; 
e. History of intraocular surgery; 
f. History of cataract extraction; 
g. History of retinal laser photocoagulation; 
h. History of glaucoma shunt or laser treatment; 
i. History of corneal refractive surgery; 
j. History of high myopia (defined as equal to, or worse than, -8.00 diopters) as well 
as those with greater than 3 diopters of astigmatism; 
k. Anterior, intermediate or posterior uveitis (active or history of) or history of 
significant intraocular infectious disease (e.g., endophthalmitis is not acceptable to 
include) or another active inflammatory disease; 
l. An SD-OCT CSF thickness of <222 µm or >318 µm (Appendix 4). 
4. Participants who have recently taken part in, or plan to take part in, any activities or 
been exposed to conditions which may affect their eyesight (e.g., scuba diving, high 
altitudes, sun gazing, laser exposure, or ultraviolet [UV] light). 
5. Participants whose job performance may be affected by participation in the study 
(e.g., need to wear night-vision goggles). 
6. Participants who, in the opinion of the investigator, do not have the ability to 
complete the study (e.g. attend all study visits) or to have necessary study 
investigations performed (e.g. unable to have complete ophthalmic examination as 
specified in the protocol).  
7. Those having received another IMP within 30 days or five half-lives (whichever is 
longer), of study start. 
8. Those having previously received hydroxychloroquine for skin conditions or 
rheumatological diseases, chloroquine for malaria, tamoxifen, amiodarone or other 
drugs that may affect the optic nerve/retina/cornea within 30 days or 5 half-lives 
(whichever is longer) of study start. There are no travel restrictions, but the choice of 
concurrent anti-malarial must be atovaquone-proguanil if the participant chooses to 
take a registered antimalarial drug while travelling. 
9. Have any of the following, based on DSM-5 criteria as assessed using the MINI: 
a. History of  psychotic disorders or current psychotic symptoms (hallucinations, 
delusions, or grossly disorganized thinking or behavior) 
b. Current (past year) suicide behavior disorder or current (past month) suidicality 
c.  or any other current diagnosis of psychiatric disorders . Note: Past history (not 
diagnosed as current) of a psychiatric disorder within the past year will be referred 
to the Study Psychiatrist or Psychologist for further evaluation and determination 
of whether the subject should be excluded from participation in the study. 
Subjects with a stable past psychiatric disorder, as determined after evaluation by 
the Study Psychiatrist or Psychologist, may be admitted to the study. If the subject 
is excluded; the person in question will be referred to their General Practitioner 
(GP). A subject admitted to the study with a psychiatric history, either self-
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medical history eCRF and any current psychiatric medication documented as a 
concomitant medication. 
10. Urine drug screen positive for cocaine, methamphetamine, amphetamines, 
methamphetamines, barbiturates, benzodiazepines, methadone, opiates, 
phencyclidine, or tetrahydrocannabinols. Note urine drug screen positive for tricyclic 
antidepressants or benzodiazepines is allowed if participant reports prescription use 
for a stable medical/psychiatric condition. Limited use of prescription or non-
prescription medications containing codeine and not believed to affect participant 
safety or the overall results of the study, may be permitted on a case-by-case basis 
following approval by the Investigator (in consultation with the Medical Monitor, as 
appropriate). 
11. Blood alcohol level > 0.0 determined using an alcohol breathalyzer. Note on 
interviewing the participant, the investigator may allow enrolment if they are satisfied 
the participant does not have alcohol dependence and can successfully complete the 
study protocol. A second blood alcohol test level > 0.0 at Week 1, Day 1 (Visit 2) 
would constitute grounds for exclusion of the participant.  
12. Participants with medical history that might compromise their ability to comply with 
the protocol. 
13. History of cancer (excluding basal or squamous cell carcinomas). 
14. Have a clinically significant ECG as determined by the investigator or QTc interval 
corrected for heart rate using the Fridericia formula (QTcF) > 450 msec. 
15. Hemoglobin, platelet counts or neutrophil counts outside the local laboratory 
reference range and are judged by the investigator to be clinically significant. A 
laboratory test may be repeated once during screening at the discretion of the 
Investigator. A subject with a hematology result outside the local laboratory reference 
range may be admitted to the study if the result is judged as not clinically significant.  
16. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total or direct 
bilirubin, gamma glutamyl transferase (GGT) or creatinine >1.5 times the upper limit 
of normal (ULN) and are judged by the investigator to be clinically significant. A 
laboratory test may be repeated once during screening at the discretion of the. If other 
biochemistry tests fall outside the local laboratory reference range, the subject may be 
admitted to the study if the out-of-range result is judged as not clinically significant 
by the investigator. 
For other eligibility criteria considerations, the investigator is referred to the IB (60P IB) or 
current US Prescribing Information for detailed information regarding warnings, precautions, 
contraindications, AEs, and other significant data pertaining to the use of tafenoquine. The 
medical monitor should be contacted if the investigator has any questions regarding subject 
eligibility. 
6.2.1. 
Justification of the Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria have been selected to minimize risk to the wellbeing of 
participants in this study. The criteria are also set to ensure a homogeneous, healthy (G6PD 
normal) study population that will facilitate the conduct of the study and the scientific 
evaluation of the study endpoints. 

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6.3. 
Subject Identification 
All participants who sign the informed consent form will be assigned a unique sequential 
participant identification number. This will be a 5-digit number (starting at 10001). The 
participant identification number will be used throughout the study as the primary 
participant’s identifier. The first digit of the subject identifier is the site number. 
6.4. 
Specific Dietary, Fluid and Other Restrictions 
6.4.1. 
General 
Participants will be informed and reminded of the following restrictions during recruitment, 
the informed consent process, and during screening and other scheduled assessments: 
Meals and dietary requirements: 
• Participants may choose to take the IMP with or without food. 
Activity: 
• No restrictions. 
6.4.2. 
Concomitant Treatment 
General concomitant medication restrictions: 
• Tafenoquine may inhibit drug transporters in the kidney. Since inhibition of these 
transporters may lead to increased exposure to medications that they excrete, when 
tafenoquine is co-administered with, substrates or inhibitors of MATE or OCT2, it 
may be advisable to re-evaluate safety and/or efficacy of the latter drugs. 
• All participants will be questioned about concomitant medication at each clinic visit. 
All concomitant medications taken during the study must be recorded with indication, 
daily dose, route of administration and start and stop dates of administration; and 
• Medications taken within 28 days before the first dose of the IMP will be documented 
as prior medications. Medications taken after the first IMP dose will be documented 
as concomitant medications. 

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7. 
INVESTIGATIONAL PRODUCTS 
All IMP are to be used only in accordance with this protocol, and not for any other purpose. 
The designated study personnel will be provided with adequate quantities of the study IMP 
(tafenoquine and placebo tablets). 
7.1. 
Description of Products 
7.1.1. 
Investigational Medicinal Product (IMP) - Tafenoquine 
Tafenoquine/placebo will be supplied by 60P/USAMMDA in tablet form for oral 
administration. The IMP products have been manufactured and tested for quality control 
purposes in accordance with good manufacturing practices (GMP) and local regulations by 
Piramal Enterprise Limited (India).  
Tafenoquine tablets for oral administration are pink, film-coated, capsule shaped tablets 
containing 125 mg of tafenoquine succinate, which is equivalent to 100 mg of free base. 
Tafenoquine tablets also contain: microcrystalline cellulose; mannitol; magnesium stearate; 
hypromellose; titanium dioxide; iron oxide; and macrogol (also known as polyethylene 
glycol). 
A detailed description of the physical, chemical and pharmaceutical properties of tafenoquine 
can be found in Section 3 of the 60P IB. 
7.2. 
Packaging, Labeling and Storage 
7.2.1. 
IMP – Tafenoquine and Placebo Tablets 
Tafenoquine/placebo tablets are manufactured by Piramal Enterprises Limited, 67-70 Sector 
II, Pithampur Industrial Area, (Formerly Piramal Healthcare Limited) Pithampur, 454775, 
India. Tafenoquine and placebo tablets are packed into child-resistant aluminum/aluminum 
blister packs with 8 tablets per pack. 
Investigational products will be provided in drug kits containing 14 blister packs of either 
tafenoquine tablets or identically matched placebo tablets in each kit. Within each kit, blister 
packs will be sub-packed into boxes containing, 3, 4, or 7 blisters packs to provide 
participants with sufficient IMP between dispensing visits, plus enough extra tablets for the 
study windows, so there should be no interruptions in dosing. Packaging and shipment of 
clinical supplies to the site will be performed by Catalent, Inc., Philadelphia, USA. Each kit 
will contain a total of 112 tablets, thus providing a sufficient supply of tablets for the entire 
study for a single participant in one kit plus 4 extra tablets. The content of the labeling will be 
in accordance with the TGA GMP requirements (Annex 13 of PIC/S 2009) and the label will 
include information regarding the identity (blinded), lot number, expiry date and storage 
conditions (both tafenoquine and placebo to maintain the blind). Drug kits used in the United 
States will have additional labeling in accordance with FDA requirements (i.e., “Caution: 
New Drug – Limited by Federal Law to Investigational Use”). Kits will have a sequential 
numeric code to blind the identity of the IMP and will be randomly assigned to participants 
by kit number. 
Tafenoquine is marginally light sensitive. Tafenoquine can be transported and stored at 
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location accessible to authorized personnel only. Storage conditions must be adequately 
monitored and appropriate temperature logs maintained throughout the study while IMP is 
stored at site. Temperature excursions are permitted to 15°C to 30°C (59°F to 86°F). 
Participants will be instructed to store their IMP in a cool, dry place out of reach of children. 
The aluminum/aluminum blister packaging protects the IMP from light. 
7.3. 
Investigational Medicinal Product Accountability 
The designated study personnel, as nominated by the investigator, are responsible for 
maintaining accurate IMP accountability records throughout the study. Dispensing, 
accountability and documentation will be in accordance with the Study Site standard SOPs. 
All products will be inventoried upon receipt by the study site designated study personnel. 
The condition of the products at the time of receipt by the site staff will be documented. 
IMP and study accountability logs will be available to the sponsor or sponsor’s representative 
as part of the study monitoring procedures. Upon completion of the study, copies of all study 
drug management records will be provided to the sponsor. Original records will be 
maintained at the Study Site with the rest of the site study records. 
7.3.1. 
Medication Adherence and Reminder System 
This study will employ a medication adherence reminder platform electronic text messaging 
system (Mosio) for all participants in the study. This system uses electronic text messaging 
reminders to notify subjects when to take their daily or weekly doses.  
Use of this system will in no way supersede or replace the study PI and/or prescribed 
medication protocol of the participants. Because the system does not change the medication 
protocol of the participants, but rather encourages adherence to the predefined protocol, use 
of this system presents minimal risk to the participants. Use of the system will be required for 
all participants in the study. 
When at home, study participants will receive an automatic text message medication 
reminder at a time within a predefined window. This notification reminds participants to take 
their medication dose and has the functionality to record the date, time, and number of tablets 
taken. There is no need for a healthcare provider to review the administration, nor would a 
healthcare provider need to be available at the time the participant takes their medication.  
The system is compliant with the Health Insurance Portability and Accountability Act 
(HIPAA), which protects the privacy and security of healthcare information. Phone numbers 
of the participants may also be collected and stored in an encrypted manner. Storing the 
phone numbers will allow for direct communication with participants, including automated 
messaging from the system web application and contact by study staff. At no time is the 
phone number visible to anyone within the system. Individuals outside the clinical sites will 
not be provided with subject names, nor will they be given access to subject research records. 
The system may provide significant benefits to study participants as well as to the other 
stakeholders in the trial. Study staff will have access to real-time and continuous adherence 
data without having to rely on self-reported data or frequent study visits by participants. 
Participants who regularly fail to take their medication will be contacted by study staff for 
retraining. 

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7.3.2. 
Participant Risk 
The Mosio system provides no more than minimal risk to participants. This system only 
introduces a smartphone-based text messaging application that reminds the user to take their 
medication, reminds the user of their next scheduled clinic visit, and stores encrypted data 
(date, time, and number of tablets taken) securely for analysis.  
All study data, including any identifiable patient information, will be obtained and encrypted 
by the application. Participants will be identified by their subject identification number 
assigned to them for the study. After the subject has taken the medication and record is made 
in the system, the encrypted data will be automatically forwarded to a secure server. The 
server is compliant with the HIPAA, which protects the privacy and security of healthcare 
information. The data will be securely stored and only accessible authorized personnel 
through two-way authentication.  
7.3.3. 
Patient Confidentiality 
The Mosio system will protect participants’ personal information to the full extent required 
by law. However, information from this study, will be collected at the study site, and 
potentially provided to the US FDA or other national regulators. Both information obtained 
by the application and information in the consent form, may be examined by the study site or 
the study site’s representatives, and may also be reviewed by the FDA and other regulatory 
agencies, and or HREC/IRB and HRPO. All of these parties are bound to safeguard the 
rights, safety and well-being of all clinical trial participants, and to maintain all information 
in confidence. 
7.4. 
Method of Assigning Participants to Treatment Groups 
Participants will be assigned to receive either tafenoquine or placebo in a 1:1 ratio using 
clinical site as a randomization variable with a permuted block randomization procedure in 
accordance with a randomization schedule generated by a Fast-Track Biostatistician. 
Centralized randomization will be performed using the electronic data management system 
(EDMS), (IBM Clinical Development) that contains a randomization module. The EDMS is 
available for randomization of participants 24 hours per day, 7 days per week from any 
computer using a web browser. 
If the participant is determined to be eligible, site personnel who are authorized to randomize 
participants and who have completed training for the IWRS, will log onto the system and 
provide the pre-assigned unique participant number. The IWRS provides the randomized 
group kit number and assigns the participant to one of the two interventions. If the participant 
is randomized and is never dispensed study drug, then the participant will be considered a 
randomization failure and an additional participant will be randomized with the next 
randomization sequence at the time he/she is randomized at that site. Likewise, if the 
participant was randomized and then is determined to not be eligible for the study, and never 
received study drug, then another participant will be randomized such that the total numbers 
of participants who were eligible, randomized, and dispensed study drug meet the enrollment 
goals.  

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7.5. 
Investigational Product Administration 
7.5.1. 
Tafenoquine/Placebo 
Participants who are randomized to receive tafenoquine/placebo will be dispensed sufficient 
blister packs and of the assigned IMP for administration between study visits. The participant 
may take the initial dose of the IMP after randomization, while still in the clinic. IMP may be 
taken with or without food.  
Subjects are provided with a diary card at randomization that contains the instructions for 
dosing and a place for the subject to record doses taken. The subject will be asked to return 
the blister packs and the diary card at each clinic visit for accountability. The electronic text 
messaging system will be used to send participants reminders to self-administer IMP and 
record the date, time, and number of tablets taken. Although the Mosio system does allow the 
participant to record the number of tablets taken, the platform is only intended to remind the 
participants to take medication and  compliance data collected via the text messaging system 
will be available to site staff for the sole purpose of confirming drug compliance in between 
in clinic visits. In the event site staff notes subject non-compliance in between clinic visits, 
site staff should contact the subject and counsel the subject on proper medication compliance. 
Data will be reviewed weekly and follow-up text messages may be sent if the subject is 
missing doses. The diary card will be examined during each clinic visit and reconciled 
against the blister packs. 
The number of tablets and date and time administered will be recorded in the eCRF. 
7.6. 
Treatment Blinding 
The study is double-blinded. As the tafenoquine and placebo tablets are identical in 
appearance, and the IMP is provided to the site in blind coded drug kits, all research staff and 
participants will be blinded.  
7.7. 
Unblinding 
Any accidental unblinding should also be reported in writing to the sponsor and LMM. The 
report should include the reason for the unblinding and the steps taken to ensure that the risks 
of this happening again in the future are minimized.  
Special care should be taken to keep the participants masked when examining study 
physician notices and documents relating to corneal deposits or when the photographer is 
taking images of these benign changes since these lesions are indicative of tafenoquine 
exposure and they have no visual consequences, participants should not be told when these 
deposits are identified during any study visits.  
The PI or designated approved study physician will make the decision to un-blind the identity 
of the IMP in the event that the study blind needs to be broken to make medical decisions 
regarding participant treatment. If it is determined that unblinding is necessary to assess AEs 
or SAEs for expedited reporting, the sponsor may decide to request unblinding of a 
participant. Site staff or sponsor’s designee approved to un-blind the IMP for an individual 
participant will log into the IWRS to obtain the name of the IMP to which the participant was 
randomized. The IWRS will automatically notify the un-blinded staff member at the Data 
Management Site who will notify the sponsor. The sponsor will be notified that an unblinding 
has occurred if unblinding has been performed by the investigator or designee. 

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7.8. 
Returns and Destruction 
Used and unused blisters will be destroyed at the site once drug accountability is final and has 
been checked by the assigned study monitor, and written permission for the destruction has 
been obtained from the sponsor. Details of the final disposition of the study drug, including a 
copy of the destruction certificate as relevant, will be documented in the site study file. 

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8. 
VISIT SCHEDULE 
A summary of the schedule of events for the study is presented in Section 1 Study Schedule 
of Events. 
8.1. 
Screening: Week -6 to Day -1 (Visit 1a and 1b) 
Participants will be recruited for screening and consented as described in Section 6 over an 
up to 6 week period. Participants will be assessed for safety laboratory testing on Day 1 of 
screening (Visit 1a). Clinical laboratory tests may be repeated one time at the discretion of 
the investigator a repeat test is warranted to assure subject eligibility. If the participant passes 
these preliminary tests (i.e., not meeting exclusion criteria), they will be further assessed at a 
second screening visit (Visit 1b) by thorough ophthalmic testing with and without pupil 
dilatation. Assessments in the schedule for the 1b visit may be conducted at the 1a visit or 
any 1a or 1b visits may be conducted on different days within the 6-week period at the 
convenience of the clinical site and the subject. The 1b visit includes visual function tests, 
ocular biometry, slit lamp examination, microperimetry, and retinal imaging, to confirm that 
no final ophthalmic exclusion criteria exist for the participant prior to enrollment. The 
ophthalmic testing procedures on Visit 1b are more time consuming and some procedures 
require the pupils to be dilated using phenylephrine and tropicamide eye drops. Blurry vision 
occurs for up to 4 hours following pupillary dilation at this second screening visit. All 
screening assessments will be performed during the period from 6 weeks to up to the first 
IMP dose. 
The following information will be obtained and assessments performed during this time: 
• Signed, written informed consent as detailed in Section 6; 
• Initial review of inclusion and exclusion criteria by the investigator to confirm 
eligibility for screening; 
• Collection of demographic data; 
• Collection of body height and weight data; 
• Medical and surgical history and details of current medications (including herbal 
products and nutritional supplements); 
• Social history of previous and current tobacco, alcohol use and drugs of abuse; 
• A complete physical examination;  
• Vital signs (blood pressure, pulse rate, respiratory rate and sublingual body 
temperature) after the participant has been resting in a seated position for 5 minutes; 
• 12-lead ECG; 
• Blood sampling for determination of the following parameters  
o CBC; 
o Biochemistry; 
o G6PD testing; 
o Methb%; 

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o Serology (HBsAg, HCV, HIV-1 and HIV-2 antibodies); 
o Serum ß-HCG pregnancy or FSH test (WOCBP or post-menopausal females 
only);  
• Alcohol breath test; 
• Urine sampling for determination of the following parameters: 
o Urinalysis (dipstick and urine microscopy if blood, leukocyte esterase, or nitrates 
are positive); and 
o Urine drug screen (amphetamines, methamphetamines, barbiturates, 
benzodiazepines, cocaine, methadone, opiates, phencyclidine, 
tetrahydrocannabinols, and tricyclic antidepressants).  
• Ophthalmic Assessments: The following ophthalmic tests will be performed at 
Screening. Given the short period of time between Screening (Visit  1b) and dosing 
(Week 1, Day 1 [Visit 2]) the ophthalmic data from Screening will be used as the 
baseline data: 
Visit 1b: 
Before pupil dilation: 
o BCVA (ETDRS letter score); 
o Color vision assessment with FM-100 hue test;  
o Mars letter contrast sensitivity test; 
o M-chart distortion test; and 
o Slit lamp examination. 
After pupil dilation: 
o MAIA microperimetry. Conducted twice with the first result discarded to 
minimize learning effect. 
o Heidelberg Spectralis SD-OCT (including wide field macular scan); 
o Heidelberg Spectralis qFAF (set of 3 images to ensure consistency in 
measurement); 
o Digital photograph of corneal surface (conventional and wide field); 
o Digital photograph of retina (conventional and wide field); 
o Slit lamp retinal examination (pupils dilated) and intraocular pressure (IOP) 
measurement 
• Psychiatric Assessments 
o M.I.N.I. English Version 7.0.2. 
• Eligibility Assessment by Investigators:  
o Final review of inclusion and exclusion criteria by the investigators to confirm 
eligibility for enrolment into study; 
Participants who complete all screening procedures and satisfy all eligibility criteria will be 
considered eligible to participate in this study.  

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If screening laboratory results are abnormal (after repeat tests as appropriate are performed) 
(e.g., HIV testing), the participant will be referred for appropriate counseling as applicable. If 
any clinically significant abnormalities are detected during screening, the participant will be 
referred for follow-up tests to a general practitioner or medical specialist as appropriate. 
8.2. 
IMP Loading Dose: Starting Day 1 of Week 1 (Visit 2) 
Participants will report to the Study Site on the morning of Day 1. After completion of the 
pre-dose assessments, they will receive a single dose of tafenoquine or placebo with water 
and their first participant drug pack will be issued. Participants will be advised to take doses 2 
and 3 in Week 1 at home. The following week, the participant will need to take their dose (2 
x 100 mg tablets) commencing 7 days after their last loading dose on Day 3 of Week 1 and 
continue weekly (every 7 days), thereafter. 
The following information will be obtained  prior to randomization to collect baseline data 
and confirm continued eligibility: 
• Confirmation of consent/signed informed consent. 
• Update information regarding any new medical conditions, medicines (including 
herbal products and nutritional supplements), surgery or illnesses since screening. 
• Update information on social history since screening. 
• C-SSRS interview. 
• Abbreviated physical examination (pre-dose). A symptom-directed physical 
examination may also be performed if it is required according to the opinion of the 
investigator. 
• Vital signs (blood pressure, pulse rate, respiratory rate and sublingual body 
temperature) after resting in a seated position for 5 minutes (pre-dose). 
• Blood sampling for determination of the following parameters: 
o CBC, MetHb% and biochemistry; and 
o PK blood sample for tafenoquine. 
• Alcohol breath test. 
• Urine sampling for determination of the following parameters: 
o Urine pregnancy test (β-HCG) (pre-dose, WOCBP participants only); 
o Urinalysis (dipstick and urine microscopy if blood, leukocyte esterase, or nitrites 
are positive);  
o Urine drug screen (amphetamines, methamphetamines, barbiturates, 
benzodiazepines, cocaine, methadone, opiates, phencyclidine, 
tetrahydrocannabinols, and tricyclic antidepressants); and 
• DHI assessment (only collected in participant reports AE of dizziness or vertigo). 
• LSEQ assessment. 
• Inclusion/exclusion criteria confirmed. 
The following will be performed after continued eligibility is confirmed: 

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• Randomization number obtained by IWRS; 
• IMP administration (2 tablets with water). 
• Dispense investigational product and provide instructions on use of diary card and 
text messaging reminder and compliance system. 
After completion of the assessments and after administration of the tafenoquine dose, 
participants will be allowed to leave the Study Site if they are considered to be in good health 
by the investigator.  
8.3. 
Treatment Period: Week 4, 12, 24, and 52 (Visits 3, 4, 5 and 6) 
Participants will report to the Study Site in the morning.  
The following assessments will be performed over the treatment period: 
• Abbreviated physical examination- a symptom-directed physical examination will be 
performed based on signs and symptom the participant has reported verbally. A 
symptom-directed physical examination may also be performed if it is required 
according to the opinion of the investigator. 
• Vital signs (blood pressure, pulse rate, respiratory rate and sublingual body 
temperature). 
• 12-lead ECG (Week 4 and 52). 
• Blood sampling for determination of the following parameters: 
o CBC;  
o Biochemistry; 
o MetHb %; 
o Plasma for PK analysis; 
• Urine sampling for determination of the following parameters: 
o Urine ß-HCG pregnancy test (WOCBP only) at Weeks 4, 12, 24 and 52; 
o Routine urinalysis (dipstick and urine microscopy if blood, leukocyte esterase, or 
nitrites are positive); and  
o Urine drug screen (amphetamines, methamphetamines, barbiturates, 
benzodiazepines, cocaine, methadone, opiates, phencyclidine, 
tetrahydrocannabinols, and tricyclic antidepressants); 
Ophthalmic Assessments: The following ophthalmic tests will be performed routinely 
during the Treatment Period at Weeks 12, 24 and 52 Ophthalmic assessments may be 
scheduled as a second visit during weeks when most of the examinations are performed to not 
overburden the length of the visit for subjects. 
Before pupil dilation: 
o BCVA (ETDRS letter score); 
o Color vision assessment with FM-100 hue test;  
o Mars letter contrast sensitivity test; 

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o M-chart distortion test; and 
o Slit lamp examination and corneal deposit grading (the Orlando system).  
After pupil dilation: 
o MAIA Microperimetry (only Weeks 24 and 52);  
o Heidelberg Spectralis SD-OCT (including wide field macula scan);  
o Heidelberg Spectralis qFAF (set of 3 images to ensure consistency in 
measurement); 
o Digital photograph of corneal surface (conventional and wide field); 
o Digital photograph of retina (conventional and wide field); 
o Slit lamp retinal examination and IOP measurement; and 
• Psychiatric Assessments 
o M.I.N.I. English Version 7.0.2; 
o DHI (only if a participant reports AE of dizziness or vertigo); and 
o LSEQ. 
• Recording AEs and any concomitant medications.  
• Electronic compliance system, diary cards and used blister packs checked. Number of 
tablets taken, date and time recorded in eCRF. Diary cards and final used blister packs 
collected at Week 52. 
Also every 4 weeks ± 1 week during the treatment period, a C-SSRS interview will be 
conducted either by telephone at any time or in person at a clinic visit at the discretion of the 
site staff. 
8.4. 
Early Termination/EOS assessments, Weeks 64 (Visit 7a and 7b) 
This visit scheduled to occur during Study Week 64, will be conducted over two days during 
this week to complete all assessments. Data will be recorded at the nominal Week 64 visit. 
Due to the long t1/2 of tafenoquine (13-15 days with an expected 65-75-day washout period), 
all participants will return to the clinic at Week 64 for their EOS visit. If a participant 
withdraws prematurely; all these study checks should be completed at the final outgoing visit, 
preferably 65-75 days after their last dose of IMP: 
• Full physical examination; 
• Vital signs (blood pressure, pulse rate, respiratory rate and sublingual body 
temperature); 
• 12-lead ECG; 
• Blood sampling for determination of the following parameters: 
o CBC and biochemistry; 
o MetHb %; 
o Serum β-HCG pregnancy test (WOCBP only); 

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• Urine sampling for determination of the following parameters: 
o Urinalysis (dipstick and urine microscopy if blood, leukocyte esterase, or nitrites 
are positive); and, 
• Ophthalmic Assessments:  
Before pupil dilation: 
o BCVA (ETDRS letter score); 
o Color vision assessment with FM-100 hue test;  
o Mars letter contrast sensitivity test; 
o M-chart distortion test; and 
o Slit lamp examination; 
After pupil dilation: 
o MAIA microperimetry; 
o Heidelberg Spectralis SD-OCT (including wide field macula scan); 
o Heidelberg Spectralis qFAF (set of 3 images to ensure consistency in 
measurement); 
o Digital photograph of corneal surface (conventional and wide field); 
o Digital photograph of retina (conventional and wide field); 
o Slit lamp retinal examination and IOP measurement 
• Psychiatric Assessments 
o M.I.N.I. English Version 7.0.2; 
o DHI (only if a participant reports AE of dizziness or vertigo); and 
o LSEQ. 
• Recording AEs and any concomitant medications.  
Also every 4 weeks ± 1 week between the Week 52 and the Week 64 visit, a C-SSRS 
interview will be conducted. 
8.5. 
Part 3 Follow-up for Ongoing AEs Weeks 76, 89, and 104 (Visits 8, 
9, and 10): 
The following are the criteria for participant continuation for additional safety assessments: 
• Ongoing AE. 
• Laboratory value is determined to be a new or continuation of an ongoing AE. 
• Diagnosis of psychiatric disorder. 
• Abnormality found on any of the following ophthalmologic examinations (only 
the test that revealed an abnormality will be repeated, unless at the discretion of 
the investigator additional testing is warranted): 

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− SD-OCT, qFAF, BCVA [ETDRS], FM-100 hue test, Mars letter contrast 
sensitivity test and M-chart. 
− Slit lamp examination and digital photograph of corneal surface (cornea 
Verticillata) and retinal digital photograph (toxic maculopathy and retinopathy 
on conventional and wide field device). 
− Microperimetry. 
Participants will report to the Study Site in the morning. 
The following assessments will be performed during this follow-up visit (if required): 
• Blood sampling as needed to follow abnormality: 
o CBC and biochemistry; 
o MetHb %; 
• Urine sampling as needed to follow abnormality: 
o Urinalysis (dipstick and urine microscopy if blood, leukocyte esterase, or nitrites 
are positive). 
• Ophthalmic Assessments (repeat only if abnormal at Week 64). Abnormal results may 
need to be further investigated using microperimetry, color vision assessment with 
FM-100 hue test, Mars letter contrast sensitivity test and M-chart. Corneal deposits 
and retinal lesions from drug toxicity at Week 64 needed to be monitored by slit lamp 
examination, SD-OCT (including wide field macula scan), qFAF and photography 
(conventional and wide field);  
• Psychiatric Assessment with M.I.N.I 7.0.2 (repeat if disorders are found at Week 64).   
• Assessment with DHI (if participant reports ongoing AE of dizziness or vertigo). 
General: 
At all follow-up visits, participants will be reminded of the following before leaving the 
Study Site: 
• Study restrictions as described in Section 6.4; 
• To return to the Study Site for the following scheduled visit; and 
• To contact the Study Site in the interim should they experience AEs or require 
treatment with any concomitant medications. 
8.6. 
Assessment and Visit Windows 
The following time-related windows will be acceptable based on logistical and operational 
considerations: 
• Out Patient Week Visits: as follows, unless otherwise indicated by the investigator: 
o Week 4 + 3 days (Visit 3); 
o Week 12 + 2 weeks  (Visit 4); 
o Week 24 + 2 weeks (Visit 5); 
o Week 52 + 2 weeks (Visit 6); 

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o Week 64 + 2 weeks (Visit 7a and 7b)  
AND if ongoing AEs are being followed; 
o Week 76 + 2 weeks (Visit 8). 
o Week 89 + 2 weeks (Visit 9). 
o Week 104 + 2 weeks (Visit 10). 
At all-time points where multiple assessments are performed and blood samples are collected, 
vital signs measurements (when relevant) will be performed before blood sampling.  
Any deviations from the above-mentioned permissible window periods will be documented 
as protocol non-compliances and will be evaluated for significance at the data review meeting 
prior to database lock. 
8.7. 
Unscheduled Visits 
In the event that a participant reports a potential AE by telephone or other means in between 
regularly scheduled visits, an unscheduled visit may be performed to do a more detailed 
analysis of the event. The assessments to be performed at unscheduled visits are at the 
discretion of the investigator but could include for example, a repeat M.I.N.I. examination if 
the subject reports a new psychiatric symptom or to repeat any questionable ophthalmic test 
results that may need to be repeated or validated (Marmor 2016). 
Additional unscheduled visits could also include repeat clinical laboratory tests in the event 
that a result is indicative of a clinically significant finding to assist in the determination of the 
resolution of an AE. Another case would be if a subject was found to have an unexplained 
marked reduction of visual acuity ≥15 letters (> 3 line change) of ETDRS BCVA at 4 meters 
(an AESI) and a repeat BCVA test was warranted sooner than the next scheduled visit. 

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9. 
ASSESSMENTS 
9.1. 
Screening and pre-IMP dosing Assessments 
Unless noted otherwise, the window period within which all screening evaluations must be 
completed, and the results reviewed by the investigator to confirm eligibility of participants, 
is from 6 weeks to one day prior to dosing with IMP. Baseline evaluations (with the 
exception of those tests that are only performed at the first screening visit) will be regarded as 
those performed immediately prior to IMP dose administration on Day 1 (Week 1 [Visit 2]). 
9.1.1. 
Demographics 
Participant demographic and baseline characteristic data to be collected on all participants 
include: date of birth, age, sex and race/predominant ethnicity.  
9.1.2. 
Height and Weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kg in indoor clothing, but 
without shoes) will be measured.  
9.1.3. 
Medical, Surgical and Current Medical Conditions 
Participants will provide a detailed medical, surgical, and medication usage during screening 
and again prior to IMP administration, in order to assess the eligibility of the participant for 
the study.  
Any event or change in the participant’s condition or health status prior to the initial 
administration of the IMP will be reported in the relevant medical history/current medical 
conditions section of the eCRF and not as an AE pre-dose. 
9.2. 
Safety 
9.2.1. 
Physical Examination 
A complete physical examination will include: 
• General appearance; 
• Skin; 
• Head, neck (including thyroid), ears, eyes, nose, mouth (including dentition), throat; 
• Heart 
• Circulation; 
• Chest; 
• Lungs; 
• Abdomen; 
• Back; 
• Extremities;  
• Lymph nodes; and 

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• Neurological examination. 
After screening evaluations, an abbreviated, symptom-directed physical examination will be 
performed focused on changes since the previous examination, but will always include at 
least: 
• General appearance; 
• Skin; 
• Heart / circulation; 
• Chest / lungs; 
• Abdomen; and 
• Brief neurological examination. 
Significant findings present prior to the administration of the IMP will be recorded in the 
relevant medical history/current medical conditions section of the participant’s eCRF. 
Significant findings made after these time points and which meet the definition of either an 
AE or a disease-related event, will be recorded as such in the relevant section of the 
participant’s eCRF. 
9.2.2. 
Vital Signs 
Vital signs including blood pressure, pulse rate, respiratory rate and sublingual body 
temperature after the participant has been resting for 5 minutes in a seated position as 
stipulated in the study schedule (Section 1 Study Schedule of Events). 
The vital signs’ normal ranges will be defined by site. 
9.2.3. 
12-lead ECG 
Standard, 12-lead ECGs will be performed at Screening and nominal Weeks 4, 52, and 64. 
The clocks on all ECG machines will be synchronized with the central clock on a daily basis. 
Participants will rest for at least 5 minutes prior to the start of recording. ECG tracings will be 
retained and labeled as per SOPs at each clinical site. 
Real-time interpretation of the tracings will be made on-site with special attention being 
given to changes in PR-, QRS- and QT-intervals as well as T-wave morphology changes and 
dysrhythmias. The QTc interval corrected for heart rate using the Fridericia formula [(QTcF 
= QT/RR)(1/3)]  (Fridericia 1920) will be calculated. Any change > 450 msec will be 
considered clinically significant. Any clinically significant findings will be discussed with the 
LMM and sponsor. The investigator will sign and date each ECG as evidence of their review. 
9.2.4. 
Laboratory Evaluations 
Evaluations of standard laboratory parameters will be performed as part of the screening and 
baseline determinations of eligibility, as well as throughout the follow-up period as part of 
the safety assessments. Details of the timing of these evaluations are presented in Section 1 
Study Schedule of Events and in Section 8 Visit Schedule. 
The investigator will document the clinical significance of all results falling outside of the 
normal reference ranges. All abnormal laboratory test results judged as being clinically 
significant by the investigator, will be reported to the LMM (and in turn the Data Safety 
Monitoring Board [DSMB]) and will be recorded as an AE. Repeated evaluations are 

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mandatory until normalization of the result(s) or until the change is no longer considered 
clinically significant. 
Hematology 
The following standard parameters will be assessed at all relevant time-points: 
• RBC count, Hb, Hct, MCH, MCV, Plt count, WBC count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils and basophils); and 
A manual blood smear will be reviewed if immature/abnormal cells are detected on the 
automated differential or if an automated differential is not able to be performed 
• MetHb %.  
The methemoglobin assay is only performed at Clinipath’s laboratory at the Mount Hospital 
(in Australia). Due to the short sample stability requirements, this sample must be 
routed/shipped to the Mount Hospital (or US equivalent laboratory) within 90 minutes of 
collection, to ensure analysis occurs within the 4-hour stability window period. An optical 
absorbance measurement will be taken using a Gem4000 analyzer (or equivalent). The Final 
Clinical Study Report (FCSR), will document the assay(s) used to measure methemoglobin.  
Biochemistry 
The following parameters will be measured at all relevant time-points: 
• BUN, creatinine, potassium, sodium, AST, ALT, ALP, GGT, total and direct 
bilirubin. 
Serology and other special laboratory investigations 
• All participants will be screened for HBsAg, anti-HCV, anti-HIV-1 and anti-HIV-2 
antibodies (if positive confirmed by a second test as per laboratory protocol).  
• G6PD status will be determined at Screening. 
Alcohol breath test, urine drug screen 
• A urine screen for drugs of abuse (amphetamines, methamphetamines, barbiturates, 
benzodiazepines, cocaine, methadone, opiates, phencyclidine, tetrahydrocannabinols, 
and tricyclic antidepressants); and 
• An alcohol breathalyzer test (Screening [Visit 1a] and Week 1, Day 1 [Visit 2] only).  
Urinalysis 
Urine will be collected for dipstick analysis with microscopy, as applicable, by a specified 
study lab.  
The following parameters will be assessed: specific gravity, pH, glucose, protein, blood, 
ketones, leukocyte esterase, and nitrates. Microscopic examination will be performed if 
blood, leukocyte esterase, or nitrates are positive. Culture and sensitivity will be performed, if 
indicated, by the microscopy results. 
Pregnancy 
All WOCBP participants will have a serum β-HCG measurement at Screening and the 
Week 64 EOS visit. A urine β-HCG test will be undertaken prior to first IMP dose (Week 1 
[Visit 2]) and at Week 4, 12, 24 and 52 visits. 

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Females who are menopausal will have this status confirmed by a serum FSH test at 
Screening. 
If a participant is found to have a positive urine pregnancy test at any stage during the study, 
a confirmatory serum β-HCG will be performed. If confirmed positive, the participant will be 
discontinued from IMP and followed as described in Section 10.11.6. 
9.2.5. 
Pharmacokinetics for Compliance  
Blood samples will be collected from Week 1 to Week 52 either by direct venipuncture or via 
an indwelling cannula inserted in a forearm vein into an ethylene diamine tetra-acetic acid 
(EDTA) purple top tube.  
The actual sample collection date and time will be entered in the PK blood collection section 
of the eCRF. Any sampling problems will be documented in the eCRF. 
The parent drug in the plasma samples will be analyzed using bioanalytical assays validated 
to meet both European Medicines Agency (EMA) or FDA requirements 
(EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2** and FDA 2001). Assays will be 
performed and the methodology will be detailed by the bioanalytical laboratory. 
9.2.6. 
Ophthalmic Assessments 
The ophthalmic assessments will be conducted at Screening at (Visit 1b or 1a depending on 
site and subject preference) and repeated at Weeks 12, 24, and 52 of the Treatment Phase and 
at the EOS visit (Week 64). Ophthalmic assessments will be repeated at Week 76 (Visit 8) 
and quarterly thereafter to 12 months if ongoing or new ophthalmic abnormalities are 
identified at the Week 64 visit. Microperimetry testing will be conducted at Screening twice 
with the first result discarded to minimize learning effect and at Weeks 24, 52 and 64. Non-
clinically significant abnormalities at Baseline (Week 1, Day 1) will be recorded as medical 
history and will only be followed up after Week 64 if the abnormality worsens during the 
Treatment Period.  
Please note, only tests that are abnormal at the Week 64 visit will be followed up in Weeks 
76, 89 or 104 (Visits 8, 9, or 10). For example, if corneal deposit was the only abnormality 
found during Week 64, then there is no need to repeat any of the ocular examinations except 
for corneal photography and corneal slit lamp examination at Weeks 76, 89 or 104. 
Therefore, not all ophthalmic testing will need to be completed in Phase 3 of the study at the 
discretion of the PI. 
Specific test parameters will be provided in the ophthalmology manual for the study. 
Routine ophthalmic tests will include the following: 
o BCVA (ETDRS); 
o Color vision assessment with FM-100 hue test. The Lanthony D15 test will be 
administered immediately prior to the FM-100 test to reduce learning affects.  
o Mars letter contrast sensitivity test; 
o M-chart; 
o Slit lamp examination of anterior and posterior segment 
o Intraocular pressure measurement 
o Microperimetry (Weeks 24, 52 and 64). 

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o SD-OCT (including wide field macula scan);  
o qFAF (set of 3 images to ensure consistency in measurement); 
o Digital photograph of corneal surface (conventional and wide field); and, 
o Digital photograph of retina (conventional and wide field) 
Abnormal results may be further investigated using microperimetry, FM-100 hue test, Mars 
contrast sensitivity letter reading test, M-chart, slit lamp examination, SD-OCT (including 
wide field macula scan) and qFAF depending on the nature of the abnormality.  
The Lions Eye Institute in Australia or the Retinal Institutes in the US will provide clinical 
site training materials, certifications of the readers and will perform the initial evaluation of 
SD-OCT, qFAF and color photos for both eyes. Color photos of the cornea and retina will be 
used as complementary images. The evaluations performed at these sites will be used for 
initial reporting of ophthalmologic AEs and SOSEs. 
The University of Wisconsin School of Medicine and Public Health, Fundus Photograph 
Reading Center will perform a masked (the site’s evaluation will not be provided) evaluation 
of SD-OCT, qFAF and color photos for both eyes. Prior to the start of the clinical trial, they 
will provide training of operators in the form of written instructions for acquiring digital 
images for SD-OCT, qFAF and color images permit uploading digital images into their 
EXCELSIOR™ data management platform as well as certification of the readers and the 
equipment prior to transfer of images to the Fundus Photograph Reading Center for 
evaluation. They will evaluate SD-OCT and qFAF scans for qualitative and quantitative 
assessment per protocol-defined outcomes. Color photos will be used as complementary 
images. On a monthly basis, they will perform data transfer to Fast-Track for inclusion in the 
main study database. In addition, they will maintain HIPAA and 21 Code of Federal 
Regulations (CFR) Part 11 compliant computer services with a technical support help desk 
for users uploading images to the EXCELSIOR™ data management platform. 
After data transfer, results from the clinical sites will be compared with that at the Fundus 
Reading Center by the data management center and the results of the comparison will be 
provided to the site PI for review.  
9.2.7. 
Psychiatric Assessment (M.I.N.I. 7.0.2) 
The administration of the M.I.N.I. 7.0.2 will be performed by designated staff or consulting 
clinical psychologists trained to administer the questionnaire to study participants. The study 
Psychiatrist or Psychologist (nominated in the study delegation log) will be consulted for 
definitive diagnosis in the event that that M.I.N.I. is indicative of a psychiatric disorder. 
The M.I.N.I. was designed as a brief structured interview in accordance with the DSM-5 and 
the International Classification of Diseases (ICD)-10. Validation and reliability studies have 
been done comparing the M.I.N.I. to the longer Structured Clinical Interview for Diagnostics 
(SCID)-P for DSM-III-R and the Composite International Diagnostic Interview (CIDI) (a 
structured interview developed by the World Health Organization [WHO]). The results of 
these studies show that the M.I.N.I. has similar reliability and validity properties, but can be 
administered in a much shorter period of time (mean 18.7 ± 11.6 minutes, median 
15 minutes) than the above referenced instruments (Amorim 1998). 
Any new or worsened psychiatric disease identified at a non-scheduled visit or during the 
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Study Psychiatrist or Psychologist for further evaluation as needed to make a diagnosis and 
capture and record AE severity and causality. As with all AEs, appropriate care and 
evaluation will be made in coordination with the LMM which may include further referral 
and/or hospitalization as required. These AE’s will continue to be followed until they are 
resolved or stabilized. Decisions regarding the participant’s continuation in the study will be 
made by the Study Psychiatrist or Psychologist in consultation with the study PI and LMM. 
9.2.8. 
Leeds Sleep Evaluation Questionnaire (LSEQ) 
The LSEQ is a participant assessment of the difficulty of falling asleep, quality of sleep, 
awakening from sleep, and behavior following wakefulness as these factors can be causative 
or related to psychiatric disorders (Zisapel 2003). This questionnaire was developed as a 
clinical investigation tool to retrospectively measure sleep patterns prior to study 
participation.  
9.2.9. 
Dizziness Handicap Inventory (DHI) 
Dizziness is common symptom that is reported frequently with varying degrees of impact on 
the individual’s quality of life. Dizziness can be caused by many different clinical conditions. 
While the impact of dizziness is predictive, this disorder can be more consistently evaluated 
by using a tool such as the DHI. The DHI is a reliable, comprehensively validated and 
clinically useful tool to measure self-perceived handicap associated with the symptom of 
dizziness from a variety of causes (Treleaven 2005).  
Participants who admit to new or worsening dizziness or vertigo during their routine AE 
monitoring queries will rate the severity of the dizziness using the DHI. The 
self-administered questionnaire takes 5-10 minutes to complete and doesn’t require special 
training to administer. Respondents choose the statement that most describes them. The 
statements are scored from 0 – 4 and scores can range from 0 – 100 (Whitney 2004). The 
questionnaire will be self-administered and scored by the designated study personnel. The 
DHI has been validated and can detect statistically significant change over time in group data 
(Enloe 1997). 
9.2.10. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a 2-page form (Appendix 7) asking questions about suicidal ideation, 
intensity of ideation, and suicidal behavior developed by Posner and collaborators at the New 
York State Psychiatric Institute (Oquendo-2003). This scale is intended for use by trained 
administrators. The questions contained in the C-SSRS are suggested probes. Ultimately, the 
determination of the presence of suicidality depends on clinical judgment. Training is 
required before administering the C-SSRS through a 30-minute interactive slide presentation 
followed by a question-answer session through the Columbia Lighthouse Project. Those 
completing the training are certified to administer the C-SSRS, and will receive a training 
certificate. As the MINI will be used to establish subject initial eligibility with respect to 
suicidality, the “Since Last Visit” version of the C-SSRS interview will be conducted at the 
randomization visit prior to the first dose and then every 4 weeks ± 1 week thereafter through 
Week 64. The interview can be conducted by telephone at all scheduled times or in person at 
the clinic visit.. At Week 1, this scale will be used to assess current suicidal ideation since the 
MINI interview. This questionnaire will be administered by a clinical staff member and 
subject responses will be recorded either on a paper CRF or electronically into an eCRF. If an 
eCRF is used, it will serve as both the source and eCRF. 

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10. 
SAFETY MONITORING 
10.1. 
Responsibilities for Ensuring the Safety of Study Participants 
The national regulatory authority (Australian Therapeutic Goods Administration [TGA]), 
FDA (through virtue of this being an IND study and that US sites are also participating), the 
study sponsor, the institution through which the research is performed and all members of the 
PI’s clinical team share responsibility for ensuring that the participants participating in this 
study are exposed to the least possible risk of AEs that may result from participation in this 
study. These responsibilities are defined in the Australian National Health and Medical 
Research Council (NHMRC) guideline “Safety monitoring and reporting in clinical trials 
involving therapeutic goods” (NHMRC 2016) and are itemized below and contained in the 
Study Safety plan (CNSWIPV001). 
10.2. 
Principal Investigator 
The PI has a personal responsibility to closely monitor study participants and an inherent 
authority to take whatever measures necessary to ensure their safety, including ensuring that 
procedures and expertise are available to cope with medical emergencies during the study. 
The PI has the authority to terminate, suspend or require changes to a clinical study for safety 
concerns and may delay an individual’s IMP administration or pause study drug 
administration in the whole trial if he/she has concerns that the study drug may place a 
participant at significant risk. Investigators should assess all AEs and act on any AEs as 
clinical care dictates. The role of the investigator with regard to safety reporting is to provide 
the sponsor with all relevant information so that an appropriate safety analysis can be 
performed.  
• Capture and assess all AEs that occur at the site as required and in accordance with 
the protocol.  
• Report to the sponsor within 24 hours of becoming aware of the SAE:  
o All SAEs, except those that are identified in the protocol as not needing 
immediate reporting. 
o Any occurrences of congenital anomaly/birth defect arising from any 
pregnancy of a participant (or partner); and 
o All Urgent Safety Measures (USMs) instigated by the site.  
• Report to the sponsor as specified in the protocol:  
o All safety critical events (see definitions in Section 10.11.1) and  
o Any additional requested information relating to reported deaths.  
• Report to the institution within 72 hours of becoming aware of the event:  
o All significant safety issues  
o All Suspected Unexpected Serious Adverse Reactions (SUSARs) arising from 
the local site.  
Only medically qualified investigators can assess an AE. Assessment of AE processes for 
handling consent for follow-up of participants (or pregnant partners of participants) are to be 

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documented in the Study Safety plan. SUSARs are to be reported to the investigator’s 
institution when in the investigator’s judgment, a SUSAR has occurred. The PI should not 
unblind the SUSAR for the purposes of reporting to their institution. 
10.3. 
Study Pharmaceutical Sponsor 
The sponsor also has an institutional responsibility to ensure participant safety and undertakes 
to promptly notify the concerned investigators, HREC/IRB, TGA and FDA of findings that 
could adversely affect the safety of participants included in the study, impact the conduct of 
the study, or alter the HREC/IRB approval/favorable opinion to continue the study. This 
includes the expedited reporting to these parties of all adverse drug reactions (ADRs) that are 
both serious and unexpected (SUSAR).  
Under 21 CFR 312.50, sponsors are responsible for selecting qualified investigators, 
providing them with the information they need to conduct an investigation properly, ensuring 
proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in 
accordance with the general investigational plan and protocols contained in the IND, 
maintaining an effective IND with respect to the investigations, and ensuring that FDA and 
all participating investigators are promptly informed of significant new adverse effects or 
risks with respect to the drug. Additional specific responsibilities of sponsors are described in 
21 CFR 312.  
Under 21 CFR 312 (c)(1) IND safety reports, the sponsor must notify FDA and all 
participating investigators (i.e., all investigators to whom the sponsor is providing drug under 
its INDs or under any investigator's IND) in an IND safety report of potential serious risks, 
from clinical trials or any other source, as soon as possible, but in no case later than 
15 calendar days after the sponsor determines that the information qualifies for reporting. 
Specifically, the sponsor should: 
• Ensure that the trial protocol has clear sections describing:  
o The assessment and management of risk (if not in an alternative document). 
The trial protocol and/or the safety monitoring plan, should describe the 
composition, roles and responsibilities of oversight committees and plans for 
ongoing safety monitoring;  
o Safety reporting definitions, procedures, responsibilities and reporting 
timelines; and  
o Any SAEs that do not require immediate reporting.  
• Keep detailed records of all reported AEs and maintain up-to-date tabulations and/or 
line listings. The sponsor may be required to provide tabulations/line listings to the 
TGA and FDA on request.  
• When communicating safety information to investigators and/or HREC/IRBs, clarify 
the impact of each report on patient safety, trial conduct or trial documentation  
• Assess and categorise the safety reports received from investigators, and report all 
SUSARs occurring in participants to the TGA and FDA under IND 129,656 (in 
accordance with (IAW) 21 CFR 312.32): 

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o For fatal or life threatening SUSARs, immediately, but no later than 
7 calendar days after being made aware of the case, with any follow-up 
information within a further 8 calendar days.  
o For all other SUSARs, no later than 15 calendar days after being made aware 
of the case.  
When determining whether a SUSAR has occurred, where the sponsor’s causality assessment 
conflicts with the assessment made by the site investigator, the site investigator’s assessment 
cannot be downgraded by the sponsor (i.e., altered from ‘related’ to ‘not related’). In this 
case, if an investigator’s judgment triggers the reporting of a SUSAR, the opinion of both the 
investigator and the sponsor should be provided with any SUSAR report sent to the TGA and 
the FDA. 
When reporting a SUSAR to the TGA and FDA, the blind should generally be broken by the 
sponsor (See Section D of ICH guideline E2A Managing Blinded Therapy Cases). In order to 
avoid introducing biases, the blind should be maintained for all other persons involved in the 
conduct or management of the trial, including those responsible for data analysis and/or 
interpretation of results.  
• Review the IB at least annually and update it when new and relevant information 
becomes available; 
• Provide the HREC/IRB and investigators with any update/addenda of the IB; 
• Provide the HREC/IRB with an annual safety report (i.e., drug safety update 
report [DSUR)]) including a clear summary of the evolving safety profile of the trial. 
This report should allow the HREC/IRBs to assess whether ongoing safety monitoring 
is being conducted appropriately and that the trial’s safety monitoring plans are being 
followed and where necessary, are being adapted to take into account new findings as 
the trial progresses.  
• Ensure that all sponsor responsibilities for safety monitoring and reporting (e.g. 
reporting SUSARs and significant safety issues to the TGA and FDA) are 
appropriately allocated or delegated. 
• Notify the TGA, FDA, HREC and investigators of all significant safety issues that 
adversely affect the safety of participants or materially impact on the continued 
ethical acceptability or conduct of the trial. Significant safety issues that meet the 
definition of a USM should be notified within 72 hours, and all other significant 
safety issues (SSI) should be notified within 15 calendar days of the sponsor 
instigating or being made aware of the issue. Examples include:  
o An SAE that could be associated with the trial procedures and that requires 
modification of the conduct of the trial;  
o A hazard to the patient population;  
o A major safety finding from a newly completed animal study (such as 
carcinogenicity); 
o A temporary halt/termination of a trial for safety reasons;  
o Recommendations of the DSMB where relevant for the safety of participants, 
such as an increase in frequency or severity of an expected ADR, single case 

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events (e.g., toxic epidermal necrolysis, agranulocytosis, hepatic failure) that 
lead to an USM.  
Often, SSIs do not fall within the definition of a SUSAR and thus are not subject to the 
reporting requirements for SUSARs. Significant safety issues usually require other action, 
such as the reporting of an USM, an amendment, a temporary halt or an early termination of a 
trial. In addition, SSIs often result in safety-related changes to trial documentation. These 
amendments should be submitted to the HREC/IRB without undue delay. 
Urgent safety measures are one type of SSI where sponsors or trial investigators act 
immediately to protect participants from an immediate hazard to their health and safety. 
Consequently, USMs are often instigated before the TGA, FDA and HREC/IRB are notified. 
In these cases, it is strongly recommended that the sponsor contact the TGA within 24 
hours of the measure being taken.  
If this initial contact is by telephone, it should be followed-up with a written notification 
provided by facsimile or e-mail within 72 hours. Table 4 illustrates the types of action that 
result from SSIs and the associated timelines for written notification. 
Table 4: 
Sponsor Reporting of SSIs 
Action 
What is communicated 
Recipients 
Timelines and further review 
USM 
Reason  
Measures taken 
Further actions planned 
TGA, FDA 
investigators, 
HREC/IRB 
Without undue delay and NLT 
72 hours of the USM being 
taken 
Notification of an 
amendment 
Details of the SSI 
Further actions planned  
 
TGA, FDA 
investigators, 
HREC/IRB 
Without undue delay and NLT 
15 calendar days 
Sponsors should submit to the 
HREC/IRB an amendment 
relating to any revised trial 
documentation without undue 
delay 
Temporary halt of 
a trial for safety 
reasons 
Reasons 
Scope of halt (i.e., 
suspension of 
recruitment, or 
cessation/interruption of 
treatment) 
 
TGA, FDA 
investigators, 
HREC/IRB 
Without undue delay and NLT 
15 calendar days of Sponsor’s 
decision to halt the trial 
Where necessary to seek 
HREC/IRB review of related 
actions (e.g., informing 
participants, or arranging 
continuing care/follow-up), a 
letter describing these actions 
should be submitted to the 
HREC/IRB within 15 calendar 
days of the temporary halt 
NLT=no later than; SSI=significant safety issue; USM=urgent safety measure. 
10.4. 
Responsibilities of the Local Australian Sponsor 
The local Australian sponsor will fulfill obligations documented in the master services 
agreement including: 
• Maintain appropriate clinical trial insurance; 

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• Interact with the TGA including but not limited to signing regulatory submissions to 
be filed with the TGA on behalf of the sponsor; 
• Communicate in a timely manner all written communications with the TGA to the 
sponsor; 
• Provide services that compliance with the Master Services Agreement, Protocol, 
applicable requirements and guidelines of the TGA, and patient privacy laws and 
regulations (collectively, “Laws”), CPMP/ICH/135/95, World Medical Association 
Declaration of Helsinki (1996 version); National Statement on Ethical Conduct in 
Human Research (NHMRC 2007a, updated May 2015); CNS SOPs and any 
authorization for the trial issued by the TGA and the terms and conditions of the 
favorable opinion of the HREC. 
10.5. 
Local Medical Monitors 
LMMs, in consultation with the DSMB, will provide medical review during the execution of 
the study. This oversight will include the reviewing of safety information and the provision of 
applicable recommendations to both the investigator and the sponsor. This review is intended 
to facilitate the early detection of safety signals and to maximize the chances for the 
continued appropriateness of the study and the protection of the study participants. 
LMMs will be responsible for the following safety monitoring: 
• Reviewing the eligibility of potential participants in consultation with the 
investigators; 
• Evaluation of study safety data on an ongoing basis to assess the relevance of findings 
to study stopping criteria; 
• Evaluation of AEs, SAEs and corresponding safety reports (including the assessment 
of severity, causality and expectedness of events); and 
• Providing reports of clinical and safety data to the DSMB. 
Under HRPO guidelines the LMM (Research Monitor) may also: 
• Observe recruitment and enrollment procedures and the consent process for 
individuals 
• Oversee study interventions and interactions;  
• Review monitoring plans and unanticipated problems involving risk to participants or 
others (Unanticipated Problems Involving Risks to Subjects or Others [UPIRTSO]) 
reports; and 
• Oversee data matching, data collection and analysis. 
• At a minimum, the LMM may discuss the research protocol with the investigators, 
interview human participants and consult with others outside of the study about the 
research. 
• The LMM shall have authority to stop a research protocol in progress, remove 
individual human participants from a research protocol and take whatever steps are 
necessary to protect the safety and well-being of human participants until the 
HREC/IRB can assess the research monitor’s report. 

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• The LMM shall have the responsibility to promptly report their observations and 
findings to the HREC/IRB, other designated official and the HRPO. 
10.6. 
Responsibilities of the Institution 
• Assess whether any safety reports received impact on medico-legal risk, the 
responsible conduct of research, adherence to contractual obligations or the trial’s 
continued site authorisation and, where applicable, facilitate the implementation of 
corrective and preventative action.  
• Develop clear guidance for investigators detailing the requirements for safety 
reporting and monitoring in clinical trials.  
10.7. 
Responsibilities of the HREC/IRB 
The sponsor, through their independent safety monitoring arrangements, has the primary 
responsibility for monitoring the ongoing safety of the IMP. The HREC/IRB should be 
satisfied that the sponsor’s arrangements are sufficiently independent and commensurate with 
the risk, size and complexity of the trial. The approving HREC/IRB should:  
• Assess the safety of proposed trials, including whether the evaluation of the 
anticipated benefits and risks is satisfactory and ensure that the sponsor has 
proportionate systems in place to mitigate and manage any identified risks. 
• Satisfy itself that the sponsor’s ongoing safety monitoring arrangements are adequate, 
including the justification for appointing/not appointing a DSMB and any ‘stopping 
rules’ or criteria for withdrawing individual participants from the trial.  
10.8. 
Responsibilities of the TGA and FDA 
The TGA or FDA may: 
• Conduct an audit of a clinical trial where necessary on safety grounds; and 
• Stop a trial where that action is in the public’s interest. 
10.9. 
Data and Safety Monitoring Board 
An independent, suitably qualified DSMB will be convened and will meet quarterly during 
the study to review safety data during the conduct of the clinical investigation. The DSMB 
will include both an independent ophthalmologist (retinal specialist) and psychiatrist.  
The DSMB will meet prior to the start of the study, quarterly during enrollment and follow-
up and at trial end to review safety data. The Board will be responsible for recommendations 
related to the safety of participants and the continuation of the study. The Board will review 
SAEs for the duration of the trial and all pregnancies and evaluate any safety issues with 
respect to trial conduct. A separate DSMB charter will be drafted for the study. The Board 
will be blinded to participants’ actual randomized group assignments but may request at any 
time that the blind be broken by the Data Management Site, if concerns arise from the 
blinded data. Ad hoc meetings will be convened if SAEs occur that are considered at least 
possibly related to the IMP. 

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10.10. 
Safety Surveillance During the Study 
Participants will be monitored and safety data collected by way of clinical interviews, 
observations and examinations and laboratory evaluations. Time points and the specific data 
collected for each of these evaluations are described in Section 8 and Section 9. 
Any signs and symptoms of ADRs to IMP will be treated symptomatically. 
10.11. 
Adverse Events 
The collection, evaluation and reporting of AEs/ADRs arising from this clinical study will be 
performed in accordance with: 
• Detailed guidance on the collection, verification and presentation of AE/ADR reports 
arising from clinical trials on medicinal products for human use (‘CT-3’) (2011/C 
172/01); 
• ICH guideline E2A: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting; and 
• ICH guideline E2F: Note for guidance on DSUR. 
The definitions of AEs, ADRs, SAEs, and SUSARs are given below. It is of the utmost 
importance that all staff involved in the conduct of clinical research is familiar with the 
content of this section. 
10.11.1. 
Definitions 
An adverse event (AE) - any untoward medical occurrence in a patient or clinical trial 
participant administered an IMP and that does not necessarily have a causal relationship with 
the treatment. 
An adverse drug reaction (ADR) – any untoward and unintended response to an IMP 
related to any dose administered. Any AE judged by either the reporting investigator or the 
sponsor as having a reasonable possibility of a causal relationship to an IMP would qualify as 
ADRs. The expression “reasonable causal relationship” means, there is evidence or argument 
to suggest a causal relationship. 
The following are examples of types of evidence that would suggest a causal relationship 
between the IMP and the AE: 
• A single occurrence of an AE that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); 
• One or more occurrences of an AE that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture). 
• An aggregate analysis of specific AEs observed in clinical trials (such as known 
consequences of the underlying disease or condition under investigation or other AEs 
that commonly occur in the study population independent of drug therapy) that 
indicates those events occur more frequently in the drug treatment group than in the a 
concurrent or historical control group. 
An AE/ADR may be: 
• A new symptom, sign or medical condition; 

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• A new diagnosis; 
• An intercurrent illness or accident; 
• An exacerbation of a pre-existing medical condition/disease; 
• The recurrence of a disease; 
• An increase in frequency or intensity of a pre-existing episodic disease or symptom; 
• An abnormal assessment (e.g., change on physical examination) if it represents a 
clinically significant finding that was not present at study start or worsened during the 
course of the study; or 
• An abnormal laboratory assessment or change in a laboratory parameter. 
Borderline abnormal laboratory findings and other objective assessments should NOT be 
routinely captured and reported as AEs, as they will be collected and analyzed separately. 
However, abnormal laboratory findings or other objective measurements that meet the 
following criteria should be captured and reported in the AE section of the eCRF: 
• The result meets the criteria for reporting as an SAE; 
• The test result is associated with accompanying symptoms; and/or; 
• It requires additional diagnostic testing or medical/surgical intervention; and/or; 
• It leads to a change in trial dosing outside of protocol-stipulated dose adjustments, or 
discontinuation from the trial, significant additional concomitant drug treatment, or 
other therapy; and/or 
• It is considered by the investigator or sponsor to be clinically significant or represent a 
clinically significant change from baseline. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE/ADR. Any abnormal test result that is determined to be an error does not 
require reporting as an AE. 
If a clinical diagnosis is associated with an abnormal laboratory finding, the relevant AE 
should be recorded as the diagnosis rather than the incidental laboratory finding (e.g. 
“hepatitis” should be recorded rather than “elevated transaminases”). 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions, 
which may, or may not, be AEs/ADRs. Planned surgical measures permitted by the clinical 
trial protocol and the condition(s) leading to these measures are not AEs if the condition was 
present before inclusion in the trial. In the latter case the condition should be reported as 
medical history. 
An ADR is regarded as an unexpected adverse reaction if its nature or severity is not 
consistent with the applicable reference safety information (Investigator’s Brochure). Events 
that add significant information on the specificity, severity or frequency of previously 
described reactions, are also regarded as unexpected.  
The expectedness of an ADR is determined by the sponsor in the reference safety information 
and will be evaluated in the context of previously observed events, rather than on the basis of 
what might be anticipated from the pharmacological properties of a medicinal product. 
For this protocol, the reference document is the 60P IB.  

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A Serious Adverse Event/Reaction (SAE/SAR) is defined as an event or reaction which: 
• Results in death; 
• Is life-threatening (the term "life-threatening" in the definition of "serious" refers to 
an event in which the participant was at immediate risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it 
was more severe); 
• Requires hospitalization or prolongs existing hospitalization, unless this is for: 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the trial and has not worsened since the start of the IMP; 
o Treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of an SAE given above and not resulting in hospital admission; 
o Cosmetic surgery or for social reasons or respite care in the absence of any 
deterioration in the participant’s general condition; 
• Results in persistent or significant disability/incapacity; 
• Is a congenital abnormality/birth defect; 
• Is considered medically important (medical and scientific judgment should be 
exercised in deciding whether other AE/ADRs are to be considered serious, such as 
important medical events that may not be immediately life threatening but may 
jeopardize the participant or may require intervention to prevent one of the other 
outcomes listed in the definition above. Examples of such events are: intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias; convulsions that do not result in hospitalization; development of drug 
dependency or drug abuse); and 
• For the purpose of this protocol an AE will be considered as serious should the AE 
constitute a possible Hy’s Law case (defined as a participant with any value of ALT 
or AST greater than or equal to 3x upper limit of normal (ULN) together with an 
increase in bilirubin to a value greater than 2x ULN (>35% direct) and NOT 
associated cholestasis (ALP value less than 2x ULN).  
A non-serious AE/ADR is any symptom or sign, which does not fulfill any of the above-
mentioned seriousness criteria. 
A Safety Critical Adverse Event is any adverse event and/or laboratory abnormality 
identified in the protocol as critical to safety evaluations that should be reported to the 
sponsor according to the reporting requirements specified in the protocol. 
A Significant Safety Issue (SSI) is any safety issue that could adversely affect the safety of 
participants or materially impact on the continued ethical acceptability or conduct of the trial. 
A Suspected Unexpected Serious Adverse Reactions (SUSAR) is any SAE where a causal 
relationship with the IMP is at least a reasonable possibility, but the event is not listed in the 
60P IB. 
An Urgent Safety Measure (USM) is any measure required to be taken in order to eliminate 
an immediate hazard to a participant’s health or safety. This type of significant safety issue 
can be instigated by either the investigator or sponsor and can be implemented before seeking 
approval from HREC/IRBs or Institutions. 

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An Unanticipated Problem Involving Risk to Subjects or Others (UPIRTSO) is defined 
as any problem or event which, in the opinion of the local investigator, was unanticipated, 
places participants or others at a greater risk of harm than was previously know or 
recognized, and was possibly related to the research procedure.  
An Adverse Events of Special Interest (AESIs) for this study are defined as: 
1. Hepatic: 
a. Possible Hy’s law case: defined as a participant with any value of ALT or AST 
above 3x ULN together with an increase in bilirubin to a value higher than 2x 
ULN and not associated with cholestasis (ALP value less than 2x ULN) (to be 
reported as an SAE as detailed above); 
b. Any ALT or AST above 3x ULN; 
c. Any elevation in bilirubin 2x ULN; 
d. Any AST or ALT above 2x ULN and (total bilirubin [TBL] >1.5x ULN); and 
e. Any AST or ALT above 2x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia 
(eosinophil percent or count above the ULN). 
2. Ophthalmic: 
a. Functional change on microperimetry test showing an abnormality in the 
paracentral region forming a ring or partial ring.  
b. New abnormality by FM-100 hue test.  
c. Significant deterioration in the Mars letter contrast sensitivity test with a change 
exceeding 0.12 logCS. 
d. Unexplained marked reduction of visual acuity ≥15 letters that persists for 
≥2 visits separated by at least one week. 
e. A >15 letter change [≥ 3 lines] change in ETDRS BCVA at 4 meters. 
3. Hematologic 
a. Methemoglobin > 10%. 
4. Other: 
a. Any other AE that, in the opinion of the investigator, is related to the IMP and 
may jeopardize the participant’s safety.  
Although not considered an AE, pregnancy in female participants will be reported as an 
event of special interest as per Section 10.11.6. 
10.11.2. 
Assessment and Recording of Adverse Events 
It is the investigator’s responsibility to document and report all AEs occurring in the clinical 
trial whether spontaneously reported by the participant, observed by the investigator (either 
directly or by laboratory or other assessments), or elicited by general questioning.  
The period of observation for collection of AEs extends from the time of dosing (Day 1, 
Week 1 [Visit 2]) through the Week 64 follow-up visit. Those participants meeting the 
criteria for additional safety follow-up (Section 8.5  will be followed every 3 months 
thereafter to a maximum of 12 months until the AE resolves or stabilizes.  
SAEs will be reported from the time of screening until 30 days following the EOS visit 
(Week 64) (if spontaneously reported by the participant). Serious adverse events experienced 

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after this 30-day period will only be reported if the investigator suspects a causal relationship 
with the study drug.  
The following information should be recorded for all AEs: 
• The name of the AE; 
• The dates of onset and resolution of the event; 
• The characteristics of the event (seriousness, intensity); 
• The action taken in response to the event (including treatment required); 
• The outcome of the event; and 
• The relationship of the event to the study drug (causality assessment) and/or to study 
participation. 
Standard toxicity grading 
The medical assessment of AE severity of the study will be recorded in accordance with the 
Common Terminology Criteria for Adverse Events v 4.03 that went into effect June 14, 2010 
(CTCAE V4.03). Note however, if the local site’s normal blood pressure ranges overlap with 
that considered to be a grade 1 toxicity according to the CTCAE, that the upper limit of the 
local sites scale will be considered the cutoff for reporting an AE. 
• Grade 1: Mild - asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; 
• Grade 2: Moderate - minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL); 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL; 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
Severity grading (AEs not included within CTCAE V4.03) 
The medical assessment of AE intensity will be provided in the participant’s eCRF. The 
maximum intensity of the event will be graded as per the following definitions: 
• Mild – Does not interfere with participant’s usual function;  
• Moderate – Interferes to some extent with the participant’s usual function; and 
• Severe – Interferes significantly with participant's usual function. 
Relationship to IMP 
The investigator must assess the relationship of each event to the IMP and decide whether, in 
his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the IMP. If there is no valid reason for suggesting a relationship, then the AE 
should be classified as “not related”. Alternatively, if there is any valid reason for suspecting 
a possible cause-and-effect relationship between the IMP and the occurrence of the AE (even 
if undetermined or untested), then the AE should be considered “related”. This should be 
documented in the participant’s source documentation and eCRF. 
The following may guide this assessment: 

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• Not related: No relationship to investigational product. Applies to those events for 
which evidence exists that there is an alternate etiology.  
• Unlikely related: Likely unrelated to the investigational product. Likely to be related 
to factors other than investigational product, but cannot be ruled out with certainty.  
• Possibly related: An association between the event and the administration of 
investigational product cannot be ruled out. There is a reasonable temporal 
association, but there may also be an alternative etiology such as the participant’s 
clinical status or underlying factors including other therapy.  
• Related: An association exists between the receipt of investigational product and the 
event. An association to other factors has been ruled out. 
Where possible, a distinction should be made between events considered related to the IMP 
and those related to protocol-mandated procedures. 
In addition to the assessment of IMP relationship, the investigator should comment on the AE 
record in the eCRF whether an AE is considered related to the participation of the participant 
(study procedures etc.). 
Outcome 
The investigator will follow up all AEs wherever possible until they have resolved or 
stabilized.  
The date of confirmation of the outcome will be recorded and the course of the AE will be 
assessed in accordance with the following classification: 
• Recovered: The AE has resolved and the participant returned to their condition prior 
to onset; 
• Recovered with sequelae: The AE resolved, but the participant has sequelae; 
• Recovering: The AE has almost resolved and the participant is returning to his 
condition prior to onset; 
• Death: The participant died; causal relationship is not object; 
• Ongoing: The AE had not resolved and the participant’s condition remained 
unchanged at the last time of observation. In case of death from a different cause, 
events ongoing at the time of death will be classified as such; and 
• Unknown. 
10.11.3. 
Action taken and follow-up of events 
All AEs must be documented and followed up by the investigator until: 
• The event is resolved; or 
• No further medically relevant information in relation to the event can be expected; 
and  
• The investigator considers it justifiable to terminate the follow-up.  
Events that are unresolved at the time of the participant’s last follow-up visit should continue 
to be followed up by the investigator for as long as medically indicated (up to 12 months). 

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The sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
All AEs should be treated appropriately. The investigator will decide upon the appropriate 
action to be taken in response to an AE, which may include one or more of the following: 
• No action taken (i.e. further observation only); 
• Dosing with the IMP is withheld and the participant withdrawn from the study; 
• Administration of a concomitant medication; 
• Hospitalization or prolongation of current hospitalization (event to be reported as an 
SAE); and 
• Other. 
10.11.4. 
Reporting of SAEs 
The investigator will take immediate appropriate action in response to SAEs to ensure 
participant safety and in an attempt to identify the causes of the event. The investigator will 
notify the LMM, the CNS Project Manager (Australian Site), Fast-Track’s Project Manager 
(US sites) and the sponsor’s Chief Medical Officer of the occurrence of any SAE within 
1 business day of becoming aware of the event. The notification should be in writing by 
email or fax and documented on a standard SAE reporting form. Reporting to the local 
HREC/IRB should follow their policies. In addition to this, fatal or life-threatening SAEs that 
the investigator suspects are related to the IMP should be reported by telephone to the 
LMM as soon as possible upon the investigator becoming aware of the event. 
Local Australian Medical Monitor 
Dr John Gillies  
Email: john.gillies@clinical.net.au 
Tel: +64 21 664 484 
CNS Project Manager:  
Leanne West 
Email: safety@clinical.net.au 
Phone: +61 7 3719 6000 
Fax: +61 7 3719 6011 
Australian Bellberry-HREC Contact:  
Operations Manager 
Email: bellberry@bellberry.com.au 
Phone: +61 8 8361 3222 
 
Local US Medical Monitor: 
Timothy Baxter, MD 
Baxter Healthcare Consulting 
Richmond, VA, USA 
Tel: +1 (804) 291-7037 
Email: timbaxter@bhccllc.com 
 
 

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Fast-Track Drugs & Biologics, LLC Project Manager 
Katrina Riggs, CCRA 
Email: kriggs@fasttrackresearch.com  
Phone: +1 301-762-2609 
 
IntegReview IRB: 
Email: integreview@integreview.com 
Telephone: 512-326-3001 
 
Sponsor’s Chief Medical Officer: 
Bryan Smith, MD, FAAFP 
Email: bryansmith@60degreespharma.com 
Phone: +1 (301) 807-8548 
The initial report will be followed up by a full written report within 3 business days or 5 
calendar days, whichever comes first unless no further information is available when the 
follow-up report will be provided as soon as possible when new information becomes 
available. Further follow-up reports will be provided as and when new information becomes 
available. Photocopies of results, consultant report(s), a summary of the outcome of the 
reaction and the investigator's opinion of IMP relationship to the SAE will accompany the 
SAE form if and when available.  
In addition to the assessments provided by the investigator, the sponsor will also perform an 
evaluation of the seriousness, causality and expectedness of all SAEs. All SAEs judged by 
either the investigator or the sponsor as having a reasonable suspected causal relationship to 
an IMP will qualify as serious ADR. If the sponsor disagrees with the investigator’s causality 
assessment, both the opinion of the investigator and the sponsor will be documented in the 
safety report. 
The LMM will notify the sponsor and all members of the DSMB of any reported SAE within 
24 hours of becoming aware of the event and will continue to provide all follow-up 
information in a timely manner. 
All SAEs will be included in the main study database. 
The TGA, FDA and HREC/IRB will be notified of all SUSARs within 7 days (for fatal and 
life-threatening SUSARs) or 15 days (all other SUSARs) of receipt of the event report.  
Submissions to TGA should be made using a Council for International Organizations of 
Medical Sciences (CIOMS) form to adr.reports@tga.gov.au or via the TGA Business 
Services (TBS) ADR submission portal. E2B reports should be emailed to 
adr.reports@tga.gov.au. For further information on SUSAR reporting to TGA, email: 
adr.reports@tga.gov.au or call +61 1800 010 624. SUSAR submissions to the FDA will be 
via MedWatch reporting. 
CNS will work with Fast-Track to submit SUSAR reports to both TGA and FDA (as per the 
transfer of obligations form submitted under IND 129,656). 
The investigator will be responsible for notification of the HREC/IRB.  
Annual safety reporting to the national Competent Authority and the Ethics Committee will 
be in agreement with ICH guideline E2F “Note for guidance on development safety update 
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involving therapeutic goods (NHMRC 2016). The DSUR compilation responsibilities will be 
described in the safety monitoring manual. 
In addition, any other safety issue, which may alter the current benefit–risk assessment of the 
IMP, will be reported by the sponsor (or delegate) on an expedited basis to Health 
Authorities, HREC/IRB and the investigator. 
Only UPIRTSOs will be reported to HRPO as per the safety manual. All UPIRTSOs will be 
reported to DVC and HRPO within a 7-day SUSAR reporting window. 
USAMRMC Office of Research Protects Contact: 
US Army Medical Research and Materiel Command  
ATTN: MCMR-RPI 
504 Scott Street 
Fort Detrick, Maryland 21702-5012 
Fax: +1 (301) 619 4165 
Tel: +1 (301) 619 6240 
Email: usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil  
10.11.5. 
Reporting of AESIs 
All AESIs (defined in Section 10.11.1) including those that do not meet the definition of an 
SAE, must be reported to the LMM and the CNS/Fast-Track Project Manager (with the 
sponsor Chief Scientific Officer on copy) within 24 hours of the investigator becoming aware 
of the occurrence of the AESI. 
10.11.6. 
Reporting of Pregnancy 
Pregnancy in a female participant during the study should be reported and followed as 
described below. Pregnancy does not constitute an AE as such and the pregnancy outcome 
will not be recorded in the eCRF unless it is considered to be an AE. 
Pregnancies will lead to discontinuation of IMP administration and the participant will be 
followed up until Week 76. 
The investigator must notify the LMM, the CNS/Fast/Track Project Manager and the 
Bellberry HREC/IRB in an expedited manner of any pregnancy occurring from the date of 
informed consent signature until 12 weeks after administration of tafenoquine. The HRPO 
will not be informed of pregnancy events. Part I of the Pregnancy Report Form 
(CNSSOPPV002 form or US Equivalent form) should be used for this notification, which 
should follow the same procedures and timelines, described for expedited AE reporting in 
Section 10.11. In all cases, the pregnancy must be followed until birth of the child, and the 
outcome of the pregnancy and birth reported as above by completing Part II of the Pregnancy 
Report Form (CNSSOPPV002 form or US Equivalent form) used for the initial notification. 
The timelines of the outcome reporting vary as follows: 
• Normal outcomes should be reported within 45 days of birth/delivery; and 
• Abnormal outcomes should be reported in an expedited manner as described in 
Section 10.11. An additional SAE Report form must be completed if the participant or 
participants’ partner sustains a serious event, while a patient clinical/fetus report 
(PCFR) must be completed should the child/fetus sustain an event. 

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11. 
DATA MANAGEMENT 
11.1. 
Data Collection 
The investigator will maintain source documents for each participant in the study. 
Information entered into eCRF will be traceable to these source documents in the 
participant’s file. The investigator must certify that the data entered into the eCRF are 
complete and accurate. 
After database lock, the investigator will retain copies of the participant data for archiving at 
the study site. 
11.2. 
Site Monitoring 
During the study, appointed study monitors will visit the site regularly to check the 
completeness of participant records, the accuracy of entries in the eCRF, adherence to the 
protocol and to ICH GCP, the progress of enrolment, and to ensure that the IMPs are being 
stored, dispensed, and accounted for according to the prescribed conditions. Key study 
personnel must be available to assist the study monitor during these visits. 
The investigator must allow the study monitor access to all relevant source documents to 
confirm their consistency with the eCRF entries. Verification of 100% of source data will be 
performed. No information in source documents regarding the identity of the participants will 
be disclosed. 
11.3. 
Database Management and Quality Control 
Data management, including the development and management of a secure database, will be 
performed in accordance with the Clinical Data Interchange Standards Consortium (CDISC) 
Study Data Tabulation Module (SDTM) requirements. The Data Management Site will 
review the data entered into the eCRF by investigational staff for completeness and accuracy. 
A formal querying process will be followed whereby the Data Management Site will work 
with CNS’s clinical monitors to post queries to the EDMS for site personnel clarification of 
any apparent erroneous entries or inconsistencies and will request additional information 
from the site as required. 
Primary source document for this study will be the participant’s research record. The source 
documents will be retained at the site. 
For this study, an EDMS will be used for the collection of the study data in an electronic 
format. The EDMS will be designed based on the protocol requirements, the approved eCRF 
layouts and specifications, and in accordance with 21 CFR Part 11. The eCRF layouts and 
specifications define and identify the applicable source data that will be collected and 
captured into the EDMS. The applicable source data will be electronically transcribed by the 
site designee onto the eCRF (data entry screens) in the EDMS. The investigator is ultimately 
responsible for the accuracy of the data entered into eCRF. Data monitoring and management 
will be performed in the EDMS by the study clinical monitor and the designated Data 
Management Site. 
In addition to eCRF data, electronic transfer of data from the Blinded Reading Site, 
responsible for SD-OCT, qFAF, and color photos evaluations of both eyes evaluations will be 
performed periodically during the study. 

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A detailed data management plan will be written by the Data Management Site and approved 
by the sponsor’s representative prior to study start. All updates to the data management plan 
must be approved before study closeout and database lock. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology (version 20.0 or later). 
Concomitant medication will be coded according to the WHO-Drug Dictionary Enhanced 
(DDE). 
After all data have been captured and reviewed, all queries have been resolved with the site 
and any protocol non-compliances that were identified during the data management processes 
have been confirmed by the site, the database will be declared to be complete and accurate, it 
will be locked and made available for data analysis. All blinded personnel may be unblinded 
at this time. Any changes to the database after that time may only be made by the data 
manager, in consultation with the sponsor and in accordance with documented database 
unlock and relock procedures. 

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12. 
STATISTICAL METHODS 
The following sections describe the statistical analysis as it is foreseen when the study is 
being planned. A detailed SAP will be finalized and approved and will provide details of all 
analyses to be performed as well as the format of listings and tables to be provided for 
completion of the FCSR. Any deviations from the SAP will be described and justified in the 
FCSR. 
12.1. 
Sample Size Calculation 
The sample size estimate is based on the assumed SOSE (serious ophthalmic safety event) 
rate, as assessed by using SD-OCT and qFAF. Based on the binomial distribution, if the true 
SOSE rate is 1% in the tafenoquine group, there is a 95% probability to observe at least one 
SOSE with 300 participants.  
This study could also be viewed as a non-inferiority safety study. The incidence of retinal 
abnormalities was conservatively assumed to be 1% (i.e., 99% without SOSE) for both 
placebo and tafenoquine group. For the primary endpoint, the specific ophthalmic 
abnormalities of interest that are not present at baseline are defined in Table 5. For secondary 
ophthalmic endpoints, the abnormality may be a new change in ophthalmic parameter when 
not present at baseline that arises concurrent to IMP therapy or a worsening of a pre-existing 
abnormality present at baseline concurrent to IMP therapy.  
A non-inferiority margin of 2.5% (treatment-placebo, in terms of SOSE rates) was considered 
to be clinically relevant, and therefore used to compare the non-inferiority between 
tafenoquine and placebo. The 2.5% non-inferiority margin is estimated from literature. On an 
Australian population scale, the prevalence of maculopathy is 1.3% in age cohorts 49-54 
years with increasing prevalence in cohorts aged 55-64 (2.6%), 65-74 (8.5%), 75-84 (15.5%), 
and 85+ (28.0%) years (Mitchell 1995). The 2.5% NI margin sets a lenient threshold to 
determine if tafenoquine causes retinal deficits beyond what is expected even in a high-risk 
group at the upper age range of 55 years for the study population. That is, if the SOSE rate 
for tafenoquine group is not more than 2.5% higher than the placebo, the safety for 
tafenoquine will be regarded as no worse than placebo. For a two-sided significance level of 
5% (α=0.025 one-sided) with 600 randomized subjects, the power is 86% (β=0.14) to test the 
NI margin.  
Analysis Sets 
Safety population: All participants who received study treatment at least once will be 
included in the safety population. This is the primary population for safety and tolerability 
analysis. 
Intention-to-Treat (ITT) population: The ITT population will consist of all participants as 
they are randomized to the study. Primary and secondary ophthalmic endpoints will be 
analyzed by ITT population. In this non-inferiority setting, analysis based on ITT population 
provides supportive evidence to analyses based on Per Protocol population. 
Per Protocol (PP) population: All participants who received at least 25% of the total planned 
dose for IMP, had at least one valid baseline and post baseline evaluations by SD-OCT and 
qFAF, and had no major protocol deviations will be included in the PP population. This is the 
primary population for the primary safety endpoint analysis and other secondary ophthalmic 
endpoints.  

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Though this is a safety study, all subjects will be analyzed as randomized in all the above 
study populations.  
12.2. 
Analysis and Presentation of Data 
12.2.1. 
General 
Detailed aspects of the analysis will be presented in the SAP which will be finalized prior to 
unblinding. 
In general, for safety analyses, descriptive statistics will be tabulated by treatment group for 
all participants. Unless otherwise stated, all safety analyses will use the Safety Analysis 
population. The analysis of AEs will consider only treatment emergent AEs (TEAEs), events 
occurring for the first time, or worsening, during or after the first administration of IMP. The 
analysis will focus on participant incidence, although for TEAEs of special interest, the 
number of events will also be provided (i.e., ophthalmic assessments). Tables summarizing 
TEAEs will be displayed by preferred term and SOC. Analysis of SAEs and the 
categorization of AEs by severity and relationship to IMP will also be included. AEs leading 
to study withdrawal or deaths on-study will also be analyzed in tables and/or listings.  
Treatment-emergent changes in vital signs and laboratory parameters will be presented using 
tabulations by group. Descriptive statistics for each parameter and/or the change from 
baseline at each time point will be provided. Shift tables for selected laboratory endpoints 
will be presented (ALT, AST, total bilrubin, hemoglobin and methemoglobin) as defined in 
the SAP. For endpoints measured on a categorical scale the number of participants and 
proportions will be provided. 
Missing data will not be imputed in general, unless otherwise specified. This is a safety study, 
thus multiplicity adjustment related to the primary and secondary safety endpoints analyses 
will not be considered.  
12.2.2. 
Subject Demographics and Baseline Characteristics 
The participant disposition and demographic data (including age, weight, height and 
race/ethnicity) will be tabulated by group and overall for both treatment groups. Study 
completion, study withdrawals, exclusions and violations will be listed and the reasons for 
withdrawal, exclusions and violations will be listed. 
Data for background and demographic variables will be listed by treatment group and 
participant. Descriptive statistics will be provided by treatment group. 
Medical, surgical and social history, current medical conditions results of laboratory 
screening tests, drug tests and any other relevant baseline information (including serology 
results, alcohol breathalyzer test, urine drug screen, and G6PD testing and pregnancy test 
results) will be listed by treatment group and participant.  
Previous and concomitant medication taken at any stage from 4 weeks prior to dosing and 
during the study period will be listed per treatment group. 
12.2.3. 
Safety Data 
All treatment emergent AE data will be summarized separately by treatment group and by 
MedDRA SOC, MedDRA preferred term (PT) and severity and relationship of each AE 
observed. 

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Vital signs and routine safety laboratory data of potential clinical concern (outside local 
laboratory normal limits) will be summarized descriptively by treatment and time point. Both 
absolute values and change from baseline will be presented.  
Shift tables (from the local laboratory reference range) will be generated for each treatment 
group to show out of range changes in laboratory parameters during the Treatment Phase.  
Vital signs will be tabulated by treatment group. 
The QT interval corrected for heart rate will be calculated using the Fridericia formula 
(QTcF) (Fridericia 1920). ECG interval data (PR, QRS, (QTcF) will be presented as 
summary statistics. The numbers and percentages of subjects with QTcF > 450 msec and 
those with clinically significant findings will be presented in a table. 
Investigational medicinal product dosing and exposure over time will be summarized by 
treatment group and provided in a listing for each participant. 
12.2.3.1. Primary Endpoint 
The primary endpoint is the proportion of participants with protocol-defined SOSE. SOSE is 
assessed by significant retinal changes from baseline using SD-OCT and qFAF. The details 
of significant protocol defined retinal changes using SD-OCT and qFAF are defined Table 5. 
A detailed list of SD-OCT and qFAF parameters assessed in this study is presented in 
Appendix 1 and Appendix 2. Clinically significant changes for quantitative measures will be 
defined as a change from baseline by a threshold taken from previously published coefficient 
of repeatability (Table 5). For qualitative assessments, new findings or worsening of findings 
from baseline exams regarded to be of clinical importance by the Blinded Reading Site will 
be considered a change from baseline. If either of the automated reading (CST or TMV) is 
missing or deemed unreliable by the Blinded Reading Site; the parafoveal (inner ring of the 
ETDRS grid; the annular zone between foveal centered 1 mm diameter circle and 3 mm 
diameter circle) retinal thickness will be used to impute the missing data. 
A descriptive summary table will be produced showing the results by each eye and across 
both eyes, for each assessment (including follow-up). The actual SD-OCT image of each eye 
will be included in the eCRF. Data from repeated tests carried out due to abnormal values 
will not be tabulated. All data, including those from repeat tests, will be provided in a listing.  
For this primary endpoint, a participant will be considered to have a clinically significant 
SOSE if any of the five parameters listed below indicates a change from baseline in either eye 
at any time point during treatment. The 95% CI of SOSE rate will be calculated by treatment 
group, using the Clopper Pearson Exact methodology for the proportion of participants who 
did experience a clinically significant deterioration. The risk difference of the SOSE rates 
between tafenoquine and placebo will be estimated. The upper limit of two-sided 95% CI for 
the risk difference will be compared against the protocol pre-specified NI margin. 

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Table 5: 
Primary Endpoint Evaluation Criteria 
Parameter 
Result (change 
from baseline) 
Criteria for Clinically Significant Change from 
Baselinea 
SD-OCT CSTb 
Yes/No 
Yes = change from baseline of at least 40 µm (15% 
change) 
SD-OCT TMVc 
Yes/No 
Yes = change of > 10% (0.86 mm3) from baseline 
SD-OCT parafoveal 
(inner ring of ETDRS 
grid) retinal thickness 
Yes/No 
Yes = change from baseline of at least 10 µm 
SD-OCT ellipsoid 
and interdigitating 
zone disruption 
Yes/No 
Manual reading; 
Yes = any ellipsoid or interdigitating zone disruption 
(within the ETDRS grid) 
Graded as: 
Foveal (central subfield) 
Parafoveal (inner or outer ring) 
Extra macular (none in grid) 
Abnormal 
quantitative auto 
fluorescence (qFAF) 
patterns  
Yes/No 
Manual reading: 
Yes = change in mid-ring qFAF8 unit from baseline of 
at least 12% 
a Note that these evaluations will be performed by the local site principal ophthalmologist. 
b CST=central subfield thickness 
c TMV=total macular volume 
12.2.3.2. Secondary Endpoints 
The incidence of AEs, SAEs, laboratory parameters and vital signs will be summarized 
descriptively by treatment group and study visit. The AEs will be summarized at ≥1% 
(common) and ≥10% (very common) level. 
For the secondary safety endpoints, the proportion of participants with an abnormal change or 
new abnormal change will be compared by a Fisher’s exact test between tafenoquine and 
placebo. The 95% CI of the abnormality rate will be summarized by Clopper Pearson Exact 
methodology. A logistic regression will be used to compare the risk of having the 
abnormality (odds ratio and 95% CI) between tafenoquine and placebo. These analysis 
methods will be applied to the following secondary safety endpoints: proportion of 
participants with abnormal changes from baseline observed on qFAF, proportion of 
participants with corneal deposits from slit lamp examination of the corneal epithelium, 
proportion of participants with new abnormal changes from baseline observed with color 
retinal digital photography (conventional and wide field), proportion of participants with new 
abnormal changes from baseline observed with microperimetry, proportion of participants 
with any new anomaly on the backlit ETDRS chart, proportion of participants with any 
clinically significant change in ETDRS BCVA (defined as >15 letter change [≥ 3 lines] of 
change in ETDRS BCVA at 4 meters),  proportion of participants who develop a new color 
deficiency using the FM-100 hue test, proportion of participants who develop a loss of 0.12 
or greater logCS on the Mars letter contrast sensitivity test, proportion of participants who 
develop a new identified psychiatric disorder, and proportion of participants with an AE of 
dizziness or vertigo and severity as assessed by the DHI. 

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For time to event safety endpoint, a log-rank test will be used to compare the time to 
onset/resolution of the event between tafenoquine and placebo. Cox regression will be used to 
compare the risk of having the safety endpoint (hazard ratio and 95% CI) between 
tafenoquine and placebo. The survival analysis methods will be applied to the endpoints of 
time to onset, and time to resolution of corneal deposits after treatment cessation. 
Change from baseline in BCVA, key SD-OCT continuous parameters, and LSEQ component 
scores will be analyzed by a random intercept mixed model to account for correlation 
between repeated measures. Treatment effect (difference and 95% CI) on the change from 
baseline variables will be estimated across study visits. 
Specifically, the following assessments will be conducted for secondary safety endpoints, and 
the extra analyses, if mentioned as below, will be applied. 
• Mean change from baseline in key SD-OCT parameters including CST, TMV 
volume, and parafoveal (inner ring of ETDRS grid) retinal thickness and the 
proportion of participants with ellipsoid or interdigitating zone disruption. The 
difference in the proportion of participants with clinically significant ophthalmologic 
changes (as defined in the primary endpoint) between treatment group and the placebo 
group will be calculated. In addition, the change from baseline in individual SD-OCT 
and qFAF parameters listed in Appendix 1 and Appendix 2 will be tabulated and 
compared between tafenoquine and placebo-treated groups. 
• Proportion of participants with abnormal changes from baseline observed on qFAF 
using the Spectralis HRA+OCT device with grey scale values extracted from these 
images for statistical analysis using qFAF software (Heidelberg Engineering). 
• Mean change from baseline in BCVA. Changes from baseline in BCVA results by the 
ETDRS chart will be tabulated and compared between the two groups. A clinically 
significant deterioration is defined as a reduction of more than 4 letters from baseline 
(Week 1, Day 1 [Visit 2]) of 0.08 logMAR. The M-chart will be used to quantify the 
severity of the distortion (if detected). An additional analysis of BCVA changes will 
include the proportion of participants experiencing a 1-4 letter change (less than one 
line of ETDRS visual acuity change), a 5-9 letter change (1 line, but less than 2-line 
change), 10-14 letter change (2 lines, less than 3 lines) or 15 or more letter change 
(3 lines or more) in BCVA from baseline. A >15 letter (> 3 line) or more change in 
ETDRS BCVA at 4 meters is considered clinically significant.  
• Proportion of participants with corneal deposits from slit lamp examination of the 
corneal epithelium. Severity of corneal deposits by impairment of vision: The 
proportion of participants with grades I to IV keratopathy (Orlando grading system for 
cornea Verticillata, a specific pattern of corneal deposits. For participants with corneal 
deposits identified from slit lamp examination, the time to first onset and time to 
resolution after treatment cessation will be tabulated. Corneal structural changes are 
defined as changes from Baseline (Week 1, Day 1 [Visit 2]) of two or more grades of 
corneal changes. These data will also be provided in a listing. 
• Time to onset of corneal deposits and overall time duration to resolution post 
treatment start. 
• Time duration to resolution of corneal deposits after treatment cessation. 

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• Proportion of participants with new abnormalities compared with baseline observed 
with color retinal digital photography (conventional and wide field); 
• Proportion of participants with new abnormalities compared with baseline observed 
with microperimetry; 
• Proportion of participants with any new anomaly on the backlit ETDRS chart; 
• Proportion of participants who develop a new color deficiency using FM-100 hue test;  
• Proportion of participants who develop a loss of 0.12 or greater logCS on the Mars 
letter contrast sensitivity test; 
• Retinal changes (structural) and the impact on macular function (functional) will be 
tabulated for each time point for each eye. The macular function tests include BCVA 
(ETDRS), Color vision assessment with FM-100 hue test, M-chart, and 
microperimetry. Clinically significant changes in any of the five tests are will be 
counted as having an impact on macular function. Retinal abnormalities on 
fundoscopy, digital fundus photography (conventional and wide field), SD-OCT and 
qFAF at Screening are considered to be structural changes but may not affect macular 
function with 12 months of treatment with tafenoquine.  
• The proportion of participants with retinal abnormalities identified from digital 
photographs will be tabulated for each time point and overall. These data will also be 
provided in a listing; 
• Proportion of participants who develop a new, current psychiatric disorder in 
accordance with the DSM-5 as assessed with the M.I.N.I 7.0.2 assessment 
questionnaire and suicidal ideation or suicide attempt by C-SSRS interview; 
• Proportion of participants with a TEAE of dizziness or vertigo and severity as 
assessed by the DHI; and 
• Mean change from baseline in GTS, QOS, AFS, and BFW as assessed by the LSEQ. 
Grading of tafenoquine induced corneal deposits (cornea Verticillata): 
The severity of cornea Verticillata (vortex pattern of benign corneal deposit) detected on slit-
lamp microscopy will be classified according to the grading system for amiodarone-induced 
cornea Verticillata proposed by Orlando 1984. Amiodarone and hydroxychloroquine are both 
cationic amphiphilic drugs which induces phospholipidosis in the form of corneal deposits 
similar to tafenoquine.  
Grade I: punctate opacities that coalesce to form a horizontal line in the inferior third of the 
cornea. This earliest sign is characterized by golden-brown micro deposits in the epithelium 
just anterior to the Bowman’s membrane. These appear as a “dusting” of the cornea at the 
inferior pupillary margin in the mid periphery. There is no fluorescein epithelial punctate 
staining, foreign body sensation or other ocular symptoms. 
Grade II: additional branching or arborization, resembling cat’s whiskers. In this stage, the 
deposits become aligned in a more linear pattern and extend from the inferior pupillary 
margin towards the limbus. This give the appearance much like that of a “cat’s whisker. 
There is a clear zone between the margin of the deposits and the limbus. 
Grade III: the branches increase to assume a verticillate or whorl-like pattern. Linear 
“filament-like” deposits seen in grade II Verticillata increase in number and extend as 

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branches from the inferior pupillary area into the visual axis. A whorled pattern is seen in the 
pupillary axis of the cornea. 
Grade IV: irregular clumps of pigment accompanying the whorled opacities. From grade III 
Verticillata, irregularly round “clumps” of golden-brown deposits can develop defining grade 
IV verticilla. 

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13. 
ETHICAL CONSIDERATIONS 
13.1. 
Ethical Principles 
The study will be conducted in accordance with:  
• The most recent version of the World Medical Association Declaration of Helsinki – 
Ethical Principles for Medical Research Involving Human Participants; 
• National Statement on Ethical Conduct in Human Research (NHMRC 2007a, updated 
May 2015); 
• Notes for Guidance on Good Clinical Practice – Annotated with Comments 
(CPMP/ICH/135/95), as adopted by the Australian TGA (July 2000); and 
• The current Clinical Trial Protocol as approved by the HREC/IRB and the 
USAMRMC HRPO. 
The PI will take care to minimize any discomfort experienced by participants during the 
study. The only invasive procedures the blood collection by cannulation/venipuncture. The 
maximum amount of blood to be collected from an individual over the entire study period is 
approximately 135 mL (Appendix 3).  
Additional blood samples may be taken for safety assessments as required by the PI or at 
times specified by the sponsor provided the total volume taken during the study does not 
exceed 140 mL during the study period. 
13.2. 
Ethical Review 
The protocol, consent forms and participant information sheets will be reviewed by the 
Bellberry-HREC, US IRB and HRPO. No study activities will be initiated prior to the 
approval of these documents by these committees. All amendments and addenda to the 
protocol will similarly be submitted to the Bellberry-HREC, IRB and HRPO for approval 
prior to their implementation. 
13.3. 
Informed Consent Procedures 
Participants will be fully informed of the nature of the study, the properties and side effects of 
the IMP and all relevant aspects of study procedures in the participant information sheet and 
informed consent document. The nature of the study, the IMP and its side effects will also be 
discussed with the participants by the investigator during recruitment. The participants may 
ask questions of the investigator or the clinic staff at any time. 
The ‘Informed Consent’ form will be signed and dated by the participants in the presence of 
an investigator. Participants will also be given a copy of their signed ‘Informed Consent’ 
form. 
In the event that the sponsor wants to perform testing on the samples that is not described in 
this protocol, additional HREC/IRB approval will be sought. 

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13.4. 
Subject Data Protection 
Participants will be informed that their data will be held on file by the Study Site and that 
these data may be viewed by staff of the Australian Local Sponsor who are responsible for 
monitoring the study according to ICH GCP and by the local US FDA. 
Upon request, the investigator(s)/institution(s) will permit direct access to source 
data/documents for trial-related monitoring, audits, HREC/IRB and HRPO review, and 
regulatory inspection(s) by the sponsor (or their appropriately qualified delegates) and 
Regulatory Authorities. Direct access includes examination, analysis, verification and 
reproduction of records and reports that are important to the evaluation of the trial. 
They will similarly be informed that a report of the study will be submitted to the sponsor 
company and may also be submitted to government agencies in Australia and overseas and 
perhaps for publication, but that they will only be identified in such reports by their study 
identification number, initials and perhaps their gender and age. The investigators undertake 
to hold all personal information in confidence. 

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14. 
ADMINISTRATIVE CONSIDERATIONS 
14.1. 
Liability/Indemnity/Insurance 
The study sponsor will ensure sufficient insurance is available to enable it to indemnify and 
hold the investigator(s) and relevant staff as well as any hospital, institution, HREC/IRB or 
the like, harmless from any claims for damages for unexpected injuries, including death, that 
may be caused by the participant’s participation in the study but only to the extent that the 
claim is not caused by the fault or negligence of the participants or investigator(s). The 
sponsor adheres to the guidelines of Medicines Australia for injury resulting from 
participation in a company-sponsored trial, including the provision of “no-fault clinical trial 
insurance” (Medicines Australia 2016). 
14.2. 
Changes to the Final Study Protocol 
Changes to the final study protocol can only be made with the prior consent of the sponsor 
and the HREC/IRB/HRPO. All such changes must be attached to, or incorporated into, the 
final protocol, and communicated to all relevant members of the Study Site staff and, if 
appropriate, to trial participants. All deviations from this study protocol will be reported on 
eCRFs and will be included in the trial master file and included in the FCSR. An assessment 
of the significance of each protocol deviation will be given in the FCSR. All 
deviations/amendments will be reported to sponsor. 
14.2.1. 
Non-Substantial Amendment 
Administrative or logistical minor changes to the protocol require a non-substantial 
amendment. Such changes include but are not limited to changes in study staff or contact 
details (e.g., sponsor instead of CRO monitors) or minor changes in the packaging or labeling 
of the IMP. An amendment deemed to be non-substantial must have no ethical implications. 
The implementation of a non-substantial amendment may be done without notification to 
HRPO. However, the HREC/IRB will receive notification of non-substantial amendments. 
14.2.2. 
Substantial Amendment 
Significant changes to the protocol require a substantial amendment. Significant changes 
include but are not limited to: new data affecting the safety of participants, change to the 
objectives/endpoints of the study, the eligibility criteria, dose regimen, study 
assessments/procedures, treatment or study duration, with or without the need to modify the 
participant information sheet and informed consent. 
Substantial amendments are to be approved by the HREC/IRB/HRPO. For HRPO purposes, 
substantial amendments may also include a change in the PI, change or addition of an 
institution, change to the HREC/IRB of Record, elimination or alteration of the consent 
process, change to the study that has regulatory implications, significant changes in the study 
design that would prompt additional scientific review or a change that could potentially 
increase risk to participants. The implementation of a substantial amendment can only occur 
after formal approval by the HREC/IRB /HRPO and must be signed by the PI. 

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14.2.3. 
Urgent Amendment 
An urgent amendment might become necessary to preserve the safety of the participants 
enrolled in the study. The requirements for approval should in no way prevent any immediate 
action being taken by the investigators or the sponsor that is in the best interests of the 
participants. Therefore, if deemed necessary, an investigator can implement an immediate 
change to the protocol for safety reasons. This means that, exceptionally, the implementation 
of urgent amendments will occur before submission to and approval by the HREC/IRB 
/HRPO. 
In such cases, the investigator must notify the sponsor within 24 hours of implementation of 
the amendment. A related substantial amendment will be written within 10 working days and 
submitted to the HREC/IRB /HRPO, together with a description of the steps, which have 
already been taken regarding implementation of this amendment. 
14.2.4. 
Clinical Data Recording 
Each participant will have a clinical file (source data) and eCRF, (for protocol specific data) 
into which relevant data will be recorded. A log of names, signatures and initials of all staff 
authorized to enter data into a participant’s Clinic File and eCRF will be kept in the site study 
file. 
Upon completion of each study visit, all eCRF data will be reviewed internally by the Study 
Site for omissions or apparent errors so that these can be corrected without delay. Any 
corrections made after the review and signature of the PI will be noted in the audit trail and 
will require re-authorization (electronic sign off) by the PI.  
All deviations from this study protocol will be documented in the trial master file and 
included in the FCSR. An assessment of the significance of each protocol deviation will be 
discussed in the FCSR.  
14.3. 
Record Retention 
All source data, clinical records and laboratory data relating to the study will be retained in 
the archive of the Study Site for a minimum of 15 years after the completion of the study in 
compliance with TGA annotations to CPMP/ICH/135/95. Data will be available for 
retrospective review or audit by arrangement with the Chief Executive Officer of the Study 
Site. Written agreement from the sponsor must precede destruction of the same. 
14.4. 
Biological Samples 
Biological samples will be retained for the time required for assessment for analysis, and may 
then be discarded.  
14.5. 
Shipment Procedures 
The site staff will be responsible for shipment of samples to the sponsor nominated 
bioanalytical laboratories for testing. All samples will be securely packed in containers 
provided by the shipping vendor. These will be shipped as per the procedures of the vendor 
together with completed shipment forms. 

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14.6. 
Monitoring 
It is the sponsor’s responsibility to ensure that the study is monitored in accordance with the 
requirements of ICH GCP. The conduct of the study will be reviewed internally by the Study 
Site in accordance with the Study Site SOPs and ICH GCP guidelines. The trial will be 
monitored according to the sponsor’s SOPs and all significant protocol deviations shall be 
reported to the sponsor and Bellberry HREC/IRB/HRPO using CNS or Fast-Track SOPS. 
14.7. 
Reporting and Communication of Results 
The data management, statistical and medical writing team appointed by the sponsor will 
collaborate to provide a detailed FCSR upon conclusion of the study. This will include 
appendices of all Tables, Listings and Figures generated during the analyses of data. The 
sponsor undertakes to ensure that all safety observations made during the conduct of the trial 
are documented in this report. 
Publication and reporting of results and outcomes of this trial will be accurate and honest, 
undertaken with integrity and transparency and in accordance with the relevant clauses 
outlined in the Agreement between the clinical sites and Fast-Track. All manuscripts will 
need to be reviewed and approved by USAMMDA and 60P before submission. The sponsor 
recognizes that the PI has a responsibility to ensure that results of scientific interest arising 
from the clinical trial are appropriately published and disseminated. Publication of results 
will be presented to fair peer-review. Authorship will be given to all persons providing 
significant input into the conception, design, and execution or reporting of the research 
according to NHMRC guidelines (NHMRC 2007b). No person who is an author, consistent 
with this definition, will be excluded as an author without his/her permission in writing. 
Authorship will be discussed between researchers prior to study commencement (or as soon 
as possible thereafter) and reviewed whenever there are changes in participation. 
Acknowledgment will be given to the study participants and staff, and collaborating 
institutions and hospitals and other individuals and organizations providing finance or 
facilities. In any press releases, publications or presentations, the sponsor’s financial 
contribution to the study and its participation in the collaboration and the trial site, shall be 
expressly acknowledged. The sponsor agrees that the Linear Clinical Research, in particular 
the PI, will be entitled to access all the de-identified clinical trial data upon completion of the 
study. Data will not be released publicly until the manuscript is accepted for publication. In 
the case of no publication, information will only be released to the public and media in 
accordance with the Linear Clinical Research’s corporate media strategy policy. 
As the IND holder and sponsor, 60P will register the trial on the National Library of 
Medicine’s Clinical Trials Registry on the world wide web at http://www.clinicaltrials.gov. 
In addition, upon study completion and finalization of the study report the results of this trial 
will be either submitted for publication in an open access journal and/or posted in a publicly 
accessible database of clinical trial results. 
However, the PI undertakes not to make any publication or release pertaining to the study 
and/or results of the study without the sponsor’s prior written consent, being understood that 
the sponsor will not unreasonably withhold its approval. 
The investigator shall not use the name(s) of the sponsor and/or of its employees in 
advertising or promotional material or publication without the prior written consent of the 
sponsor. The sponsor shall not use the name(s) of the investigator and/or the collaborators in 

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advertising or promotional material or publication without having received his/her and/or 
their prior written consent(s). 
The sponsor has the right to publish the results of the study at any time provided the PI has 
provided input into the manuscript within a 30-day time frame from request. 
14.8. 
Discontinuation of the Study 
The sponsor, PI, HREC/IRB and Regulatory Authorities independently reserve the right to 
discontinue the study at any time for safety or other reasons. This will be done in consultation 
with the sponsor where practical. In the event of premature trial termination or suspension, 
the above-mentioned parties will be notified in writing by the terminator/suspender stating 
the reasons for early termination or suspension (with the exception of the sponsor’s 
responsibility for notifying the Regulatory Authorities). After such a decision, the sponsor 
and the investigator will ensure that adequate consideration is given to the protection of the 
participants’ interest and safety. All ongoing participants will be followed up for a minimum 
of 65-75 days after administration of tafenoquine and will be scheduled for an early 
discontinuation visit or EOS evaluation visit (whichever is applicable). At this visit all 
assessments scheduled for the EOS evaluations (Week 64) will be performed as described in 
section 8.4. 
14.9. 
Study Audit 
Audits may be carried out by sponsor quality assurance representatives, local authorities or 
authorities to whom information on this study has been submitted. All documents pertinent to 
this study must be made available for such inspections after adequate notice of intention to 
audit. 

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April 14, 2010. URL:  https://wayback.archiveit.org/7993/20170404155027/  
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dvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM212591.pdf      
(accessed September 2017). 

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Schlagenhauf P, Tschopp A, Johnson R, et al. Tolerability of malaria chemoprophylaxis in 
non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four 
army study. Br Med J 2003; 327(7423): 1078. 
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric 
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interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59 Suppl 20: 22-33; quiz 34-57. 
Study 6. Metabolism and pharmacokinetics of 14C-WR238605 in beagle dogs (Report 
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Study 9. Metabolism and pharmacokinetics of 14C-WR238605 in beagle dogs and in the 
Rhesus monkey (Report number HRC/WRI 5/8771, dated 23 March 1987). Huntingdon 
Research Centre (HRC) Ltd, Huntingdon, Cambridgeshire, UK. 
Study 030. A Randomized, Double Blind, Placebo Controlled Evaluation of Weekly 
Tafenoquine (WR238605/SB252263) Compared to Mefloquine for Chemosuppression of 
Plasmodium falciparum in Western Kenya (Report number SB-252263/RSD-101KZH/1, 
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Study 033. A randomized, double-blind, comparative study to evaluate the safety, tolerability 
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Study 043. Evaluation of weekly tafenoquine (SB 252263/WR 238605) compared to placebo 
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APPENDIX 1. SD-OCT FINDING 
OCT CST – automated segmentation performed by the Heidelberg Spectralis OCT device 
will generate an average thickness of the retina in the central 1 mm zone, measured from 
top of the Internal Limiting Membrane (ILM) to bottom of the RPE (in µm). 
OCT TMV – automated segmentation performed by the Heidelberg Spectralis OCT device 
will generate an average thickness of the retina in the central 6 mm zone, from the top of 
ILM to the bottom of RPE which provides a volume measurement of the central 6 mm 
zone (in cubic millimeters). 
OCT Parafoveal (inner ring) and perifoveal (outer ring) Retinal Thickness – 
automated segmentation performed by the Heidelberg Spectralis OCT device will generate 
an average thickness of the retina in a rim region between the central 1 mm and 3 mm 
diameter rings and 3 and 6 mm diameter rings, measured from top of the ILM to bottom of 
the RPE (in µm). 
OCT Subretinal Fluid Thickness – manual measure of greatest linear height of any sub 
retinal fluid (if present) (in µm). 
En face OCT ellipsoid zone disruption – manual measurement of the greatest linear 
extent of ellipsoid layer loss due to foveal photoreceptor damage based on en face OCT 
scans segmented to the level of ellipsoid zone. Results will be reported as normal or 
abnormal. 
En face OCT retinal pigment epithelium layer disruption – manual measurement of the 
greatest linear extent of loss of RPE layer due to drug toxicity based on en face OCT scans 
segmented to the level of RPE layer. Results will be reported as normal or abnormal. 
En face OCT interdigitation zone disruption – manual measurement of the greatest 
linear extent of preserved interdigitating layer due to perifoveal photoreceptor damage 
based on en face OCT scans segmented to the level of interdigitating layer. Results will be 
reported as normal or abnormal. 

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APPENDIX 2. qFAF FINDINGS 
Increase in quantitative auto fluorescence in central macula – The Delori grid is placed 
on the qFAF image with its edge just touching the optic nerve head. There are 29 zones 
within the grid and average qFAF units in the 4 rings are calculated after blood vessels are 
masked. A 12% increase in qFAF units in the mid ring (8 zones) would exceed test-retest 
variability and will be considered a change from baseline. 
Area of abnormal auto fluorescence– quantitative assessment of any abnormal patterns 
of auto fluorescence in the macular region that may be indicative of disease of the RPE 
(Donnalpally 2017). The pattern of auto-fluorescence will be reported as normal or 
abnormal. 
Decrease in auto fluorescence in central macula – qualitative assessment of decreased 
intensity of auto fluorescence noted within the central 6000 µm diameter is indicative of 
decreased function of RPE, masking or even RPE atrophy. This will be reported as Yes/No 
to presence of hyper-auto fluorescence or hypo-auto fluorescence. 
Geographic atrophy of the RPE – quantitative measure of areas of missing RPE; no 
production of auto fluorescence (area of the region of hypo-auto fluorescence), 
representing region of RPE death (in square millimeters). 

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APPENDIX 3. ESTIMATE OF TOTAL BLOOD VOLUME 
COLLECTED DURING THE STUDY PERIOD 
Note: 
Total blood sampling volume for the individual participants participating in the study is 
approximately 135 mL. 
The actual times of blood sampling may change. Additional blood samples may be taken for 
safety assessments as required by the PI or at times specified by the sponsor, provided the 
total volume taken during the study does not exceed 140 mL during the study including 
planned blood draws. 
Procedure 
Sample 
Volume per 
sample 
(mL) 
No. 
samples per 
participant  
Total 
volume per 
participant 
(mL) 
Laboratory test 
G6PD testing 
Blood volume for this sample will come 
from 4 mL hematology tube at screening 
 
CBC  
4 
8 
32 
 
MetHb% 
4 
7 
28 
 
Biochemistry 
5 
7 
35 
 
Serology 
5 
1 
5 
 
Endocrinology 
(pregnancy) 
5 
2 
10 
Pharmacokinetic test PK analysis 
5 
5 
25 
 
 
 
TOTAL 
135 

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APPENDIX 4. CENTRAL FOVEAL THICKNESS (CENTRAL 1 MM 
CIRCLE) ON SPECTRALIS DEVICE 
Normative interval based on a literature review of the following publications: 
Mean = 260 to 280 µm: take 270 µm (across different races) 
SD ranges from 16 to 24:  take 24 µm (the largest study has this SD) 
Mean ± 2 SD = 222 to 318 µm (cover male and female range) using 24 µm as the SD 
 
Citation 
CFT Finding 
Grover 2009 
20-40 years old:  275 ± 24 (N = 19) 
41-60 years old:  269 ± 22 (N = 20) 
61+ years old:  
263 ± 20 (N = 11) 
Wenner 2011 
N = 34 adults aged 19-30 years old. 
29 scan pattern:  281 ± 17 
49 scan pattern:  281 ± 17 
97 scan pattern:  281 ± 17 
Choovuthayakorn 2012 
N = 368 adults aged 49 ± 17 years old. 
Whole group:  259 ± 19  
Male:   
 
265 ± 19 
Female:   
252 ± 18 
Appukuttan 2014 
N = 105 adults aged 20-75 years’ old 
Whole group:  260 ± 19 
Male:   
 
266 ± 19 
Female:   
255 ± 16 
 

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APPENDIX 5. LEEDS SLEEP EVALUATION QUESTIONNAIRE 
 

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APPENDIX 6. DIZZINESS HANDICAP INVENTORY  
 
 

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DIZZINESS HANDICAP INVENTORY (CONT) 
 
 
 

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APPENDIX 7: COLUMBIA-SUICIDE SEVERITY RATING SCALE 
 
 
 

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APPENDIX 8: PROTOCOL AMENDMENTS 
Version 
Date 
Significant Revisions  
7.0 
21Nov2018 
• For clarity, the C-SSRS interview will be conducted every 4 weeks ± 1 week 
rather than monthly to be consistent with the weekly study schedule. Also the 
interview can be conducted by phone at all visits or in person, if logistically more 
practical at clinic visits. The responses can be recorded onto a paper CRF or 
directly into an eCRF. 
• The list of acceptable methods of birth control and sterilization procedures have 
been expanded. Flexibility to the timing of the 1a and 1b visits was added to allow 
sites to schedule subjects optimally for both to complete all assessments. 
• Laboratory exclusion criteria were revised for clarity.  
• Section 2.1. The following sentence was added: Tafenoquine under the tradename 
of KODATEF™ was approved by the Australian Therapeutic Goods 
Administration in September 2018. 
• Section 5.4. The data to be collected for early withdrawal of subjects was clarified 
with respect to recording dates of withdrawal or lost to follow-up to be recorded 
on the eCRFs. 
6.0 
05Aug2018 
• The names and locations of the two US sites and site principal investigators were 
added where appropriate (Cover Page, Synopsis, Section 5.8). 
• A central IRB, Integreview IRB, will be used for the US sites. IRB relevant 
language was added to the protocol (Cover Page). 
• A local medical monitor (LMM), to be named, was added for the US sites (Cover 
Page). 
• The name of the bioanalytical laboratory for the US site PK analysis was added 
(Cover Page). 
• The mfERG evaluation was removed from the study as secondary ophthalmic 
evaluation (Synopsis, Section 1, Section 2.1.1.3, Section 3, Section 5.2.2, Section 
8.1, Section 8.5, Section 9.2.6, Section 10.11.1, Section 12.2.3.2). 
• The C-SSRS to be conducted at baseline and monthly through Week 64 was 

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added as an assessment based on US FDA request (Synopsis, Section 1, Section 3, 
Section 8.2, Section 8.3). 
• The proportion of subjects with suicidal ideation or suicide attempt by C-SSRS 
interview was added as a secondary endpoint (Synopsis, Section 5.2.2, and 
Section 12.2.3.2) 
• The male birth control exclusion criteria was removed from the protocol as male 
birth control for men is not a recommendation in the FDA approved product label 
for tafenoquine (Synopsis, Section 1, Section 6.1). 
• The window for the Weeks 12, 24, 52, 64, 76, 89, and 194 visits were changed 
from  ± 1 week to  ± 2 weeks (Section 1, Section 8.6). 
• Section 2.1 and Section 5.3  - Information about the US FDA approvals of 
tafenoquine for the prophylaxis or malaria and the radical cure treatment of P 
vivax malaria was added. 
• Section 3 and Section 5.6 - Visit dates were updated. 
• Section 5.1  - Clarification of the screening visits activities was provided. 
• Section 5.5.1.2. - Serious hypersensitivity reactions were added as a possible 
systemic reaction. 
• Section 6  - The racial groups (all) included in the study was clarified. Also, the 
responsible persons for reviewing subject eligibility was revised due to the 
addition of the US clinical sites. 
• Section 6.2, exclusion criteria #2, hemolytic anemia was added. 
• Section 6.2, exclusion criteria #9a, “History of  psychotic disorders or current 
psychotic symptoms (hallucinations, delusions, or grossly disorganized thinking 
or behavior) was added and #9b “Current (past year) suicide behavior disorder” 
was also added. 
• Section 6.3  - Explanation that the first digit of the subject ID number will reflect 
the site number was added. 
• Section 7.2.1  - “Temperature excursions are permitted to 15°C to 30°C (59°F to 
86°F)” was added to be consistent with the US Prescribing Information. 

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Date 
Significant Revisions  
• Section 7.3.1 and 7.3.2 were revised for clarity of the Mosio system. 
• Section 7.5.1 was revised to clarify the use of the diary cards and the Mosio 
system for drug compliance. 
• Section 8.5 was clarified that ophthalmologic assessments to be conducted during 
the Part 3 follow-up visits (in the event of an ongoing AE) only included those 
that revealed an abnormality or any additional assessments needed to evaluate the 
abnormality at the discretion of the investigator. 
• Section 9.1 was clarified regarding the definition of baseline assessments. 
• Section 9.2.7 added that psychiatric conditions could be further evaluated by a 
Study Psychiatrist or Psychologist. 
• Section 9.2.10 was added to describe the C-SSRS. 
• Section 10.11.1.1 -  Methemoglobin > 10% was added as an AESI. 
• Section 10.11.4 - Reporting Information of SAEs for US sites was added. 
• Section 12.2.3 - Shift tables will be presented for selected laboratory tests was 
added in addition to mean and change from baseline levels. 
• Section 15 - The Oquendo reference for the C-SSRS assessment was added. 
• Appendix 4 – Placing a copy of the MINI exam as an appendix was removed. 
• Appendix 7 - The C-SSRS assessment was added. 
5.0 
02 Apr 2018 
• Section 1.0 – The Study Schedule of Events was revised to allow 6 weeks for 
screening, a ± 3 days window at Week 4, and a ±1 week window at Week 12. 
• Section 5.4 (Individual Subject Withdrawal) was clarified to provide more details 
regarding the assessments to be performed in the event of subject withdrawal. 
• Section 6.2 Exclusion Criteria were revised as follows: 
Criterion #10 – A new sentence was added to provide for the use of prescription 
and non-prescription medications containing codeine. 
Criterion #15 – Language was added to allow the Investigator to include subjects 
with out-of-range hematology results that were not judged as clinically significant. 
Criterion #16 – Language was added to allow the Investigator to include subjects 

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with out-of-range biochemistry results that were not judged as clinically 
significant. 
• Section 8.6 (Assessment and Visit Windows) – The Visit Windows were updated 
to be consistent with the revised Study Schedule. 
4.0 
07 Feb 2018 
• Due to slow recruitment of subjects at Linear Clinical Research, it was decided to 
expand this study to a multisite study and clinical sites in the United States. 
• Randomizations will use clinical site as a stratification variable as the study was 
changed to a multisite study. 
• Exclusion criteria #3(l) was revised to an SD-OCT CSF thickness of <222 µm or 
>318 µm instead of from <240 µm to >300 µm. This change was also made to 
Appendix 5. This criteria was established based on the SD of this measurement from 
several published studies and rather than use the smaller of the two ranges of SD of 
16, it was changed to the larger SD of 24 to set the range at a well established 95% 
confidence interval for the normal range of thickness in the literature for normative 
values. 
• Normal medical urinalysis was removed as an inclusion criterion as other 
biochemistry parameters were considered more indicative of a clinically significant 
medical condition. 
• Hematology and biochemistry inclusion parameters were deleted and instead, 
specific ranges for hematology and biochemistry laboratory values were added as two 
new exclusion criteria (criteria 15 and 16). 
• Clarification of the psychiatric exclusion criterion was added. 
• Updated section 7.2.1 to reflect the investigational product storage temperature on 
the drug label to 15°C to 25°C. 
3.0 
20 Sep 2017 
• Adjusted protocol to reflect FDA advice “FDA comments on the May 31st, 2017, 
submission to IND 129656”. 
• The proposed primary endpoint evaluation criteria shown in Table 4 was 
considered too strict by the Agency, leading to the possibility of a large number of 
participants being assessed as having a significant retinal change from baseline. The 

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Agency recommended that the OCT CST be revised to define a change from baseline 
of at least 40 µm as clinically significant. The Agency also recommended that OCT 
TMV be revised to define a change from baseline of 10% or more as clinically 
significant. 
• The Agency requested the actual SD-OCT image of the ach eye be included in the 
eCRF. 
• The Agency requested that the analysis of BCVA is based on a one line, 2 line or 
3 or great line change in BCVA from baseline. A three-line change in ETDRS BCVA 
at 4 m should be considered clinically significant. This adjustment was made but 
included letter changes to avoid rounding errors. 
• The Agency suggested FM-100 colour vision test (gold standard) is used in 
preference to the Farnsworth-Munsell (FM) 15 hue test. This should be a binocular 
test with the Lanthony D15 test administered prior to disrupt learning effects.  
• The Agency requested that the grading of corneal deposits does not use the LOCS 
III transparency grading scale (Chylack 1993). This scale has previous been adjusted 
in version 2.0, dated 19 July 2017. 
• The Agency requested copies of the CRF, OCT protocol handbook, and FAF 
protocol handbook be submitted for review. 
• ECG at baseline and at least one follow-up time point was requested during the 
treatment period. 
• The Agency requested monitoring of all patients in the study for safety out to 10 
to 12 weeks (Week 62 to 64) after the last dose of tafenoquine because of its long 
washout period (65-75 days). The participants who experience an AE would then 
continue in the follow-up phase as per the protocol. 
• The protocol should specify the assay(s) used to measure methemoglobin. 
• The Agency requested that participants who are withdrawn from the study before 
Week 12 are not replaced and that all randomized participants, including participants 
who discontinue treatment early, continue to be followed through study completion. 
Reasons for study discontinuation should be documented on the eCRF and the 
protocol should provide details for how participants who withdraw from the study 

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prematurely or discontinue treatment will be handled in the statistical analyses. 
• The Agency recommended sample size calculations and primary analysis be 
based on an alpha level of 5% two-sided. 
• The Agency recommended that participants are analyzed as they are randomized 
in the study. 
• The Agency recommended that the definitions of the primary endpoint listed in 
Section 5.2.1 and 12.2.3.1 of the protocol is modified to remove reference to the TQ 
group, as the primary endpoint should be applicable to both treatment arms in the 
study. 
• Section 9.2.6 Clarified that the trained sub-investigators will be performing the 
M.I.N.I. and not specifically trained psychiatric nurses. 
• Adjusted wording so subject is substituted for participant. 
• Adjusted descriptions of corneal and retinal photography to include both 
conventional and wide field imaging (to capture 200° of internal angle of the retina). 
• OCT will include wide field macular scan. 
• qFAF will be a set of 3 images to ensure consistency in measurements. 
• Updated Section 5.1 and 5.6. Recommended volume of water to take tablets is 
180 mL not 240 mL. Aligns to FDA advice provided for Study TQ-2016-01 (PK 
study). 
• Updated Section 6, 7.7, 8.1 and 10.5 to clarify that the sub-investigator is 
responsible for non-ophthalmic and ophthalmic eligibility assessments at Linea 
Clinical Research and the Lion’s Eye Institute respectively. The sub-investigator will 
confirm eligibility with the PI as appropriate. The PI may further confirm eligibility 
with the LMM.  
• Updated Section 6.2. SD-OCT thickness for exclusion criteria is now aligned with 
Appendix 5 (230-310 µm) which is the mean + 2 standard deviations. 
• Section 8.2. Clarified dosing starts on Day 1, Week 1 (3 day loading dose of 2 x 
100 mg tablets for 3 days, followed by weekly dosing (2 x 100 mg tablets) on the 
same day as Day 3, starting 7 days later.  

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Date 
Significant Revisions  
• Section 8.2. Removed 60 minute window after procedures for releasing from 
clinic. At the judgment of the investigator 
• Section 8.3. Removed “Week 1, Day 1” as this Visit 2 is covered in Section 8.2 
and was confusing. 
• Section 8.6. Removed pre-dose observations within 60 minutes prior to dosing 
and other specific interval discussions. Week windows are adequate.  
• Section 9.2.6. Clarified that a study nurse or research physician who is trained in 
the M.I.N.I. 7.0.2 may administer the test. This was later clarified in version 3.0 to 
only allow sub-investigators trained on the M.I.N.I. by Dr. Sheehan (inventor). 
2.0 
19 Jul 2017 
• Updated Table 1 text to reflect separation of Screening and EOS over 2 
consecutive days, separating EOS into Visits 7a and 7b. Also to outlined the order of 
eye assessments to be clearer and added biometry assessments and MARS contrast 
sensitivity test. 
• Adjusted primary endpoint measure wording. 
• Adjusted “proportion of participants who develop a loss of 0.12 or greater 
logarithm of contrast sensitivity (LogCS) on the MARS contrast sensitivity test. 
• Adjusted SD-OCT parameters to examine the ellipsoid and interdigitating zone 
integrity and continuity.  
• TMV and parafoveal inner ring of ETDRS grid thickness will also be examined. 
• Retinal digital photography to be conventional and wide field to enable detection 
of subtle peripheral toxicity. 
• Table 4: Included quantitative assessment of both central subfield and inner zone 
of the ellipsoid zone for SD-OCT 
• Table 4: Included grading of ellipsoid zone as present (complete), patchy (some 
disruption), or absent. 
• Table 4: Clarified Lions Eye Institute would be responsible for the primary read 
• Included interdigitating zone integrity testing 
• Updated Section 2.3.2 with Table 3 Adverse Events occurring in >1% of 
Participants in the Tafenoquine ACR Group and with an Incidence Numerically 

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Greater than in the Placebo Group 
• Updated Section 6.2. Updated Exclusion criteria 9 to manage subjects who have a 
positive finding on M.I.N.I at Screening for follow-up referral to their GP after Study 
Psychiatrist diagnosis. 
• Minor adjustments to other exclusion criteria. 
• Section 6.4.2 removed references to phenformin, butformin and pilsicamide 
which are not available in Australia.  
• Updated Section 7.2.4. Included handling of new or worsening psychiatric AE by 
M.I.N.I to reflect HREC/HRPO questions 
• Section 7.3. Updated with information about the Medication Adherence and 
Reminder System (Mosio) (Section 7.3.1, 7.3.2 and 7.3.3) 
• Updated Section 7.5.1 with compliance mechanism using Mosio 
• Updated Section 7.7. Participants are not to be told about corneal deposits. 
• Adjusted Section 8.1. Clearer sequence of ophthalmic testing. 
• Updated Section 8.3. Clearer sequence of ophthalmic testing. Included Orlando 
grading system for corneal deposits and not the cataract grading system (Chylack). 
Clarified abnormal follow-up would include the MARS contrast sensitivity test. Slit 
lamp examination and digital photograph of corneal surface will examine cornea 
Verticillata and retinal digital photography will examine toxic maculopathy and 
retinopathy on conventional and wide field images. 
• Updated Section 8.4. Full field ERG incorporating ISCEV standards, MARS letter 
contrast sensitivity and M-Chart will be used to follow-up abnormal findings. Corneal 
deposits and retinal lesions from drug toxicity at Week 52 need to be monitored by 
slit lamp examinations, SD-OCT, qFAF and photography. 
• Updated Section 8.5. EOS ophthalmic visits scheduled over two days. Clarified 
sequence of ophthalmic testing. 
• Updated Section 9.2.5. Clarified ophthalmic testing sequence. Results from 
blinded fundus reading center will be reviewed by PI. 
• Updated Section 9.2.6. Handling of new or worsening psychiatric AE by M.I.N.I 

Clinical Study Protocol  
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to reflect HREC/HRPO questions. 
• Section 10.11.1. Clarified significant deterioration in the MARS contrast 
sensitivity test in an AESI. 
• Section 12.2.3.1. Clinically significant changes for quantitative measures will 
include a threshold taken from previously published coefficients of repeatability. If 
automated reading is missing or unreliable, the parafoveal (inner ring of the ETDRS 
grid), the annular zone between foveal center (1 mm diameter circle and 3 mm 
diameter circle) and retinal thickness will be used to impute missing data. 
• Table 5 updated. 
• Section 12.3.3.2 updated. Includes proportion of participants who develop a loss 
of 0.12 or greater log CS on the MARS contrast sensitivity test.  
• En face reflectivity profile of the ellipsoid and interdigitating zone (integrity and 
continuity). Orland 1984 grading system for cornea Verticillata grading used to 
replace “cataract” system of Chylack 1993 
• Updated Section 14.2.1. All non-substantial changes will be notified to the 
HREC/HRPO 
• Updated Section 15.0. Included reference for M.I.N.I version 7.0.2 (Sheehan 
1998). Deleted Chylack 1993. Added Orlando 1984 and Donnalpally 2017.  
• Appendix 1: Updated to state “qualitative assessment of disruption of ellipsoid 
layer in the central subfield and inner zone indicative of photoreceptor dysfunction.” 
• Updated with OCT parafoveal assessments (inner ring of EDTRS grid) 
• En face OCT ellipsoid zone disruption 
• En face OCT retinal pigment epithelium layer disruption 
• En face OCT ellipsoid zone preservation 
• En face OCT interdigitating zone preservation 
• Appendix 2: Updated to Area of abnormal auto fluorescence – quantitative 
assessment of any abnormal areas of auto fluorescence in the macular region that may 
be indicative of disease of the RPE.  
• Added/adjusted. Areas of abnormal auto fluorescence, decrease in auto 

Clinical Study Protocol  
CONFIDENTIAL AND 
PROPRIETARY 
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Protocol Version 7.0 
Dated 29Nov2018 
Page 141 of 141 
 
Version 
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Significant Revisions  
fluorescence in the central macula and geographic atrophy of the RPE. 
• Appendix 2: Cited Donnalpally 2017 
• Appendix 5. Clarified units of measurement