Conditions: Malaria, Vivax
Keywords: Safety Artemisinin Combination Therapy Efficacy Tafenoquine Superiority Primaquine Radical cure Vivax ACT Plasmodium vivax malaria Dihydroartemisinin-piperaquine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 150
Healthy volunteers: no

Brief summary:
Tafenoquine (TQ) is an 8-aminoquinoline anti-malarial drug which is in development as a single-dose treatment for the radical cure of P.vivax malaria when given with standard doses of chloroquine. Currently, the only available drug for radical cure is primaquine (PQ) which requires administration over 14 days, resulting in poor compliance. In Indonesia, chloroquine has been replaced by artemisinin-based combination therapy (i.e. ACTs) due to widespread chloroquine resistance. This study will evaluate the efficacy and safety of a single dose of tafenoquine when co-administered with an ACT (i.e. DHA-PQP). This single-center, double-blind, double-dummy, randomized study will test the superiority of DHA-PQP plus TQ against DHA-PQP alone in the prevention of P. vivax malaria relapse at 6 months. The study will be conducted in male Indonesian soldiers diagnosed with P.vivax malaria on return from deployment to a malarious region of Indonesia. A PQ plus DHA-PQP comparator arm is included to provide an informal comparison against the standard 14 day treatment for P.vivax malaria in Indonesia. Subjects who are glucose-6-phosphate dehydrogenase deficient (G6PD deficient) will be excluded due to the risk of acute hemolysis following dosing with 8-aminoquinolines drugs. Subjects who have a recurrence of P.vivax malaria during the study will be treated with an ACT plus PQ (0.5mg/kg for 14 days), in line with local treatment guidelines. At the end of the 6 month follow up period, any subject who has not relapsed will be given open label PQ (0.5mg/kg daily for 14 days) to minimize the likelihood of relapse after the study. Approximately 200 subjects will be screened to achieve 150 randomized subjects. The total duration of study for each subject will be 180-195 days. This study is being carried out to support registration of TQ in Indonesia and other countries where ACTs are first line therapy.

Detailed description:

Arms:
arm 1: Subjects will receive open label DHA-PQP, 3 or 4 tablets per day (according to the body weight) from Day 1 to Day 3. They will receive double-blind 300 mg single dose of tafenoquine (TQ) on Day 1 and matched-placebo for primaquine (PQ) from Day 1 to Day 14. arm 2: Subjects will receive open label DHA-PQP, 3 or 4 tablets per day (according to body weight) from Day 1 to Day 3. They will receive double-blind 15 mg primaquine (PQ) from Day 1 to Day 14 and matched-placebo for tafenoquine (TQ) on Day 1. arm 3: Subjects will receive open label DHA-PQP, 3 or 4 tablets per day (according to body weight) from Day 1 to Day 3. They will receive double-blind matched-placebo for tafenoquine (TQ) on Day 1 and matched-placebo for primaquine (PQ) from Day 1 to Day 14.

Interventions: intervention 1: Tafenoquine intervention 2: Matched-Placebo for Tafenoquine intervention 3: Primaquine intervention 4: Matched-Placebo for Primaquine intervention 5: Dihydroartemisinin-piperaquine (DHA-PQP) intervention 6: ACT plus PQ (Rescue medication) intervention 7: PQ (End of study treatment)
Intervention descriptions: intervention 1: This intervention is provided as tablet containing 150 mg of tafenoquine. Two tablets of this formulation will be administered orally with water as a single dose after a meal. Dose will be taken at least 3 hours after DHA-PQP. intervention 2: This intervention contains tafenoquine matched-placebo. Two tablets of this formulation will be administered orally with water as a single dose after a meal. Dose will be taken at least 3 hours after DHA-PQP. intervention 3: This intervention is provided as over-encapsulated tablet containing 15 mg of primaquine. One capsule of this formulation will be administered orally with water as a single dose after a meal for 14 days. Dose will be taken at least 3 hours after DHA-PQP (Days 1, 2 and 3). intervention 4: This intervention contains primaquine matched-placebo. One capsule of this formulation will be administered orally with water as a single dose after a meal for 14 days. Dose will be taken at least 3 hours after DHA-PQP (Days 1, 2 and 3). intervention 5: This formulation is provided as tablet containing 320 mg of piperaquine tetrasphosphate (as the tetrahydrate; PQP) and 40 mg dihydroartemisinin (DHA). This tablet will be administered orally as single dose for 3 days. For subjects weighing \<75 kg, 3 tablets will be administered per day. For subjects weighing \>=75 kg, 4 tablets will be administered per day. Dose will be taken at least 3 hours after last food intake. No food will be allowed for at least 3 hours after dosing. intervention 6: Subjects with relapse during the 180 day follow up period will be given an ACT plus PQ 0.5 mg/kg for 14 days as rescue medication. intervention 7: Subjects who do not relapse during the study will receive PQ 0.5mg/kg for 14 days at the end of the study.

Protocol document:
Prot_000.pdf: 
2015N232546_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
200894
1
OXTREC 9-16/Protocol 200894 Amendment Number 01/Date 20-APR-2017
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Study 200894: A double-blind, double-dummy, randomized, 
parallel group, placebo-controlled superiority study to evaluate 
the efficacy and safety of tafenoquine (SB-252263, WR238605) 
co-administered with dihydroartemisinin-piperaquine (DHA-
PQP) for the radical cure of Plasmodium vivax malaria
Compound Number:
SB-252263  
Development Phase:
IIIB
Effective Date:
20-APR-2017
Protocol Amendment Number:  01
Author (s):
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N232546_00
2016-JAN-27
Original
2015N232546_01
2017-APR-20
Amendment No. 1

A secondary study objective has been added to compare the efficacy of 
dihydroartemisinin- piperaquine (DHA-PQP) plus primaquine relative to DHA-PQP 
alone.  

A vital signs assessment has been added at Day 2 to permit evaluation of time to fever 
clearance (secondary objective)

The Oxford Tropical Diseases Research Ethics Committee (OXTREC) project 
number (9-16), amendment number and date has been added to the footer of each
page

The secondary medical monitor has been updated to Dr 
MD
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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OXTREC 9-16/Protocol 200894 Amendment Number 01/Date 20-APR-2017
MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After-hours Cell
Number
Site Address
Primary 
Medical 
Monitor
GlaxoSmithKline 
Research & 
Development 
Limited
Iron Bridge Road 
Stockley Park 
West, Uxbridge, 
Middlesex, UB11 
1BT, UK
Secondary 
Medical 
Monitor
GlaxoSmithKline 
Research & 
Development 
Limited
Iron Bridge Road 
Stockley Park 
West, Uxbridge, 
Middlesex, UB11 
1BT, UK
SAE 
contact  
information 
Medical 
monitor as 
above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): Not applicable  
PPD
PPD
PPD
PPD
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OXTREC 9-16/Protocol 200894 Amendment Number 01/Date 20-APR-2017
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200894
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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OXTREC 9-16/Protocol 200894 Amendment Number 01/Date 20-APR-2017
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200894........................................................8
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.1.1.
Global P.vivax Malaria .................................................................13
2.1.2.
Vivax malaria in Indonesia ...........................................................13
2.1.3.
Clinical Management ...................................................................14
2.1.4.
Study Background .......................................................................14
2.2.
Brief Tafenoquine Background....................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................22
4.3.
Type and Number of Subjects.....................................................................22
4.4.
Design Justification.....................................................................................23
4.5.
Dose Justification........................................................................................25
4.6.
Benefit:Risk Assessment ............................................................................26
4.6.1.
Risk Assessment .........................................................................27
4.6.2.
Benefit Assessment.....................................................................30
4.6.3.
Overall Benefit:Risk Conclusion...................................................30
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............31
5.1.
Inclusion Criteria.........................................................................................31
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Run-in Failures............................................................34
5.4.
Withdrawal/Stopping Criteria.......................................................................34
5.4.1.
Liver Chemistry Stopping Criteria ................................................36
5.4.1.1.
Study Treatment Restart or Rechallenge....................37
5.4.2.
Hemoglobin Stopping Criteria ......................................................38
5.4.3.
QTc Stopping Criteria ..................................................................39
5.5.
Subject and Study Completion....................................................................39
6.
STUDY TREATMENT ............................................................................................40
6.1.
Treatment Assignment................................................................................40
6.2.
Planned Dose Adjustments.........................................................................41
6.3.
Blinding.......................................................................................................41
6.4.
Packaging and Labeling..............................................................................42
6.5.
Preparation/Handling/Storage/Accountability..............................................42
6.6.
Compliance with Study Treatment Administration.......................................43
6.7.
Study Treatment Overdose.........................................................................43
6.8.
Treatment after the End of the Study ..........................................................44
6.9.
Concomitant Medications and Non-Drug Therapies....................................45
6.9.1.
Permitted Medications and Non-Drug Therapies..........................45
6.9.1.1.
Concomitant Medications ...........................................45
6.9.1.2.
Rescue Medication.....................................................45
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................45


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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................47
7.1.
Time and Events Table...............................................................................48
7.2
Screening and Critical Baseline Assessments ............................................51
7.3
Unscheduled Visits .....................................................................................53
7.4
Efficacy.......................................................................................................53
7.5
Safety .........................................................................................................54
7.5.1
Adverse Events (AE) and Serious Adverse Events (SAEs)..........54
7.5.1.1
Protocol-Defined SAE (Hb drop).................................54
7.5.1.2
Time period and Frequency for collecting AE 
and SAE information...................................................54
7.5.1.3
Method of Detecting AEs and SAEs ...........................55
7.5.1.4
Follow-up of AEs and SAEs........................................55
7.5.1.5
Cardiovascular and Death Events ..............................55
7.5.1.6
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................56
7.5.1.7
Regulatory Reporting Requirements for SAEs............56
7.5.2
Physical Exams ...........................................................................57
7.5.3
Vital Signs....................................................................................57
7.5.4
Electrocardiogram (ECG).............................................................57
7.5.5
Clinical Safety Laboratory Assessments ......................................58
7.6
Pharmacokinetics .......................................................................................59
7.6.1
Blood Sample Collection..............................................................59
7.6.2
Sample Analysis ..........................................................................59
7.7
Genetics .....................................................................................................60
8.
DATA MANAGEMENT ...........................................................................................60
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................61
9.1
Hypotheses.................................................................................................61
9.2
Sample Size Considerations.......................................................................61
9.2.1
Sample Size Assumptions ...........................................................61
9.2.2
Sample Size Sensitivity................................................................61
9.2.3
Sample Size Re-estimation or Adjustment...................................62
9.3
Data Analysis Considerations .....................................................................62
9.3.1
Analysis Populations....................................................................62
9.4
Key Elements of Analysis Plan ...................................................................62
9.4.1
Secondary Analyses ....................................................................63
10
STUDY GOVERNANCE CONSIDERATIONS........................................................64
10.1
Posting of Information on Publicly Available Clinical Trial Registers............64
10.2
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................64
10.3
Quality Control (Study Monitoring) ..............................................................65
10.4
Quality Assurance.......................................................................................65
10.5
Study and Site Closure ...............................................................................65
10.6
Records Retention......................................................................................66
10.7
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................67
10.8
Review Committees....................................................................................67
11
REFERENCES.......................................................................................................68


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12
APPENDICES........................................................................................................70
12.1
Appendix 1: Abbreviations and Trademarks................................................70
12.2
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................72
12.3
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................76
12.3.1
Definition of Adverse Events........................................................76
12.3.2
Definition of Serious Adverse Events...........................................77
12.3.3
Definition of Cardiovascular Events .............................................78
12.3.4
Recording of AEs and SAEs ........................................................79
12.3.5
Evaluating AEs and SAEs............................................................80
12.3.6
Reporting of SAEs to GSK...........................................................81
12.4
Appendix 4: WHO Definition of Severe Malaria...........................................83
12.5
Appendix 5: Prohibited Medications for Study Entry....................................84
12.6
Appendix 6: Country Specific Requirements...............................................89
12.7
Appendix 7: Protocol Changes....................................................................90


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1.
PROTOCOL SYNOPSIS FOR STUDY 200894
Rationale
Almost half of the 239 million population of Indonesia live in malaria-endemic areas. 
According to recent WHO estimates, the number of new cases of malaria in Indonesia is 
approximately two million per year [Murray, 2014]. The ratio of P. falciparum: P.vivax
infections among diagnosed and reported cases is around 1:1.  From a global malaria 
control and eradication perspective, P. vivax presents the greatest challenge, due to its 
ability to establish a dormant liver stage, the hypnozoite. Relapsing P.vivax malaria is 
caused by hypnozoite activation after initial infection. Severe anaemia, malnutrition and 
respiratory distress are among the symptoms caused by P.vivax infections and cases of 
severe malaria resulting in fatal outcome can occur [Price, 2009, Baird, 2013]. 
The current standard of care for radical cure of P. vivax malaria in most endemic 
countries is chloroquine for clearance of acute parasitemia plus primaquine (15mg or 
30mg once daily for 14 days) to clear the liver stages of the parasite and prevent disease 
relapse. In Indonesia, chloroquine has been replaced by artemisinin-based combination 
therapies (ACTs) for the treatment of blood stage disease due to widespread chloroquine 
resistance. The Indonesian national treatment policy recommends co-administration of 
primaquine (PQ) with an ACT for radical cure of P.vivax malaria. 
Tafenoquine (TQ, SB-252263 and WR 238605) is an 8-aminoquinoline anti-malarial 
drug being co-developed by GlaxoSmithKline and Medicines for Malaria Venture with 
historical support of the Walter Reed Army Institute of Research. It is a synthetic 
analogue of primaquine in development for the radical cure of P. vivax malaria, as a 
single dose co-administered in other studies with standard doses of chloroquine.  The 
shorter course of tafenoquine offers the potential for improved compliance and thus 
effectiveness of relapse prevention, compared with the longer duration regimen for 
primaquine. Tafenoquine has been evaluated in >4000 subjects for the treatment and 
prevention of plasmodial infections during Phase I, II and III clinical studies.
This study will evaluate the efficacy and safety of a single dose of tafenoquine (300mg)
co-administered with an Artemisinin Combination Therapy (ACT) in the radical 
treatment of P. vivax malaria in order to support registration of tafenoquine in Indonesia 
and other countries where ACTs are first line therapy. Dihydroartemisinin-piperaquine 
(DHA-PQP) has been selected as the ACT for this study since it is highly efficacious 
against the chloroquine resistant P.vivax of Eastern Indonesia. Subjects who are glucose-
6-phosphate dehydrogenase (G6PD) deficient will be excluded due to the hemolytic risk 
associated with 8-aminoquinoline drugs.
We have performed a tafenoquine/ACT interaction study (GSK Study 200951). This 
drug-drug interaction (DDI) study assessed the pharmacokinetics and safety of 
tafenoquine when co-administered with DHA-PQP in healthy subjects and demonstrated 
no interactions requiring dose adjustment. However, given the piperaquine-induced QTc 
elongation observed, DHA-PQP will be dosed and ECGs monitored, in accordance with 
the product label. 


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OXTREC 9-16/Protocol 200894 Amendment Number 01/Date 20-APR-2017
Objectives/Endpoints
Objectives
Endpoints
Primary

To determine the efficacy of tafenoquine 
co-administered with DHA-PQP for the 
radical cure of P. vivax malaria, relative to 
DHA-PQP alone at 6 months.

Subjects with relapse-free efficacy six 
months post-dosing.
Secondary

To characterize the efficacy of tafenoquine 
relative to primaquine when co-
administered with DHA-PQP.

Subjects with relapse-free efficacy six 
months post-dosing.

To determine the efficacy of primaquine 
co-administered with DHA-PQP relative to 
DHA-PQP alone.

Subjects with relapse-free efficacy six 
months post-dosing.

To determine the efficacy of tafenoquine 
co-administered with DHA-PQP relative to 
DHA-PQP alone at four months.

Subjects with relapse-free efficacy four 
months post-dosing.

To determine the blood stage efficacy of 
tafenoquine in subjects with P.vivax
malaria when co-administered with DHA-
PQP.

Time to relapse.

Time to fever clearance (in subjects with 
fever at baseline).

Time to parasite clearance.

Percentage of subjects with recrudescence.

To assess the safety of tafenoquine in 
subjects with P. vivax malaria when co-
administered with DHA-PQP.

Incidence and severity of adverse events, 
SAEs, clinically significant abnormal 
laboratory tests, ECGs and vital signs.

Change from baseline in methemoglobin.

Change from baseline in QTcF.

Incidence of protocol defined SAEs (i.e. a 
decrease in hemoglobin of ≥30% or >3 
g/dL from baseline or, a drop in 
hemoglobin below 7.0g/dL, in the first 15 
days).

To evaluate the pharmacokinetics of 
tafenoquine when co-administered with 
DHA-PQP in adult subjects with P.vivax
malaria.

Population PK parameters for tafenoquine 
including oral clearance (CL/F) and volume 
of distribution (V/F).


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In addition, the study has the following objectives:

To explore the genetics of recurrence of P.vivax malaria by evaluating the 
incidence of genetically homologous and heterologous P.vivax infections.

To explore the relationship between CYP2D6 genotype and risk of P.vivax
relapse.

To explore the relationship between the pharmacokinetics of tafenoquine co-
administered with DHA-PQP and pharmacodynamic endpoints (if applicable).
Overall Design

Study 200894 is a double-blind, double-dummy, randomized, parallel group, placebo-
controlled superiority study. The study will be conducted as a collaboration between 
the Eijkman Institute of Molecular Biology (Jakarta), Eijkman Oxford Clinical 
Research Unit (within the Eijkman Institute, Jakarta), Faculty of Medicine, University 
of Indonesia (Jakarta) and the Indonesian army. The protocol will require appropriate 
ethics committee approval. 

Approximately 150 subjects will be enrolled from the Indonesian army returning 
from deployment in a heavily malarious region of Indonesia (e.g. Papua) and 
diagnosed with P. vivax malaria based on microscopic examination (confirmed by a 
second microscopist). 

At Day 1, subjects will be screened for G6PD deficiency using a suitable Point of 
Care Test (e.g. Fluorescent Spot Test) in order to exclude those who are G6PD 
deficient. G6PD deficiency will also be assessed by a quantitative spectrophotometric 
assay but the results will not be available at the time of randomization. 

Subjects who have undergone screening and meet the label requirements for DHA-
PQP dosing can receive open label DHA-PQP if the clinician deems that appropriate 
and at least 3 hours have elapsed since last food intake. Thus, DHA-PQP may be 
commenced whilst the results of the hematology, clinical chemistry or G6PD 
deficiency screening tests are pending. Once all laboratory evaluations are available 
and subject eligibility is confirmed, they will be randomized to blinded study 
treatment on a 1:1:1 basis.  The first dose of blinded study treatment (tafenoquine, 
primaquine or placebo) will be administered with food at least 3 hours after dosing 
with DHA-PQP on Day 1 or Day 2.

Parasitological assessments will be conducted throughout the treatment and follow-up 
periods and on recurrence (if applicable). 

Blinded study treatment will be administered daily, directly observed by site staff, for
14 days.

Duration of study:  Up to 195 days, including screening (Day 1) and randomization to 
treatment (Day 1 or Day 2), 14 daily visits while receiving blinded study treatment 
and seven follow-up visits (Days 21, 28, 60, 90, 120, 150 and 180). Subjects who do 


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not relapse by Day 180 will attend a follow up visit on Day 195, following 14 days of 
open label primaquine. 

Subjects will be closely observed throughout the study by clinical and laboratory 
investigations (vital signs, ECGs, routine hematology/clinical chemistry) and 
measurement of peripheral blood methemoglobin level at selected visits. 

Methemoglobin level will be determined by an independent assessor to avoid any 
potential for unblinding following 8-aminoquinoline dosing. 

Blood samples for TQ pharmacokinetic analyses will be drawn as follows: pre-dose, 
6-12 hours and 24-48 hours post blinded study treatment, Day 7, Day 14, Day 28, 
Day 60 or at relapse (up to 60 days post dose).

Hemoglobin decreases of ≥30% or >3g/dL from baseline or, a drop in absolute 
hemoglobin to <7.0g/dL in the first 15 days of the study, will be reported as a 
protocol-defined SAE even if asymptomatic and not requiring medical intervention. 
Blinded study treatment will be stopped immediately if a subject meets the protocol-
defined SAE criteria for Hb drop together with clinical or laboratory evidence of 
hemolysis.

Subjects diagnosed with recurrent P.vivax malaria during the study will receive an 
ACT plus PQ 0.5mg/kg daily for 14 days as rescue treatment and will be requested to 
continue to attend the scheduled study visits through to Day 180. 

The primary analysis population will be the Intent To Treat (ITT) population

A subject is considered to have completed the double-blind study if they are 
randomized to blinded study treatment and complete the Day 180 visit. 

Subjects who have not relapsed prior to the Day 180 visit, will be given open label 
PQ 0.5mg/kg daily for 14 days to minimize the likelihood of P.vivax recurrence after 
the end of the study. These subjects will return for a final safety follow up visit 15 
days later.
Treatment Arms and Duration

The total duration of study for each subject is 180 – 195 days. 

All subjects will receive standard doses of open label DHA-PQP on Days 1-3. 

Subjects will be randomized to one of three parallel treatment groups in a double 
blind fashion:
o
TQ (300mg single dose)
o
PQ (15mg single daily dose for 14 days)
o
Placebo (daily for 14 days)
Visually matched placebos will be used to maintain the blind. 


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Type and Number of Subjects

The study population will consist of male subjects, aged ≥18 years who have a 
positive smear for P.vivax and are G6PD normal.

Approximately 200 subjects will be screened to achieve 150 randomized subjects for 
a total of 50 evaluable subjects per treatment group. All subjects who are randomized 
and receive at least one dose of blinded study treatment will be included in the intent-
to-treat population. Subjects will not be replaced if they withdraw early from the 
study.
Analysis
The primary efficacy endpoint of subjects with relapse-free efficacy 6 months post-
dosing will be analyzed using survival analysis techniques. If it is not possible to 
completely recruit the study from a single battalion but at least 120 subjects have been 
randomized, a blinded review of the relapse data will be conducted, with the intention to 
stop enrolment early if this review predicts that the combined relapse rate will be ≥26.7% 
at the end of the follow up period (based on sample size assumptions). Kaplan-Meier 
estimates will be made of the overall six month relapse rate, using all of the data 
available at that time. If this relapse criterion is met, enrolment will stop and the study 
will be analyzed once all the existing subjects have completed the 6 months follow up. If 
the blinded review predicts that the relapse rate will be < 26.7%, further subjects will be 
recruited from a second battalion, up to a maximum of 150 subjects in total.


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2.
INTRODUCTION
Tafenoquine (TQ, SB-252263 and WR 238605) is an 8-aminoquinoline anti-malarial 
drug being co-developed by GlaxoSmithKline and Medicines for Malaria Venture
(MMV) with historical support of the Walter Reed Army Institute of Research. It is a 
synthetic analogue of primaquine (PQ) in development for the radical cure of 
Plasmodium vivax (P. vivax) malaria, as a single dose co-administered with standard 
doses of chloroquine.  The shorter course of TQ offers the potential for improved 
compliance and thus effectiveness of relapse prevention, compared with the longer 
duration regimen for PQ. 
In Indonesia, chloroquine has been replaced by artemisinin-based combination therapies 
(ACTs) for the treatment of blood stage disease due to the widespread emergence of 
chloroquine resistance. The Indonesian national treatment policy recommends co-
administration of PQ with an ACT for radical cure of P.vivax malaria. 
The study will evaluate TQ co-administered with an ACT in order to support registration 
of TQ as a radical cure of P.vivax malaria in Indonesia and other countries where ACTs 
are first line therapy. 
2.1.
Study Rationale
2.1.1.
Global P.vivax Malaria
Malaria is a leading cause of morbidity and mortality in many developing countries with 
an estimated 300 to 500 million clinical cases every year. P. vivax malaria accounts for 
almost 50% of malaria cases outside of Africa and is increasingly recognized as a barrier 
to malaria elimination due to its ability to establish a dormant liver stage, the hypnozoite. 
Relapsing P.vivax malaria is caused by hypnozoite activation after the initial infection. 
The disease is associated with more severe impact than previously appreciated, including 
significant risk of death with delayed or inadequate treatment [Price, 2009, Baird, 2013]. 
P. vivax has been shown to be associated with substantial morbidity, particularly severe 
anaemia, respiratory distress and malnutrition.
2.1.2.
Vivax malaria in Indonesia
In Indonesia, almost half of the 239 million population live in malaria-endemic areas 
[Herdiana, 2013].  The WHO recently estimated there were approximately two million 
new cases of malaria in Indonesia during 2013 [Murray, 2014]. However, the true 
incidence of malaria is unknown since laboratory-confirmation is rare and only 
approximately one fifth of subjects with symptomatic malaria seek treatment at 
government health facilities [Karyana, 2008].
Endemic vivax malaria occurs throughout the Indonesian archipelago except where 
excluded by more than 3000 meters (m) of altitude, urbanization or elimination areas of 
Java and Bali. The overall proportion of Plasmodium falciparum:Plasmodium vivax
among diagnosed and reported cases is about 1:1. In Papua, Indonesia’s most eastern 
province, malaria is highly prevalent and the ratio of P.falciparum to P.vivax malaria is 
about 2:1. 


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2.1.3.
Clinical Management
The current standard of care for radical cure of P. vivax malaria in most endemic 
countries is chloroquine for clearance of acute parasitemia plus PQ (15mg or 30mg once
daily for 14 days) to clear the liver stages of the parasite and prevent disease relapse. 
However, the efficacy of this regimen is threatened by the emergence and spread of 
chloroquine-resistant P. vivax in regions such as South East Asia [Lee, 2009, Sutanto, 
2009, Sutanto, 2010, Price, 2014], the Indian subcontinent [Dua, 1996] and in South 
America [Soto, 2001]. In Indonesia, P. vivax resistance to chloroquine is widespread
ranging from 43% in Sumatera Island to >80% in Papua [Sumawinata, 2003, Sutanto, 
2010]. In 2004, the use of chloroquine was replaced by ACTs as first line therapies in 
Indonesia. The national malaria control program is aiming to eliminate the disease by 
2030 [Kusriastuti, 2012].
There is a need to provide alternative treatments to manage P.vivax relapse over and 
above PQ which is the only treatment currently widely available. PQ is administered as a 
once a day oral dose for 7-14 days and it is widely accepted that this long hypnozoiticidal 
dosing regimen (compared to 3 day treatment for clearance of blood stage malaria 
parasites) leads to reduced compliance and hence reduced clinical efficacy.
2.1.4.
Study Background
The objective of this study is to evaluate the efficacy and safety of a single dose of TQ 
(300mg) co-administered with an ACT for the radical treatment of P. vivax malaria in 
Indonesian soldiers returning from a malarious region e.g. Papua. The study is designed 
to demonstrate the superiority of TQ plus dihydroartemisinin-piperaquine (DHA-PQP) 
compared to DHA-PQP alone as a radical cure. The DHA-PQP alone arm is required to 
assess the underlying relapse rate within the setting of this clinical study. A PQ plus 
DHA-PQP comparator arm is included to characterize the efficacy of TQ by providing an 
informal concurrent benchmark against a treatment that has activity against liver-stage 
hypnozoites.
In the Phase IIB programme, a single 300mg dose of TQ co-administered with standard 
doses of chloroquine was more efficacious than chloroquine alone for prevention of P.
vivax malaria relapse with a similar safety profile [Llanos-Cuentas, 2014]. The incidence 
of gastrointestinal (GI)-related AEs was similar following single doses of TQ 300mg and 
PQ 15mg for 14 days.
In recent studies, less than 10% of subjects with P. vivax malaria experienced relapse/re-
infection after treatment with DHA-PQP plus PQ over a 12 month follow up period in 
Indonesia [Pasaribu, 2013, Sutanto, 2013].  Both TQ and PQ can cause acute hemolysis if 
given to subjects with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Subjects 
who are G6PD deficient will be excluded from the study. 
Preliminary data suggest there may be a relationship between CYP2D6 activity and PQ 
anti-relapse efficacy. In a small cohort, subjects who had low activity phenotype of 
CYP2D6 had reduced PQ efficacy compared to subjects who were extensive 
metabolizers [Bennett, 2013]. It has been hypothesized that polymorphisms in CYP2D6 
may decrease formation of an active metabolite of PQ resulting in increased risk of 


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relapse. The relationship between CYP2D6 genotype and risk of P.vivax relapse 
following treatment with TQ or PQ will be explored in this study. The study will also 
examine the pharmacokinetics of TQ when co-administered with DHA-PQP in subjects 
with P.vivax malaria.
Prior to commencing this study, a TQ/ACT interaction study was performed (GSK Study 
200951). This drug-drug interaction (DDI) study assessed the safety and 
pharmacokinetics of TQ when co-administered with DHA-PQP in three parallel groups 
of n=24 healthy subjects. As expected, PQP-induced prolongation of the QTc interval 
was observed. Whilst an absolute difference in QTcF elongation was observed between 
the DHA-PQP alone group and the DHA-PQP plus TQ group, confidence intervals 
overlapped and the difference was not considered clinically significant. No significant 
effect of TQ on the PK of DHA or PQP was found. There was a 12% (1 – 26%, 90% CI) 
increase in the AUC0-inf of TQ when co-administered with DHA-PQP but this is not 
deemed to be clinically significant, with PK parameters not reaching those previously 
seen with higher doses that have been tolerated and safely used in other studies. 
Therefore, no dose adjustments were deemed necessary for co-administration of TQ and 
DHA-PQP in the present study. No new safety signals were noted in Study 200951 but 
ECG monitoring will be performed in the present study in accordance with the DHA-
PQP label (Eurartesim SmPC).
2.2.
Brief Tafenoquine Background
TQ has been shown to have an acceptable safety profile in the treatment and prevention 
of plasmodial infections in pre-clinical models and during Phase I, II and III clinical 
studies in >4000 adult subjects (including >1000 females). The most common AEs 
included nausea, vomiting, abdominal pain, diarrhoea and vortex keratopathy (reversible 
corneal deposits). Gastrointestinal AEs appeared to increase with increasing dose and 
were more common in the fasted versus fed state. Mild, reversible corneal changes were 
mainly observed in repeat dose studies and were similar to those seen with other drugs 
including chloroquine. Methemoglobinemia has been observed with larger total doses of 
TQ than are being considered for the treatment of P.vivax malaria and is most likely 
secondary to TQ induced oxidative stress within red blood cells. Please refer to the TQ 
Investigator Brochure for more information [GlaxoSmithKline Document Number 
GM2007/00152/09, SB-252263 Investigator’s Brochure]. All members of the 8-
aminoquinoline class of drugs, including TQ and PQ, induce hemolysis in subjects with 
G6PD deficiency. G6PD is a housekeeping enzyme responsible for protection against 
oxidant stress. The effects of oxidant stress in subjects with G6PD deficiency are most 
apparent in red blood cells. TQ is thus being developed for treatment of patients with 
sufficient levels of G6PD enzyme activity.  


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To determine the efficacy of 
tafenoquine co-administered with 
DHA-PQP for the radical cure of 
P. vivax malaria, relative to DHA-
PQP alone at 6 months.

Subjects with relapse-free efficacy six 
months post-dosing (i.e. clearance of initial 
infection without subsequent microscopically 
confirmed recurrence during the 6 month 
follow up).
Secondary

To characterize the efficacy of 
tafenoquine relative to 
primaquine when co-administered 
with DHA-PQP.

Subjects with relapse-free efficacy six 
months post-dosing.

To determine the efficacy of 
primaquine co-administered with 
DHA-PQP relative to DHA-PQP 
alone.

Subjects with relapse-free efficacy six 
months post-dosing.

To determine the efficacy of 
tafenoquine co-administered with 
DHA-PQP relative to a DHA-
PQP alone at four months.

Subjects with relapse-free efficacy four 
months post-dosing.

To determine the blood stage 
efficacy of tafenoquine in 
subjects with P.vivax malaria 
when co-administered with DHA-
PQP.

Time to relapse.

Time to fever clearance (in subjects with 
fever at baseline).

Time to parasite clearance.

Percentage of subjects with recrudescence
(blood stage treatment failure) on or before 
Day 14 (i.e. a recurrence of P. vivax parasites 
which is genetically homologous to the 
baseline P. vivax infection).

To assess the safety of 
tafenoquine in subjects with P. 
vivax malaria when co-
administered with DHA-PQP.

Incidence and severity of adverse events and 
SAEs.

Incidence of clinically significant abnormal 
clinical laboratory tests, ECGs and vital 
signs.

Key safety endpoints of interest:


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Objectives
Endpoints
o
GI tolerability – incidence of 
abdominal pain, heartburn, diarrhoea, 
constipation, nausea and vomiting.
o
Change from baseline in 
methemoglobin
o
Change from baseline in QTcF
o
Incidence of protocol-defined SAEs 
(i.e. a decrease in hemoglobin of 
≥30% or >3 g/dL from baseline; or, a 
drop in absolute hemoglobin to < 
7.0g/dL, in the first 15 days) 

To evaluate the pharmacokinetics 
of tafenoquine when co-
administered with DHA-PQP in 
adult subjects with P.vivax
malaria.

Population PK parameters for tafenoquine 
including but not limited to oral clearance 
(CL/F) and volume of distribution (V/F).
Exploratory

To explore the genetics of 
recurrence of P.vivax malaria.

Incidence of genetically homologous and 
genetically heterologous P.vivax infections 
(determined by PCR). 

Whole genome sequencing of multiple 
parasite genes will be undertaken, if parasite 
count allows (to be reported separately).

To examine the relationship 
between CYP2D6 genotype and 
risk of P.vivax relapse.

Percentage of subjects relapsing analyzed 
according to CYP2D6 genotype.

To explore the relationship 
between the pharmacokinetics of 
tafenoquine co-administered with 
DHA-PQP and pharmacodynamic 
endpoints (if appropriate).

Population PK (e.g. tafenoquine plasma 
concentrations) and selected 
pharmacodynamic (PD) endpoints (e.g., 
relapse-free efficacy, change in 
methemoglobin).
With regards to the efficacy endpoints, it should be noted that it is not possible to 
determine if a subject’s recurrence of malaria is a relapse or recrudescence. For the 
purposes of this protocol, the term “relapse” will be used to describe any recurrence of 
P.vivax malaria after clearance of the initial infection. “Recrudescence” applies to the 
term relating to recurrence for Days 1-14 of the study, where a genetically homologous 


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parasite is suggestive of recrudescence. Therefore, within this protocol, recrudescence 
will represent a subset of all the relapses captured. This definition of “relapse” is 
consistent with the definition used in the global tafenoquine studies, as agreed with the 
United States FDA.
4.
STUDY DESIGN
4.1.
Overall Design

Study 200894 is a double-blind, double-dummy, randomized, parallel group, placebo-
controlled superiority study. The study will be conducted as a collaboration between 
the Eijkman Institute of Molecular Biology (Jakarta), Eijkman Oxford Clinical 
Research Unit (within the Eijkman Institute, Jakarta), Faculty of Medicine, University 
of Indonesia (Jakarta) and the Indonesian army. The protocol will require appropriate 
ethics committee approval.

Approximately 150 subjects will be enrolled from the Indonesian army returning 
from deployment in a heavily malarious region of Indonesia (e.g. Papua) and 
diagnosed with P. vivax malaria based on microscopic examination (confirmed by a 
second microscopist). 

Informed consent process: Research team leaders will meet commanders and the 
troops to explain the concept and importance of voluntary informed consent prior to 
inviting subjects to participate in the study. Subjects will give written informed 
consent prior to any screening assessments being undertaken. The written consent 
will be obtained by a site team member who is independent of the subject (i.e. not the 
subject’s commander or supervisor) and the voluntary nature of the study will be 
emphasised (See Section 7.2).

At Day 1, subjects will be screened for G6PD deficiency using a suitable Point of 
Care Test (e.g. Fluorescent Spot Test) in order to exclude those who are G6PD 
deficient (See Study Reference Manual, SRM). G6PD deficiency will also be 
assessed by a quantitative spectrophotometric assay but the results will not be 
available at the time of randomization. If results are discordant, the subject will be 
reviewed and appropriate G6PD testing will be repeated.

Subjects who have undergone screening and meet the label requirements for DHA-
PQP dosing can receive open label DHA-PQP if the clinician deems that appropriate 
and at least 3 hours have elapsed since last food intake. Thus, DHA-PQP may be
commenced whilst the results of the hematology, clinical chemistry or G6PD 
deficiency screening tests are pending. Once all laboratory evaluations are available 
and subject eligibility is confirmed, they will be randomized to blinded study 
treatment on a 1:1:1 basis. The first dose of blinded study treatment will be 
administered with food at least 3 hours after dosing with DHA-PQP, on Day 1 or Day 
2 (see Section 7.2).


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
Blood smears will be done twice daily, 6-12 hours apart until two consecutive 
negative smears are obtained. Additional blood smears will be done throughout the 
treatment and follow up period and on recurrence (if applicable). 

An on-site clinic will be established at the army base, which will be available 24 
hours a day and 7 days a week for the duration of the study. 

Blinded study treatment will be administered daily, directly observed by site staff, for
14 days.

Duration of study:  Up to 195 days, including screening (Day 1) and randomization to 
treatment (Day 1 or Day 2), 14 daily visits while receiving blinded study treatment 
and seven follow-up visits (Days 21, 28, 60, 90, 120, 150 and 180). Subjects who do 
not relapse by Day 180 will attend a follow up visit on Day 195, following 14 days of 
open label primaquine.

Plasmodium PCR genotyping will be performed on all baseline samples and in 
subjects who relapse to explore the proportion of heterologous and homologous 
relapses using appropriate PCR markers as well as define baseline genetic variability. 
Parasite whole genome sequencing will also be performed in a similar fashion, if 
parasite counts allow; these data will be reported separately. 

Subjects will be closely observed throughout the study by clinical and laboratory 
investigations including vital signs, ECGs, routine hematology/clinical chemistry and 
peripheral blood methemoglobin (metHb) levels at selected visits. This allows 
subjects who have a recurrence (e.g. those that happen to be randomized to the DHA-
PQP alone arm) to be rapidly identified and safely managed minimizing the risk of 
serious clinical consequences of recurrence.

MetHb will be determined by an independent assessor to avoid any potential for 
unblinding following 8-aminoquinoline dosing (refer to SRM). 

Subjects will be asked to report to the clinic at any time of the night or day should 
they feel unwell or develop a fever. Any subject diagnosed with recurrent P.vivax
malaria (defined as a positive blood smear with or without vivax symptoms) will 
receive an ACT plus PQ 0.5mg/kg daily for 14 days and will be requested to continue 
to attend the scheduled study visits through to Day 180. 

Blood samples for TQ pharmacokinetic analyses will be drawn at the following times: 
pre-dose, 6-12 hours and 24-48 hours post blinded study treatment, Day 7, Day 14, 
Day 28, Day 60 or at relapse (up to 60 days post dose).

Hemoglobin decreases of ≥30% or >3g/dL from baseline or, a drop in absolute 
hemoglobin to <7.0g/dL, in the first 15 days will be reported as a protocol-defined 
SAE even if asymptomatic and not requiring medical intervention. Blinded study 
treatment will be stopped immediately if a subject meets the protocol-defined SAE 
criteria for Hb drop together with clinical or laboratory evidence of hemolysis (refer 
to Section 5.4.2 and Section 7.5.1.1).


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
Exploratory CYP2D6 genotype analyses will be undertaken to test the hypothesis that 
null and/or intermediate metabolizers of 8-aminoquinoline drugs are more at risk of 
P. vivax relapse with PQ but not TQ [Bennett, 2013].

The primary analysis population will be the Intent To Treat (ITT) population

A subject is considered to have completed the double-blind study if they are 
randomized to blinded study treatment and complete the Day 180 visit. 

Subjects who have not relapsed prior to the Day 180 visit will be given open label PQ 
0.5mg/kg daily for 14 days to minimize the likelihood of P. vivax recurrence after the 
end of the study. These subjects will return for a final safety follow up visit 15 days 
later.

If it is not possible to completely recruit the study from a single battalion but at least 
120 subjects have been randomized, a blinded review of the relapse data will be 
conducted, with the intention to stop enrolment early if this review predicts that the 
combined relapse rate will be ≥26.7% at the end of the follow up period (based on 
sample size assumptions). Kaplan-Meier estimates will be made of the overall six 
month relapse rate, using all of the data available at that time. If this relapse criterion
is met, enrolment will stop and the study will be analyzed once all the existing 
subjects have completed the 6 months follow up. If the blinded review predicts that 
the relapse rate will be < 26.7%, further subjects will be recruited from a second 
battalion, up to a maximum of 150 subjects in total (See Section 9.2.3).

The study design schematic is provided in Figure 1.


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Figure 1
200894 Study Design Schematic
Screening
Treatment Period
Follow-Up Period
Open 
label-PQ
(only for 
subjects 
who do 
not 
relapse)
Day 1
14 days 
Day 
21
Day 
28
Day 
60
Day 
90
Day 
120
Day 
150
Day 
180
Day 
195***
Withdrawn 
from 
Treatment
Follow-Up Assessments (Days 21-180)
Relapse**
Informed 
Consent
Signed
Treatment 
Completed
DHA-PQP (Days 1-3) plus blinded 
treatment for 14 days DOT
(starting Day 1 or Day 2)
Open label DHA-PQP 3 or 4 tablets per day (according to weight) on Days 1-3 plus blinded study treatment as follows:
1)  Tafenoquine 300 mg single dose on Day 1 and placebo for primaquine on Day 1-14*
2)  Primaquine 15mg on Days 1-14 and placebo for tafenoquine on  Day 1*
3)  Placebo for tafenoquine on Day 1 and placebo for primaquine on Days 1-14*
* Blinded study treatment will start on Day 1 or Day 2 and continue for 14 days
** Subjects who relapse  before D180 will receive immediate rescue treatment  (ACT + PQ 0.5mg/kg daily for 14 days) and attend FU visits
***Subjects who do not relapse before D180 will receive open label PQ (0.5mg/kg daily for 14 days) and return for Day 195 visit 
Withdrawal –
attend w/d visit


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4.2.
Treatment Arms and Duration
Subjects will receive open label DHA-PQP plus blinded tafenoquine or blinded 
primaquine or placebo as shown in the table below. Visually matching placebo 
medication will be used to maintain the blinding.
Open label DHA-
PQP 
Blinded Tafenoquine 
or Placebo
Blinded Primaquine 
or Placebo 
Arm 1
DHA-PQP alone 
(placebo arm)
Open label DHA-PQP 
tablets *
Single daily dose on 
Days 1-3
Placebo to match 
tafenoquine tablets 
150mg (2 tablets)
Single dose on Day 1
or 2
Placebo to match 
overencapsulated 
primaquine  tablets 
15mg (1 capsule)
Single daily dose  for 
14 days commencing 
Day 1 or 2
Arm 2
DHA-PQP plus 
tafenoquine 300mg  
single dose
Open label DHA-PQP 
tablets*
Single daily dose on 
Days 1-3
Tafenoquine tablets 
150mg (2 tablets)
Single dose on Day 1
or 2
Placebo to match 
overencapsulated 
primaquine tablets 
15mg (1 capsule)
Single daily dose  for 
14 days commencing 
Day 1 or 2
Arm 3
DHA-PQP plus 
primaquine 15mg 
for 14 days
Open label DHA-PQP 
tablets*
Single daily dose on 
Days 1-3
Placebo to match 
tafenoquine tablets 
150mg (2 tablets)
Single dose on Day 1
or 2
Overencapsulated 
primaquine  tablets 
15mg (1 capsule)
Single daily dose for 
14 days commencing 
Day 1 or 2
* Open label DHA-PQP (piperaquine tetraphosphate (PQP) 320mg/ dihydroartemisinin (DHA) 
40mg) tablets will be dosed according to weight (3 tablets per day for subjects weighing <75Kg 
and 4 tablets per day for subjects weighing ≥75Kg).
4.3.
Type and Number of Subjects
Approximately 200 subjects will be screened to achieve 150 randomized subjects for a 
total of 50 evaluable subjects per treatment group. All subjects who are randomized and 
receive at least one dose of blinded study treatment will be included in the intent-to-treat 
population. Subjects will not be replaced if they withdraw early from the study.


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4.4.
Design Justification
Selection of soldiers as study population: The study will be conducted in male soldiers 
diagnosed with P.vivax malaria following return to a malaria non-endemic area of 
Indonesia after a recent deployment to a heavily malarious region (e.g. Papua). This study 
model has been selected as it should provide a reliable estimate of the true relapse rate 
(rather than overall recurrence rate) following TQ co-dosed with DHA-PQP since in this 
setting recurrent parasitemias are most likely to arise from re-activated hypnozoites rather 
than re-infection. It is recognized that members of the armed forces are considered a 
vulnerable population for clinical trials [ICH Guidance for Industry. Guideline E6 ]. 
Special attention will be paid to ensuring that the commanders and troops understand the 
concept and importance of voluntary informed consent prior to commencing the study 
(See Section 7.2). The study will undergo appropriate ethics committee review.
This is a soldier study population and only male subjects will be recruited. However, the 
safety profile of TQ has also been evaluated in over 1000 females who participated in 
Phase I, II and III clinical studies. The data indicate similar tolerability of TQ in males 
and females with the exception of G6PD heterozygous females who are at increased risk 
of mild to moderate hemoglobin declines. The safety of TQ in this population is being 
evaluated in a separate study (Study TAF116564). TQ will be contraindicated in pregnant 
and lactating females.
Selection of ACT: DHA-PQP has high efficacy rates (>95%) for clearing the blood stage 
infection of P.vivax in regions of Indonesia where chloroquine resistance is common 
[Ratcliff, 2007, Hasugian, 2007]. Both DHA-PQP and artesunate –amodiaquine are first 
line treatments for P.falciparum and P.vivax in Indonesia, although DHA-PQP is 
preferred due to its superior efficacy and better tolerability compared to other ACTs 
[Hasugian, 2007] (See Section 4.5).
Justification for DHA-PQP alone arm (relapse control arm): All subjects will receive the 
standard 3 day course of DHA-PQP which is expected to clear the initial blood stage 
infection. The inclusion of the DHA-PQP alone arm provides a relapse prevention 
placebo-control arm for the primary comparison of TQ versus no anti-hypnozoite 
treatment to confirm and quantify TQ efficacy in preventing relapse. Therefore, no 
subject will be left untreated for their acute malarial infection. All subjects will be under 
close observation and will be asked to report to the clinic at any time if they feel unwell 
or develop a fever. The research team aims to treat recurrent acute malaria at the earliest 
possible stage thereby ensuring subject safety and minimizing discomfort as a 
consequence of having malaria. Subjects who develop a recurrent parasitemia 
(symptomatic or asymptomatic) will receive immediate rescue treatment according to 
local treatment guidelines (see Section 6.9.1.2). On-site clinic facilities will be available 
24 hours, 7 days a week to ensure the prompt management of any subject who relapses 
during the study. To ensure that all subjects do receive anti-hypnozoite treatment, 
subjects who have not relapsed by Day 180 will be dosed with PQ 0.5mg/kg daily for 14 
days to minimize the likelihood of P.vivax recurrences after the end of the study.
The DHA-PQP alone arm is considered crucial to the study design to evaluate the true 
efficacy of TQ in preventing relapse. The underlying relapse rate following a course of 


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DHA-PQP cannot be assumed from historical data due to the natural variation in both 
infection rates and relapse rates among infected subjects. Therefore, it is essential to 
measure the relapse rate following treatment with DHA-PQP alone in the same setting 
and time as the study treatment arms.
Although local treatment guidelines recommend an ACT plus PQ for radical cure of P. 
vivax, in real life, PQ is used infrequently because of concerns about its potential to cause 
red cell hemolysis in G6PD deficient subjects and facilities for assessing G6PD status are 
lacking. Additionally, compliance with unsupervised PQ is low. 
As an alternative, PQ could be considered as the primary control arm in a study designed 
to demonstrate non-inferiority. However, a superiority design study will provide more 
robust evidence of efficacy of TQ, given the lack of agreement over dose and duration of 
PQ dosing. Of note, a non-inferiority study would also require hundreds of additional 
subjects. 
Primaquine comparator arm: PQ is selected as the benchmark comparator for this study 
as PQ plus DHA-PQP is a first line treatment regimen for radical cure of P. vivax malaria 
in Indonesia. Inclusion of this arm provides a context against which to interpret the 
observed TQ efficacy rate. A statistical comparison for non-inferiority between the TQ 
and PQ regimen will not be performed due to the inadequate sample size. A 1:1:1 
randomization ratio will be used to ensure a sufficiently large cohort of subjects in the PQ 
arm to obtain a precise estimate of the efficacy of PQ.
A TQ alone arm has not been included as the drug is absorbed more slowly than ACTs or 
CQ  and therefore a delayed fever clearance time was observed when this drug (even 
though used at 4 times the dose in this study) was used alone to treat P. vivax subjects 
(refer to the Investigator Brochure).
Study duration: A six month study duration is considered sufficiently long to demonstrate 
a statistical difference in the incidence of relapse between DHA-PQP and DHA-PQP plus 
TQ. It is anticipated that at least 50% of subjects in the DHA-PQP alone arm will have 
relapsed by 6 months compared to less than 15% in the DHA-PQP plus TQ arm. A recent 
Indonesian study reported a relapse rate of 78% at 6 months following artesunate alone 
which is a shorter acting schizonticidal drug than DHA-PQP [Sutanto, 2013]. Therefore, 
a lower relapse rate may be expected in the DHA-PQP arm in this study. The study is 
powered to demonstrate a 35% difference in the relapse rate between the DHA-PQP 
alone arm and the DHA-PQP plus TQ arm, assuming a 10% drop out rate.
Justification for qualitative G6PD phenotyping: G6PD deficient subjects will be excluded 
from the study on the basis of a suitable Point of Care test e.g. Fluorescent Spot Test 
(FST) rather than a quantitative spectrophotometric phenotype assay. The FST test is 
sufficiently sensitive to identify G6PD deficient male subjects and is a more practical test 
to conduct on-site at the army base. This approach has been used successfully in other 
anti-relapse studies [Nelwan, 2015, Sutanto, 2013]. The qualitative test will be backed up
by the quantitative phenotype assay performed at the Eijkman Institute with results 
available shortly after enrolment. Given that the subjects are all males, intermediate 
G6PD values are unlikely to be encountered and the FST is highly reliable at identifying 
truly deficient male hemizygotes [Baird, 2015, Bancone, 2014].  


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Rationale for Interim Blinded Data Review: It is not possible to predict whether the target
number of 150 subjects can be enrolled from one battalion. Additionally, there is 
uncertainty regarding the effect size of DHA-PQP plus TQ compared to DHA-PQP alone 
in preventing P. vivax relapse in this study setting, with the possibility that the study may 
be over-powered. Therefore, a blinded review of the relapse data will be undertaken if it 
is not possible to completely recruit 150 subjects from one battalion but at least 120 
subjects have been enrolled, with the intention of stopping enrolment if this review 
predicts that there will be sufficient relapses at the end of the 6 month follow up to 
provide sufficient power to show a meaningful clinical difference. Kaplan-Meier 
estimates will be made of the overall six month relapse rate, using all of the data 
available at that time in order to predict the relapse rate at the end of the 6 month follow 
up. This blinded review will only be performed if the study site considers that 150 
subjects will not be yielded from one battalion but at least 120 subjects have been 
enrolled to ensure an adequate safety database for the DHA-PQP plus TQ regimen (see 
Section 9.2.3).
4.5.
Dose Justification
Justification for tafenoquine dose: 
A completed Phase IIB randomized, double-blind, dose-ranging study evaluated single 
doses of TQ (50mg to 600mg) co-administered with standard doses of the blood stage 
schizonticide, chloroquine in subjects with P.vivax malaria. The study demonstrated a 
clear dose-response with regard to prevention of relapse. Doses of 300mg and 600mg 
were both highly efficacious and superior to placebo, but with no evidence of additional 
efficacy with the higher dose [Llanos-Cuentas, 2014]. There were no new safety concerns 
of note identified in this study; the overall incidence of adverse events was similar across 
TQ doses. Thus, based on the Phase IIb data and those from a safety study 
[GlaxoSmithKline Document Number 2013N172577_00, Study TAF110027] that 
estimated the hemolytic potential of TQ in subjects heterozygous for G6PD deficiency,  
the  300mg dose was selected for evaluation in the ongoing Phase III programme in 
conjunction with a chloroquine. Additional supporting data for the 300mg TQ dose is 
available in the Investigator Brochure which includes a full description of the data from 
previously conducted studies.
Justification of DHA-PQP dose regimen: 
The DHA-PQP dose regimen will be in accordance with the approved European 
prescribing information for Eurartesim (Eurartesim SmPC). Headache, anaemia, QTc 
prolongation, tachycardia, asthenia and pyrexia are the most common adverse events 
associated with this regimen in adults. Clinical trial data showed that QTc prolongation 
occurred more frequently and to a larger extent following Eurartesim than with 
comparators. In a Phase III study, before the third dose of Eurartesim, 3/767 patients 
(0.4%) had a QTcF value of >500ms versus none in the comparator group (Eurartesim 
SmPC). Modest QTc prolongation was also detected on Day 2 following dosing with 
DHA-PQP plus PQ in a recent Indonesian soldier study; the effect returned to baseline by 
Day 7 (Nelwan, 2015). No clinically significant drug-drug interaction was observed 
between DHA-PQP and TQ in GSK Study 200951. However, given the piperaquine-


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induced QTc elongation observed, ECGs will be monitored in line with the Eurartesim 
prescribing information.
Justification of primaquine dose
Subjects in the PQ treatment arm will receive a 15mg dose of PQ for 14 days (equivalent 
to 0.25mg/kg in a 60kg subject), in line with the local treatment guidelines [Kusriastuti, 
2012]. Subjects who have a recurrence of P.vivax during the study will be treated with an 
ACT plus PQ 0.5mg/kg for 14 days (equivalent to 30mg in a 60kg subject), which is in 
line with local treatment guidelines for P. vivax relapse.
Mild gastrointestinal upset occurs in about 10% of subjects taking PQ on an empty 
stomach, is dose-related and is improved by dosing with food [Fryauff, 1995]. Red cell 
hemolysis and methemoglobinemia are the two main hematological toxicities associated 
with PQ (Primaquine SmPC). Routine blood examinations (including blood cell counts 
and hemoglobin determinations) will be performed in line with the prescribing 
information. Acute hemolysis can occur if PQ is given to subjects with G6PD deficiency. 
All subjects who are G6PD deficient at screening will be excluded from this study. An 
independent assessor will determine metHb levels in order to avoid any potential for 
unblinding due to the anticipated increases in metHb following 8-aminoquinoline dosing 
(refer to SRM). 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with TQ can 
be found in the Investigator Brochure. The following section outlines the potential key 
risks associated with study treatment and mitigation strategy for this protocol. For a full 
description of all potential risks associated with study treatment, please refer to Section 6
of the Tafenoquine Investigator Brochure and to the SmPC’s for primaquine and DHA-
PQP.


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4.6.1.
Risk Assessment
Potential Key Risks of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Treatments 
Hemolysis in G6PD-deficient subjects
Tafenoquine and primaquine are 8-
aminoquinolines, a class of drug known to exert 
oxidative effects on hemoglobin (Hb). In patients 
with G6PD deficiency (or other disorders of 
erythrocytic pentose phosphate pathway of 
glucose metabolism) hemolysis is expected due 
to red blood cells (RBCs) lack of capacity to 
protect itself against oxidative effects of such 
drugs. Hemolysis has been reported in G6PD 
deficient patients inadvertently recruited into 
previous TQ studies.

All subjects who are G6PD deficient will be 
excluded. Subjects with Hb levels <8g/dL
will also be excluded.

Hematological study treatment stopping 
criteria are provided.

Subjects will be closely monitored around 
the expected time of Hb drop to enable 
intervention if required.

Recommendations for clinical management 
of hemolysis will be provided as part of the 
investigator training.
Methemoglobinemia 
Methemoglobinemia has been observed in 
previous studies associated with larger total 
doses of tafenoquine than are being considered 
for clinical investigation.  Risk factors have been 
assessed and include a strong relationship 
between metHb development, tafenoquine
dose, and body surface area.
The 300mg dose recommended for this study 
should pose minimal risk of causing elevations 
of metHb of clinical concern.
Methemoglobinemia has also been observed 
following administration of large doses of 
primaquine and in NADH methemoglobin 
reductase deficient individuals.

MetHb percentage will be monitored non-
invasively at selected times throughout the 
study.


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Potential Key Risks of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
QTcF prolongation
The product labelling for DHA-PQP (Eurartesim 
SmPC) notes that in clinical trials, QTc 
prolongation occurred more frequently and to a 
larger extent following DHA-PQP than with 
comparators. Before the 3rd dose, in one of two 
Phase III studies, 3/767 (0.4%) subjects were 
reported to have a QTc value >500msec versus 
none in the comparator group.  Absorption of 
piperaquine is increased in the presence of fatty 
food which may increase its effect on QTc 
interval.
Preclinical studies determined that tafenoquine 
has a low potential for QTc prolongation. A 
tafenoquine thorough QT study did not show 
elongation of the QTcF at clinical doses. In the 
200951 DDI study, the greatest increase in QTc 
was observed 4 hours after the last dose of 
DHA-PQP in both the DHA-PQP+TQ group and 
the DHA-PQP alone group; this time point will 
be a key point of interest for ECGs in this study.
The label for primaquine (US prescribing 
information) notes that primaquine has the 
potential for QT interval prolongation and 
advises the need for ECG monitoring in subjects 
with relevant underlying comorbid conditions, as 
well as during concomitant administration with 
QT interval prolonging agents.

ECG monitoring will be conducted in this 
study appropriate to DHA-PQP and 
primaquine labels. Study treatment 
stopping criteria are provided for QTc 
prolongation.

DHA-PQP will be dosed without food.


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Potential Key Risks of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Design
Risk of relapse in DHA-PQP alone arm
Subjects in the DHA-PQP alone arm are at 
increased risk of relapse during the study 
compared to subjects randomized to DHA-
PQP+primaquine or DHA-PQP+tafenoquine

Subjects will be under close observation 
throughout the study and will receive 
standard of care treatment at first sign of 
recurrent malaria (symptomatic or 
asymptomatic). On site clinic facilities will be 
available 24 hours a day, 7 days a week to 
ensure prompt management of any subject 
who develops recurrent malaria.

At the end of the study, any subject who has 
not relapsed will be given open label PQ 
0.5mg/kg daily for 14 days to minimize the 
likelihood of relapses after the study.
Risk of partial study unblinding 
Increases in methemoglobin anticipated in the 
8-aminoquinoline arms could partially unblind 
the study.

The site will employ an independent metHb 
assessor who will not have access to other 
data for the study. The data will be handled 
securely by an independent data manager 
at GSK. The other site staff, CRAs and GSK 
study team will not have access to the 
metHb data prior to unblinding the 
database.

Selection of PQ dose (15mg rather than 
30mg) will reduce the likelihood of partial 
unblinding due to increases in metHb.


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4.6.2.
Benefit Assessment
In the absence of radical cure treatment, a percentage of subjects with P. vivax malaria 
will relapse due to the liver being infected with hypnozoites (the dormant form of the 
parasite).  P. vivax can cause a debilitating fever as it preferentially invades reticulocytes 
as well as causing bystander hemolysis, which can also lead to the development of 
anemia. Repeated relapses are similarly debilitating and may result in further episodes of 
fever, weight loss, malnutrition and high output heart failure. Other consequences are loss 
of work, time at school missed and hospitalization due to vomiting, dehydration and 
anemia (resulting in the need for transfusion). 
Subjects may benefit from participating in this study since they will be closely followed 
for 6 months, thus ensuring that any malaria recurrences will be appropriately treated and
concurrent conditions managed. Any subject who has not relapsed by the 6 month 
timepoint will be treated with open label PQ for 14 days, to ensure that all participants 
receive anti-hypnozoite medication as part of the study. In the future, patients with 
P.vivax malaria may benefit from TQ since it can be administered as a single oral dose 
(due to its long half life) and is therefore a more convenient treatment regimen compared 
with the standard 14 day regimen of PQ, with the potential to improve patient 
compliance. Improved compliance should lead to improved clinical outcomes for patients 
with P. vivax malaria by further reducing relapse rates.  
4.6.3.
Overall Benefit:Risk Conclusion
TQ is being developed with the aim of a benefit:risk profile which is at least as good as 
the current standard therapy PQ. It is anticipated that this study will demonstrate that a 
convenient single dose of TQ is effective and safe when given in conjunction with an 
ACT for radical cure of P. vivax malaria and has a comparable profile to a 14 day 
regimen of PQ (15mg). All subjects will be closely observed and any adverse effects 
associated with study treatment or relapses of malaria will be promptly managed to 
minimize any risk to subjects participating in the study. G6PD deficient subjects will be 
excluded to avoid hemolytic risks associated with hypnozoite treatment.


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5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the TQ Investigator Brochure.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE and SEX
1. Male subjects ≥18 years at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. The subject has a positive Giemsa smear for P. vivax (mixed infection with 
P.falciparum is acceptable).
3. The subject has a parasite density of >20 /µL. 
4. Glucose-6-phosphate dehydrogenase (G6PD) normal using a suitable qualitative 
assessment e.g. NADPH qualitative fluorescent spot test (Trinity Biologicals, USA).
5. The subject has a QTcF of <450 msec.
N.B. Reading based on an average of triplicate ECGs obtained over a brief 
recording period by machine.
6. The subject is willing and able to comply with the study protocol.
INFORMED CONSENT
7. Capable of giving signed informed consent as described in Section 7.2 which includes 
compliance with the requirements and restrictions listed in the consent form and in 
this protocol.


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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Severe P.vivax malaria as defined by WHO criteria (see Section 12.4 Appendix 4).
2. Severe vomiting (no food or inability to take food during the previous 8 hours).
3. Screening hemoglobin (Hb) concentration <8g/dL.
4. Liver function test ALT >2 x ULN.
5. Any clinically significant concurrent illness (e.g., pneumonia, septicemia), significant 
pre-existing conditions (e.g., renal disease, malignancy, Type 1 diabetes), conditions
that may affect absorption of study treatment (e.g., vomiting, severe diarrhea), or 
clinical signs and symptoms of severe cardiovascular disease (e.g., uncontrolled 
congestive heart failure, severe coronary artery disease). These abnormalities may be 
identified on the screening history and physical or laboratory examination.
6. History of hypersensitivity, allergy or adverse reactions to DHA or other artemisinins, 
piperaquine, tafenoquine or primaquine.
CONCOMITANT MEDICATIONS
7. Subject has previously received treatment with tafenoquine, or has received treatment 
with any other investigational drug within 30 days of study entry or within 5 half-
lives, whichever is longer.
8. Subject has taken anti-malarials (e.g., ACTs, mefloquine, primaquine, quinacrine) or 
drugs with anti-malarial activity within the past 30 days (see Section 12.5 Appendix 
5).
9. Subjects who will likely require the use of medications from the prohibited 
medications list or have taken them in the past 30 days  (see Section 12.5 Appendix 
5) which include the following medications and medication classes:

Drugs with hemolytic potential

Drugs known to prolong the QTc interval including:
o
Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, 
procainamide, quinidine, hydroquinidine, sotalol).
o
Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, 
haloperidol, mesoridazine, pimozide, or thioridazine) and antidepressive 


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CONCOMITANT MEDICATIONS
agents.
o
Certain antimicrobial agents, including agents of the following classes: 
macrolides (e.g. erythromycin, clarithromycin), fluroquinolones (e.g. 
moxifloxacin, sparfloxacin), imidazole and triazole antifungal agents and 
also pentamidine and saquinavir.
o
Certain non-sedating antihistamines (e.g. terfenadine, astemizole, 
mizolastine).
o
Cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, 
levomethadyl, methadone, vinca alkaloids, arsenic trioxide.

The biguanides: phenformin and buformin (but excluding metformin-see 
Section 6.9.2).

Drugs that are substrates of the renal transporters OCT2, MATE1 and MATE2 
and have a narrow therapeutic index (for example, the antiarrhythmic agents: 
dofetilide, procainamide and pilsicainide).
RELEVANT HABITS
10. Anticipated to be unable to consume daily study treatment under direct supervision by 
the research team.
11. Previous participation in the present clinical trial, i.e., subjects experiencing relapse 
during or after the study period may not be enrolled as a new subject.
12. History of illicit drug abuse or heavy alcohol intake, such that full participation in the 
study could be compromised.
CONTRAINDICATIONS 
13. Any contraindication in the opinion of the Investigator to DHA-PQP or primaquine 
administration (refer to locally approved prescribing information for primaquine)
such as:

Family history of sudden unexplained death (DHA-PQP)

Known congenital QTc prolongation (DHA-PQP)

Known history of a medical condition known to prolong the QT interval: 
e.g.myxoedema, cardiomyopathies, recent myocardial infarction (DHA-
PQP)

History of symptomatic cardiac arrhythmias or with clinically relevant 


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bradycardia (DHA-PQP)

Cardiac illnesses predisposing to arrhythmias e.g. severe hypertension, left 
ventricular hypertrophy, cardiomyopathies, cardiac failure with reduced 
ejection fraction (DHA-PQP)

Presence of an electrolyte disturbance particularly hypokalemia, 
hypocalcemia, hypomagnesemia (DHA-PQP)

Rheumatoid arthritis, lupus erythematosus and other systemic conditions 
that may cause granulocytopenia (primaquine)

History of hemolytic anemia, methemoglobinemia and leucopenia 
(primaquine)
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events.
Any subject who receives DHA-PQP but is not subsequently randomized to blinded study 
treatment will be deemed a Screen Failure.
5.4.
Withdrawal/Stopping Criteria
A subject may withdraw from the study or discontinue study treatment at his/her own 
request, or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural or administrative reasons. If a subject withdraws from the study, he/she may 
request destruction of any samples taken, and the investigator must document this in the 
site study records. 
Premature Study Withdrawal
A subject is considered to be withdrawn prematurely from the study if they do not 
complete the Day 180 assessment. Subjects may be prematurely discontinued from the 
study for any of the following reasons:

Adverse event

Protocol deviation

Study closed/terminated


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
Loss to follow-up

Consent withdrawal

Subject or investigator non-compliance

At the request of the subject, investigator, or sponsor
Subjects are not obligated to state the reason for withdrawal from this study. However, 
the reasons for withdrawal, or failure to provide a reason, must be documented by the 
investigator on the Completion/Withdrawal section of the electronic Case Record Form 
(eCRF). If a subject is withdrawn from the study for any reason, the investigator should 
make every effort to perform the study evaluations as specified in the Time and Events 
table for the Withdrawal visit as applicable.
Premature Withdrawal of Study Treatment
If a subject prematurely discontinues from study treatment for any reason or reaches the 
primary endpoint of relapse, they should continue to attend study visits to Day 180. The 
reason for withdrawal from treatment should be recorded in the electronic case record 
form (eCRF). Given the long half life of tafenoquine, the maximal pharmacodynamic 
effects such as potential hemolysis or methemoglobinemia may occur several days after 
completion of dosing. These data will be recorded, as they comprise an essential 
evaluation that needs to be done before discharging any subject from the study. 
Therefore, the investigator should continue following subjects for all protocol 
assessments, up to and including Day 180 whenever possible. The subject should be 
given appropriate rescue therapy according to local treatment guidelines if they develop a 
malarial recurrence (see Section 6.9.1.2). 
Subjects should discontinue taking study treatment if they meet any of the criteria below:

Intolerable AEs:

Any grade 4 AE or toxicity in the absence of compelling evidence that the 
AE is not related to investigational product(s)

Clinically significant laboratory results considered by the investigator to warrant 
withdrawal from the study treatment

Liver chemistry stopping criteria  (refer to Section 5.4.1 and Section 12.2
Appendix 2)

Hemoglobin stopping criteria: Given the hemolytic potential of TQ and PQ in 
subjects with G6PD deficiency, study specific hematologic stopping criteria will 
be employed (refer to Section 5.4.2)

QTc stopping criteria (refer to Section 5.4.3)
When QT or hemolytic stopping criteria are met, this must be promptly reported by the 
investigator to GSK as a Serious Adverse Event (see Section 7.5)


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Subjects Lost to Follow Up
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record.

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*


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As blinded tafenoquine study treatment is administered as a single dose, the above 
criteria for stopping medication do not apply. However, the liver safety required actions 
and follow up assessments must be followed if the stopping criteria are met – see 
Appendix 2 (Section 12.2). The liver safety follow-up assessments will be carried out by 
a local commercial laboratory where possible. If assessments are not available in 
Indonesia, samples will be stored in Indonesia until such time as a Material Transfer 
Agreement (MTA), if necessary, is formally approved for the transfer of the sample to the 
designated laboratory for analysis. 
Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2 (Section 12.2).
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met, are 
not allowed by any subject participating in this study.


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5.4.2.
Hemoglobin Stopping Criteria
Blinded study treatment will be stopped immediately in any subject who meets the 
protocol-defined criteria for Hb drop (See Section 7.5.1.1) AND has EITHER clinical 
evidence of hemolysis OR laboratory evidence of hemolysis based on an assessment of 
the  tests listed below.  These laboratory tests will be performed immediately once a 
protocol-defined Hb drop is noted by the investigator.
Hematology

Hemoglobin

Hematocrit

Platelets

WBC

RBC

Reticulocytes
Clinical Chemistry

Creatinine

BUN

Total bilirubin

Indirect bilirubin

AST

ALT

Alkaline phosphatase

CPK

LDH

Visual inspection of urine and dipstick
Subjects will also be required to have a repeat G6PD quantitative phenotype test to 
confirm that they are not G6PD deficient. G6PD genotyping may be performed if repeat
phenotyping would not define G6PD status (e.g. transfusion given or high reticulocyte 
count).  


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5.4.3.
QTc Stopping Criteria
Study treatment will be stopped if any of the following criteria are met:
• QTcF >500 msec 
• Uncorrected QT >600msec 
These criteria should be based on the average QTcF value of triplicate ECGs. For 
example, if an ECG demonstrates a prolonged QTcF interval, two more ECGs should be 
obtained over a brief period, and then the averaged QTcF values of the three ECGs
should be used to determine whether the subject should then be discontinued from the 
study. ECG monitoring during the following 24-48 hours should be applied for subjects
found to have a prolongation to this extent. 
For subjects with underlying bundle-branch block, the criteria is QTcF ≥530msec.
5.5.
Subject and Study Completion
A completed subject is one who has been randomized to blinded study treatment and has 
a day 180 assessment.
The end of the study is defined as the last subject’s last visit.


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6.
STUDY TREATMENT
‘Blinded study treatment’ refers to tafenoquine, primaquine and the corresponding 
placebos. 
Study Treatment
Product name:
Tafenoquine
(SB-252263)
Matched-Placebo 
for Tafenoquine
Primaquine 
Matched-
Placebo for 
Primaquine
DHA-PQP 320/40
dihydroartemisinin-
piperaquine
Formulation 
description:
Each tablet will 
contain 150mg 
tafenoquine
Each tablet will 
contain 
tafenoquine 
matched-placebo
Each over-
encapsulated 
tablet will contain
15mg primaquine 
Each capsule 
will contain 
primaquine 
matched-
placebo
Each tablet will 
contain 320mg 
piperaquine 
tetrasphosphate 
(as the 
tetrahydrate;PQP) 
and 40mg 
dihydroartemisinin 
(DHA)
Unit dose 
strength(s)
/Dosage level(s):
150 mg
tafenoquine
Placebo
Equivalent to 
15mg primaquine 
base
Placebo
Equivalent to 40mg 
DHA and 320 PQP 
base
Route of 
Administration:
Administer 
orally
Administer orally
Administer orally
Administer 
orally
Administer orally
Dosing 
instructions:
Administer 2 
tablets with 
water as a 
single dose 
after a meal.
Dose to be 
taken at least 3 
hours after 
DHA-PQP
Administer 2 
tablets with water 
as a single dose 
after a meal.
Dose to be taken 
at least 3 hours 
after DHA-PQP
Administer 1 
capsule daily 
with water as a 
single dose after 
a meal for 14 
days. 
Dose to be taken
at least 3 hours 
after DHA-PQP 
(Days 1, 2 and 
3). 
Administer 1 
capsule daily 
with water as a 
single dose 
after a meal for 
14 days. 
Dose to be 
taken at least 3 
hours after 
DHA-PQP 
(Days 1, 2 and 
3).
Single dose for 3 
days
3 tablets per day 
for subjects <75Kg
4 tablets per day 
for subjects 75Kg
Dose to be taken at 
least 3 hours after 
last food intake. No 
food to be taken for 
at least 3 hours 
after dosing
6.1.
Treatment Assignment
Subjects will be assigned to one of three blinded treatment arms: DHA-PQP alone, DHA-
PQP plus TQ or DHA-PQP plus PQ in accordance with the randomization schedule 
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software.
Subjects will be randomized via an interactive web recognition system (IWRS) to blinded 
study treatment after beginning administration of open label DHA-PQP. Each subject 
scheduled to receive blinded study treatment will receive a treatment allocation number 
(i.e. randomization number) via the IWRS system on Day 1. The treatment allocation 


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ratio will be 1:1:1. Once a randomization number has been allocated to a subject, it 
cannot be re-assigned to any other subject.
Open label DHA-PQP will be administered daily over three consecutive days. Each dose 
will be taken at least 3 hours after the last food intake and no food will be taken for 3 
hours after each dose. If a subject vomits within 30 minutes of taking DHA-PQP on Days 
1 to 3, the whole dose should be re-administered; if the subject vomits within 30-60 
minutes, half the dose should be re-administered. Repeat dosing with DHA-PQP should 
not be attempted more than once. If the repeat dose is vomited on Day 1, the subject 
should be withdrawn from the study and given appropriate rescue medication as outlined 
in Section 6.9.1.2.
Blinded study treatment will be administered daily over 14 days together with food (at 
least 3 hours after dosing with DHA-PQP on Days 1, 2 and 3). If the subject vomits 
within 1 hour following dosing, a repeat dose should be given. If the repeat dose is 
vomited on Day 1, the subject should be withdrawn from the study and given appropriate 
rescue medication as outlined in Section 6.9.1.2. 
6.2.
Planned Dose Adjustments
No planned dose adjustment is allowed.
6.3.
Blinding
This will be a double-blind study and both subject and study staff will remain blinded to 
treatment. The following will apply:

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator. 

Investigators have direct access to the subject’s individual study treatment via the 
IWRS system but this information should only be acquired in the case of an 
emergency.

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment.

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of 


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the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.

The independent metHb assessor at the site and the independent data manager at 
GSK will have access to the metHb data which could potentially unblind them to 
the 8-aminoquinoline treatment arms. However, these data will be handled and 
stored securely and these personnel will not have access to other data for the 
study.
6.4.
Packaging and Labeling
The following study treatment will be provided for each subject:

Open label DHA-PQP tablets sufficient for 3 days dosing (3 or 4 tablets per day 
according to weight –refer to Section 6) 

One bottle containing 2 tafenoquine tablets (150mg per tablet) or 2 matched 
placebo tablets

One bottle containing 16 overencapsulated primaquine tablets (15mg per 
overencapsulated tablet) or 16 matched placebo capsules (i.e. sufficient for 14 
days dosing and 2 spare capsules)
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.


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6.6.
Compliance with Study Treatment Administration
Subjects will receive all doses of study treatment at the site directly from the investigator 
or designee, under medical supervision. The date and time of each dose administered in 
the clinic will be recorded in the source documents.  The dose of study treatment and 
study subject identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study treatment.  
6.7.
Study Treatment Overdose
An overdose for this study will be considered as any dose of study treatment that is more 
than the planned dose for each dosing occasion. 
DHA-PQP
No specific antidote for DHA-PQP has been identified. In the event that overdose or 
toxicity does occur, individuals should stop the mediation. Symptomatic and supportive 
therapy should be given as appropriate, including ECG monitoring because of the 
possibility of QTc interval prolongation.
Tafenoquine
No specific antidote for tafenoquine has been identified.  In the event that overdose or 
toxicity occurs, individuals should be managed with appropriate supportive measures and 
clinical judgement.  Immediate induction of emesis and/or gastric lavage is not 
recommended. Hemodialysis is unlikely to be clinically useful as tafenoquine is highly 
protein-bound.
Methemoglobinemia has been observed in clinical trials at therapeutic doses of 
tafenoquine; clinically significant levels could possibly be encountered in overdose.  
Signs and symptoms of methemoglobinemia include (but are not limited to) blue 
discoloration of the skin and lips, and shortness of breath.


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Primaquine
No specific antidote for PQ has been identified. In the event that overdose or oxicity 
occurs, individuals should stop the medication and be managed with appropriate
supportive measures and clinical judgement. Immediate induction of emesis and/or
gastric lavage is not recommended.
Symptoms of PQ overdose include abdominal cramps, vomiting, burning, epigastric pain,
central nervous system and cardiovascular disturbances, cyanosis, methemoglobinemia, 
moderate leukocytosis or leukopenia and anemia.
In the event of an overdose of any study treatment the investigator or treating physician
should:
1. Contact the Medical Monitor immediately
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until resolution.
3. Obtain a plasma sample for pharmacokinetic (PK) analysis if requested by the 
Medical Monitor (determined on a case-by-case basis)
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.8.
Treatment after the End of the Study
All subjects who complete the Day 180 visit and have not had a recurrence of P.vivax
malaria, will be treated with open label PQ (0.5mg/kg daily for 14 days) to minimize the 
likelihood of P.vivax relapses occurring after the end of the study. This medication will 
be sourced locally and will be taken together with food. Subjects who receive open label 
PQ at the end of the study will be required to return to the clinic for a safety follow up 
visit, 15 days later. PQ administration at the end of the study will be recorded in the 
eCRF.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.


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6.9.
Concomitant Medications and Non-Drug Therapies
6.9.1.
Permitted Medications and Non-Drug Therapies
6.9.1.1.
Concomitant Medications
All subjects can be given paracetamol, with caution during the study but administration 
time must be recorded in the eCRF. Allowable antibiotics are penicillins, cephalosporins, 
carbapenems and aminoglycosides (please refer to Section 12.5, Appendix 5). If the 
investigator considers that other antibiotics are required, the Medical Monitor should be 
consulted on a case by case basis.  
Antiemetic choice should be based around the risk of further QTc prolongation over and 
above that which may be caused by DHA-PQP and in line with the approved prescribing 
information for DHA-PQP (refer to SRM). 
All concomitant medications (prescription and non-prescription) taken during the study 
should be recorded in the eCRF. The minimum requirement is drug name, date of 
administration and reason for administration.
6.9.1.2.
Rescue Medication
Subjects diagnosed with P.vivax relapse (i.e. a positive blood smear with or without vivax 
symptoms) during the 180 day follow up period will be given an ACT plus PQ 0.5mg/kg 
for 14 days as rescue medication.  These subjects will continue to be monitored for safety 
and efficacy at all scheduled visits through Day 180. Details of rescue medication 
including reason for the rescue medication will be recorded in the eCRF. Rescue 
medication will be sourced locally. 
6.9.2.
Prohibited Medications and Non-Drug Therapies
The following drugs are prohibited for use from 30 days prior to screening: 

Anti-malarials and other medicines with known anti-malarial activity.

Drugs with hemolytic potential.

Drugs other than PQP known to prolong the QTc interval.

Drugs known to interact with DHA-PQP or primaquine (refer to Eurartesim and 
primaquine SmPCs).

Drugs excreted via renal transporters MATE, MATE2-K and OCT2.
Results from an in vitro renal transporters study showed that tafenoquine inhibits the 
renal transporters MATE1, MATE2-K AND OCT2.  Inhibition of these transporters 
may explain mild, transient, asymptomatic increases of creatinine observed in 
previous clinical studies and may lead to increased exposure to medications excreted 
via these transporters.  The following drugs are therefore prohibited for use from 30 


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days prior to study entry and for a period of 21 days following the blinded dose of 
tafenoquine.

Anti-diabetic drugs of the biguanide class:
o
Phenformin
o
Buformin

Anti-arrhythmic drugs:
o
Dofetilide
o
Procainamide
o
Pilsicainide
Metformin, another biguanide anti-diabetic, may continue to be taken provided the 
subject has serum creatinine below the upper limit of normal and has no concomitant 
medical condition that increases the risk of lactic acidosis.
The use of herbal remedies during the course of the study should be avoided. However, if 
taken this should be recorded in the eCRF under concomitant medication. 
See Appendix 5 in Section 12.5 for a non-exhaustive list of prohibited medicines and 
further guidance.


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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table (Section 7.1).
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The IRB/IEC would be informed of any safety issues that require alteration of 
the safety monitoring scheme or amendment of the Informed Consent Form. 

No more than 150mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.


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7.1.
Time and Events Table
                                                                             Procedures
Visit Day (Treatment Period Days 1-14)
1
1
2b
3
4
5
6
7
8
9
10
11
12
13
14 
Pre DHA-PQP
DHA-PQP
Blinded meda
Written Informed Consent
x
Subject Demography
x
Medical History
x
Disease History 
x
Signs & Symptoms
x
x
Therapy History
x
Inclusion/Exclusion Criteria
x
Efficacy Assessments
Blood smears
x
xc
xc
x
x
Plasmodium PCR genotyping/sequencing
x
Safety Assessments
Concomitant Medication
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical Examination 
x
x
x
x
Vital Signs d
x
x
xo
x
x
12-lead ECG e,
x
x
x
Adverse Events f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serious Adverse Events g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
G6PD (phenotyping) h
x
G6PD/CYP2D6 (genotyping) i
x
Laboratory Assessments
Hematology/Clin.Chem/urinalysis j
x
x
x
x
x
Methemoglobinl
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PK sampling
x
xk
x
x
Investigational Product
Dispense Open Label DHA-PQP
x
x
x
Dispense Blinded Study Treatment (access IWRS on day 1 only)
x
x
x
x
x
x
x
x
x
x
x
x
x
x


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Time and Events Table (Continued) 
Procedures
Visit Day (Follow Up Period)
21
28
60
90
120
150
180
195p
(only for subjects 
who have not 
relapsed prior to 
Day 180)
Relapse
Withdrawal
from study
Window
-/+3d
-3d, +15d
-16 d, 
+15d
-14d, +15d
-14d, +15d
-14d, 
+19d
-/+10d
Day 180 + 
15d to 21d
Efficacy Assessments
Parasitological Assessment (blood 
smears)
x
x
x
x
x
x
x
x
x
Plasmodium PCR 
genotyping/sequencing
x
Safety Assessments
Concomitant Medication
x
x
x
x
x
x
x
x
x
x
Physical Examination
x
x
x
x
x
x
x
x
x
Vital Signs d
x
x
x
x
x
x
x
x
x
12-lead ECG e
x
x
x
Adverse Events 
x
x
x
x
x
x
x
x
x
x
Serious Adverse Events 
x
x
x
x
x
x
x
x
x
x
Dispense rescue treatment (ACT+PQ)
x
Laboratory Assessments
Hematology/Clinical Chemistry 
x
x
x
x
x
  xm
 xm
Methemoglobinl
x
x
x
x
x
PK Sampling 
x
x
xn
Open Label Primaquine
Dispense open label PQ –only for 
subjects who have not relapsed prior to 
D180
x


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Time and Event Table Notes:
a) Blinded study treatment may be started on Day 1 or Day 2. If started on Day 2, blinded primaquine/placebo is given from Day 2-15. 
b) If a subject starts blinded study treatment on Day 2, the following assessments should be completed on Day 15: Concomitant medication, AEs/SAEs, 
methemoglobin, dispense blinded study treatment.
c)
Blood smears to be taken twice daily until two consecutive negative smears 6-12 hours apart.
d) Vital signs include height and weight (screening only), blood pressure, temperature, heart rate and respiratory rate.
e) ECGs will be done in triplicate on Day 1 (prior to DHA-PQP). Subsequent ECGs will be done as single ECGs unless prolonged QTcF is seen. ECG 
timings post baseline will be as follows: 1) Before the last of the three daily doses of DHA-PQP 2) 4 hours (window -1 to +2 hours) after last dose of 
DHA-PQP, 3) Day 7,  4) Day 28 and 5) relapse/withdrawal if within 28 days post-dose. 
f)
Adverse events are recorded from the time of the first dose of study treatment. 
g) Serious adverse events are recorded from the time of consent in order to fulfil international regulatory requirements.
h) G6PD phenotyping to be performed by suitable qualitative test (refer to SRM) and quantitative spectrophotometric analysis. 
i)
Blood sample to be collected for CYP2D6 genotyping and stored for possible G6PD genotyping. Sample for G6PD genotyping may be analyzed in 
the event of an SAE due to hemoglobin decline where a repeat G6PD phenotype assay would not define G6PD status (e.g. transfusion given or high 
reticulocyte count).
j)
Dipstick urinalysis to be only done at screening.
k)
PK samples must be taken 6-12 hours and 24-48 hours post blinded dose of tafenoquine.  
l)
Methemoglobin will be measured daily up to Day 14, alternate days up to Day 28 and on Day 60. 
m) Hematology/clinical chemistry to be done at relapse/withdrawal (up to Day 120 only).
n) PK will be done as close to the time of relapse as possible (up to Day 60 only).
o) Vital signs on Day 3 will be done immediately after ECGs (ie before the last of the three daily doses of DHA-PQP and 4 (-1 to +2) hours after the last 
dose of DHA-PQP.
p) The D195 assessment is only required for subjects who do not relapse prior to D180 and receive open label primaquine (0.5mg/kg daily for 14 days) 
at the end of the study. Subjects who have relapsed prior to Day 180 will complete the study at D180.


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7.2
Screening and Critical Baseline Assessments
Informed Consent Procedure
Signed, written, dated informed consent must be obtained from each potentially eligible 
subject before any study specific procedure is undertaken. The research team leaders will 
meet commanders and troops to explain the concept and importance of voluntary 
informed consent prior to inviting subjects to participate in the study. The person 
obtaining written consent must be independent of the subject to ensure consent is 
voluntary (i.e not the subject’s commander or supervisor) to avoid perceptions of 
coercion or undue influence on a military subject. The subject’s commander or supervisor 
must not be in the room during the consent process. Informed consent will be obtained on 
an individual basis, rather than as a group, ensuring that each subject has the opportunity 
to ask questions about the study.
Following informed consent, the following clinical and laboratory assessments will be 
conducted as described below (see Time and Events Table Section 7.1)
a) Procedures to be performed prior to DHA-PQP administration

Demographic data will be collected to include details of year of birth, gender, race 
and ethnicity.

Medical history will be collected including cardiovascular history and associated 
risk factors.  

A physical examination will be conducted including:
o
Cardiovascular examination
o
Abdominal examination including an assessment of splenomegaly
o
Respiratory examination

Vital signs will be assessed including height, weight, systolic and diastolic blood 
pressure, temperature (oral, axillary or tympanic), heart rate and respiratory rate. 
The same methodology should be used for measurement of temperature for all 
subjects.

Investigators will assess P. vivax malaria symptoms at baseline. The incidence and 
severity (defined as absent, mild, moderate, severe, or unknown) of the following 
symptoms will be recorded: chills and rigours, headache, dizziness, abdominal 
pain, anorexia, nausea, vomiting, diarrhea, pruritis or itching, and coughing. The 
date of onset of symptoms will also be recorded. The investigator or designee can 
also assess and record any other P. vivax malaria symptoms.

Blood smears for parasitological assessment will be collected and examined for 
asexual parasite count and gametocyte blood count (see Section 7.4 and the SRM 
for further details).

Current and prior medications will be reviewed including any anti-malarial 
medication that has been used.


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
A blood sample will be collected for Plasmodium genotyping analysis. An 
additional blood sample will be collected for future exploratory plasmodium 
whole genome sequencing (if parasite counts allow) (See Section 7.4 and Section
7.7).

G6PD status will be assessed using the Fluorescent Spot Test (FST) or other 
suitable Point of Care Test (see SRM) to determine the subject’s eligibility. An 
additional Point of Care Test (in development) may also be performed but the 
results of this test would not be used for eligibility. The quantitative 
spectrophotometric G6PD analysis will also be performed but results will not be 
available at the time of randomization. If results are discordant, the subject will be 
reviewed and appropriate G6PD testing will be repeated.

Hematology and clinical chemistry assessments will be performed (refer to 
Section 7.5.5).

Methemoglobin levels will be assessed using a non-invasive machine. This 
assessment will be performed by an independent person who will not participate 
in any other study procedures at the site. The data will be transmitted securely to 
GSK data management and will not be shared with other site staff unless result is 
above a preset threshold that requires a safety assessment (refer to SRM).

12 lead ECG will be performed with the subject in a semi-supine position 
having rested in this position for at least 10 minutes beforehand. Measurements 
that deviate substantially from previous readings will be repeated immediately. 
Three (3) measurements will be taken at screening, five minutes apart.
o
The mean heart rate, RR interval, QRS duration, uncorrected QT interval 
and QTcF (QT corrected by Friderica’s formula) will be calculated from 
automated ECG readings and abnormal findings will be recorded in the 
eCRF. The mean value recorded pre-DHA-PQP will be classified as 
baseline.

A blood sample will be collected for CYP2D6 genotyping and possible G6PD 
genotyping. The extracted nucleic acid sample for G6PD genotyping will be 
stored and may be analyzed in the event of an SAE due to hemoglobin decline 
where a repeat G6PD phenotype assay would not define G6PD status (e.g. 
transfusion given or high reticulocyte count).
Subjects who have undergone screening and meet the label requirements for DHA-
PQP dosing  can receive open label DHA-PQP if the clinician deems that 
appropriate (e.g. symptomatic disease), and at least 3 hours have elapsed since last 
food intake. Thus, DHA-PQP may be commenced whilst the results of the 
hematology, clinical chemistry or G6PD deficiency screening tests are pending.
Once these laboratory test results are available and the subject eligibility is 
confirmed, they will be randomized via the IWRS to blinded study treatment. The 
first dose of blinded study treatment will be administered with food at least 3 hours 
after DHA-PQP on Day 1 or Day 2.


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7.3
Unscheduled Visits
Subjects will be encouraged to return for an unscheduled visit if they feel unwell or 
develop a fever at any time during the 180 day study period. The subject should be 
assessed for any adverse events and other procedures conducted as clinically indicated in 
order to diagnose/rule out malarial recurrence or explain other symptoms and signs. 
7.4
Efficacy
Parasitology

Asexual parasite counts
Microscope blood slides will be prepared prior to the first dose of DHA-PQP at screening 
on Day 1 to confirm the diagnosis of P. vivax malaria, and then twice a day, 6-12 hours 
apart for the first 3 days, or until 2 consecutive negative thick blood smears are obtained.  
Where the subject receives DHA/PQP < 6 hours from midnight on Day 1, a second Day 1 
slide may be omitted.
Microscope blood slides will be prepared at subsequent visits on Days 7, 14, 21, 28, 60, 
90, 120, 150 and 180 (refer to Section 7.1 Time and Events table). In addition, blood 
films should be obtained whenever parasitological re-assessment is required and at the 
relapse visit or withdrawal visit as applicable. For detailed instructions on the 
methodology for staining and counting please refer to the SRM.
Slides are considered negative after review of 100 high-power fields. A negative slide 
refers to the absence of asexual parasites only.

Gametocyte counts
In the same way, thick film slides will be read for gametocytes on Day 1 (prior to the first 
dose of DHA-PQP) and then twice a day 6-12 hours apart for the first 3 days or until 2 
consecutive negative thick blood smears are obtained. Slides will be prepared at 
subsequent visits on Days 7, 14, 21, 28, 90, 120, 150 and 180 (refer to Section 7.1 Time 
and Events Table).
External quality control
A proportion of slides from the study site will be examined in Indonesia by an 
independent laboratory, blinded to treatment assignment. The procedure for quality 
control will be described in the SRM.
Parasite Genotyping and Whole Genome Sequencing
A sample will be collected for subsequent DNA extraction and PCR analysis of 
Plasmodium species on all subjects at screening (Day 1; pre-dose) and if necessary, at the 
time of the first recurrence. PCR of the P. vivax genes, such as PvMSP-1, PvCSP and 
PvAMA-1, as well as any other markers deemed appropriate, will be used to distinguish 
between genetically homologous and genetically heterologous infection.
A further sample will be taken for subsequent parasite exploratory whole genome
sequencing at baseline and if occurring, at the time of first recurrence (refer to Section 
7.7). 


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7.5
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1). Blinded safety will be reviewed on a monthly basis by a GSK/MMV safety 
review board which includes a reviewer independent of the study sponsors.
7.5.1
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3 (Section 12.3). The 
investigator and their designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
7.5.1.1
Protocol-Defined SAE (Hb drop)
A Hb drop is defined as any ONE of the following occurring in the first 15 days of the 
study:

a relative hemoglobin decrease of ≥30% from baseline, or

an absolute hemoglobin decrease of >3g from baseline, or

a drop in absolute  hemoglobin to < 7.0g/dL.
All protocol-defined Hb drops must be reported as an SAE, even if asymptomatic and not 
requiring medical intervention. 
If a protocol-defined SAE (Hb drop) is noted, hematology and clinical chemistry tests 
will be performed immediately and subjects will be required to have a repeat G6PD 
quantitative phenotype test to confirm they are not G6PD deficient (refer to Section 
5.4.2).
7.5.1.2
Time period and Frequency for collecting AE and SAE information

AEs will be collected from the start of study treatment until the follow-up contact 
(see Section 7.5.1.4), at the timepoints specified in the Time and Events Table 
(Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.3 Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 


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time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Section 12.3 Appendix 3.
7.5.1.3
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.5.1.4
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 3 (Section 12.3).
7.5.1.5
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 (Section 12.3) and all deaths, 
whether or not they are considered SAEs, specific Cardiovascular (CV) and Death 
sections of the CRF will be required to be completed.  These sections include questions 
regarding cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.  
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.


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7.5.1.6
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Occurrence of malaria is an efficacy endpoint for this study. Consequently malaria should 
not typically be reported as an AE/SAE and will not be subject to the standard process for 
expedited reporting of SAEs to GSK (even though the event may meet the definition of a 
serious adverse event).  The occurrence of malaria and any associated signs and 
symptoms must instead be recorded on the study Malaria Signs and Symptoms (i.e., 
Disease-Related Event [DRE]) page in the subject’s eCRF.  
The following are considered to be the common signs and symptoms associated with 
malaria infection/relapse which should not be reported as AEs/SAEs but captured on the 
DRE page. However, this should be done ONLY IF confirmed with a positive slide 
reading for the presence of P. vivax malaria at the time symptoms are reported.  If any of 
the following symptoms are reported and the slide read is negative, they should be 
reported as an AE or SAE as usual.

Pyrexia

Chills

Rigor

Headache
These DREs will be monitored by the GSK Safety Review Team on a routine basis. 
However, if the following condition applies, then the event should be reported as an SAE 
using the standard process:
“The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual subject.”
If the above condition is met then record the event on the SAE page rather than the DRE 
page and report promptly (i.e., expedited reporting, see Appendix 3, Section 12.3) to 
GSK.
As the occurrence of malaria is an efficacy endpoint for this study, should malaria be 
reported as an SAE, it will not be subject to expedited reporting regardless of the 
“expectedness” or “relatedness” of the event.
7.5.1.7
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a 
product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 


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comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.5.2
Physical Exams
Physical examinations will be done at the timepoints indicated in the Time and Events 
Table (Section 7.1).

A brief physical examination will include, at a minimum, assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.5.3
Vital Signs
Vital signs will be measured at the timepoints indicated in the Time and Events table 
(Section 7.1) in a semi-supine position after 5 minutes rest and will include temperature, 
systolic and diastolic blood pressure and pulse rate and respiratory rate. Height and 
weight will be recorded at Screening only.
7.5.4
Electrocardiogram (ECG)
12 lead ECGs will be done in triplicate on Day 1 (record the average of triplicate ECGs 
obtained over a brief recording period in the eCRF). Subsequent ECGs will be done as 
single ECGs unless prolonged QTcF is seen, in which case the average of triplicate ECGs 
obtained over a brief recording period will be calculated and recorded in the eCRF. ECG 
timings will be as follows: 

Day 1  
Prior to start of DHA-PQP 

Day 3  
Before the last of the three daily doses of DHA-PQP

Day 3  
4 hours after the last dose of DHA-PQP (window -1 hr to +2 hrs) 

Day 7

Day 28

Relapse/withdrawal (if within 28 days post-dose)
12-lead ECGs will be obtained using an ECG machine that measures HR, PR, QRS, RR 
and uncorrected QT intervals. QTcF will be calculated from automated QT and HR 
readings (See SRM).  


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7.5.5
Clinical Safety Laboratory Assessments
Clinical chemistry and hematology samples will be analyzed by the local laboratory. All 
protocol required laboratory assessments, as defined in Table 1 and Table 2, must be 
conducted in accordance with SRM and at the timepoints indicated in the Protocol Time 
and Events Schedule (Section 7.1).
All laboratory data will be used for the purpose of safety analysis and reporting for this 
study.  Any laboratory tests the attending physician or investigator deems necessary for 
the care and safety monitoring of the study subjects will be conducted by the local 
laboratory.  All laboratory results that are considered clinically significant should be 
recorded as AEs.
Hemoglobin and/or hematocrit measurements that deviate substantially from previous 
readings should be immediately repeated via venous sampling.  If a protocol-defined Hb 
drop is observed upon repeat testing (Section 7.5.1.1), all additional clinical chemistry 
labs should be obtained immediately.
If, after Day 3, platelet counts are <5×104 per µL, the test should be repeated or 
confirmed with a manual slide reading.
Table 1
Hematology Tests
Hemoglobin
Hematocrit
Platelets
MCV
WBC
RBC
WBC 
Differential
(neutrophils and 
lymphocytes as a 
minimum)
Table 2
Clinical Chemistry Tests
Creatinine
BUN
Total bilirubin
Indirect bilirubin
AST
ALT
ALP
CPK
Urinalysis will be conducted at screening. Urine (approximately 20mL mid-stream urine) 
will be analyzed for protein, glucose, ketones, bilirubin, blood, nitrites and urobilinogen 
by dipstick method.  Sediment microscopy will be performed if the leukocyte, nitrites, 
protein, or occult blood is abnormal and will include analysis for white blood cells, red 
blood cells, hyaline casts, granular casts and cellular casts.
Methemoglobin status will be assessed daily up to Day 14, on alternate days up to Day 28 
and on Day 60 (or at relapse/withdrawal from study) (See Section 7.1). Subjects with 
anemia may have symptomatic methemoglobinemia at levels lower than subjects with 
normal hemoglobin levels (symptoms typically do NOT occur with metHb values <20% 
in subjects with normal hemoglobin levels).  


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All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be reported as AEs and then tests repeated until 
the values return to normal or baseline.  If such values do not return to normal within a 
period judged reasonable by the investigator, the etiology should be identified and the 
sponsor notified.
7.6
Pharmacokinetics
7.6.1
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of TQ (and potentially other study 
treatment as deemed appropriate) will be collected at the time points indicated in Section 
7.1, Time and Events Table.  The actual date and time of each blood sample collection 
will be recorded.  The timing of PK samples may be altered and/or PK samples may be 
obtained at additional time points, at the discretion of GSK, to ensure thorough PK 
monitoring. 
All pharmacokinetic blood samples will be held and stored in Indonesia until such time 
that an MTA, if necessary, is formally approved for the transfer of the specimen to the 
designated laboratory for PK analysis. If the MTA is approved, samples will be shipped 
to the Aptuit Laboratory, Italy for analysis and returned to Indonesia, once the analysis is 
completed, where they will be stored for up to 5 years. 
The validated bioanalytical methodology used for measuring concentrations of TQ for 
pharmacokinetic analysis is not currently performed in Indonesia. Therefore, samples will 
be analyzed at the laboratory that is conducting the TQ analysis in the global programme 
in order to generate data to regulatory standards, in accordance with Indonesian 
requirements.
Details of the PK blood sample collection, processing and storage procedures are 
provided in the SRM.
7.6.2
Sample Analysis
Plasma sample analysis will be performed under the control of PTS, GlaxoSmithKline, 
the details of which will be included in the SRM. Concentrations of TQ will be 
determined using the currently approved validated bioanalytical methodology. Raw data 
will be archived at the bioanalytical site (detailed in the SRM).
Plasma samples stored in Indonesia may be used for analysis of primaquine PK or 
immunological studies e.g. examining seromarkers of hypnozoite carriage. These analyses 
would be done at the Eijkman Institute and/or University of Indonesia, Jakarta, Indonesia.
Any additional analyses on these stored samples will require prior agreement from GSK 
and the local Ethics Committee.


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7.7
Genetics
Samples will be collected for genetic testing as follows:

CYP2D6 genotyping - a sample will be collected to examine the relationship between 
CYP2D6 genotype and risk of P. vivax relapse. The analysis will be performed at the 
Eijkman Institute.

G6PD genotyping - a sample will be collected for extraction of nucleic acid which 
will be stored for potential G6PD genotyping in the event of a hemolytic event. In this 
circumstance, the sample may be analyzed if repeat G6PD phenotyping would not 
define G6PD status (e.g. transfusion given or high reticulocyte count).  The analysis 
will be performed at the Eijkman Institute.

Plasmodium PCR genotyping- samples will be taken at screening and at the time of 
malaria recurrence (if applicable) to explore the genetics of baseline diversity and 
recurrence of P.vivax malaria. The analysis will be performed at the Eijkman 
Institute.

Plasmodium whole genome sequencing- samples will be taken at screening and at the 
time of malaria recurrence (if applicable) for whole genome sequencing in order to 
better understand the biology of P.vivax at baseline and genetic drivers of relapse.
These samples will be held and stored in Indonesia until such time that an MTA, if 
necessary, is formally approved for the transfer of the specimens to the Sanger, 
Institute, UK where they will be pooled with other samples from the global TQ 
studies, in order to standardize the methodology across the TQ programme. This 
analysis will only be done if parasite counts allow and results will be reported 
separately. The samples will be returned to Indonesia where they will be destroyed, 
once the analysis is completed. 
Details of the sample collections for genetic testing (including volume of blood to be 
collected), processing and storage procedures are provided in the SRM.
8.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events (including SAEs) and concomitant medications terms will be 
coded using the current MedDRA (Medical Dictionary for Regulatory Activities)
used at the data lock point and an internal validated medication dictionary, 
GSKDrug.  


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
CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1
Hypotheses
The study is designed to test superiority of DHA-PQP plus TQ against DHA-PQP alone 
in the prevention of P. vivax malaria relapse. The null hypothesis for the primary 
endpoint is that the 6-month relapse-free efficacy is not different between the DHA-PQP 
plus TQ and DHA-PQP alone treatment groups. The alternative hypothesis is that the 
relapse-free efficacy of the treatments is different. The hypothesis test will be two-sided 
and tested at the 5% significance level.
9.2
Sample Size Considerations
9.2.1
Sample Size Assumptions
The sample size for the study is based on the comparison of the primary endpoint (i.e. 
relapse-free efficacy at 6 months post-dosing) between the DHA-PQP alone group versus 
DHA-PQP plus TQ. The comparison will be based on a Log rank test for the difference 
in relapse-free survival rates over 6 months using all the subjects in the intent to treat
population.
It is assumed that the relapse-free efficacy will be 50% on DHA-PQP alone, 85% on 
DHA-PQP plus PQ, and 85% on DHA-PQP plus TQ. In order to detect a clinically 
meaningful difference of 35%, a sample size of 50 subjects per group will provide >90% 
overall power for the primary efficacy comparison, allowing for a 10% withdrawal rate. 
A trial of 150 subjects, with the given assumptions about DHA-PQP, DHA-PQP plus PQ, 
and DHA-PQP plus TQ relapse rates would expect to see 40 relapses: a combined relapse 
rate across all treatments of 26.7%. In addition, a DHA-PQP plus PQ arm will be used as 
a benchmark to help further interpret the observed relapse efficacy of DHA-PQP plus 
TQ.
9.2.2
Sample Size Sensitivity
An overall power of 80% will be maintained if the relapse-free efficacy of the DHA-PQP 
plus TQ combination is 80% rather than the expected 85% (corresponding to a combined 
relapse rate across all treatments of 28.3%), or if the relapse-free efficacy of DHA-PQP 
plus TQ is 85% but the efficacy of DHA-PQP alone is 55% (a combined relapse rate 
across all treatments of 25%).


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9.2.3
Sample Size Re-estimation or Adjustment
If the study has not achieved its target of 150 subjects by six months, but at least 120 
subjects have been enrolled, a blinded review of the relapse data will be conducted. 
Kaplan-Meier estimates will be made of the overall six month relapse rate, using all of 
the data available at that time. If the Kaplan-Meier estimate of the overall combined 
relapse rate at 6 months is less than 26.7%, further subjects will be recruited from a 
second battalion, up to a maximum of 150 subjects in total. If the Kaplan-Meier estimate 
is 26.7% or greater, the study will have sufficient power to show a meaningful clinical 
difference without requiring further subjects from a second battalion. In this scenario, 
recruitment will be stopped and all current subjects will be followed up for the full six 
months. Even if the relapse rate is shown to be higher than anticipated, the minimum 
number of subjects which will be recruited is 120, to ensure an adequate safety database 
for the DHA-PQP plus TQ treatment regimen.
9.3
Data Analysis Considerations
9.3.1
Analysis Populations
The following populations are defined for the analysis of the data to be collected as part 
of this study. All decisions on eligibility for inclusion in these populations will be made 
prior to unblinding at the end of each part.
Safety Population: all randomized subjects who received at least one dose of blinded 
study treatment. If subjects receive a treatment different to their randomized treatment, 
they will be analyzed according to the treatment actually received. This will be the 
primary population for all safety analyses and data presentations.
Intent to Treat (ITT) Population: all randomized subjects who received at least one 
dose of blinded study treatment. Subjects will be analyzed according to their randomized 
treatment. This population will be the primary population for all efficacy analyses.
Per Protocol (PP) Population: all subjects in the ITT population for whom there were 
no major protocol violations (to be defined in the study analysis plan). This population 
will be used for sensitivity/supporting analyses of efficacy data only.
9.4
Key Elements of Analysis Plan
The primary comparison of interest will be the treatment difference over 6 months 
between DHA-PQP plus TQ and DHA-PQP alone using a Logrank test. Point estimates 
will be derived from Kaplan Meier methods and include all subjects in the ITT 
population. Subjects who were lost to follow up or did not relapse by the end of the 
follow up will be censored at the time of withdrawal or completion of the study.
Note that data from the Day 195 visit will be not used in the assessment of relapse at 6 
months. The last data to be used is the data from the Day 180 visit.


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Subjects will be considered to have demonstrated relapse- free efficacy at six months if 
all of the following are true:

Subject had a non-zero P.vivax asexual parasite assessment on Day 1. (Subjects 
who do not meet this criteria will be censored, with time to relapse censored at 0 
days).

Subject demonstrated initial clearance of P.vivax parasitemia. (Subjects who do 
not meet this criteria will be considered to have relapsed with time to relapse = 0 
days).

Subject had a non-zero P.vivax asexual parasite assessment on Day 1. (Subjects 
who do not meet this criteria will be censored, with time to relapse censored at 0 
days)

Subject demonstrated initial clearance of P.vivax parasitaemia. (Subjects who do 
not meet this criteria will be considered to have relapsed with time to relapse = 0 
days)

Subject has no positive asexual P.vivax parasite count at any assessment prior to 
the scheduled Day 180 visit following initial parasite clearance. (Subjects who do 
have a positive count will be considered to have relapsed with time to relapse = 
(date of first positive count) – (date of Day 1 visit) days).

Subject did not take a concomitant medication with anti-malarial activity 
(excluding study treatment) at any point between day 1 and the scheduled Day 
180 visit. (Subjects who did take a drug with anti-malarial activity but never had a 
positive asexual P.vivax parasite count after initial clearance will be censored, 
with time to relapse censored at (date of medication start) – (date of Day 1 visit) 
days).

Subject has a scheduled Day 180 assessment, and is parasite free at this time 
point. (Subjects who do not have a Day 180 visit and have not already failed or 
been censored will be censored at (date of final parasite assessment) – (date of 
Day 1 visit) days).
All statistical testing will be performed using a significance level of 0.05.
9.4.1
Secondary Analyses
For evaluation of the secondary efficacy comparisons, 95% confidence intervals will be 
provided for the treatment differences of i) DHA-PQP plus TQ versus DHA-PQP plus 
PQ and ii) DHA-PQP plus PQ versus DHA-PQP alone. An exploratory p-value will also 
be provided for the DHA-PQP plus PQ versus DHA-PQP alone comparison. 
A secondary per protocol analysis will also be performed, excluding subjects who deviate 
significantly from the protocol. If a subject misses a scheduled study visit from day 28 
onwards, they will automatically be excluded from the per protocol population.
Statistical comparisons (i) DHA-PQP plus TQ versus DHA-PQP alone,  ii) DHA-PQP 
plus TQ versus DHA-PQP plus PQ and iii) DHA-PQP plus PQ versus DHA-PQP alone) 
of secondary efficacy endpoints (relapse-free efficacy at 4 months, time to relapse, 


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percentage of subjects with recrudescence, parasite clearance time, fever clearance time) 
will also be performed using survival analysis methodology.
A further sensitivity analysis will be performed in which all subjects will be categorized 
as either successes or failures at 6 months, analyzed using Exact methods. Subjects taking 
medication with anti-malarial efficacy during the study will be classified as failures in 
this analysis.
All safety endpoints will be based on the safety population and presented in tabular 
and/or graphical format and summarised descriptively according to GSK’s Integrated 
Data Standards Library (IDSL) standards.
10
STUDY GOVERNANCE CONSIDERATIONS
10.1
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to site initiation, GSK will obtain favourable opinion/approval from the appropriate 
regulatory agency to conduct the study in accordance with ICH Good Clinical Practice 
(GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable. 

Obtaining signed informed consent prior to participation in the study

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol.  


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10.3
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors (or designee) will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK (or their designee) will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
or their representative may conduct a quality assurance assessment and/or audit of 
the site records, and the regulatory agencies may conduct a regulatory inspection 
at any time during or after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. If GSK determines such action is needed, GSK will 
discuss the reasons for taking such action with the investigator or the head of the 
medical institution (where applicable).  When feasible, GSK will provide advance 
notification to the investigator or the head of the medical institution, where
applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 


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applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

The investigator must retain Investigator Site Files for 25 years from the final 
Clinical Study report date. The final retention date for Investigator Site Files will 
be provided at the same time as the Clinical Study report or equivalent results 
summary (local country law will apply where longer retention periods apply).

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.


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10.7
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
10.8
Review Committees
Blinded safety data will be reviewed on a monthly basis by a GSK/MMV safety review 
board which includes a reviewer independent of the study sponsors. 


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11
REFERENCES
Baird, J. K. Evidence and implications of mortality associated with acute Plasmodium 
vivax malaria. Clinical microbiology reviews, 2013: 26(1), 36-57.
Baird, J. K., Dewi, M., Subekti, D, et al. Noninferiority of glucose-6-phosphate 
dehydrogenase deficiency diagnosis by a point-of-care rapid test vs the laboratory 
fluorescent spot test demonstrated by copper inhibition in normal human red blood cells. 
Translational Research, 2015: 165 (6) 677-688.
Bancone, G., Chu, C. S., Somsakchaicharoen, R., et al. Characterization of G6PD 
Genotypes and Phenotypes on the Northwestern Thailand-Myanmar Border.  PloS one, 
2014: 9(12), e116063.
Bennett, J. W., Pybus, B. S., Yadava, A., et al. Primaquine failure and cytochrome P-450 
2D6 in Plasmodium vivax malaria. New England Journal of Medicine, 2013: 369(14), 
1381-1382.
Dua, V. K., Kar P.K, and Sharma V.P. Chloroquine resistant Plasmodium vivax malaria 
in India. Tropical Medicine & International Health 1.6 1996: 816-819.
Fryauff, D.J.B.L., Baird K., Basri, H.A.S.A.N., et al. Randomised placebo-controlled trial 
of primaquine for prophylaxis of falciparum and vivax malaria. The Lancet, 1995: 
346(8984); 1190-1193.
Hasugian, A.R., Purba, H.L.E., Kenangalem., et al.  Dihydroartemisinin-piperaquine 
versus artesunate-amodiaquine: superior efficacy and posttreatment prophylaxis against 
multidrug-resistant Plasmodium falciparum and Plasmodium vivax malaria. Clin Infect 
Dis, 2007: 44(8), 1067-1074. 
Herdiana, H., Fuad A., Asih P.B et al. Progress towards malaria elimination in Sabang 
municipality, Aceh, Indonesia." Malar J 12, 2013 (42): 10-1186.
ICH Guidance for Industry. Guideline E6 Good Clinical Practice: Consolidated Guidance 
1996
Karyana, M., Burdarm, L., Yeung, S., et al. Malaria morbidity in Papua Indonesia, an 
area with multidrug resistant Plasmodium vivax and Plasmodium falciparum. Malar J 
2008, 7(148), 10-1186.
Kusriastuti, R., and Asik S. New Treatment Policy of Malaria as a Part of Malaria 
Control Program in Indonesia. Acta Med Indones - Indones J Intern Med  2012: 44.3; 
265-269.
Lee K.S, Kim T.H, Kim E.S et al. Short report: Chloroquine-resistant Plasmodium Vivax 
in the Republic of Korea.Am. J. Trop. Med. Hyg 2009; 80 (2):215-217.
Llanos-Cuentas A., Lacerda MV., Rueangweerayut R., et al. Tafenoquine plus 
chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria 
(DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study. 
The Lancet. 2014 Vol.383 | Number 9922 March 22.
Murray, C. J., Ortblad, K. F., Guinovart, C. et al, Global, regional,and national incidence 
and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis 
for the Global Burden of Disease Study 2013. The Lancet, 2014, 384(9947), 1005-1070.


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Nelwan, E.J., Ekawati LL., Tjahjono B. et al, Randomized trial of primaquine 
hypnozoitocidal efficacy when administered with artemisinin-combined blood 
schizontocides for radical cure of Plasmodium vivax in Indonesia. BMC Medicine, 2015, 
Dec 11:13 (1), 294.
Pasaribu A.P., Chokejindachai., W, Sirivichayakul C et al. A randomized comparison of 
dihydroartemisinin-piperaquine and artesunate-amodiaquine combined with primaquine 
for radical treatment of Vivax malaria in Sumatera, Indonesia. Journal of Infectious 
Diseases, 2013; 208: 1906-1913.
Price R.N., Douglas NM., Anstey NM. New developments in Plasmodium vivax malaria: 
severe disease and the rise of chloroquine resistance. Curr Opin Infect Dis. Oct 
2009;22(5):430-435.
Price, R.N., von Seidlein, L., Valecha, N.,et al. Global extent of chloroquine-resistant 
Plasmodium vivax: a systematic review and meta-analysis. The Lancet Infectious 
Diseases, 2014: 14(10), 982-991.
Ratcliff, A., Siswantoro, H., Kenangalem, E. et al. Two fixed-dose artemisinin 
combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an 
open-label randomised comparison. The Lancet, 2007; 369(9563), 757-765.
SB-252263 Investigator’s Brochure. GlaxoSmithKline Document Number 
GM2007/00152/09. Version 13 Effective Date: 7 December 2015.
Soto, J., Toledo J., Gutierrez P.  Luzz, M. et al. Plasmodium vivax clinically resistant to 
chloroquine in Colombia. Am. J. Trop. Med and Hyg. 2001; 65( no.2):90-93.
Study TAF110027 GlaxoSmithKline Document Number 2013N172577_00.  A Phase I 
Study to Investigate the Haemolytic Potential of Tafenoquine in Healthy Subjects with 
Glucose-6-Phosphate Dehydrogenase Deficiency and the Safety and Tolerability of 
Tafenoquine in Acute Plasmodium vivax Malaria Patients with Glucose-6-Phosphate 
Dehydrogenase Deficiency.  Effective Date:  December 2013.
Sumawinata, I. W., Leksana, B., Sutamihardja, et al. Very high risk of therapeutic failure 
with chloroquine for uncomplicated Plasmodium falciparum and P. vivax malaria in 
Indonesian Papua. Am.J. of Trop Med and Hyg, 2003: 68(4), 416-420.
Sutanto I., Endawati D., Ling LH et al. Evaluation of chloroquine therapy for vivax and 
falciparum malaria in southern Sumatra, western Indonesia. Malaria Journal. 2010; 9; 
52.
Sutanto I., Suprijanto S., Nurhayati PM and Baird J.K. Resistance to chloroquine by 
plasmodium vivax at Alor in the Lesser Sundas archipelago in Eastern Indonesia.  Am. J. 
Trop. Med. Hyg. 2009; 81(2):338-342.
Sutanto I., Tjahjono B., Basri H., et al. Randomized, open-label trial of primaquine 
against vivax malaria relapse in Indonesia. Antimicrob Agents Chemother. Mar 2013; 
57(3):1128-1135.


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12
APPENDICES
12.1
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACT
Artemisinin-based combination therapy
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BUN
Blood Urea Nitrogen
CRA
Clinical Research Associate
CRF
Case Report Form
CPK
Creatine Phosphokinase
CQ
Chloroquine
CV
Cardiovascular
d
Day
DHA-PQP
Dihydroartemisinin Piperaquine
DOT
Directly observed therapy
DRE
Disease-Related Event
DDI
Drug-drug Interaction
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FCT
Fever clearance time
FDA
Food and Drug Administration
FST
Fluorescent Spot Test
FU
Follow Up
HR
Heart rate
GI
Gastrointestinal
G6PD
Glucose-6-phosphate Dehydrogenase
GSK
GlaxoSmithKline
GCP
Good Clinical Practice
g
Grams
g/dL
Grams per Deciliter
Hb
Hemoglobin
Hct
Hematocrit
HIV
Human Immunodeficiency Virus
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
INR
International Normalized Ratio
ITT
Intention to Treat
IWRS
Interactive web recognition test
kg
Kilograms


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LDH
Lactate Dehydrogenase
m
Meter
MTA
Material Transfer Agreement
MSDS
Material Safety Data Sheet
MCV
Mean Cell Volume
MMV
Medicines for Malaria Venture
MetHb
Methemoglobin
µg.h/mL
Microgram Hours per milliliter
µL
Microliters
mg
Milligrams
mL
Milliliters
MTA
Material Transfer Agreement
PCR
Polymerase chain reaction
PCT
Parasite clearance time
PD
Pharmacodynamics
PGx
Pharmacogenetics
PK
Pharmacokinetics
PQ
Primaquine
RAP
Reporting and Analysis Plan
RBC
Red Blood Count
SAE
Serious Adverse Event
SRM
Study Reference Manual
TQ
Tafenoquine
ULN
Upper Limit of Normal
WBC
White Blood Count
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
EURARTESIM
NONMEM


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12.2
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen)
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for pharmacokinetic (PK) 
analysis, obtained as soon as possible and 
within 24 hours of last dose, if liver event 
occurs within 60 days post-dose6.

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).


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granted

If restart/rechallenge not  allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography)
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   


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4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM. 
Note: Hepatitis B surface antigen test is not required at the screening visit.
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369.


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Note: If any liver event follow up assessments are not available locally in Indonesia, 
samples will be stored for possible export to laboratories where the analyses are 
available, pending MTA approval from the Ministry of Health.


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12.3
Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 


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the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.3.2
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 


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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
12.3.3
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias


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
Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.


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12.3.5
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.3.6
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data.

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail.

Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.4
Appendix 4: WHO Definition of Severe Malaria
The WHO defines severe malaria as those that present with:  confusion or drowsiness 
with extreme weakness (prostration).
In addition, the following may develop:

Cerebral malaria, defined as unrousable coma not attributable to any other cause 
in a patient with malaria

Generalized convulsions

Severe normocytic anaemia (<5 g/dL)

Hypoglycaemia (blood glucose < 2.2 mmol/L or < 40 mg/dL)

Metabolic acidosis (plasma bicarbonate < 15 mmol/L) with respiratory distress

Fluid and electrolyte disturbances

Acute renal failure (serum creatinine >265 µmol/L)

Acute pulmonary edema and adult respiratory distress syndrome (ARDS)

Circulatory collapse or shock

Abnormal bleeding

Jaundice with organ dysfunction

Hemoglobinuria

Hyperparasitemia (>2%/100,000/µL in low intensity transmission areas or >5% or 
250,000/µL in areas of high stable malaria transmission intensity)
NOTE: This definition of severe malaria was formulated for P. falciparum but other 
published data for P. vivax support this and so for the purposes of this trial this definition 
of severe disease will be adopted.
References: 
“Management of Severe Malaria: A Practical Handbook.” 2nd Edition Geneva, World 
Health Organisation 2000.
Price RN, Douglas NM, Anstey NM. New developments in Plasmodium vivax malaria: 
severe disease and the rise of chloroquine resistance. Curr Opin Infect Dis. 2009 
Oct;22(5):430-5.
World Health Organization. Severe falciparum malaria. Transactions of the Royal 
Society of Tropical Medicine and Hygiene, 2000:94(Suppl. 1):1–90.


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12.5
Appendix 5: Prohibited Medications for Study Entry
The following drugs are not permitted to be taken during the study:
1) Acetylsalicylic acid

Note: Paracetamol is the recommended antipyretic agent (but must be used with 
caution due to a potential interaction with piperaquine; see below)
2) Antimalarials:

4-aminoquinolines (amodiaquine, chloroquine)

8 aminoquinolines (primaquine, pamaquine)

Artemisinin derivatives

Aryl-aminoalcohol (halofantrine, lumefantrine)

Atovaquone

Tetracycline e.g. doxycycline 

Quinine, quinidine, quinacrine, mefloquine

Proguanil
3) Drugs with antimalarial activity:
This list serves to provide examples of more commonly used drugs with antimalarial 
activity, but is not exhaustive. 

Albendazole

Allopurinol 

Clindamycin 

Diamidines (e.g., Pentamidine)

Fluroquinolones e.g. ciprofloxacin, nalidixic acid sparfloxacin 

Glibenclamide 

Indinavir, Saquinavir and Ritonavir 

Isoniazid 

Probenecid

Rifampicin

Sulfacetamide

Sulfadiazine, Sulfadoxine or Sulfalene/pyrimethamine, 
Sulfamethoxazole/trimethoprim, Sulfasalazine (and other sulfonamides)


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4) Drugs known to cause QTc prolongation:
The following drugs are prohibited for a period of 14 days following the start of study 
treatment:

Amiodarone

Antidepressant agents (e.g. citalopram

Antifungal agents (e.g. imidazole and triazole)

Non-sedating antihistamines (e.g. astemizole, mizolastine, terfenadine)

Arsenic trioxide

Bepridil

Cisapride

Diphenamil

Disopyramide

Dofetilide

Domperidone

Droperidol

Fluoroquinolones (e.g. moxifloxacin, sparfloxacin)

Haloperidol

Hydroquinidine

Ibutilide

Isotalol

Ketoconazole (oral or IV, but topical preparations are allowed)

Levomethadyl

Lidoflazine

Macrolides (e.g. azithromycin, erythromycin, clarithromycin, roxithromycin)

Mesoridazine


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
Methadone

Neuroleptics e.g. chlorpromazine and other phenothiazines, sertindole, sultopride

Pentamidine

Pimozide

Probucol

Procainamide hydrochloride

Saquinavir

Thioridazine

Sotalol

Sulfapyridine

Vinca alkaloids
5) Drugs excreted via the renal transporters MATE1, MATE2-K AND OCT2:
The following drugs excreted via the renal transporters MATE1, MATE2-K and OCT2 
are prohibited for a period of 21 days following the blinded dose of tafenoquine:

Phenformin

Buformin

Dofetilide

Procainamide

Pilsicainide
Note: Metformin is also excreted via MATE1, MATE-2 and OCT2 but may continue to 
be taken provided the subject has a serum creatinine below the upper limit of normal and 
has no concomitant medical conditions that increase the risk of lactic acidosis.
6) Others-miscellaneous:

Phenazopyridine 

Phenylhydrazine 

Chloramphenicol


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7) Primaqine interactions (source eMC):

Contraindicated with other potentially hemolytic drugs and depressants of 
myeloid elements of bone marrow
In addition, refer to locally approved prescribing information.
8) DHA-PQP interactions (source SmPC):
Piperaquine is an inhibitor of CYP3A4 and CYP2C19 and may increase plasma 
concentrations of other substrates for this enzyme. Drugs which have a narrow 
therapeutic index and are substrates for CYP3A4 or CYP2C19 should not be taken during 
this study, for example:  

Antiretroviral products 

Cyclosporine

Omeprazole
Piperaquine is metabolised by CYP3A4 in vitro. Drugs and food which inhibit CYP3A4 
may lead to a marked increase in piperaquine concentration resulting in an excerabation 
of the effect on QTc. Therefore, drugs and other substances which inhibit CYP3A4 are 
prohibited for a period of 14 days after last dose of DHA-PQP administration, for 
example: 

Some protease inhibitors (eg amprenavir, atazanavir, indinavir, nelfinavir, 
ritonavir)

Nefazodone

Verapamil
Additionally, CYP3A4 inducing products may lead to reduced piperaquine plasma 
concentrations and should not be given during the study as follows:

Carbamazepine

Phenytoin

Phenobarbital

St. John’s wort (Hypericum perforatum)


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The following drugs may be administered with caution during the study:
Piperaquine has the potential to increase the rate of metabolism for CYP2E1 substrates 
resulting in reduced plasma concentrations. Caution is advised if administered with drugs 
metabolised via this pathway e.g.

Paracetamol

Theophylline

Anaesthetic gases (enflurane, halothane, isoflurane)
DHA administration may result in slight decrease in CYP1A2 activity. Caution is advised 
if co-administered with drugs metabolised by this enzyme that have a narrow therapeutic 
index e.g.

Theophylline
The following antibiotics are permitted during study:
The following antibiotics can be used after inclusion and during the study:

Penicillins (e.g. penicillin, ampicillin, amoxicillin, amoxicillin+clavulanate, 
cloxacillin)

Cephalosporins (e.g. ceftazidime, ceftriaxone)

Aminoglycosides (e.g. gentamicin)

Carbapenems (e.g. meropenem and imipenem)


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12.6
Appendix 6: Country Specific Requirements
There are no country specific requirements


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12.7
Appendix 7: Protocol Changes
Amendment 1
The primary reason for this amendment is to include a comparison of the efficacy of 
dihydroartemisinin-piperaquine (DHA-PQP) co-administered with primaquine as a 
radical cure for P.vivax malaria versus DHA-PQP alone, as a secondary study objective. 
This protocol revision was requested by the Indonesian regulatory agency (Badan POM). 
Other revisions are as follows:

A vital signs assessment has been included at Day 2 to permit evaluation of time 
to fever clearance (secondary study objective). This assessment was omitted in 
error from the final protocol (version dated 27th January 2016). 

The name and contact details of the secondary medical monitor have been revised

The Oxford Tropical Research Ethics Committee (OXTREC) project number (9-
16), amendment number and date has been added to the footer of each page, as 
required by the ethics committee
Footer of Each Page
ADDED TEXT
OXTREC 9-16 /Protocol 200894 Amendment Number 01/Date 20-APR-2017
Medical Monitor/Sponsor Information Page
PREVIOUS TEXT
Role
Secondary 
Medical 
Monitor
Name
Day Time Phone 
Number and email 
address
After hours Cell 
Number
Site Address
GlaxoSmithKline 
Research & 
Development 
Limited
Iron Bridge Road 
Stockley Park 
West, Uxbridge, 
Middlesex, UB11 
1BT, UK
PPD
PPD
PPD


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REVISED TEXT
Role
Secondary 
Medical 
Monitor
Name
Day Time Phone 
number and email 
address
After hours Cell 
Number
Site Address
GlaxoSmithKline 
Research & 
Development 
Limited
Iron Bridge Road 
Stockley Park 
West, Uxbridge, 
Middlesex, UB11 
1BT, UK
Section 1 Protocol Synopsis Objectives/Endpoints
ADDED TEXT
Secondary Objective

To determine the efficacy of primaquine co-
administered with DHA-PQP relative to DHA-PQP 
alone.
Endpoints

Subjects with relapse-free 
efficacy six months post-dosing
Section 3. OBJECTIVE(S) AND ENDPOINT (S)
ADDED TEXT
Secondary Objective

To determine the efficacy of primaquine co-
administered with DHA-PQP relative to DHA-PQP 
alone.
Endpoints

Subjects with relapse-free 
efficacy six months post-dosing
Section 7.1 Time and Events Table
ADDED TEXT
One vital signs assessment added to Time and Events table for Day 2
PPD
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Section 9.4.1 Secondary Analyses
PREVIOUS TEXT
The primary efficacy comparison is of DHA-PQP plus TQ versus DHA-PQP alone for 
relapse free-efficacy at 6 months, but a 95% confidence interval for the treatment 
difference of DHA-PQP plus TQ versus DHA-PQP plus PQ will also be generated, to 
support evaluation of this secondary treatment comparison.
A secondary per protocol analysis will also be performed, excluding subjects who deviate 
significantly from the protocol. If a subject misses a scheduled study visit from day 28 
onwards, they will automatically be excluded from the per protocol population.
Statistical comparisons (DHA-PQP plus TQ versus DHA-PQP alone, and DHA-PQP plus 
TQ versus DHA-PQP plus PQ) of secondary efficacy endpoints (relapse efficacy at 4 
months, time to relapse, percentage of subjects with recrudescence, parasite clearance 
time, fever clearance time) will also be performed using survival analysis methodology.
REVISED TEXT
For evaluation of the secondary efficacy comparisons, 95% confidence intervals will be 
provided for the treatment differences of i) DHA-PQP plus TQ versus DHA-PQP plus 
PQ and ii) DHA-PQP plus PQ versus DHA-PQP alone. An exploratory p-value will also 
be provided for the DHA-PQP plus PQ versus DHA-PQP alone comparison. 
A secondary per protocol analysis will also be performed, excluding subjects who deviate 
significantly from the protocol. If a subject misses a scheduled study visit from day 28 
onwards, they will automatically be excluded from the per protocol population.
Statistical comparisons (i) DHA-PQP plus TQ versus DHA-PQP alone, ii) DHA-PQP 
plus TQ versus DHA-PQP plus PQ and iii) DHA-PQP plus PQ versus DHA-PQP alone) 
of secondary efficacy endpoints (relapse-free efficacy at 4 months, time to relapse, 
percentage of subjects with recrudescence, parasite clearance time, fever clearance time) 
will also be performed using survival analysis methodology.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
200894
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 200894: A double-
blind, double-dummy, randomized, parallel group, placebo-
controlled superiority study to evaluate the efficacy and 
safety of tafenoquine (SB-252263, WR238605) co-
administered with dihydroartemisinin-piperaquine (DHA-
PQP) for the radical cure of Plasmodium vivax malaria
Compound Number
:
SB-252263
Effective Date 
:
06-Sep-2019
Description:
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 200894.
This RAP is intended to describe the planned safety, efficacy and tolerability
analyses required for the study. 
This RAP will be provided to the study team members to convey the content of 
the blinded data review, Statistical Analysis Complete (SAC) and PK deliverables.
RAP Author(s): 
Approver
Date
Approval Method
Principal Statistician (Biostatistics)
N/A
N/A – Initial Lead 
author (critical 
components)
Director Clinical Pharmacology (CPMS)
21-Aug-2019
E-mail 
Confirmation
Director, Statistics (Biostatistics)
N/A
N/A – Replacement 
Lead author (final 
RAP)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD


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RAP Team Approvals: 
Approver
Date
Approval Method
Clinical Investigation Lead (Global Health, 
Clinical Development)
21-Aug-2019
E-mail 
Confirmation
Manager (ID, CPSSO Data Management)
21-Aug-2019
E-mail 
Confirmation
Medical Director (SERM, GCSP)
23-Aug-2019
E-mail 
Confirmation
Principal Programmer/Analyst (Biostatistics)
22-Aug-2019
E-mail 
Confirmation
Clinical Statistics and Clinical Programming Line Approvals: 
Approver
Date
Approval Method
Statistics Director (Biostatistics)
06-Sep-2019
E-signature
Programming Manager (Biostatistics)
28-Aug-2019
E-signature
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses.................................................................................11
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Final Analyses (Excluding PK Data)............................................................11
3.2.
Analysis of PK Data....................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
5.1.
Study Treatment & Sub-group Display Descriptors.....................................14
5.2.
Baseline Definitions ....................................................................................14
5.2.1.
Change from Baseline .................................................................14
5.3
Examination of Covariates, Other Strata and Subgroups............................15
5.3.1
Covariates and Other Strata ........................................................15
5.3.2
Examination of subgroups ...........................................................15
5.4
Multiple Comparisons and Multiplicity .........................................................15
5.5
Subject vs Participant Terminology.............................................................15
5.6
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................17
6.1.
Overview of Planned Study Population Analyses........................................17
7.
EFFICACY ANALYSES..........................................................................................18
7.1.
Primary Efficacy Analyses ..........................................................................18
7.1.1.
Endpoint / Variables.....................................................................18
7.1.2.
Summary Measure ......................................................................18
7.1.3.
Population of Interest...................................................................18
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................18
7.1.5.
Statistical Analyses / Methods .....................................................18
7.1.5.1.
Statistical Methodology Specification..........................18
7.2.
Secondary Efficacy Analyses......................................................................21
7.2.1.
Endpoints / Variables...................................................................21
7.2.2.
Summary Measures.....................................................................21
7.2.3.
Population of Interest...................................................................21
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................21
7.2.5.
Statistical Analyses / Methods .....................................................21
7.2.5.1.
Statistical Methodology Specification..........................21
7.3.
Exploratory Efficacy Analyses.....................................................................24
7.3.1.
Endpoints / Variables...................................................................24
7.3.2.
Summary Measure ......................................................................24


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7.3.3.
Population of Interest...................................................................24
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events ................24
7.3.5.
Statistical Analyses / Methods .....................................................24
8.
SAFETY ANALYSES .............................................................................................27
8.1.
Adverse Events Analyses ...........................................................................27
8.1.2 Overview of Planned Adverse Event Analyses...................................27
8.2.
Adverse Events of Special Interest Analyses..............................................28
8.3.
Clinical Laboratory Analyses.......................................................................28
8.3.1.
Haemoglobin Declines and Related Laboratory 
Parameters..................................................................................28
8.4.
Other Safety Analyses ................................................................................29
9.
PHARMACOKINETIC ANALYSES.........................................................................29
10. REFERENCES.......................................................................................................31
11. APPENDICES........................................................................................................32
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................32
11.2.
Appendix 2: Schedule of Activities ..............................................................34
11.2.1.
Protocol Defined Schedule of Events...........................................34
11.3.
Appendix 3: Assessment Windows .............................................................37
11.3.1.
Definitions of Assessment Windows for Analyses........................37
11.4.
Appendix 4: Study Phases and Treatment States for Adverse Event 
Data............................................................................................................38
11.4.1.
Study Phases ..............................................................................38
11.4.1.1.
Study Phases for Concomitant Medication .................38
11.4.1.2.
Treatment States for Adverse Event Data ..................38
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................39
11.5.1.
Reporting Process .......................................................................39
11.5.2.
Reporting Standards....................................................................39
11.5.3.
Reporting Standards for Pharmacokinetics..................................40
11.6.
Appendix 6: Derived and Transformed Data ...............................................40
11.6.1.
General........................................................................................40
11.6.2.
Study Population..........................................................................41
11.6.3.
Efficacy........................................................................................42
11.6.4.
Safety ..........................................................................................48
11.7.
Appendix 7: Reporting Standards for Missing Data.....................................50
11.7.1.
Premature Withdrawals................................................................50
11.7.2.
Handling of Missing Data.............................................................50
11.7.2.1.
Handling of Missing and Partial Dates ........................50
11.7.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................51
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................52
11.8.1.
Laboratory Values........................................................................52
11.8.2.
ECG.............................................................................................53
11.8.3.
Vital Signs (Normal Ranges)........................................................53
11.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ......................54
11.9.1.
Pharmacokinetic NONMEM Dataset Specification.......................54
11.9.2.
Population Pharmacokinetic (PopPK) Methodology.....................57
11.9.2.1.
Pharmacokinetic Model Development.........................57


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11.9.2.2.
Predictive Check ........................................................57
11.9.2.3.
Model Development....................................................57
11.9.2.4.
Covariate analysis ......................................................58
11.9.2.5.
Model refinement........................................................58
11.9.2.6.
Model evaluation ........................................................58
11.10. Appendix 10: Abbreviations & Trade Marks ................................................59
11.11. Appendix 11: List of Data Displays..............................................................61
11.11.1. Study Population Tables..............................................................62
11.11.2. Efficacy Tables ............................................................................66
11.11.3. Efficacy Figures ...........................................................................69
11.11.4. Safety Tables...............................................................................70
11.11.5. Safety Figures .............................................................................77
11.11.6. Pharmacokinetic Tables...............................................................79
11.11.7. Pharmacokinetic Figures .............................................................79
11.11.8. ICH Listings .................................................................................80
11.11.9. Non-ICH Listings..........................................................................84
11.11 Appendix 12: Example Mock Shells for Data Displays ................................86


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 200894:
Revision Chronology:
2015N232546_00
27-JAN-2016
Original
2015N232546_01
20-APR-2017
A secondary study objective was added to compare the 
efficacy of dihydroartemisinin-piperaquine (DHA-PQP) 
plus primaquine relative to DHA-PQP alone. 
A vital signs assessment was added at Day 2 to permit 
evaluation of time to fever clearance (secondary 
objective).


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Gastrointestinal (GI) tolerability was listed as an endpoint in the protocol. Data from 
phase 3 studies of tafenoquine, reported since the protocol was finalised, have abated 
previous concerns with regards GI tolerability, and hence this endpoint will not be 
specifically analysed. GI AEs will however still be reported in summaries of adverse 
events (AEs).
Additional study populations have been defined:
The Safety Open Label, Primaquine phase, Non-Relapsers (Safety OL)
Population, has been defined for the summaries of adverse events for the participants who 
did not relapse during the double-blind phase and went onto the open-label primaquine 
phase at the end of the study. 
The PK population has been defined as all participants for whom at least one 
systemic tafenoquine concentration, and associated sample date/time is available.  
The ITT population has been renamed to the microbiologic-intent-to-treat population 
(mITT) and the definition updated to include the need for participants to have 
microscopically-confirmed P. vivax parasitemia at baseline. 
The primary analysis uses a Cox’s proportional hazards model as opposed to the log rank 
test as described in the protocol.
At the time of finalising the full RAP, it had been established that a blinded data review 
was not required due to 150 participants having been randomised. Details of the blinded 
data review are therefore not included in the RAP. It was also known that recruitment 
was from 2 battalions.
For the analysis of dichotomous endpoints, logistic regression analysis will be performed 
as opposed to exact methods as defined in the protocol. This enables battalion to be 
adjusted for in analyses.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objective
Primary Endpoint
To determine the efficacy of tafenoquine 
co-administered with DHA-PQP for the 
radical cure of P.vivax malaria, relative to 
DHA-PQP alone at 6 months.  
Participants with relapse-free efficacy six 
months post-dosing (i.e. clearance of initial 
infection without subsequent microscopically 
confirmed recurrence during the 6 month 
follow up).
Secondary Objectives
Secondary Endpoints
To characterize the efficacy of 
tafenoquine relative to primaquine when 
co-administered with DHA-PQP.
Participants with relapse-free efficacy six 
months post-dosing.
To determine the efficacy of primaquine 
Participants with relapse-free efficacy six 


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Objectives
Endpoints
co-administered with DHA-PQP relative 
to DHA-PQP alone
months post-dosing. 
To determine the efficacy of tafenoquine 
co-administered with DHA-PQP relative 
to DHA-PQP alone at four months. 
Participants with relapse-free efficacy four 
months post-dosing.
To determine the blood stage efficacy of
tafenoquine in participants with P.vivax
malaria when co-administered with DHA-
PQP. 
Time to relapse.
Time to fever clearance (in participants with 
fever at baseline).
Time to parasite clearance.
Percentage of participants with recrudescence
(blood stage treatment failure) on or before 
Day 14 (i.e. a recurrence of P. vivax parasites 
which is genetically homologous to the 
baseline P. vivax infection). 
To assess the safety of tafenoquine in 
participants with P.vivax malaria when 
co-administered with DHA-PQP.
Incidence and severity of adverse events and
Serious Adverse Events (SAEs).
Incidence of clinically significant abnormal 
clinical laboratory tests, Electrocardiogram 
(ECGs) and vital signs. 
Change from baseline in methaemoglobin.
Change from baseline in Frederica’s QT 
Interval Corrected for Heart Rate (QTcF).
Incidence of protocol defined SAEs (i.e. a 
decrease in haemoglobin of ≥30% or >3 g/dL 
from baseline or, a drop in haemoglobin below 
7.0 g/dL, in the first 15 days). 
To evaluate the pharmacokinetics of 
tafenoquine when co-administered with 
DHA-PQP in adult participants with 
P.vivax malaria. 
Population PK parameters for tafenoquine 
including oral clearance (CL/F) and volume of 
distribution (V/F). 
Exploratory Objectives
Exploratory Endpoints
To explore the genetics of recurrence of 
P.vivax malaria
Incidence of genetically homologous and 
heterologous P.vivax infections (determined 
by PCR). 
Whole genome sequencing of multiple 
parasite genes will be undertaken, if parasite 
count allows (to be reported separately, and 
not detailed in this RAP). 
To explore the relationship between 
CYP2D6 genotype and risk of P.vivax
relapse.
Percentage of participants relapsing analyzed 
according to CYP2D6 genotype. 
To explore the relationship between the 
pharmacokinetics of tafenoquine co-
administered with DHA-PQP and 
pharmacodynamic endpoints (if 
appropriate).
Population PK (e.g. tafenoquine plasma 
concentrations) and selected 
pharmacodynamic (PD) endpoints (e.g. 
relapse-free efficacy, change in 
methaemoglobin). 


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With regards to the efficacy endpoints, it should be noted that it is not possible to 
determine if a participant’s recurrence of malaria is a relapse, re-infection or 
recrudescence. For the purposes of this RAP, the term “relapse” will be used to describe
any recurrence of P. vivax malaria after clearance of the initial infection. 
“Recrudescence” applies to the term relating to recurrence for Days 1-14 of the study, 
where a genetically homologous parasite is suggestive of a recrudescence. Therefore, 
within this RAP, recrudescence will represent a subset of all of the relapses captured. 


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features
A double-blind, double-dummy, randomized, parallel group, placebo-
controlled superiority study. 
Approximately 150 participants will be enrolled from the Indonesian army 
returning from deployment in a heavily malarious region of Indonesia.
Duration of study: Up to 195 days, including screening (Day 1), and 
randomization to treatment (Day 1 or Day 2), 14 daily visits while receiving 
blinded study treatment and seven follow-up visits (Days 21, 28, 60, 90, 120, 
150 and 180). Participants who do not relapse by Day 180 will attend a follow 
up visit on Day 195, following 14 days of open label primaquine. 
Dosing
All participants will receive open label DHA-PQP on Study Days 1-3, together 
with TQ or PQ and matching placebo beginning on Study Day 1 or 2. TQ, or 
matching placebo, will be given as a single 300mg dose. Participants will 
receive PQ, 15mg once daily, or matching placebo, for 14 days. 
Time & 
Events
See Appendix 2: Schedule of Activities
Treatment 
Assignment
Participants will be randomised 1:1:1 to receive TQ, the active comparator 
PQ or Placebo.
GSK RANDALL NG will be used to generate randomisation schedules. 
Treatment allocation will occur by centralised randomisation using GSK 
RAMOS, accessed via an Interactive Web Recognition System (IWRS). 


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2.4.
Statistical Hypotheses
The null hypothesis for the primary endpoint is that the 6-month relapse-free efficacy is 
not different between the DHA-PQP plus TQ and DHA-PQP alone treatment groups. The 
alternative hypothesis is that the relapse-free efficacy of the treatments is different. The 
hypothesis will be two-sided and tested at the 5% significance level.
3.
PLANNED ANALYSES
The PK data will not be available at the time of reporting the study. PK data will 
therefore be reported separately at a later date. 
3.1.
Final Analyses (Excluding PK Data)
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
All participants have completed (or withdrawn from) the study as defined in the 
protocol.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management (with the exception 
of PK data).
All criteria for unblinding the randomisation codes have been met. 
Randomisation codes have been distributed according to RandAll NG procedures.
3.2.
Analysis of PK Data
The analysis of PK data will be performed after all required database cleaning activities 
for PK data have been completed and final database release and database freeze have
been declared by Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened
All participants who were screened for 
eligibility.
Study 
Population
Enrolled
All randomised participants.
Study 
Population
Safety
All randomised participants who received 
at least one dose of blinded study treatment.
If participants receive a treatment different 
to their randomized treatment, they will be 
Study 
Population
Safety


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Population
Definition / Criteria
Analyses Evaluated
analysed according to the treatment actually 
received.
Safety Open 
Label, PQ phase, 
Non-Relapsers 
(Safety OL)
All participants in the safety population 
who did not relapse during the double-blind phase 
and went onto the open-label primaquine phase at 
the end of the study.
Study 
Population
Safety
Microbiologic-
Intent-To-Treat
(mITT)
All randomized participants who received 
at least one dose of blinded study treatment and 
have microscopically-confirmed P. vivax
parasitaemia at baseline.
Participants will be analysed according to 
their randomized treatment.
Efficacy
Per-Protocol (PP)
All participants in the mITT population for 
whom there were no major protocol deviations
that impact the primary endpoint. 
Protocol deviations that would exclude 
participants from the PP population are defined 
in Section 4.1 (Protocol Deviations) and 
Appendix 1 (Protocol Deviation Management 
and Definition for Per-Protocol Population).
Sensitivity/ 
supporting analyses 
of efficacy data
PK population
All participants for whom at least one systemic 
tafenoquine concentration, and associated 
sample date/time is available. 
PK
NOTES: 
Please refer to Appendix 11: List of Data Displays which details the population to be used for each display being
generated.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.
Important deviations which result in exclusion from the per protocol analysis 
population (major deviation) will also be summarised and listed. (Please refer to
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol
Population).
Protocol deviations will be tracked by the study team throughout the conduct of 
the study in accordance with the Protocol Deviation Management Plan.
Data will be reviewed prior to unblinding (where possible) and freezing the 
database to ensure all important deviations and deviations which may lead to 
exclusion from the analysis are captured and categorised on the protocol 
deviations dataset. Where it is not possible to review the data prior to unblinding, 
e.g. if a participant received an incorrect container number, the data will be 
reviewed before freezing the database.  


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This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations for 
screening failures will also be provided. This summary will be based on data as 
recorded on the inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order in TLF
2
Tafenoquine + DHA-PQP
TQ+DHA-PQP 
2
3
Primaquine + DHA-PQP
PQ+DHA-PQP
3
1
Placebo + DHA-PQP
DHA-PQP only
1
Treatment comparisons will be displayed as follows using the descriptors as specified:
TQ+DHA-PQP vs DHA-PQP only
PQ+DHA-PQP vs DHA-PQP only
TQ+DHA-PQP vs PQ+DHA-PQP
For the open-label phases participants will be summarised according to their randomised 
treatment group, with totals also provided. 
5.2.
Baseline Definitions
For all endpoints, the baseline value will be the latest pre-treatment assessment with a 
non-missing value, including those from unscheduled visits. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
Asexual parasite and gametocyte counts
If there are multiple pre-treatment assessments, a participant will be considered to have a 
positive (non-zero) baseline count if any of the assessments are positive.  They will only 
be considered to have a zero baseline count if all the pre-treatment assessments are 
negative (zero).
5.2.1.
Change from Baseline
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
NOTES:
The baseline definition will be footnoted on all change from baseline displays.


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5.3
Examination of Covariates, Other Strata and Subgroups
5.3.1
Covariates and Other Strata
Battalion, weight and baseline P.vivax asexual parasite count will be included as 
covariates in the time-to-event analysis of relapse-free efficacy at 6 months. 
Battalion will be derived based on participant numbers as follows:
Battalion
Participant Numbers
Battalion 1
001-074
Battalion 2
075- 164
5.3.2
Examination of subgroups
If the treatment by battalion interaction is found to be statistically significant in the Cox’s 
Proportional Hazards analysis of time to relapse, then the analysis will be conducted 
separately for each battalion. Similarly, the analysis of relapse-free efficacy at 4 months, 
and the Kaplan-Meier curves for time to relapse will be produced separately for each 
battalion.
5.4
Multiple Comparisons and Multiplicity
The primary comparison of interest is the comparison between TQ+DHA-PQP and DHA-
PQP only for the primary endpoint, relapse-free efficacy over 6 months, in the mITT 
population; this is the only primary efficacy comparison so no multiplicity adjustment is 
needed. 
5.5
Subject vs Participant Terminology
In this RAP the term participant is used when describing the planned reporting and 
analysis. In the data displays, trial participants should be referred to as “subjects”.
5.6
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Study Phases and Treatment States for Adverse Event Data
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Reporting Standards for Missing Data
11.8
Appendix 8: Values of Potential Clinical Importance


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Section
Component
11.9
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
11.11
Appendix 11: List of Data Displays
11.11
Appendix 12: Example Mock Shells for Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Safety population or Safety OL 
population except the overview of analysis populations and the diagnostic comparisons 
which will be based on the screened population.
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications 
and exposure and treatment compliance will be based on GSK Core Data Standards. 
Details of the planned displays are presented in Appendix 11: List of Data Displays.
Categorical variables will be summarized by the number and percentage of participants, 
and the continuous parameters will be summarized by n, mean, median, sample standard 
deviation, minimum and maximum unless otherwise specified. 
The study population tables presented using the Safety Population will be presented from 
administration of first study medication (including DHA-PQP) until Day 180 visit. The 
tables presented using the Safety OL population will be presented from Day 180 visit + 1 
day until Day 180 visit + 21 days.  


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7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The primary endpoint is relapse-free efficacy during the six months post-dosing. 
7.1.2.
Summary Measure
Hazard ratio for risk of relapse over the six months post-dosing. 
7.1.3.
Population of Interest
The primary efficacy analyses will be based on the microbiologic-Intent-To-Treat 
population, unless otherwise specified. 
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated will be the hypothetical effect if all participants had 
stayed on their randomised medication. 
The time to the first P. vivax relapse will be used in the analysis. 
Participants who discontinue treatment will be included in the analysis and handled the 
same as participants who remain on treatment as described in Section 11.6.3.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays, and
will be based on GSK data standards and statistical principles.
7.1.5.1.
Statistical Methodology Specification
The primary endpoint is the comparison between TQ+DHA-PQP and DHA-PQP only. A 
description of the analyses for the comparisons between TQ+DHA-PQP and PQ+DHA-
PQP and also PQ+DHA-PQP and DHA-PQP only are also described in this section but 
are regarded as secondary endpoints.
Further details regarding the planned analysis and relapse free definition can be found in 
Section 11.6.3.
Primary Statistical Analyses
Endpoint / Variables
Relapse-free efficacy six months post-dosing 
Model Specification
Cox’s Proportional Hazards (CPH) model, including terms for battalion and treatment for 
calculation of Hazard Ratios


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Primary Statistical Analyses
Kaplan-Meier estimates of relapse-free efficacy rate and time to relapse for each treatment 
group
mITT population
Model Checking & Diagnostics
The proportional hazards assumption should be assessed via a check of the Kaplan-Meier curves. 
The shape of the curves should be similar for the 3 treatment groups with the separation between 
the curves remaining proportional across time. A complementary log-log plot may also be used to 
check the proportional hazards assumption. If the proportional hazards assumption is violated a 
logistic regression model will be performed instead using a binary response variable of relapse free 
vs relapse and including battalion and treatment as covariates. 
The treatment by battalion interaction will be assessed at the 10% level of significance. The CPH 
model will be refitted, including the main effects of treatment and battalion, and the treatment by 
battalion interaction. If the interaction is found to be statistically significant, then the nature of the 
interaction will be examined to determine if the results from the two battalions are homogeneous 
(treatment differences are in the same direction) or heterogeneous (treatment differences in 
different directions). If the latter, then the results will be presented separately for each battalion. 
The impact of baseline P.vivax asexual parasite count and of weight on the treatment effect will be 
assessed by refitting the CPH model, separately for each continuous covariate, including the main 
effects of treatment, battalion, baseline parasite count/ weight and the treatment by baseline 
parasite count/ weight interaction. The interactions will be assessed at the 10% level of 
significance. If an interaction is found to be statistically significant, then the nature of the interaction 
will be examined by plotting the estimated hazards ratio and 95% CI vs baseline parasite count/ 
weight.
Model Results Presentation
Summary of the proportion of participants with relapse-free efficacy at six months by 
treatment group as n (%), including the sub-reasons for why participants are not considered 
relapse-free defined in Section 11.6.3 (Table 2.5).  Note, only the sub-reasons that apply to the 
population being displayed will be included.  
Analysis table (Table 2.8) will show:
Number of participants with an observed relapse and numbers of participants censored 
(censored prior to 6 months, and censored relapse-free at 6 months)
Estimates for time to relapse: 1st quartile, median, 3rd quartile and associated 95% 
confidence intervals
Kaplan-Meier estimate and 95% confidence interval of the relapse-free efficacy rate at 6 
months for each treatment
Hazard ratio of TQ+DHA-PQP vs DHA-PQP only over the first 6 months and associated 
95% CI and p-value from Cox’s proportional hazards analysis. 
Hazard ratio of TQ+DHA-PQP vs PQ+DHA-PQP (secondary endpoint) over the first 6 
months and associated 95% CI.
Hazard ratio of PQ+DHA-PQP vs DHA-PQP only (secondary endpoint) over the first 6 
months and associated 95% CI. 
Kaplan-Meier survival curves will also be produced (Figure 2.1).
Subgroup Analyses
If the treatment by battalion interaction is found to be statistically significant in the Cox’s 


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Primary Statistical Analyses
Proportional Hazards analysis, the analysis will be conducted separately for each battalion. 
Similarly, the Kaplan-Meier curves for time to relapse will be produced separately for each 
battalion.
Sensitivity and Supportive Statistical Analyses
Per Protocol population
Repeat primary analysis with Per Protocol population. 
Summary of the proportion of participants with relapse-free efficacy by treatment group as 
n (%), including the sub-reasons for why participants are not considered relapse-free defined in 
Section 11.6.3 (Table 2.7).  Note, only the sub-reasons that apply to the population being displayed 
will be included.  
Analysis table (Table 2.10) will show:
Number of participants with an observed relapse and numbers of participants censored 
(censored prior to 6 months, and censored relapse-free at 6 months)
Estimates for time to relapse: 1st quartile, median, 3rd quartile and associated 95% 
confidence intervals
Kaplan-Meier estimate and 95% confidence interval of the relapse-free efficacy rate at 6 
months for each treatment. 
Hazard ratio of TQ+DHA-PQP vs DHA-PQP only, TQ+DHA-PQP vs PQ+DHA-PQP and 
PQ+DHA-PQP vs DHA-PQP only over the first 6 months and associated 95% CI and p-value
(TQ+DHA-PQP vs DHA-PQP) from Cox’s proportional hazards analysis.
Kaplan-Meier survival curves will also be produced (Figure 2.2).
Logistic Regression (Censored Participants Excluded)
Logistic regression analysis, including terms for battalion and treatment.
Response variable = relapse free (confirmed at 6 months) vs relapse (confirmed relapse at 
or prior to 6 months). Participants who are censored prior to 6 months will be excluded from the 
analysis.
mITT population.
Presentation of results (Table 2.11):
Number and percentage of participants considered relapse free and relapsers.
Odds ratio of odds of relapse for TQ+DHA-PQP vs DHA-PQP only, TQ+DHA-PQP vs 
PQ+DHA-PQP and PQ+DHA-PQP vs DHA-PQP only and 95% CI for the odds ratios.
Model checking: Goodness of fit tests and residual plots (pearson and deviance residuals
to detect outliers and/or influential points) will be produced.
Logistic Regression (Missing = Failure analysis)
See Section 11.6.3 for derivation of missing=failure dataset 
Logistic regression analysis, including terms for battalion and treatment.mITT population.
Presentation of results (Table 2.12):
Number and percentage of participants considered relapse free and relapsers.
Odds ratio of odds of relapse for TQ+DHA-PQP vs DHA-PQP only, TQ+DHA-PQP vs 
PQ+DHA-PQP and PQ+DHA-PQP vs DHA-PQP only and 95% CIs
Model checking: Goodness of fit tests and residual plots (pearson and deviance residuals 
to detect outliers and/or influential points) will be produced.
By genetic classification of First P. vivax Recurrence
Repeat primary analysis censoring participants with homologous infections (Table 2.13) 
and censoring participants with heterologous infections (Table 2.14), present: 
Number of participants with an observed relapse and numbers of participants censored


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Primary Statistical Analyses
Kaplan-Meier estimate and 95% confidence interval of the relapse-free efficacy rate at 6 
months for each treatment.
Kaplan-Meier quartile estimates and 95% confidence intervals of time to relapse
Kaplan-Meier survival curves will also be produced (Figure 2.3 and Figure 2.4).
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoints / Variables
Relapse-free efficacy four months post-dosing
Time to relapse
Time to fever clearance
Time to asexual parasite clearance
Time to gametocyte clearance
Percentage of Participants with Recrudescence
7.2.2.
Summary Measures
The summary measure for all time to event endpoints will be hazard ratios. For the 
percentage of participants with recrudescence the treatment difference will be calculated. 
7.2.3.
Population of Interest
The secondary efficacy analyses will be based on the microbiologic-Intent-To-Treat 
population. 
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated will be the hypothetical effect if all participants had 
stayed on their randomised medication. 
The time to the first event of interest (i.e. P. vivax relapse, fever clearance, asexual 
parasite clearance or gametocyte clearance) will be used in the analysis. 
Participants who discontinue treatment will be included in the analysis and handled the 
same as participants who remain on treatment as described in Section 11.6.3. 
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays. The
format of data displays will be based on GSK data standards and statistical principles.
7.2.5.1.
Statistical Methodology Specification
Secondary Statistical Analyses
Endpoints / Variables
Relapse-free efficacy at 4 months


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Secondary Statistical Analyses
Time to relapse
Time to fever clearance
Time to asexual parasite clearance
Time to gametocyte clearance
Model Specification
mITT population
Estimates for time to endpoint will be determined for each treatment group using Kaplan-Meier 
methods. 
Cox’s proportional hazards analysis, including terms for battalion and treatment for calculation 
of Hazard Ratios for time to fever clearance, time to asexual parasite clearance, time to 
gametocyte clearance, and relapse-free efficacy at 4 months.
Model Checking & Diagnostics
The proportional hazards assumption should be assessed including a check of the Kaplan-
Meier curves. The shape of the curves should be similar for the treatment groups with the 
separation between the curves remaining proportional across time. A complementary log-log 
plot may also be used to check the proportional hazards assumption.
If the proportional hazards assumption is violated a logistic regression model will be performed 
instead using a binary response variable of event vs no event (e.g. fever clearance vs no fever 
clearance) and including battalion and treatment as covariates.
Model Results Presentation
Time to relapse is covered in Table 2.8. 
Tables 2.16 to Table 2.19:
Number of participants with the endpoint and number censored
Estimates for time to the endpoint: 1st quartile, median, 3rd quartile and associated 95% 
confidence intervals
For the relapse-fee efficacy at 4 months endpoint only, the Kaplan-Meier estimate and 
95% confidence interval of the relapse-free efficacy rate for each treatment at 4 months. 
For time to parasite clearance, time to fever clearance and relapse-free efficacy at 4 
months:
Hazard ratio (TQ+DHA-PQP vs DHA-PQP only, TQ+DHA-PQP vs PQ+DHA-PQP and 
PQ+DHA-PQP vs DHA-PQP only) and 95% confidence interval. 
Kaplan-Meier survival curves will be produced for time to fever clearance (Figure 2.5), time 
to asexual parasite clearance (Figure 2.6), and time to gametocyte clearance (Figure 2.7).
Subgroup Analyses
No subgroup analyses are planned for time to fever clearance, time to asexual parasite 
clearance, or time to gametocyte clearance. For relapse-free efficacy at 4 months, if the treatment 
by battalion interaction is found to be statistically significant in the analysis of the primary endpoint 
(relapse-free efficacy at 6 months), the analysis will be conducted separately for each battalion.
Sensitivity and Supportive Analyses
No sensitivity analyses are planned for these endpoints.
Secondary Statistical Analyses
Endpoint / Variable
Percentage of Participants with Recrudescence - see Section 11.6.3 for derivations including 
censoring


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Secondary Statistical Analyses
Model Specification
Descriptive statistics only
95% Wilsons confidence intervals for percentage of participants with recrudescence in each 
treatment group, and the treatment difference in the percentages with 95% Newcombe 
confidence intervals (TQ+DHA-PQP vs DHA-PQP only, TQ+DHA-PQP vs PQ+DHA-PQP and 
PQ+DHA-PQP vs DHA-PQP only).
mITT population 
Model Checking & Diagnostics
Only summary statistics are planned for this endpoint therefore no model checking is required. 
Model Results Presentation
Summary table showing the number of participants with recrudescence or censored, 
percentage of participants with recrudescence and 95% CI for each treatment group, plus 
treatment difference and 95% CI (Table 2.20).
Subgroup Analyses
No subgroup analyses are planned for this endpoint.
Sensitivity and Supportive Analyses
No sensitivity analyses are planned for this endpoint.


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7.3.
Exploratory Efficacy Analyses
7.3.1.
Endpoints / Variables
Incidence of genetically homologous and genetically heterologous P. vivax infections 
(determined by PCR)
Percentage of participants relapsing by CYP2D6 genotype
By metabolizer class
By activity score
7.3.2.
Summary Measure
Number and percentage of participants in each category at the end of the study. 
7.3.3.
Population of Interest 
The exploratory efficacy analyses will be based on the microbiologic-Intent-To-Treat 
population.
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events
The summary statistics will be based on available data only. 
7.3.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays.
These will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.3.1 will be 
summarised using descriptive statistics and listed.
Exploratory Statistical Analyses
Endpoint / Variable
Incidence of genetically homologous and genetically heterologous P. vivax infections 
(determined by PCR)
See Section 11.6.3 for derivation of a relapse.
Model Specification
Descriptive statistics only. 
mITT population 
Model Checking & Diagnostics
Only summary statistics are planned for this endpoint therefore no model checking is required. 
Model Results Presentation
Summary table (n and %) (Table 2.21) showing the proportion of participants in each 
treatment group with P. vivax relapse infections classified as genetically heterologous or 
homologous
n will be the number of participants with a relapse
Bar chart of the percentage of participants on each treatment arm with genetically 
heterologous or homologous infections, with 95% Wilson confidence intervals (Figure 2.8)


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Exploratory Statistical Analyses
Subgroup Analyses
No subgroup analyses are planned for this endpoint.
Sensitivity and Supportive Analyses
No sensitivity analyses are planned for this endpoint.
Exploratory Statistical Analyses
Endpoint / Variable
Percentage of participants relapsing by CYP2D6 genotype – Metabolizer Class. 
Model Specification
mITT population
Logistic regression model adjusting for derived CYP2D6 metabolizer class (poor + intermediate 
combined, or extensive + ultra combined, due to low numbers of poor and ultra metabolisers in 
the study) within treatment arm (models fitted separately for each treatment arm)
One-sided test at the 5% significance level (given published data indicating reduced CYP2D6 
metabolism decreases PQ efficacy)
Model Checking & Diagnostics
Goodness of fit tests and residual plots (pearson and deviance residuals to detect outliers 
and/or influential points) will be produced.
Model Results Presentation
Number and percentage of participants relapse free in each metaboliser class grouping within 
each treatment arm
Adjusted odds ratio, 90% CI and p-value
Subgroup Analyses
No subgroup analyses are planned for this endpoint.
Sensitivity and Supportive Analyses
No sensitivity analyses are planned for this endpoint.
Exploratory Statistical Analyses
Endpoint / Variable
Percentage of participants relapsing by CYP2D6 genotype – Activity Score
Model Specification
mITT population
Logistic regression model adjusting for qualitative CYP2D6 Activity Score (AS) within treatment 
arm (models fitted separately for each treatment arm)
Model Checking & Diagnostics
Goodness of fit tests and residual plots (pearson and deviance residuals to detect outliers 
and/or influential points) will be produced.
Model Results Presentation
Degrees of freedom, wald chi-square and p-value of the type III effect of AS in the model
Subgroup Analyses
No subgroup analyses are planned for this endpoint.


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Sensitivity and Supportive Analyses
No sensitivity analyses are planned for this endpoint.
Additional Efficacy Summaries
P. vivax asexual parasite counts (Table 2.1), mITT population:
Summary statistics (n, median, Q1, Q3, min and max) at each timepoint by treatment 
group.
Other malarial asexual parasite counts (Table 2.2), P. vivax gametocyte counts (Table 2.3), 
other malaria gametocyte counts (Table 2.4), mITT population:
Summary statistics (n, median, Q1, Q3, min and max) at each timepoint by treatment 
group.
Summary of participants with P. vivax gametocyte emergence post baseline (n, %), mITT 
population, by treatment group.
Summary of participants with P. falciparum asexual parasite emergence post baseline (n, %), 
mITT population, by treatment group. 
Summary of the number of relapses per subject (n, %), mITT population, by treatment group.


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8.
SAFETY ANALYSES
The safety analyses will be based on the Safety and Safety OL populations, unless 
otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs) and Serious 
(SAEs) will be based on GSK Core Data Standards. The details of the planned displays 
are provided in Appendix 11: List of Data Displays.
In addition to the standard displays the following study specific tables will be produced:
Summary of protocol-defined SAEs (Hb drop). Hb drops will be identified from 
the SAE page of the eCRF and confirmed by laboratory data. The laboratory data will be 
checked during programming to ensure there were no protocol-defined SAEs that were 
not reported as such.
Summary of grade 3 and grade 4 AEs.
AEs related to drug will be identified as either related to DHA-PQP or related to blinded 
study medication, per the ‘Relationship to Investigational Product’ flag in the eCRF.
8.1.2 Overview of Planned Adverse Event Analyses
Counting of AEs will be based on the number of participants – not the number of AEs. 
For example, if a participant reports the same AE on three occasions within the relevant
time interval, that AE will only be counted once. If a participant experiences the same AE 
(i.e. same preferred term) more than once, they are counted only once under the count for 
the preferred term.  If a participant experiences more than one AE in a SOC, they will 
only be included once in the count for the SOC, but will appear in the count for each 
appropriate preferred term within the SOC.  Therefore, the sum of the numbers of 
participants with each preferred term event within a SOC may exceed the total number of 
participants with at least one event.  For the summary of AEs by maximum intensity, 
participants who experience the same event several times with different intensity will 
only be counted once with the maximum intensity.
The recurrence of P. vivax malaria and any associated signs and symptoms are recorded 
as Disease Related Events (DREs) and will not be included in the AE data displays, but 
will be listed separately.
Adverse Events will be summarized by treatment group and as specified in Appendix 11
and presented in order of descending frequency.  The tables presented using the Safety 
Population will be presented from administration of first study medication (including 
DHA-PQP) until Day 180.. The tables presented using the Safety OL population will be 
presented from Day 180 visit + 1 day until Day 180 visit + 21 days.  


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8.2.
Adverse Events of Special Interest Analyses
Categories for AEs of Special Interest are defined in Section 11.6.4. 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data may highlight additional adverse 
events of special interest (AESIs), therefore the list of terms to be used for each event of 
interest and the specific events of interest will be based on the safety review team (SRT) 
agreements in place at the time of reporting. AESIs will be identified prior to the 
unblinding of the study. The details of the planned displays are provided in Appendix 11:
List of Data Displays.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 11: List of Data
Displays.
In addition to the standard displays the following study specific displays will be 
produced:
Tables: 
Summary of clinical chemistry / haematology abnormalities defined as values 
outside of the clinical concern range as defined in Section 11.8.1.
Summary of haemoglobin categories of change from baseline (categories defined 
as <=20 g/L, >20 g/L to <=30 g/L, > 30 g/L).
Summary of haemoglobin declines over the first 28 days (categories defined as 
<=20 g/L, >20 g/L to <=30 g/L, > 30 g/L or >=30%). 
Figures: 
Maximum absolute methaemoglobin value over 28 days
Change from baseline in methaemoglobin over time
Data recorded at unscheduled assessments will not be included in tables and figures but 
will be listed, unless it fits into a visit window per Section 11.3.1.
8.3.1.
Haemoglobin Declines and Related Laboratory Parameters
If a participant has a >30g/L decline from baseline haemoglobin or is found to be G6PD 
deficient, a haematological profile plot will be produced for the participant (Figure 3.3). 
This will display their haemoglobin, reticulocytes (if available), methaemoglobin and 
bilirubin results (total and indirect bilirubin on same plot) at each visit.  The participant


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ID, treatment group, sex, age and G6PD status (quantitative assay) should be included as 
a header for each participant’s plot.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 11: List of Data Displays.
In addition to the standard displays the following study specific tables will be produced:
Summary of QTcF values by category and visit. Categories for each post baseline 
timepoint are defined as: 
Absolute QTcF:
450 msec
>450 to 480 msec
>480 to 500 msec
>500 msec
Increase from baseline QTcF:
0 to <30 msec 
≥30 to <60 msec
≥60 and absolute QTcF480 msec
≥60 and absolute QTcF>480 msec
Summary of absolute and change from baseline in methaemoglobin
Details of blood transfusions will be listed.
Where triplicate assessments are performed (i.e. at baseline), the mean of the 3 
assessments will first be derived and the summary statistics will be presented using the 
mean of the assessments. For categorical data, e.g. ECG findings, the worst case should 
be presented where data is taken in triplicate.
9.
PHARMACOKINETIC ANALYSES
PK analyses will be the responsibility of Clinical Pharmacology Modelling and 
Simulation within GSK.
A sparse sampling scheme has been employed in the study. Predictive checks will be 
performed based on the existing TQ POPPK model developed with data from the Phase 3 
studies. With adequate predictive performance, the model will be utilized to generate the 
post hoc PK parameters for individual participants from the current study. These PK 
parameters will then be utilized to characterize their systemic exposure.
In case of lack of fits between model predictions and observed data, the existing model 
developed with Phase 3 data may be adjusted to characterize TQ PK. In this scenario, the 
tafenoquine systemic concentration- time data will be utilized in a population PK analysis 
to estimate the fixed-effects parameters (including oral clearance (CL/F), volume of 


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distribution (V/F)) as well as the corresponding random effects (between- and within-
subject variability) parameters as data permit.  
In the event that the sparseness of the data does not support estimation of some PK 
parameters (e.g. rate of absorption), the model population parameters may be fixed to 
previously obtained parameter estimates from the population PK meta-analysis 
performed at the end of Phase 3 studies.
Additionally, if data permit, exploratory PK/PD analyses for TQ data may be undertaken 
to examine any relationship between PK parameters (e.g. systemic exposure) and/or 
clinical outcome (relapse-free efficacy) or safety parameters (e.g. change in QTcF or
MetHb). Any exposure-response analyses based on emerging data will be described in 
detail in the study report.   
Any deviation from the planned analysis will be described in detail in the study report.


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10.
REFERENCES
Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 
Activity Score: Translating Genotype Information into a Qualitative Measure of 
Phenotype. Clin Pharmacol Ther. 2008; 83:234-242.
GlaxoSmithKline Document Number 2015N232546_01 200894, A double blind, double-
dummy, randomised, parallel group, placebo-controlled superiority study to evaluate the 
efficacy and safety of tafenoquine (SB-252263, WR238605) co-administered with 
dihydroartemisinin-piperaquine (DHA_PQP) for the radical cure of Plasmodium vivax 
malaria. (Amendment 1 – 20-APR-2017)
GUI_137354, Information for Authors: Reporting and Analysis Plan (RAP), Global
SOP_54838, Development, Review & Approval of Reporting & Analysis Plan (RAP), 
Global
Supportive Templates (for RAP), IMMS Example: Reporting and Analysis Plan (RAP) 
Template_Core Safety Reporting Standards


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11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management and Definitions
for Per Protocol Population
Major protocol violations could impact the ability to assess efficacy and the primary 
endpoint for the study. A participant meeting any of the following criteria will be 
excluded from the Per Protocol population:
Number
Exclusion Description
01
Participant does not have a scheduled parasitology assessment within window for any of 
the Day 1-141, Day 21, Day 28, Day 60, Day 90, Day 120, Day 150 or Day 180 visits prior 
to first relapse or end of study (early withdrawal or end of follow-up)2. 
02
When in the clinic on Days 1 to 14, participant vomited a dose of study medication and 
either vomited the redose, or a redose was not given. Or participant did not take required 
number of DHA-PQP tablets on Days 1-3.
03
Violation of any of the following entry criteria:
Participant had a severe malaria infection (exclusion #1)
Participant had severe vomiting or diarrhoea (exclusion #2)
Participants liver function test was > 2 x ULN (exclusion #4)
04
The participant has taken/received:
Anti-malarials (e.g., artemisinin-based combination therapies (ACTs), mefloquine, 
primaquine, quinacrine) or drugs with anti-malarial activity within the past 30 days.
Treatment with any investigational drug within 30 days of study entry, or within 5 
half-lives, whichever is longer.
A concomitant medication with an anti-malarial activity prior to first relapse or end 
of study (early withdrawal or end of follow-up). A list of all concomitant medications will be 
reviewed by a GSK clinician prior to unblinding the study, and classified accordingly
05
Participant did not take blinded study medication with food on Days 1-3. 
06
Participant who met study treatment withdrawal criteria, as defined in protocol Section 5.4, 
but was not withdrawn from study treatment. 
07
Participant received incorrect treatment.
08
Participants taking dose outside of the clinic that was not observed by a site staff member.
1For the twice daily blood smears on days 1-3, when determining exclusion from the PP population, 
participants were excluded if they didn’t have at least one assessment on each day, without having first 
demonstrated clearance. The time of the assessments will not be used since visit windows around the 6-12 
hour duration have not been defined.
2On study days 1-3, participants were scheduled to have twice daily blood smears until they had two 
consecutive negative smears, 6-12 hours apart. Due to errors in the parasite counts, 3 participants
(participant numbers ,
 and 
) were incorrectly concluded to have negative smears which were in-fact 
positive, and hence missed a subsequent parasitology assessment during days 1-3. These participants will 
not be excluded from the PP population as a result of this missed assessment.
During the study, the data is reviewed on an ongoing basis, with protocol deviations 
(PDs) identified by programmatic checks and manual review. These deviations are 
PP
D
PP
D
P
P


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assessed by data management and clinical (with input from others as required), and are 
entered into the deviations log, with the ‘Important’ flag set accordingly. 
The per protocol population exclusion flag is a derived variable in the analysis and 
reporting dataset (ADaM.ADDV). This variable is not captured in the SI or SDTM 
datasets. As for the ‘important PD’ flag, data is reviewed throughout the study to identify 
participants who should be excluded from the PP population. At DBR, additional 
programmatic checks are performed by the clinical programming team to further check 
for PDs. A spreadsheet of any PDs identified is provided to data management and 
clinical, who will add them to the deviations log with appropriate flags if not already 
included. 
A listing will be produced for the safety population showing the individual participant 
numbers for each important protocol deviation. A table will be produced showing the 
number and percentage of participants with major protocol deviations, overall and by 
type of deviation.


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11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events


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11.3.
Appendix 3: Assessment Windows
11.3.1.
Definitions of Assessment Windows for Analyses
Analysis Set / 
Domain
Parameter 
(if applicable)
Target 
Analysis Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
mITT, PP, Safety
All
Day 1
Day 1
Day 1
Day 1
mITT, PP, Safety
All
Day 2
Day 2
Day 2
Day 2
mITT, PP, Safety
All
Day 3
Day 3
Day 3
Day 3
Safety
ECG
4 hours after last DHA-
PQP dose
3 hours after 
last DHA-
PQP dose
6 hours after 
last DHA-
PQP dose
4 hours after 
last DHA-
PQP dose
mITT, PP, Safety
All
Day 4
Day 4
Day 4
Day 4
mITT, PP, Safety
All
Day 5
Day 5
Day 5
Day 5
mITT, PP, Safety
All
Day 6
Day 6
Day 6
Day 6
mITT, PP, Safety
All
Day 7
Day 7
Day 7
Day 7
mITT, PP, Safety
All
Day 8
Day 8
Day 8
Day 8
mITT, PP, Safety
All
Day 9
Day 9
Day 9
Day 9
mITT, PP, Safety
All
Day 10
Day 10
Day 10
Day 10
mITT, PP, Safety
MetHB
Day 11
Day 11
Day 11
Day 11
mITT, PP, Safety
MetHB
Day 12
Day 12
Day 12
Day 12
mITT, PP, Safety
MetHB
Day 13
Day 13
Day 13
Day 13
mITT, PP, Safety
MetHB
Day 14
Day 14
Day 17
Day 14
mITT, PP, Safety
All except MetHB
Day 14
Day 11
Day 17
Day 14
mITT, PP, Safety
All
Day 21
Day 18
Day 24
Day 21
mITT, PP, Safety
All
Day 28
Day 25
Day 43
Day 28
mITT, PP, Safety
All
Day 60
Day 44
Day 75
Day 60
mITT, PP, Safety
All
Day 90
Day 76
Day 105
Day 90
mITT, PP, Safety
All
Day 120
Day 106
Day 135
Day 120
mITT, PP, Safety
All
Day 150
Day 136
Day 169
Day 150
mITT, PP, Safety
All
Day 180
Day 170
Day 190
Day 180
Safety OL
All
Day 180 visit + 15-21 
days
Day 180 visit 
+ 15 days
Day 180 visit 
+ 21 days
Day 195
Note: Data collected after the nominal day 180 study visit, i.e. after the start of open label PQ for non-relapsers, will not 
be slotted to any visit up to and including the day 180 visit, regardless of the study day. Only the Day 195 visit window 
will be considered for slotting.
For all data summarised by visit, the nominal visit description will be used. Unscheduled 
and withdrawal visit data will be slotted into a scheduled visit window, but the data will 
only be included in summaries and figures if no scheduled visit exists within the same 
window. If there are multiple assessments within the same window which are not 
unscheduled visits, the earliest result will be used in the summaries and figures. If only 
unscheduled visits are included in the same window, the earliest of these results will be 
used in summaries and figures.


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11.4.
Appendix 4: Study Phases and Treatment States for
Adverse Event Data
11.4.1.
Study Phases
Study Phase
Definition
DHA-PQP only
Time of first administration of DHA-PQP to time of first dose of blinded study 
medication – 1 minute
Double blind
Time of first administration of blinded study medication to Day 180 visit
Open-label PQ 
phase, Non-
Relapsers
Day 180 visit + 1 day to Day 180 visit+21 days for participants who do not relapse prior 
to Day 180 visit
Data collected outside of the above study phases, e.g. an AE with a start date after the 
Day 180 visit, for a participant not entering the open-label PQ phase, will be listed only.
11.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is within 30 days prior to the date of first dose 
of study medication (including DHA-PQP).
Concomitant
Medications with a start date on or after the first dose of study medication (including 
DHA-PQP), or where the medication is ongoing on the date of the first dose of study 
medication.
NOTES: 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
11.4.1.2.
Treatment States for Adverse Event Data
Treatment State
Definition
Onset Time Since 
1st Dose (Days)
If Blinded Treatment Start Date ˃ AE Onset Date = AE Onset Date – Blinded 
Treatment Start Date
If Blinded Treatment Start Date ≤ AE Onset Date = AE Onset Date – Blinded 
Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on eCRF or value is missing. Can be marked as either 
related to DHA-PQP and/or blinded study medication. 
Onset in Month 1
Blinded Treatment Start Date/Time ≤AE Start Date/Time ≤ Blinded Treatment Start 
Date + 29 Days
Note that onset time is relative to the first dose of double-blind treatment medication. An 
SAE occurring after the first dose of DHA-PQP, but prior to the participant receiving 
randomised treatment would therefore have a negative onset time since first dose.


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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Reporting Process
Software
The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
: /arenv/arprod/sb252263/mid200894/final_01 (final analyses, excluding PK)
: /arenv/arprod/sb252263/mid200894/final_02 (PK analyses)
Analysis Datasets 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & 
ADaM IG Version 1.0).
Generation of RTF Files
RTF files will be generated for all tables at SAC.
11.5.2.
Reporting Standards
General
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location:
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):
4.03 to 4.23: General Principles
5.01 to 5.08: Principles Related to Data Listings
6.01 to 6.11: Principles Related to Summary Tables
7.01 to 7.13: Principles Related to Graphics 
Formats
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated.
Numeric data will be reported at the precision collected on the eCRF.
The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s, including: 
Proportions and their Confidence Intervals will be presented to 3 decimal places.
Rates and their 95% Confidence Intervals will be presented to 1 decimal place
Planned and Actual Time
Reporting for tables, figures and formal statistical analyses:
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.
The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.
Reporting for Data Listings: 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).


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Unscheduled or unplanned readings will be presented within the participant’s listings. 
Unscheduled Visits
Unscheduled visits will not be included in summary tables unless they slot into a missing 
planned visit (see Section 11.3.1) in which case they will be reported as the planned visit.
Unscheduled visits will not be included in figures unless they slot into a missing visit (see 
Section 11.3.1) in which case they will be reported as the planned visit.
Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
All unscheduled visits will be included in listings.
Some scheduled laboratory results (eg Alkaline phosphatase and creatinine 
phosphokinase for specific participants) had to be recorded in the database as unscheduled visits 
to accommodate multiple laboratory codes per visit. These will however be considered scheduled 
visits according to the visit slotting described above and reported accordingly.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays
Refer to IDSL Statistical Principles 7.01 to 7.13. 
11.5.3.
Reporting Standards for Pharmacokinetics
Pharmacokinetic Concentration Data
NONMEM/Pop PK 
File
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data specification 
detailed in Section 11.9.1 Population Pharmacokinetic (PopPK) Dataset 
Specification.
11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Analysis Time Point
If there are multiple assessments within the same window which are not unscheduled 
visits, the earliest result will be used in the summaries. All values will be listed. 
For ECGs, if there are multiple assessments at the same visit, the mean will be derived 
and used in any derivation of summary statistics but if listed, all data will be presented.
Participants having both High and Low values for Normal Ranges at any post-baseline 
visits for safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential Clinical 
Importance summary tables.


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Study Day
Study Day 1 is defined as the day the first dose of DHA-PQP was taken. 
Study day >1 is calculated as the number of days from the date of the Study Day 1:
Ref Date = Missing             → Study Day = Missing 
Ref Date < Date of Study Day 1   → Study Day = Ref Date – Date of Study Day 1    
Ref Data ≥ Date of Study Day 1    → Study Day = Ref Date – (Date of Study Day 1) + 1    
Study Day 180 refers to a time point exactly 179 days after Study Day 1, whereas the ‘Day 180 
visit’ refers to the nominal Day 180 assessments which did not necessarily occur on Study Day 
180.
11.6.2.
Study Population
Demographics
Body Mass Index (BMI)
Calculated as Weight (kg) / [Height (m)2]
Baseline Fever
A participant is considered to have had a fever at baseline if the have a temperature 
recorded in their vital signs data >37.4ºC at any point prior to the first dose of study medication 
(including DHA-PQP).
Prior and Concomitant Medications
Medications will be coded using the latest version of GSK Drug.
Prior medications = medications taken within the 30 days prior to the date of the first dose 
of DHA-PQP.
Any medications with stop dates earlier than 30 days before the date of the first dose of 
DHA-PQP will not be reported in tables and listings.
Concomitant medications = medications with start date on or after the start date of the first 
dose of DHA-PQP, or ongoing on the start date of the first dose of DHA-PQP.
Medications taken prior to the study and continuing during the study will be summarised as
both prior medications and concomitant medications. 
See Section 11.7.2.1 for the handling of missing and partial dates.
Treatment Compliance
All study medication should be administered in the presence of the Investigator or study 
nurse, and ingestion confirmed. 
On any day of in clinic dosing, a participant will be classified as compliant with daily 
administered dose if they do not vomit the initial dose or if they are successfully re-dosed.
A participant is considered to be compliant with blinded medication if they successfully 
administer 12 doses of blinded PQ study medication and a single dose of blinded TQ medication
(note, the blinded medication does not need to have been observed for a subject to be considered 
compliant). 
Participants who were randomized but did not report a treatment start date will be 
categorised as having zero doses.


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Treatment Compliance
PQ / PQ placebo blinded treatment compliance will be calculated based on the formula:
PQ / PQ placebo Blinded Treatment Compliance = Number of Actual doses / 14 
Compliance could be greater than 100% if there are events of overdose.
The number of participants taking <12 or ≥12 doses of PQ/PQ placebo will also be 
summarised.
TQ / TQ placebo compliance will be summarised as if they successfully administered the 
dose (yes/no).
DHA-PQP compliance will be summarised by number of compliant doses. If a subject 
vomits within 30 minutes of taking DHA-PQP on Days 1 to 3, the whole dose should be re-
administered; if the subject vomits within 30-60 minutes, half the dose should be re-administered. If 
a subject vomits their dose and does not receive a re-dose as described, they will be considered 
non-compliant for that dose. If they vomit the re-dose, they will also be considered non-compliant for 
that dose.
G6PD Deficiency
A participant will be considered to be G6PD deficient if their fluorescent spot test has a 
result of ‘G6PD Deficient’.
11.6.3.
Efficacy
Efficacy endpoints
Relapse free efficacy at six months
Relapse is defined as any recurrence of P.vivax malaria after clearance of the initial 
infection. 
Participants will be considered to have demonstrated relapse-free efficacy at six months if 
all of the following are true (also described in Figure 1):
Participant had a non-zero P.vivax asexual parasite count at baseline. Participants who do 
not meet this criterion will be censored, with time to relapse censored at 0 days. 
Participant demonstrated initial clearance pf P.vivax parasitemia. This is defined as two 
negative asexual P. vivax parasite counts, with at least 6 hours between the counts, and no positive 
counts in the interval. Participants who do not meet this criterion will be censored with time to 
relapse censored at 0 days. 
Participant has no positive asexual P.vivax parasite count at any assessment prior to or on 
Day 180 visit following initial parasite clearance. Participants who do have a positive count will be 
considered to have relapsed with time to relapse = (date of first positive count) – (date of Study Day 
1) days.
Participants did not take a concomitant medication with anti-malarial activity (excluding 
study treatment) at any point between Study Day 1 and their last parasite assessment. Participants 
who did take a drug with anti-malarial activity but never had a positive asexual P.vivax parasite 
count after initial clearance will be censored with time to relapse censored at (date of last negative 
parasite assessment prior to concomitant medication start) – (date of Study Day 1) days. If a 
participant has not had a negative assessment prior to the concomitant medication start date, they 
will be censored at 0 days. 


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Efficacy endpoints
Participant is parasite-free at 6 months. This is defined as a negative asexual P. vivax
parasite count at the first parasite assessment performed on or after Study Day 170. 
Participants who do not have a Day 180 visit and have not already failed or been censored 
will be censored at (date of final parasite assessment) – (date of Study Day 1) days). 
If a participant has a relapse outcome and a censored outcome, they will be considered to 
be a relapse, even if the time point of the relapse is later than the time point of censoring. For 
example, a participant who took a medication with anti-malarial activity at Study Day 32, but 
remained parasite-free after initial clearance until Study Day 68 will be treated as a relapse at Study 
Day 68.
Figure 1
Flowchart of algorithm for relapse-free efficacy at 6 months
Relapse free efficacy at four months
Relapse is defined as any recurrence of P.vivax malaria after clearance of the initial 
infection. 
Participants will be considered to have demonstrated relapse-free efficacy at four months if 
all of the following are true (also described in Figure 2):
Participant had a non-zero P.vivax asexual parasite count at baseline. Participants who do 
not meet this criterion will be censored, with time to relapse censored at 0 days. 
Participant demonstrated initial clearance of P.vivax parasitemia. This is defined as two 
negative asexual P. vivax parasite counts, with at least 6 hours between the counts, and no positive 
counts in the interval. Participants who do not meet this criterion will be censored with time to 
relapse censored at 0 days. 
Participant has no positive asexual P.vivax parasite count at any assessment prior to or on 


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Efficacy endpoints
Study Day 135 following initial parasite clearance. Participants who do have a positive count will be 
considered to have relapsed with time to relapse = (date of first positive count) – (date of Study Day 
1) days.
Participants did not take a concomitant medication with anti-malarial activity (excluding 
study treatment) at any point between Study Day 1 and their first parasite assessment after Study 
Day 105 (up to and including Study Day 135). Participants who did take a drug with anti-malarial 
activity but never had a positive asexual P.vivax parasite count after initial clearance will be 
censored with time to relapse censored at (date of last negative parasite assessment prior to 
concomitant medication start) – (date of Study Day 1) days. If a participant has not had a negative 
assessment prior to the concomitant medication start date, they will be censored at 0 days.
Participant is parasite-free at 4 months. This is defined as a negative asexual P. vivax
parasite count at the first parasite assessment performed on or after Study Day 105 (up to and 
including Study Day 135). 
Participants who do not have a Day 120 visit and have not already failed or been censored 
will be censored at (date of final parasite assessment prior to Day 120) – (date of Study Day 1) 
days. 
If a participant has a relapse outcome and a censored outcome, they will be considered to 
be a relapse, even if the time point of the relapse is later than the time point of censoring. For 
example, a participant who took a medication with anti-malarial activity at Study Day 32, but 
remained parasite-free after initial clearance until Study Day 68 will be treated as a relapse at Study 
Day 68.
Figure 2
Flowchart of algorithm for relapse-free efficacy at 4 months


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Efficacy endpoints
Relapse free efficacy at 6 months missing=failure definition
In addition to those with a positive asexual P. vivax parasite count at any assessment prior 
to or on Study Day 190, the following participants will also be defined to have relapsed:
Participant did not demonstrate initial clearance of P. vivax parasitaemia (i.e. did not have 
two negative asexual P. vivax parasite counts, with at least 6 hours between the counts, and no 
positive counts in the interval)
Participant took a concomitant medication with anti-malarial activity at any point between 
Study Day 1 and their last parasite assessment. A list of all concomitant medications will be 
reviewed by a GSK clinician prior to unblinding the study, and classified accordingly.
Participant does not have a parasite assessment between Study Day 170 and 190.
Participants with a zero P. vivax asexual parasite count at baseline will be excluded from 
the analysis.
Genetic classification of relapse (heterologous/homologous)
Relapse-free efficacy at 6 months will be assessed separately according to whether the first P. vivax
re-infection is homologous or heterologous to the original infection. The definition is as detailed 
above but heterologous infections will be censored at the time at which they occur for the endpoint 
looking at homologous infections only; and homologous infections will be censored at the time at 
which they occur for the endpoint looking at heterologous infections only. 
Recrudescence
A participant will be considered to have had a recrudescence if the following are true: 
Included in mITT population
Participant had a positive P. vivax asexual parasite count at baseline and demonstrates 
clearance (i.e. two negative asexual P. vivax parasite counts, with at least 6 hours between the 
counts, and no positive counts in the interval). 
Participant has a positive genetically homologous asexual P. vivax parasite count on or 
before Study Day 14, after their zero count in days 1 to 5.
The following participants will have a censored time to recrudescence of 0 days:
Participant had no asexual P. vivax parasites at baseline.
Participant had a positive P.vivax asexual parasite count at baseline but had no subsequent 
zero asexual parasite count within study Days 1-5. 
If a participant does not meet the definition of recrudescence, but took a concomitant 
medication with anti-malarial activity between Study Day 1 and Study Day 14, they will be censored, 
with time to recrudescence censored at (date of last negative parasite assessment prior to 
concomitant medication start) – (date of Study Day 1). If a participant has not had a negative 
assessment prior to the concomitant medication start date, they will be censored at 0 days.
All other participants will be censored with time to recrudescence censored at their last 
parasite assessment on or before Study Day 14, with time to recrudescence = (date of final parasite 
assessment) – (date of Study Day 1). 
Number of Relapses
A participant is considered to have had at least one relapse if they:
demonstrated initial clearance of P.vivax parasitemia (defined as two negative asexual P. 


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Number of Relapses
vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the 
interval) 
subsequently had a positive asexual P.vivax parasite count at any assessment up to and 
including their Day 180 visit. 
A participant is considered to have had a subsequent relapse if they:
demonstrated clearance of P.vivax parasitemia following their previous relapse (defined as 
a negative asexual P. vivax parasite count) 
subsequently had a positive asexual P.vivax parasite count at any assessment up to and 
including their Day 180 visit.
Clearance time
Parasite (PCT)
Defined as: time needed to clear asexual parasite from the blood i.e. parasite numbers 
falling below the limit of detection in the thick blood smear and remaining undetectable ≥6 hours 
later. 
If a participant has a non-zero asexual P. vivax parasite count at baseline, and prior to 
Study Day 8 has two negative counts with at least 6 hours between the counts and no positive 
parasite counts within this time period, parasite clearance time will be defined as the time elapsed 
between the first dose of study medication (including DHA-PQP) and the first of these negative 
counts (measured in hours).
Participants with a negative parasite count at baseline will be censored with a parasite 
clearance time of 0 hours. All other participants will be censored at the time of the last non-missing 
assessment prior to Study Day 8.
Gametocyte (GCT)
Defined as: time from first dose until the first slide that was gametocyte negative and 
remained so at the next slide reading. 
Any participant with negative P. vivax gametocytes at baseline will be censored with a time 
to gametocyte clearance of 0 days.
For all other participants, gametocyte clearance will be considered to have been achieved 
once a negative gametocyte value has been seen, unless the next gametocyte count is 
positive. Time to clearance will then be defined as (time to first negative value) – (time of 
first dose of study medication including DHA-PQP).
Subjects who fail to reach this endpoint will be censored at the visit of their final gametocyte 
assessment.
Fever (FCT)
Defined as: time from first dose of treatment to the time when body temperature falls to 
normal and remains normal for at least 48 hours up to the Day 7 visit.
Any participant who does not have a temperature in excess of 37.40C at any point prior to 
the first dose of study medication (including DHA-PQP) on Study Day 1 will be censored with a 
fever clearance time of 0 hours. Participants will also be censored at time 0 if the method of 
temperature measurement is not consistent throughout Study Days 1 to 7 (i.e., method is not 
consistently oral, tympanic, or axillary).
Fever clearance is considered to have been achieved once an initial temperature of 
>37.40C is reduced to a value ≤37.40C, in the absence of value >37.40C in the following 48 hours 


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Clearance time
up to the Day 7 visit.
Participants who do not demonstrate this endpoint prior to final assessment of Study Day 3 
will be censored at that time point. 
Participants with missing data in Study Days 1-3 will be censored at the last available 
temperature assessment, if they do not meet the definition of fever clearance before the Day 7 visit.
CPD2D6 Activity and Metabolizer Phenotype
Eijkman Institute will provide CYP2D6 *alleles which will be used to derive metabolizer 
class (Poor metabolizer (PM), Intermediate metabolizer (IM), Extensive metabolizer (EM), Ultra 
metabolizer (UM)).
Each of the two CYP2D6 *alleles, comprising the genotype, will be assigned a value 
relative to its activity compared to the *1 reference allele:
  Value of 0 for null activity alleles: *3, *4, *5, *6, *7, *8, *11, *15
  Value of 0.5 for reduced activity alleles: *9, *10, *14, *17, *29, *41
  Value of 1 for fully functional alleles: *1, *2, *35 
  For all *alleles that are not captured above, the activity score will be determined prior to 
unblinding the data.
  Alleles denoting gene duplications, represented by ‘xN’, will receive double the non-
duplicated value. For example, *1xN will receive a value of 2 whereas *1 receives a value of 1.
The CYP2D6 Activity Score (AS) [Gaedigk, 2008] is then calculated as the sum of activity
values from the two alleles comprising the genotype.  For example, a participant with 2 null alleles 
will have an AS of 0; one null and one reduced activity allele will have a score of 0.5; or one null 
allele and one fully functional allele will have an AS of 1. 
The CYP2D6 phenotype will be classified based on the AS and follows the Dutch 
Pharmacogenomics Working Group [DPWG] classification scheme, where:
Poor metabolizer if AS = 0
Intermediate metabolizer if AS = 0.5 or 1
Extensive metabolizer if AS = 1.5 or 2
Ultra metabolizer if AS ≥ 2.5


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11.6.4.
Safety
Adverse Events
Adverse Events
All AEs reported up to and including the Day 180 visit (Day 195 visit for participants who do 
not relapse during the study) following enrolment of a participant into the study will be documented 
for participants in the Safety Population (or Safety OL Population).
These will be recorded and coded using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA). All terms applied will be reviewed by a GSK physician prior to 
unblinding. If any malaria related coded terms are considered to have lost useful information in the 
coding step (e.g., if a verbatim term of ‘Plasmodium vivax malaria’ is mapped to ‘malaria’), he/she 
will recommend a study-specific code, which will be documented. The process will be completed 
prior to study unblinding.
If the grade/intensity is missing for an AE, it will be considered severe/Grade 3 if an AE, or 
Grade 4 if an SAE and the participant is alive, or Grade 5 if an SAE and the participant dies (i.e. the 
highest intensity possible) for the summary of AEs by maximum intensity.
See Section 11.7.2 for more information on missing and partial dates.
Common AEs are those occurring in ≥5% of participants in any treatment group.
The recurrence of malaria and any associated signs and symptoms are recorded as 
Disease Related Events (DREs) and will not be classified as AEs.
AE’s of Special Interest
AEs of special interest are:
Haematological events
AEs with a system organ class (SOC) of “Nervous System Disorders”
AEs with a SOC of “Psychiatric Disorders”
AEs with a SOC of “Renal and Urinary Disorders”
AEs with a SOC of “Hepatobiliary Disorders”
Haematological events will be identified by GSK physicians, prior to unblinding, from a list of all 
unique preferred terms observed within the study. 
Laboratory Parameters
If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ is present, the number of decimal places of x will be 
used to determine how much to add or subtract in order to impute the corresponding numeric 
value. 
Example 1: 2 decimal places = ‘< x‘ becomes x – 0.01
Example 2: 1 decimal place  = ‘> x’ becomes x + 0.1
Example 3: 0 decimal places = ‘< x’ becomes x – 1   
Where laboratory assessments were conducted at more than one laboratory, e.g. a single 
participant may have had their data analysed at different laboratories at different visits, the 
results will be pooled in the summaries, i.e. all data will be included regardless of the laboratory 
at which the sample was analysed. A review by the GSK clinical team has shown the normal 
ranges to be sufficiently similar across the different laboratories, thus pooling of the data is 
appropriate.


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Vital Signs – Mean Arterial Blood Pressure
To be calculated (to 1 decimal place) where systolic and diastolic blood pressure are both 
present at the same timepoint:


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11.7.
Appendix 7: Reporting Standards for Missing Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General
A participant is considered to have completed the double-blind study if they are 
randomized to blinded study treatment and complete the Day 180 visit. 
A participant is considered to have completed the open-label PQ phase of the 
study if they are included in the safety OL population and complete the Day 195 
visit.
Withdrawn participants will not be replaced in the study.
All available data from participants who were withdrawn from the study will be 
listed and all available planned data will be included in summary tables and 
figures, unless otherwise specified.
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General
Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
These data will be indicated by the use of a “blank” in participant listing 
displays. Unless all data for a specific visit are missing in which case the data is 
excluded from the table. 
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers
Any participants with outlying results may be excluded in additional ad hoc
summaries and/or statistical analyses.  These will be documented along with the 
reason for exclusion in the clinical study report, but the primary conclusions will 
remain based on the full population sets.  
11.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in participant listing displays.
Adverse 
Events
It is not possible to record partial dates in the eCRF for AEs. 
Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.
AEs with entirely missing start dates will be assumed to have started during the 
double-blind treatment phase for reporting. AEs where the start date is equal to 
that of blinded study medication, but where the start time is unknown will be 
assumed to have started during the double-blind treatment phase. AEs with an 
onset date on or after that of DHA-PQP administration, and where blinded 
medication was taken on a later date, will be considered to have started during 
the DHA-PQP phase.
AEs with missing end dates and/or times are not anticipated to affect reporting


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Element
Reporting Detail
(with the exception that duration will be missing in the listings of AEs). 
Concomitant 
medications 
/ Medical 
History
Missing Dates
Where the start or stop date of a concomitant medication record is entirely 
unknown and is totally missing at the time of reporting, the eCRF flags 'Taken 
prior to study?' and 'Ongoing medication?' will be used in order to derive 
whether it is prior or concurrent. 
If these flags are also missing, then it will be assumed that it is concurrent. 
In the event that use of the same medication is recorded at more than one visit 
(and if this has not been collapsed to one record), the eCRF flags will be cross-
checked for both records.
Partial Dates
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will 
be used for the month
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day 
(dependent on the month and year) and ‘Dec’ will be used for the month.
The recorded partial date will be displayed in listings.
11.7.2.2.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Relapse-
free efficacy 
and time to 
event 
endpoints
For all analyses of the mITT population, participants will not be excluded from 
any statistical analyses. 
From the Day 28 assessment onwards, participants who have not relapsed but 
fail to have an evaluable parasite smear within the visit window for any
scheduled visit will be excluded from the PP population. 
See Section 11.6.3 for further details on how missing assessments will be 
censored.
Derived 
variables
For derived variables, details of how any missing eCRF data will be handled are 
provided in Section 11.6


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11.8.
Appendix 8: Values of Potential Clinical Importance
11.8.1.
Laboratory Values
Element
Reporting Detail
F2 flag  
Denotes a value that has increased or decreased from baseline by more than a 
specified amount.
F3 flag 
Denotes a value that falls outside an extended normal range. 
This range is independent of any change from baseline or other values. 
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Haemoglobin
G/L
F2
Decline from baseline 
≥30% or decline from 
baseline >30 g/L
g/dL
F3
7
Platelets
x109/L
F3
50
Lymphocytes
x109/L
F3
0.5
4
Eosinophils
x109/L
F3
1.5
Reticulocytes
x1012/L
F3
1xULN
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
BUN (Urea) b 
mmol/L
F3
11.067
Creatininea
mol/L
F2
3x baseline
F3
3x ULN
Aspartate aminotransferase
IU/L
F3
3x ULN
Alanine aminotransferase
IU/L
F3
3x ULN
Alkaline phosphatase
IU/L
F3
2.5xULN
Total bilirubin
mol/L
F3
1.5x ULN
Indirect bilirubin
mol/L
F3
1.5x ULN
Creatine kinase a
IU/L
F3
5x ULN
CTC AE criteria
FDA industry toxicity grading scale for healthy volunteer adults and adolescents in preventative vaccine trials


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11.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTcF Interval
msec
> 480
Change from Baseline
Increase from Baseline QTcF
msec
≥60
NOTE: Both criteria (absolute and change from baseline) must be met to be of clinical concern. 
11.8.3.
Vital Signs (Normal Ranges)
The following normal ranges will be applied to vital signs (note that a value falling 
outside of the associated range does not mean that the value is necessarily of potential 
clinical concern).
Vital Sign 
Parameter
Units
Lower1
Upper1
Systolic Blood 
Pressure
mmHg
90
120
Diastolic Blood 
Pressure
mmHg
60
80
Respiratory Rate
Breaths/minute
12
18
Heart Rate
Beats/minute
60
100
Temperature
°C
36.5
37.3
1 These values represent the normal range for vital sign parameters. Values < lower limit or > upper limit 
should be flagged.


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11.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
11.9.1.
Pharmacokinetic NONMEM Dataset Specification
Item Name
Description
Code
Derivation/Comments
Dataset
ID
NONMEM sequential 
number starting at 1 
identifying each 
participant
00001 – 99999
Sequential identifier for 
each participant starting 
at 1.
CENT
Centre Identification
27 = Indonesia
Additional centre 
numbers to be added 
based on where patients 
are recruited
PT
Patient Identification 
Number
As per randomization;
Retain all participants 
with at least one 
measurable PK sample 
for the TQ analyte(s)
STUDY
9=200894
TRTGRP
Treatment group for 
each study
24: 200894 - 300 mg arm
HEALTHY
Healthy volunteer or 
patient
1: Healthy volunteer
2: Patient
Studies 200951, 201780 
and TAF114582 are all in 
Healthy volunteers (i.e., 
HEALTHY=1)
DOSE
Dose amount (mg) for 
tafenoquine (TQ, 
SB252263)
Fill in the intended dose 
amount (mg) in all cells 
for each patient.
TQ
AMT
Dose amount (mcg) 
for tafenoquine
If EVID=1, AMT= Dose amt in 
mcg for tafenoquine
If EVID=0, AMT= 0
TQ
DAY
Study day relative to 
the start of study
Day = day of study 
relative to the TQ dose


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Item Name
Description
Code
Derivation/Comments
Dataset
DATE
Date of dose or 
sample collected. 
MM/DD/YYYY
TIME
Time of dose sample 
collected.
HH:MM (24 hr)
RTLD
Relative time of 
sample from most 
recent TQ dose (hr)
Numeric
If negative assign 0
RTFD
Relative time of 
sample from first TQ 
dose (hr)
Numeric
If negative assign 0
TQ
Plasma TQ 
concentrations 
(ng/mL)
Numeric
If EVID = 1, DV = “.” 
If CODE > 0 then DV = “.”
Else DV= conc. Value
Where ADPC .AVAL ne “”or 
ADPC.ANL01FL=”Y”
Then TQ=ADPC.AVAL
3 decimal places.
TQ
LNTQ
Ln transformed 
Plasma TQ 
concentrations 
Numeric
6 decimal places.
TQ
CODE
Drug concentration 
result code
0 = Measurable conc.
0 when EVID=1
1 = NQ/BQL
2 = NA/NR/NS/IS
MDV
Missing Data Value 
(drug concentration)
1 = Yes, 0 = No
If EVID = 1, MDV = 1
If EVID = 0 and CODE>0, 
MDV = 1 , otherwise MDV =0
EVID
Event indicator (flag 
for NONMEM)
1 = Dose
0 = PK Sample
VOMIT
Vomit within 180 min 
of dose 
1 = Yes, vomited
0 = No
0 = PK observations
-99=missing
-99 if missing in datasets
CNTY
Country
11 = Indonesia
Other countries to be 
added where participants 
recruited
For the 114582, all are in 
the USA (as per the IB).


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Item Name
Description
Code
Derivation/Comments
Dataset
AGE
Baseline Age of 
participant (yr)
GEN
Gender of the 
Participant (1=M,2=F)
1=Male, 
2 =Female
RACE
Race of the Participant 1=White,  
2=Black or african american,  
3=Oriental or asian, 
4= Hispanic,
5=Other
6= American indian or Alaska 
native
7= Multiple
-99 =Missing
WT
Baseline Weight of 
Participant (kg)
BMI
Baseline Body mass 
Index (kg/m2)
1 decimal
PARA
Baseline parasitemia
1=Yes
0=No
-99 for all of these studies
CONMEDS
Concomitant 
medications
Add if available as
1=Yes
0=No
-99= Missing
1 – for participants who 
have medications 
identified as being 
concomitant (could 
include participants taking 
medications that are 
identified as starting prior 
and becoming 
concomitant)
0 – for participants who 
do not take any 
concomitant medications 
(they may have had prior 
medications recorded 
only or no medications 
recorded at all)
-99 is used when 
concomitant medication 
data is not collected in a 
study
FORMU
Formulation
1= Tablet
2= Capsule
DUPLI
Duplicate records
DUPLI =1 for all 
concentrations 
DUPLI =2 for the duplicate 
concentration records for a 
specific date and time
DUPLI=3 for samples with 
missing DATE/TIME records 
This variable is only 
provided for Study 582 
Part 2 and Study 564 
files. 
If no concentrations and 
time record, then we can 
exclude the records


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Item Name
Description
Code
Derivation/Comments
Dataset
(but concentration is 
available)
DUPLI=4 for a duplicate 
(second) dosing record 
where no vomiting of any 
doses occurs.
11.9.2.
Population Pharmacokinetic (PopPK) Methodology
11.9.2.1.
Pharmacokinetic Model Development
The population PK analysis will be performed in the following sequence of steps:
Predictive check with existing POPPK model.
Model development
Covariate analysis.
Model refinement.
Model evaluation.
11.9.2.2.
Predictive Check
The starting point for the analysis will be the existing population PK model developed
based on data from Phase 3 studies (TAF112582 Part 2 and TAF116564). Predictive 
check of observed INSPECTOR data with the existing POPPK model will be performed 
through visual predictive checks. If the existing model adequately predicts the data, then 
the model will be used to generate the post hoc PK parameters for participants enrolled in 
the INSPECTOR study (e.g. NONMEM option MAXEVAL=0). These PK parameters 
may then be used to characterize the systemic TQ exposure. If there is lack of fit between 
the model predictions and observed INSPECTOR data, then the model may be adjusted 
as described in the following steps. 
11.9.2.3.
Model Development
Based on analysis of the DETECTIVE Part1 and 2 data, a 2 compartment model will be 
used as a starting point for the structural model for further analysis. Briefly, a two 
compartment model with first order elimination and absorption (Ka) with a lagtime, 
CL/F, Vc/F, V3/F, Q/F and an additive error model adequately fitted the log-transformed 
plasma concentration data for tafenoquine. Based on results of preliminary analysis, log 
concentrations may be utilized for model building. 
Since the sparse PK sampling may not allow reliable estimation of all PK parameters, 
information about some PK parameters may be borrowed from historic population PK 


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model (e.g. absorption rate constant Ka). Alternatively, the data from this study may be 
combined with PK data from historic studies for population PK modeling as appropriate. 
11.9.2.4.
Covariate analysis
Covariate analysis will be performed for tafenoquine to explore measurable sources of 
PK variability. Covariate effects will be considered for the model parameters clearance 
(CL/F) and volume of distribution (Vc/F), and may be explored for a limited number of 
other parameters deemed appropriate, depending upon the physiological plausibility.
11.9.2.5.
Model refinement
Model refinement steps will be performed, including, where appropriate, exploration of 
model improvement through reparameterization, interpretation of magnitude of the 
variability, interpretation of standard errors of the fixed and random effects parameters, 
and simplification of covariate models. A covariate may be retained or removed from the 
final model based on clinical and physiological relevance. Those covariates with minimal 
clinically relevant impact may be excluded from the final model for parsimony. 
11.9.2.6.
Model evaluation
Non-parametric bootstrapping may be performed to test model robustness. The precision 
of parameters may also be estimated from bootstrap runs. The model performance may be 
evaluated by performing predictive check. A visual predictive check method will be 
utilized to evaluate model performance. At least 200 replicates of the original dataset will 
be simulated, based on the final model, and a 95% prediction interval (PI) computed for 
the concentration-time profile based on the simulated datasets. The observed 
concentration versus time data will be overlaid on this prediction interval to visually 
assess the concordance between the simulated and observed data. 


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11.10.
Appendix 10: Abbreviations & Trade Marks
Abbreviations
Abbreviation
Description
ACT
Artemisinin-Based Combination Therapy
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Events of Special Interest
AS
Activity Score
AUC0-t
Area Under the Concentration-time Curve from Time of Dosing to Last 
Quantified Concentration
AUC0-inf
Area Under the Concentration-time Curve Extrapolated to Infinity
A&R
Analysis and Reporting 
BSV
Between subject variability
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL/F
Oral Clearance
CPH
Cox Proportional Hazards
CS
Clinical Statistics
CSR
Clinical Study Report
DHA-PQP
Dihydroartemisinin Piperaquine
DP
Decimal Places
DRE
Drug Related Event
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EM
Extensive Metaboliser
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
G6PD
Glucose-6-phosphate Dehydrogenase
GI
Gastrointestinal
GSK
GlaxoSmithKline
GUI
Guidance
HARP
Harmonisation of Analysis and Reporting Project
Hb
Haemoglobin
Hct
Human Chorionic Gonadotropin
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IM
Intermadiate Metaboliser
IMMS
International Modules Management System
ITT
Intent To Treat
IWRS
Interactive Web Recognition System
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Microbiologic-Intent to Treat


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Abbreviation
Description
OL
Open label
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PM
Poor Metaboliser
PP
Per Protocol
PQ
Primaquine
PT
Preferred Term
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RTF
Rich Text Format
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SDTM
Study Data Tabulation Model
SOC
System Organ Class
SOP
Standard Operation Procedure
TLF
Tables, Listings & Figures 
TQ
Tafenoquine
T1/2
Terminal Phase Elimination Half-Life
UM
Ultra Metaboliser
V/F
Volume of Distribution
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
SAS
NONMEM


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11.11.
Appendix 11: List of Data Displays
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.34
Efficacy
2.1 to 2.29
2.1 to 2.11
Safety
3.1 to 3.43
3.1 to 3.12
Pharmacokinetic
4.1 
4.1
Section
Listings
ICH Listings
1 to 31
Non-ICH Listings
32 to 49
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn or TTEn
EFF_Tn or TTEn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Non-Standard displays are indicated in the ‘IDSL/Example Shell’.
Deliverable
Delivery
Description
Headline
Headline Results
SAC
Final Statistical Analysis Complete (excluding PK data)
PK
Final analysis of PK data


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11.11.1.
Study Population Tables
Study Population Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Participant Disposition
1.1
Safety
ES1
Summary of Subject Disposition for the Participant Conclusion 
Record
ICH E3, FDAAA, EudraCT
Include a total column.
SAC
1.2
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
Include a total column.
SAC
1.3
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment, by Battalion
Page by Battalion.
Include a total column.
SAC
1.4
Safety
ES4
Summary of Subject Disposition at Each Study Phase
ICH E3
Separate phase for: Blinded treatment 
and Open-label PQ treatment
Include a total column.
SAC
1.5
Screened
IE1
Summary of Inclusion/Exclusion Criteria Deviations for 
Screening Failures
Only include data for screening failures 
(inclusion or exclusion deviations for 
randomised subjects will be captured 
within the important protocol 
deviations).
SAC
1.6
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC
1.7
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure, 
by Battalion 
Journal Requirements
SAC
1.8
Enrolled
NS1
Summary of Number of Subjects by Country and Site ID
EudraCT/Clinical Operations
SAC
1.9
Enrolled
NS1
Summary of Number of Subjects by Battalion
SAC
Protocol Deviations
1.10
Safety
DV1
Summary of Important Protocol Deviations
ICH E3
SAC


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Study Population Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Populations Analysed
1.11
Screened
SP1
Summary of Study Populations
IDSL
Headline, PK
1.12
Safety
SP2
Summary of Exclusions from the Per Protocol Population
IDSL
SAC
Demographic and Baseline Characteristics
1.13
Safety
DM1
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
Include age, sex, ethnicity, geographic 
ancestry, weight, height, BMI,.
Height, Weight and BMI are collected in 
VITALS_SCR_CR. VITALS where 
VISITNUM=10 and PTMNUM=20. All 
other parameters are collected on 
DEMO.
Headline
1.14
Safety
DM1
Summary of Demographic Characteristics by Battalion
Table as overall Demographics table 
but paged by battalion.
SAC
1.15
Safety
DM1
Summary of Baseline Characteristics
Include G6PD Enzyme activity (IU/gHb) 
only.
G6PD enzyme activity is collected in 
G6PD_PHENO_3.
SAC
1.16
Safety
DM1
Summary of Baseline Characteristics by Battalion
Table as overall Baseline 
Characteristics table but paged by 
battalion.
SAC
1.17
Enrolled
DM11
Summary of Age Ranges
EudraCT
SAC
1.18
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC
1.19
Safety
DM6
Summary of Race and Racial Combinations Details
SAC


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Study Population Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Prior and Concomitant Medications and Conditions
1.20
Safety
CM1
Summary of Prior Medications
Add footnote ‘Only medications taken 
prior to the start date and time of first 
dose of study medication (open-label 
DHA-PQP), and within 30 days of Study 
Day 1 are included.’
ICH E3
SAC
1.21
Safety
CM1
Summary of Concomitant Medications (DHA-PQP only and 
Double Blind Phase)
ICH E3
Headline
1.22
Safety OL
CM1
Summary of Concomitant Medications (Open-Label, PQ Phase, 
Non-Relapsers)
ICH E3
SAC
1.23
Safety
CM1
Summary of Paracetamol Usage (DHA-PQP only and Double 
Blind Phase)
SAC
1.24
Safety
POP_T1
Summary of Malarial Signs and Symptoms
SAC
1.25
Safety
POP_T6
Number (%) of Subjects with Fever at Baseline
Fever is defined as a temperature 
>37.4ºC
SAC
1.26
Safety
MH1
Summary of Current Medical Conditions by Body System 
ICH E3
Taken from Medical Conditions eCRF 
page. 
SAC
1.27
Safety
MH1
Summary of Past Medical Conditions by Body System
ICH E3
Taken from Medical Conditions eCRF 
page.
SAC
1.28
Safety
MH4
Summary of Current Specific Medical Conditions 
Taken from Disease History eCRF 
page. 
SAC
1.29
Safety
MH4
Summary of Past Specific Medical Conditions
Taken from Disease History eCRF 
page.
SAC
1.30
Safety
POP_T2
Summary of Splenomegaly at Baseline
SAC


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Study Population Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
1.31
Safety
POP_T2
Summary of Previous Episodes of Malaria
Include category for unknown, if 
necessary.
SAC
Exposure and Treatment Compliance
1.32
Safety
POP_T3
Summary of Study Medication Compliance and Exposure
ICH E3
Headline
1.33
Safety
POP_T5
Summary of Subjects for Whom Treatment Medication was 
Observed
SAC
Diagnostic
1.34
Screened
POP_T4
Comparison of G6PD Fluorescent Spot Test (FST) and 
Enzyme Activity Test
SAC


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11.11.2.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Parasite counts
2.1
mITT
EFF_T1
Summary of P.vivax Asexual Parasites at all Timepoints 
SAC
2.2
mITT
EFF_T1
Summary of Other Malarial Asexual Parasites at all Timepoints 
Page by parasite
SAC
2.3
mITT
EFF_T1
Summary of P.vivax Gametocytes at all Timepoints 
SAC
2.4
mITT
EFF_T1
Summary of Other Malarial Gametocytes at all Timepoints 
Page by gametocyte
SAC
Relapse free efficacy
2.5
mITT
EFF_T2
Summary of Relapse-Free Efficacy at 6 Months
SAC
2.6
mITT
EFF_T2
Summary of Relapse-Free Efficacy at 6 Months by Battalion
SAC
2.7
PP
EFF_T2
Summary of Relapse-Free Efficacy at 6 Months
SAC
2.8
mITT
TTE1
Survival Analysis of Relapse-free Efficacy over 6 months 
See mock shells example template. 
Headline
2.9
mITT
EFF_T7
Summary of Covariate and Treatment*Covariate Interaction 
Significance For Cox Proportional Hazards Model of Relapse-
Free Efficacy Over 6 Months
SAC
2.10
PP
TTE1
Survival Analysis of Relapse-free Efficacy over 6 months 
SAC
2.11
mITT
EFF_T3
Logistic Regression Analysis of Relapse-free Efficacy at 6 
months (Subjects Censored Prior to 6 Months  Excluded)
Add footnote: 
“Subjects who do not demonstrate initial 
clearance, take a concomitant medication 
with anti-malarial
activity, have a missing Day 180 
assessment, or have a zero P. vivax 
asexual parasite count at baseline
are excluded from the analysis.”
SAC


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Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
2.12
mITT
EFF_T3
Logistic Regression Analysis of Relapse-free Efficacy at 6 
months  (Missing = Failure Analysis)
Add footnotes:
“Subjects who do not demonstrate initial 
clearance, take a concomitant medication 
with anti-malarial activity or have a 
missing Day 180 assessment are 
counted as relapses.”
“Subjects with a zero P. vivax asexual 
parasite count at baseline are excluded 
from the analysis.”
SAC
2.13
mITT
TTE1
Survival Analysis of Genetically Heterologous Relapse-Free 
Efficacy over 6 Months – Homologous P. vivax Relapses 
Censored
Add footnote: Homologous relapses are 
censored at the point at which they occur. 
SAC
2.14
mITT
TTE1
Survival Analysis of Genetically Homologous Relapse-Free 
Efficacy over 6 Months – Heterologous Relapses Censored
Add footnote: Heterologous relapses are 
censored at the point at which they occur.
SAC
2.15
mITT
EFF_T2
Summary of Relapse-Free Efficacy at 4 Months
SAC
2.16
mITT
TTE1
Survival Analysis of Relapse-free Efficacy over 4 months 
See mock shells example template. 
SAC
Time to Event endpoints
2.17
mITT
TTE3
Analysis of Time to Asexual Parasite Clearance
Give time in hours.
SAC
2.18
mITT
TTE3
Analysis of Time to Gametocyte Clearance
Give time in hours.
SAC
2.19
mITT
TTE3
Analysis of Time to Fever Clearance
Give time in hours.
SAC
Other Efficacy endpoints
2.20
mITT
TTE6
Analysis of Recrudescence (Blood Stage Failure) Rates
SAC
2.21
mITT
EFF_T4
Incidence of Genetically Homologous and Genetically 
Heterologous P. vivax Infections (determined by PCR)
SAC
2.22
mITT
EFF_T9
Number (%) of Subjects Within Each CYP2D6 Metaboliser 
Class
SAC


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Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
2.23
mITT
EFF_T5
Analysis of Subjects with Relapse-Free Efficacy at 6 Months 
by CYP2D6 Metaboliser Class – Logistic Regression – Poor 
and Intermediate Metabolisers vs Extensive and Ultra 
Metabolisers
SAC
2.24
mITT
EFF_T8
Effect of CYP2D6 Activity Score (AS) on Relapse-Free 
Efficacy at 6 Months – Logistic Regression
SAC
2.25
mITT
EFF_T6
Summary of P. vivax Gametocyte Emergence
SAC
2.26
mITT
EFF_T6
Summary of P. falciparum Asexual Parasite Emergence
n row does not need to be presented. 
Column 1 category should read: “Number 
of subjects with emergent P.falciparum at 
any stage”. 
SAC
2.27
mITT
TTE1
Survival Analysis of Relapse-free Efficacy over 6 months – by 
Battalion
See mock shells example template. 
Only produce display if more than one 
battalion is included in study and 
interaction is significant. 
SAC
2.28
mITT
TTE1
Survival Analysis of Relapse-free Efficacy over 4 months – by 
Battalion
See mock shells example template. 
Only produce display if more than one 
battalion is included in study and 
interaction is significant. 
SAC
2.29
mITT
EFF_T10
Summary of the Number of Relapses per Subject
SAC


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11.11.3.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Relapse free efficacy
2.1
mITT
TTE10
Kaplan-Meier Survival Curves for Time to Relapse
Headline
2.2
PP
TTE10
Kaplan-Meier Survival Curves for Time to Relapse
SAC
2.3
mITT
TTE10
Kaplan-Meier Survival Curves for Time to Genetically 
Heterologous Relapse – Homologous P. vivax Relapses 
Censored
SAC
2.4
mITT
TTE10
Kaplan-Meier Survival Curves for Time to Genetically 
Homologous Relapse – Heterologous P. vivax Relapses 
Censored
SAC
2.5
mITT
TTE10
Kaplan-Meier Survival Curves for Time to Fever Clearance
Give time in hours.
SAC
2.6
mITT
TTE10
Kaplan-Meier Survival Curves for Time to Parasite Clearance
Give time in hours.
SAC
2.7
mITT
TTE10
Kaplan-Meier Survival Curves for Time to Gametocyte 
Clearance
Give time in hours.
SAC
2.8
mITT
EFF_F1
Incidence (95% Confidence Interval) of Genetically Homologous 
and Genetically Heterologous P. vivax relapses
SAC
2.9
mITT
TTE10
Kaplan-Meier Survival Curves for Time to Relapse – by Battalion
Only produce display if treatment by 
battalion interaction is significant.
SAC
2.10
mITT
EFF_F2
Estimated Hazard Ratio (95% CI) for Time to Relapse by 
Baseline Asexual Parasite Count (TQ+DHA-PQP Vs DHA-PQP 
Only)
Only produce display if treatment by 
baseline asexual parasite count 
interaction is significant.
SAC
2.11
mITT
EFF_F2
Estimated Hazard Ratio (95% CI) for Time to Relapse by Weight
(TQ+DHA-PQP Vs DHA-PQP Only)
Only produce display if treatment by 
weight interaction is significant.
SAC


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11.11.4.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable
Adverse Events (AEs)
3.1
Safety
AE1
Summary of All Adverse Events by System Organ Class, 
Preferred Term and Treatment Phase
ICH E3
Add footnote: ‘Events are ordered 
based on Total incidence’.
Include total column.
Include DHA-PQP only and Double-
Blind treatment phases.
SAC
3.2
Safety OL
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term (Open-Label, PQ Phase, Non-Relapsers)
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.
Include total column.
SAC
3.3
Safety
AE3
Summary of All Adverse Events During the Double-Blind 
Treatment Phase, by Preferred Term and Frequency 
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.  
Add footnote: ‘Events are ordered 
based on incidence in TQ+DHA-PQP 
arm’.
Include total column.
SAC
3.4
Safety
AE3
Summary of Common (>=5% in Any Treatment Group) 
Adverse Events During the Double-Blind Treatment Phase by 
Overall Frequency
ICH E3
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.  
Add footnote: ‘Events are ordered 
based on incidence in TQ+DHA-PQP 
arm’.
Include total column.
Headline


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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable
3.5
Safety
AE15
Summary of Common (>=5% in Any Treatment Group) Non-
serious Adverse Events During the Double-Blind Treatment 
Phase by System Organ Class and Preferred Term (Number 
of Subjects and Occurrences)
FDAAA, EudraCT
Include total column.
SAC
3.6
Safety
AE5A
Summary of All Adverse Events During the Double-Blind 
Treatment Phase by System Organ Class, Preferred Term and
Maximum Intensity
IDSL
Order events in descending order by 
total incidence within each treatment 
group.  Add footnote: ‘Events are 
ordered based on total incidence within 
each treatment group’
SAC
3.7
Safety
AE3
Summary of Common (>=5%) Grade 2-4 Adverse Events
During the Double-Blind Treatment Phase by Overall 
Frequency
ICH E3
Include total column.
SAC
3.8
Safety
AE1CP
Summary of DHA-PQP-Related Adverse Events (as Reported 
by the Investigator) During the Double-Blind Treatment Phase
by System Organ Class and Preferred Term
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.  
Add footnote: ‘Events are ordered 
based on incidence in TQ+DHA-PQP 
arm’
Include total column.
Headline
3.9
Safety
AE1CP
Summary of Blinded Treatment-Related Adverse Events (as 
Reported by the Investigator) During the Double-Blind 
Treatment Phase, by System Organ Class and Preferred Term 
IDSL
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.  
Add footnote: ‘Events are ordered 
based on incidence in TQ+DHA-PQP 
arm’
Headline


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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable
3.10
Safety
AE5A
Summary of Blinded Treatment-Related Adverse Events (as 
Reported by the Investigator) During the Double-Blind 
Treatment Phase, by Maximum Intensity, System Organ Class
and Preferred Term
IDSL
Order events in descending order by 
total incidence within each treatment 
group.  Add footnote: ‘Events are 
ordered based on total incidence within 
each treatment group’
SAC
3.11
Safety
AE3
Summary of Common (>=5%) Blinded Treatment-Related 
Grade 2-4 Adverse Events During the Double-Blind Treatment 
Phase, by Overall Frequency
ICH E3
SAC
3.12
Safety
AE1
Summary of Adverse Events During the Double-Blind 
Treatment Phase, with Onset On or Prior to Study Day 29 by 
System Organ Class and Preferred Term
Add footnote: ‘Events are ordered 
based on Total incidence’
Headline
Serious and Other Significant Adverse Events
3.13
Safety
AE1
Summary of Serious Adverse Events by System Organ Class, 
Preferred term and Treatment Phase
Add footnote: ‘Events are ordered 
based on Total incidence’
Include total column.
Include DHA-PQP only and Double-
Blind treatment phases.
Headline
3.14
Safety OL
AE1CP
Summary of Serious Adverse Events with Onset During the 
Open-Label, PQ Only Treatment Phase by SOC and Preferred 
Term 
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.  
Add footnote: ‘Events are ordered 
based on incidence in TQ+DHA-PQP 
arm’. Include total column.
Headline
3.15
Safety
AE16
Summary of Serious Adverse Events by System Organ Class, 
Preferred Term and Treatment Phase (Number of Subjects 
and Occurrences)
FDAA, EudraCT
Include total column.
Include DHA-PQP only and Double-
Blind treatment phases.
SAC


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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable
3.16
Safety
AE1CP
Summary of Adverse Events During the Double-Blind 
Treatment Phase Leading to Withdrawal from the Study by 
System Organ Class and Preferred Term
IDSL
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.  
Add footnote: ‘Events are ordered 
based on incidence in TQ+DHA-PQP 
arm’
Include total column.
Headline
3.17
Safety
AE1CP
Summary of Adverse Events During the Double-Blind 
Treatment Phase Leading to Discontinuation from Study 
Treatment by System Organ Class and Preferred Term
IDSL
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.  
Add footnote: ‘Events are ordered 
based on incidence in TQ+DHA-PQP 
arm’
Include total column.
Headline
3.18
Safety
AE1CP
Summary of Adverse Events of Special Interest During the 
Double-Blind Treatment Phase by System Organ Class and
Preferred Term 
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.  
Add footnote: ‘Events are ordered 
based on incidence in TQ+DHA-PQP 
arm’
Include total column.
Headline
3.19
Safety
AE3
Summary of protocol defined Hb SAEs During the Double-
Blind Treatment Phase
SAC


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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable
3.20
Safety
AE3
Summary of Grade 3 and Grade 4 Adverse Events During the 
Double-Blind Treatment Phase by Preferred Term
Include Grade 3 and Grade 4 events 
only.
Order events in descending order by 
incidence in TQ+DHA-PQP arm only.  
Add footnote: ‘Events are ordered 
based on incidence in TQ+DHA-PQP 
arm’
Include total column.
SAC
Laboratory: Chemistry
3.21
Safety
LB1
Summary of Chemistry Data
Present values for all treatment groups 
and valid lab parameters at each visit.
Headline
3.22
Safety
LB1
Summary of Chemistry Changes from Baseline
ICH E3
Present change from baseline values 
for all treatment groups and valid lab 
parameters at each visit. 
Headline
3.23
Safety
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
SAC
3.24
Safety
SAFE_T1
Summary of Clinical Chemistry Laboratory Data Outside the 
Reference Range (F3)
SAC
Laboratory: Haematology
3.25
Safety
LB1
Summary of Haematology Data
Present values for all treatment groups 
and valid lab parameters at each visit.
Headline
3.26
Safety
LB1
Summary of Hematology Changes from Baseline
ICH E3
Present change from baseline values 
for all treatment groups and valid lab 
parameters at each visit. 
Headline


CONFIDENTIAL
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable
3.27
Safety
LB15
Summary of Worst Case Hematology Results Relative to 
Normal Range Post-Baseline Relative to Baseline
ICH E3
SAC
3.28
Safety
SAFE_T1
Summary of Haematology Laboratory Data Outside the 
Reference Range (F3)
SAC
3.29
Safety
SAFE_T2
Summary of Categories of Change from Baseline 
Haemoglobin (G/L) Data by Time
Headline
3.30
Safety
SAFE_T3
Summary of Haemoglobin Declines Over First 28 Days
SAC
Laboratory: Urinalysis
3.31
Safety
UR1
Summary of Urinalysis Dipstick Results
IDSL
SAC
Hepatobiliary (Liver)
3.32
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
SAC
3.33
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC
ECG
3.34
Safety
EG1
Summary of ECG Findings
IDSL
SAC
3.35
Safety
EG2
Summary of Absolute ECG Values by Visit
Include Heart Rate, RR Interval, QRS 
Duration, Uncorrected QT Interval and 
QTcF
SAC
3.36
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
Include Heart Rate, RR Interval, QRS 
Duration, Uncorrected QT Interval and 
QTcF
SAC
3.37
Safety
SAFE_T5
Summary of QTcF Values by Category and Visit
Headline
3.38
Safety
EG11
Summary of Maximum Increase in QTcF Values Post-Baseline 
Relative to Baseline Category over the First 7 Days
Headline


CONFIDENTIAL
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable
Vital signs
3.39
Safety
VS1
Summary of Absolute Values in Vital Signs by Visit
ICH E3
Include Systolic Blood Pressure, 
Diastolic Blood Pressure, Mean Arterial 
Blood Pressure, Respiratory Rate and
Temperature.
SAC
3.40
Safety
VS1
Summary of Change From Baseline in Vital Signs by Visit
ICH E3
Include Systolic Blood Pressure, 
Diastolic Blood Pressure, Mean Arterial 
Blood Pressure, Respiratory Rate and
Temperature.
SAC
3.41
Safety
VS3
Summary of Worst Case Vital Sign Results Relative to Normal 
Range Post-Baseline Relative to Baseline
IDSL
SAC
Methaemoglobin
3.42
Safety
LB1
Summary of Absolute Values in Methaemoglobin by Visit
SAC
3.43
Safety
LB1
Summary of Change From Baseline in Methaemoglobin by 
Visit
SAC


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11.11.5.
Safety Figures
Safety: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Adverse Events
3.1
Safety
AE10
Common (>=5% in Any Treatment Group) Adverse Events and 
Relative Risk During the Double-Blind Treatment Phase
IDSL
SAC
Laboratory
3.2
Safety
LB11
LFT Profile Plots
Only for subjects with >3 ULN in ALT 
or AST.  
Add footnote to this effect.
The subject ID, treatment group, sex, 
age and race should be included as a 
header for each subject’s plot.
Include Alk. Phos, ALT, AST, Total 
Bili., and Indirect Bili.
SAC
3.3
Safety
LB11
Haematology Profile Plots
Only for subjects with a >30g/L decline 
from baseline haemoglobin or  found to 
be G6PD deficient
Add footnote to this effect.
The subject ID, treatment group, sex, 
age and G6PD status should be 
included as a header for each subject’s 
plot.
Parameters to include are 
haemoglobin, reticulocytes (if 
available), methaemoglobin and 
bilirubin results (total and indirect 
bilirubin on same plot)
SAC


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Safety: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.4
Safety
LB11
Clinical Chemistry Profile Plots
Only for subjects change from baseline 
in urea or creatinine > 50%
Add footnote to this effect.
The subject ID, treatment group, sex, 
age and race should be included as a 
header for each subject’s plot.
Parameters to include are creatinine 
and urea (present the results relative to 
ULN).
SAC
3.5
Safety
LB10
Distribution of Maximum LFTs by Treatment Group
SAC
3.6
Safety
LB7
LFT Shift from Baseline to Maximum Value
SAC
3.7
Safety
LB8
Matrix Display of Maximum LFT Values
SAC
3.8
Safety
SAFE_F1
Maximum Absolute Methaemoglobin Value Over 28 Days
SAC
3.9
Safety
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT
IDSL
SAC
3.10
Safety
LIVER9
Scatterplot of Maximum ALT vs. Maximum Total Bilirubin
IDSL
SAC
Methaemoglobin
3.11
Safety
SAFE_F2
Change from Baseline in Methaemoglobin over time
Display up to 28 days
SAC
Vital Signs
3.12
Safety
LB9
Boxplot of Mean Arterial Blood Pressure by Timepoint and 
Treatment Group
IDSL Display LB9 includes the ULN and 
identifies subjects who have a value 
>2xULN. The ULN is not defined for 
arterial blood pressure, so this is not 
required. The figure should just include 
all of the data at each visit.
SAC


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11.11.6.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
PK General Summaries
4.1
PK
PK05
Population PK parameters
To be done by CPMS
PK Study 
Report
11.11.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
PK General Summaries
4.1
PK
PK17
Mean Concentration-Time plot
To be done by S&P
PK


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11.11.8.
ICH Listings
ICH: Listings
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Participant Disposition
1
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2
Safety
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC
4
Safety
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
ICH E3
SAC
5
Safety
TA1
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
6
Safety
DV2
Listing of Important Protocol Deviations
ICH E3
SAC
7
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC
Populations Analysed
8
Safety
SP3
Listing of Subjects Excluded from Any Population
ICH E3
SAC, PK
Demographic and Baseline Characteristics
9
Safety
DM2
Listing of Demographic Characteristics
ICH E3
Include year of birth, age, sex, ethnicity, 
height, weight and BMI.
SAC
10
Safety
DM9
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
11
Safety
CM3
Listing of Prior and Concomitant Medications
IDSL
Include concomitant medications and 
prior medications taken within 30 days 
of first dose of study medication
SAC


CONFIDENTIAL
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ICH: Listings
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Exposure and Treatment Compliance
12
Safety
EX3
Listing of Exposure Data
ICH E3
See mock shell example for additional 
columns to be included. 
SAC
Adverse Events
13
Safety
AE8
Listing of All Adverse Events by Treatment Phase
ICH E3
Include DHA-PQP only and Double-
Blind treatment phases.
Include flag for double blind period
SAC
14
Safety
AE8
Listing of All Adverse Events with Onset During the Open-Label 
Treatment Phase
ICH E3
Add footnote: Listing includes AEs 
reported by non-relapsers who entered 
the open-label treatment phase, and 
any reported by relapsers after their 
Day 180 study visit.
SAC
15
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events with 
Onset During the Double-Blind Treatment Phase
ICH E3
SAC
16
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events with 
Onset During the Open-Label Treatment Phase
ICH E3
Add footnote: Listing includes AEs 
reported by non-relapsers who entered 
the open-label treatment phase, and 
any reported by relapsers after their 
Day 180 study visit.
SAC
17
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms and Verbatim Text
IDSL
SAC


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ICH: Listings
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Serious and Other Significant Adverse Events
18
Safety
AE8
Listing of Fatal Serious Adverse Events by Treatment Phase
ICH E3
Include DHA-PQP only and Double-
Blind treatment phases.
SAC
19
Safety OL
AE8
Listing of Fatal Serious Adverse Events with Onset During the 
Open-Label Treatment Phase
ICH E3
SAC
20
Safety
AE8
Listing of Non-Fatal Serious Adverse Events by Treatment 
Phase
ICH E3
Include DHA-PQP only and Double-
Blind treatment phases.
SAC
21
Safety OL
AE8
Listing of Non-Fatal Serious Adverse Events with Onset During 
the Open-Label Treatment Phase
ICH E3
SAC
22
Screened 
AE8
Listing of Serious Adverse Events – Screening Failures
SAC
23
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC
24
Safety
AE8
Listing of Adverse Events Leading to Withdrawal From Study / 
Permanent Discontinuation of Study Treatment with Onset 
During the Double-Blind Treatment Phase
ICH E3
SAC
25
Safety
AE8
Listing of Disease Related Events with Onset During the Double-
Blind Treatment Phase
ICH E3
SAC
Hepatobiliary (Liver)
26
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
IDSL
SAC
27
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
IDSL
SAC


CONFIDENTIAL
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ICH: Listings
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
All Laboratory
28
Safety
LB5
Listing of Laboratory Data with Abnormalities of Potential Clinical 
Importance
SAC
29
Safety
LB5
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC
30
Safety
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC
31
Safety
UR2A
Listing of Urinalysis Data 
ICH E3
SAC


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11.11.9.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Demographic and Baseline Characteristics 
32
Screened
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
SAC
33
Safety
DM2
Listing of Baseline Characteristics
Include G6PD enzyme activity (IU/gHb) 
and baseline P.vivax asexual parasite 
count.
SAC
34
Safety
POP_L1
Listing of Malaria Signs and Symptoms at Baseline
SAC
35
Safety
MH2
Listing of Past and Current Medical Conditions
SAC
36
Safety
POP_L2
Listing of Diagnostic Test Results
SAC
Compliance
37
Safety
POP_L3
Listing of Compliance Data
SAC
Efficacy
38
mITT
EFF_L1
Listing of Results of Efficacy Endpoints
SAC
39
mITT
EFF_L2
Listing of Malarial Parasite Counts
SAC
40
mITT
EFF_L3
Listing of Time to Fever Clearance Data
SAC
Hepatobiliary (Liver)
41
Safety
LIVER5
Listing of Liver Event Results and Time of Event Relative to 
Treatment
SAC
42
Safety
LIVER6
Listing of Liver Event Information for RUCAM Score
SAC
43
Safety
LIVER7
Listing of Liver Biopsy Details
SAC
44
Safety
LIVER8
Listing of Liver Imaging Details
SAC
ECG
45
Safety
EG3
Listing of ECG Values
SAC


CONFIDENTIAL
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Non-ICH: Listings
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
46
Safety
EG5
Listing of ECG Findings
SAC
Vital Signs
47
Safety
VS4
Listing of Vital Signs
Include mean arterial BP
SAC
Blood Transfusions
48
Safety
SAFE_L2
Listing of Blood Transfusions
SAC
Pharmacokinetic
49
PK
PK07
Listing of PK concentrations for the Tafenoquine treatment 
group
PK


CONFIDENTIAL
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11.11
Appendix 12: Example Mock Shells for Data Displays
Population
: Safety
POP_T1
Summary of Malarial Signs and Symptoms
Programmers’ note: Repeat for all signs and symptoms collected at baseline, including those categorised as 
other (i.e. summarise the free text since it has been recorded consistently across subjects).
Programmers’ note: If a subject has any symptom present (regardless of severity, and including “Other”), they 
will be classed as “Yes” in the “Any malarial signs and symptoms present” row. If all symptoms are recorded as 
absent they will be “No”. 
Symptom
Severity
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP only
Total
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Any malarial signs and 
symptoms present
Yes
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
No
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Chills and rigours
Absent
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Mild
xx (xx%)
xx (xx%)
xx (xx%)
xxx (xx%)
Moderate
xx (xx%)
xx (xx%)
xx (xx%)
xxx (xx%)
Severe
xx (xx%)
xx (xx%)
xx (xx%)
xxx (xx%)
Headache
...
...
...
...
...
Other - fever
Absent
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Mild
xx (xx%)
xx (xx%)
xx (xx%)
xxx (xx%)
Moderate
xx (xx%)
xx (xx%)
xx (xx%)
xxx (xx%)
Severe
xx (xx%)
xx (xx%)
xx (xx%)
xxx (xx%)
...
...
...
...
...


CONFIDENTIAL
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Population
: Safety
POP_T2
Summary of Splenomegaly at Baseline
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP only
Total
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Does the patient currently 
have splenomegaly?
Yes
xx (xx%)
xx (xx%)
xx (xx%)
xxx (xx%)
No
xx (xx%)
xx (xx%)
xx (xx%)
xxx (xx%)


CONFIDENTIAL
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Population
: Safety
POP_T3
Summary of Study Medication Compliance and Exposure
TQ+DHA-PQP PQ+DHA-PQP
DHA-PQP only Total
(N=xx)
(N=xx)
(N=xx)
(N=xx)
  Number of compliant doses of DHA-PQP 
n
Xx
Xx
Xx
xxx
0
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
2
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
3
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
  Was subject compliant* with blinded treatment 
dosing?
n
Xx
Xx
Xx
xxx
Yes
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
No
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
  Was subject compliant with TQ / TQ placebo dosing?
n
Xx
Xx
Xx
xxx
Yes
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
No
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
  Blinded PQ / PQ placebo compliance (%)
n
Xx
Xx
Xx
Xx
Mean
xx
xx
xx
xx
SD
xx
xx
xx
xx
Min
xx
xx
xx
xx
Median xx
xx
xx
xx
Max
xx
xx
xx
xx
  Total Number of Doses of PQ / PQ Placebo Taken
n
Xx
Xx
Xx
xxx
<12
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
≥12
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Missingxx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)


CONFIDENTIAL
200894
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Note: A dose which was vomited but where the patient was successfully re-dosed was considered to be compliant.
*A subject is considered compliant with dosing if they successfully administered 12 or more doses of PQ or PQ 
matched placebo and a single dose of TQ or TQ matched placebo. 


CONFIDENTIAL
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Population: All subjects screened
POP_T4
Comparison of G6PD Fluorescent Spot Test (FST) and G6PD Enzyme Activity Test
Result of Fluorescent Spot Test 
(FST)
G6PD Normal
G6PD Deficient Other
Not Done
G6PD enzyme activity
(IU/gHb)
n
xx
xx
xx
xx
Mean
xx.xx
xx.xx
xx.xx
xx.xx
SD
xx.xxx
xx.xxx
xx.xxx
xx.xxx
Median
xx.xx
xx.xx
xx.xx
xx.xx
Min
xx.x
xx.x
xx.x
xx.x
Max
xx.x
xx.x
xx.x
xx.x
Note: The site median for G6PD enzyme activity is 7.29 IU/gHb. 70% of the site median is 5.1 IU/gHb.


CONFIDENTIAL
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Population
: Safety
POP_T5
Summary of Subjects for Whom Treatment Medication was Observed
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP only
Total
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Number of doses of DHA-PQP Observed
n
Xx
Xx
Xx
xxx
0
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
2
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
3
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Was Tafenoquine/Tafenoquine Placebo Dosing 
Observed?
n
Xx
Xx
Xx
xxx
Yes
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
No
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Number of doses of Primaquine/Primaquine
Placebo Observed
n
Xx
Xx
Xx
xxx
<12
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
12
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
13
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
14
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Note: If a subject vomited their dose and was re-dosed, both doses must have been observed, and it will 
count as a single dose within the table.


CONFIDENTIAL
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Population
: Safety
POP_T6
Number (%) of Subjects with Fever at Baseline
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP only
Total
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Fever
n
Xx
Xx
Xx
xxx
Yes
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
No
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Note: Fever is defined as a temperature >37.4ºC.


CONFIDENTIAL
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Population: Microbiologic Intent-to-Treat
EFF_T1
Summary of P.vivax asexual parasites at all time points 
Parasite: Parasite (units)
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP only
Total
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Day 1 (1st assessment)
n
Xx
Xx
Xx
xxx
Median
x.xx
x.xx
x.xx
x.xx
Q1
x.xx
x.xx
x.xx
x.xx
Q3
x.xx
x.xx
x.xx
x.xx
Min.
x.xx
x.xx
x.xx
x.xx
Max.
x.xx
x.xx
x.xx
x.xx
Day 1 (2nd assessment)
n
Xx
Xx
Xx
xxx
Median
x.xx
x.xx
x.xx
x.xx
Q1
x.xx
x.xx
x.xx
x.xx
Q3
x.xx
x.xx
x.xx
x.xx
Min.
x.xx
x.xx
x.xx
x.xx
Max.
x.xx
x.xx
x.xx
x.xx
Programmer’s note: Repeat for all visits where slide reading is performed (Day 2 1st assessment, Day 2 2nd
assessment, Day 3 1st assessment, Day 3 2nd assessment, Day 7, Day 14, Day 21, Day 28, Day 60, Day 90, Day 120, 
Day 150, Day 180). 


CONFIDENTIAL
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Population: <Microbiologic Intent-to-Treat / Per Protocol>
EFF_T2
Summary of Relapse-Free Efficacy at 6 Months
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP 
only
Total
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Subjects with relapse-free efficacy at 6 months (primary 
analysis)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
1. Subjects failing to demonstrate initial parasite clearance
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
2. Subjects with recurrence of parasitaemia in 6 months after 
initial clearance
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
3. <Subjects take drug with anti-malarial action in first 6 
months (and were not parasitaemic)>
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
4. Subjects who are not confirmed parasite-free at 6-month 
assessment
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Note: Subjects who meet any of the <three/four> criteria will not be considered to be relapse-free at 6 months 
in the primary analysis approach. 


CONFIDENTIAL
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Programmers note: Subjects who do not have a 6-month assessment and do not meet any of the other criteria 
defined should be included in the “subjects who are not confirmed parasite-free at 6-month assessment” 
category.
Population: Microbiologic Intent-to-Treat
TTE1
Survival Analysis of Relapse-Free Efficacy over 6 Months
TQ+DHA-PQP
(N=xxx)
PQ+DHA-PQP
(N=xxx)
DHA-PQP only
(N=xxx)
Number of Subjects
  Subjects observed to relapse prior to or at 6 months
  xx (xx%)
  xx (xx%)
  xx (xx%)
  Censored, prior to 6 month assessment [1]
  xx (xx%)
  xx (xx%)
  xx (xx%)
  Censored, relapse-free at 6 months
    
  xx (xx%)
  xx (xx%)
  xx (xx%)
Relapse-free efficacy rate at 6 months [2]
  Estimate
  xx%
  xx%
  xx%
  95% CI
(xx%, xx%)
(xx%, xx%)
(xx%, xx%)
Estimates for time to relapse (Days) [2]
  1st Quartile
xx.x
xx.x
xx.x
    95% CI
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
  Median
xx.x
xx.x
xx.x
    95% CI
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
  3rd Quartile
xx.x
xx.x
xx.x
    95% CI
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
Hazard ratio vs DHA-PQP only [3]
  Estimate
x.xxx
x.xxx
  95% CI
(x.xxx, x.xxx)
(x.xxx, x.xxx)
  p-value 
x.xxx
x.xxx
  
Hazard ratio vs PQ+DHA-PQP [2]
  Estimate
x.xxx


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  95% CI
(x.xxx, x.xxx)
Number needed to treat per treatment group before one extra 
success was seen compared to DHA-PQP only
Xx (xx,xx)
Xx (xx,xx)
[1] Subjects are censored if they did not have P.vivax at baseline, or took a drug with anti-malarial action 
despite not having malaria parasites, or did not have a 6 month assessment.
[2] Kaplan-Meier methodology
[3] Estimated from Cox’s Proportional Hazards Analysis, adjusting for Battalion.
A hazard ratio<1 indicates a lower chance of relapse compared to DHA-PQP only.


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Population: Microbiologic Intent-to-Treat
EFF_T3
Logistic Regression Analysis of Relapse-Free Efficacy at 6 Months (Subjects Censored Prior to 6 Months 
Excluded)
Comparison with DHA-PQP Only
-----------------------------------------
Treatment Group
N
n
Subjects Relapse 
Free (%)
Subjects 
Relapsed (%)
Adjusted Odds
Ratio of Relapse
95% CI
p-value
TQ+DHA-PQP
Xx
Xx
Xxx (xx%)
Xxx (xx%)
x.xx
(x.xx, x.xx)
0.xxx
PQ+DHA-PQP
Xx
Xx
Xxx (xx%)
Xxx (xx%)
x.xx
(x.xx, x.xx)
0.xxx
DHA-PQP Only
Xx
xx
Xxx (xx%)
Xxx (xx%)
Note: Model includes terms for battalion and treatment.
An odds ratio <1 represents a smaller chance of relapse compared to DHA-PQP only.


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Population: Microbiologic Intent-to-Treat           
TTE3
Analysis of Time to <Asexual Parasite Clearance>
TQ+DHA-PQP
(N=xxx)
PQ+DHA-PQP
(N=xxx)
DHA-PQP only
(N=xxx)
Number of Subjects
  Relapse
xx (xx%)
xx (xx%)
  xx (xx%)
  Censored
xx (xx%)
xx (xx%)
  xx (xx%)
Estimates for Time to Clearance (Days) [1]
  1st Quartile
xx.x
xx.x
xx.x
    95% CI
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
  Median
xx.x
xx.x
xx.x
   95% CI
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
  3rd Quartile
xx.x
xx.x
xx.x
    95% CI
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
Adjusted Hazard Ratio vs DHA-PQP only [2]
  Estimate
x.xx
x.xx
  95% CI
(x.xx, x.xx)
(x.xx, x.xx)
  p-value
x.xxx
x.xxx
Adjusted Hazard ratio vs PQ+DHA-PQP [2]
  Estimate
x.xxx
  95% CI
(x.xxx, x.xxx)
[1] Kaplan-Meier methodology


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[2] Estimated from Cox’s proportional Hazards Analysis, adjusting for Battalion.
A hazard ratio <1 indicates a lower risk of [endpoint] compared to DHA-PQP only.
Population: Microbiologic Intent-to-Treat
EFF_T4
Incidence of Genetically Homologous and Genetically Heterologous P. vivax Infections (determined by PCR)
TQ+DHA-PQP
(N=xx)
PQ+DHA-PQP
(N=xx)
DHA-PQP only
(N=xx)
n [1]
Xx 
Xx 
Xx 
P. vivax classified as genetically heterologous by PCR
Xx (xx%)
Xx (xx%)
Xx (xx%)
P. vivax classified as genetically homologous by PCR
Xx (xx%)
Xx (xx%)
Xx (xx%)
[1] n = number of subjects with an infection


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Population: Microbiologic-Intent-to-Treat
TTE6
Summary of recrudescence (blood stage failure) rates
TQ+DHA-PQP
(N=xx)
PQ+DHA-PQP
(N=xx)
DHA-PQP only
(N=xx)
Number of Subjects
  Recrudescence before Study Day 14
  xx (xx%)
  xx (xx%)
  xx (xx%)
  Censored
  xx (xx%)
  xx (xx%)
  xx (xx%)
Recrudescence rate
  Estimate
  xx%
  xx%
  xx%
  95% CI
(xx%,xx%)
(xx%,xx%)
(xx%,xx%)
Difference from DHA-PQP only
  Estimated Difference
   xx%
   xx%
  95% CI
(xx%, xx%)
(xx%, xx%)
Difference from PQ+DHA-PQP
  Estimated Difference
   xx%
  95% CI
(xx%, xx%)


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Population: Microbiologic-Intent-to-Treat
                                                 EFF_T5
Analysis of Subjects with Relapse-Free Efficacy at 6 Months by CYP2D6 Metaboliser Class - Logistic Regression
Treatment Group
n
Number of Subjects
Adjusted Odds
90% CI
p-value
  Effect Tested
Relapse Free
Ratio vs. EM+UM
TQ+DHA-PQP
  Poor or Intermediate Metaboliser 
xx
xx (xx%)
x.x
(x.x, x.x)
x.xxx
  Extensive or Ultra Metaboliser            xx
xx (xx%)
PQ+DHA-PQP
   Poor or Intermediate Metaboliser
xx
xx (xx%)
x.x
(x.x, x.x)
x.xxx
   Extensive or Ultra Metaboliser       
xx
xx (xx%)
DHA-PQP only
   Poor or Intermediate Metaboliser
xx
xx (xx%)
x.x
(x.x, x.x)
x.xxx
   Extensive or Ultra Metaboliser       
xx
xx (xx%)
Note: Model includes term for CYP2D6 Metaboliser Class. Metaboliser class is determined from the CYP2D6 
activity score (AS) as follows: Poor AS=0; Intermediate AS=0.5 or 1; Extensive AS=1.5 or 2; Ultra AS≥2.
A value over 1 represents benefit over the Extensive Metaboliser + Ultra Metaboliser group.


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Population: Microbiologic-Intent-to-Treat
EFF_T6
Summary of P.vivax Gametocyte Emergence
TQ+DHA-PQP
(N=xx)
PQ+DHA-PQP
(N=xx)
DHA-PQP only
(N=xx)
Total
(N=xx)
n
Xx
xx
xx
xx
Number of subjects with emergent gametocytes post-
baseline
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Note: Subjects who had P.vivax gametocytes at baseline are not included.


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Population: Microbiologic-Intent-to-Treat
Table EFF_T7
Summary of Covariate and Treatment*Covariate Interaction Significance For Cox Proportional Hazards Model 
Terms in the model
Degrees of Freedom
Wald Chi-Square
p-value
Battalion
xx
x.xx
x.xxx
Treatment*Battalion
xx
x.xx
x.xxx
Baseline Asexual Parasite Count
xx
x.xx
x.xxx
Treatment*Baseline Asexual Parasite 
Count
xx
x.xx
x.xxx
Model fitted first with covariate and treatment, then with covariate, treatment and treatment by covariate 
interaction


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Population: Microbiologic-Intent-to-Treat
Table EFF_T8
Effect of CYP2D6 Activity Score (AS) on Relapse-Free Efficacy at 6 Months – Logistic Regression
Degrees of Freedom
Wald Chi-Square
p-value
CYP2D6 Activity Score [1]
    DHA-PQP Only
xx
x.xx
x.xxx
    TQ+DHA-PQP
xx
x.xx
x.xxx
    PQ+DHA-PQP
xx
x.xx
x.xxx
[1] Model fitted with CYP2D6 Activity Score + battalion separately for each Treatment.
Note: p-value from a 2-sided test presented.


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Population: Microbiologic-Intent-to-Treat
Table EFF_T9
Number (%) of Subjects Within Each CYP2D6 Metaboliser Class
TQ+DHA-PQP
(N=xx)
PQ+DHA-PQP
(N=xx)
DHA-PQP only
(N=xx)
CYP2D6 Metaboliser Class
    Poor Metaboliser
xx (xx%)
xx (xx%)
xx (xx%)
    Intermediate Metaboliser
xx (xx%)
xx (xx%)
xx (xx%)
    Extensive Metaboliser
xx (xx%)
xx (xx%)
xx (xx%)
    Ultra Metaboliser
xx (xx%)
xx (xx%)
xx (xx%)
Metaboliser class is determined from the CYP2D6 activity score (AS) as follows: Poor AS=0; Intermediate AS=0.5 
or 1; Extensive AS=1.5 or 2; Ultra AS≥2.5.


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Population: Microbiologic-Intent-to-Treat
Table EFF_T10
Summary of the Number of Relapses per Subject
TQ+DHA-PQP
(N=xx)
PQ+DHA-PQP
(N=xx)
DHA-PQP only
(N=xx)
Number of Relapses
    n
xx
xx
xx
    0
xx (xx%)
xx (xx%)
xx (xx%)
    1
xx (xx%)
xx (xx%)
xx (xx%)
    2
xx (xx%)
xx (xx%)
xx (xx%)
    3
xx (xx%)
xx (xx%)
xx (xx%)


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Population: Safety
Table SAFE_T1
Summary of Chemistry Data Outside the Reference Range
Lab Test: <Parameter (units)>
Clinical Concern 
Category
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP only
Timepoint
(N=xx)
(N=xx)
(N=xx)
Day 1
n
xx  (xx%)
xx  (xx%)
xx  (xx%)
Low
xx  (xx%)
xx  (xx%)
xx  (xx%)
High 
xx  (xx%)
xx  (xx%)
xx  (xx%)
Day 3
n
xx  (xx%)
xx  (xx%)
xx  (xx%)
Low
xx  (xx%)
xx  (xx%)
xx  (xx%)
High 
xx  (xx%)
xx  (xx%)
xx  (xx%)
…
Any Time On-treatment
n
xx  (xx%)
xx  (xx%)
xx  (xx%)
Low
xx  (xx%)
xx  (xx%)
xx  (xx%)
High 
xx  (xx%)
xx  (xx%)
xx  (xx%)


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Population: Safety
                                                 SAFE_T2
Summary of Categories of Change from Baseline Haemoglobin (G/L) Data by Treatment and Time
              
    
Treatment
N
Visit
Haemoglobin drop
n
Mean
SD 
Median
Min 
Max
TQ+DHA-PQP
xx
Day 3
<=20 g/L
xx
xxx.x
xxx.xx
xxx.x
xx
xx
>20 g/L to <=30 g/L  xx
xxx.x
xxx.xx
xxx.x
xx
xx
>30 g/L              xx
xxx.x
xxx.xx
xxx.x
xx
xx
<=20 g/L
xx
xxx.x
xxx.xx
xxx.x
xx
xx
>20 g/L to <=30 g/L  xx
xxx.x
xxx.xx
xxx.x
xx
xx
>30 g/L              xx
xxx.x
xxx.xx
xxx.x
xx
Xx


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Population: Safety
                                                 SAFE_T3
Summary of Haemoglobin Declines over first 28 days
  
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP only
Total
Maximum decline from baseline
  <=20 g/L
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
  >20 g/L to <=30 g/L            xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
  >30 g/L or >=30%              xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)


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Population: Safety
SAFE_T4
Summary of Time on Treatment Before Liver Event
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP only
(N=xx)
(N=xx)
(N=xx)
Subjects reporting at least one liver event
xx  (xx%)
xx  (xx%)
xx  (xx%)
Subjects with events occurring while receiving study treatment
xx  (xx%)
xx  (xx%)
xx  (xx%)
Subjects with events occurring after stopping study treatment
xx  (xx%)
xx  (xx%)
xx  (xx%)
Time from start of treatment to event (days)
  n
xx
xx
xx
  Mean
  x.x
  x.x
  x.x
  sd
  x.x
  x.x
  x.x
  Median
  x.x
  x.x
  x.x
  Minimum
  x.x
  x.x
  x.x
  Maximum
xx.x
xx.x
xx.x
Time from most recent treatment to event (days)*
  n
xx
xx
xx
  Mean
  x.x
  x.x
  x.x
  sd
  x.x
  x.x
  x.x
  Median
  x.x
  x.x
  x.x
  Minimum
  x.x
  x.x
  x.x
  Maximum
xx.x
xx.x
xx.x
* For events which occur during treatment, time from treatment to event is set to one day.


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Population: Safety
SAFE_T5
Summary of QTcF Values (msec) by Category and Visit
TQ+DHA-PQP
PQ+DHA-PQP
DHA-PQP only
Actual Relative Time
  Result
(N=xx)
(N=xx)
(N=xx)
Maximum post baseline change
  n
xx
xx
xx
  Increase 0 - <30
xx (xx%)
xx (xx%)
xx (xx%)
  Increase >=30 - <60 
xx (xx%)
xx (xx%)
xx (xx%)
  Increase >=60 and QTcF <=480
xx (xx%)
xx (xx%)
xx (xx%)
  Increase >=60 and QTcF >480
xx (xx%)
xx (xx%)
xx (xx%)
Baseline
  n
xx
xx
xx
  <=450
xx (xx%)
xx (xx%)
xx (xx%)
  >450 to <=480
xx (xx%)
xx (xx%)
xx (xx%)
  >480 to <=500
xx (xx%)
xx (xx%)
xx (xx%)
  >500
xx (xx%)
xx (xx%)
xx (xx%)
Day 3
  n
xx
xx
xx
  <=450
xx (xx%)
xx (xx%)
xx (xx%)
  >450 to <=480
xx (xx%)
xx (xx%)
xx (xx%)
  >480 to <=500
xx (xx%)
xx (xx%)
xx (xx%)
  >500
xx (xx%)
xx (xx%)
xx (xx%)
  Increase 0 - <30
xx (xx%)
xx (xx%)
xx (xx%)
  Increase >=30 - <60 
xx (xx%)
xx (xx%)
xx (xx%)
  Increase >=60 and QTcF <=480
xx (xx%)
xx (xx%)
xx (xx%)
  Increase >=60 and QTcF >480
xx (xx%)
xx (xx%)
xx (xx%)
...
Note: If triplicate measurements are reported at a timepoint (as planned on Day 1, and occasionally


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occurring at other visits), the data summarized in the table is the mean of the triplicate measurements.
Note: Day 1 pre DHA-PQP dose is considered as baseline.


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Population: Microbiologic Intent to Treat
EFF_F1
Incidence (95% Confidence Interval) of Genetically Homologous and Genetically Heterologous P. vivax Infections 
n = number of P. vivax relapses
Bars represent 95% Wilson confidence intervals
Note to programmers: Include Bars for all 3 treatment groups.


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Population: Microbiologic Intent to Treat
EFF_F1
Estimated Hazard Ratio (95% CI) for Time to Relapse by Weight (TQ+DHA-PQP Vs DHA-PQP Only)
Note: Estimates are derived from a model containing terms for treatment, batallion, weight and the treatment 
by weight interaction.


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Population: Safety
                                                 SAFE_F1
             Plot of Maximum Absolute Methaemoglobin Value Over 28 Days by Treatment Group


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Population: Safety
                                                 SAFE_F2
             
Plot of Change in Methaemoglobin over time by Treatment Group


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Population: Safety                             
                                                EX3
Listing of Exposure Data
Randomised
Treatment
Site
ID   
Unique 
Subj.   
Actual 
Treatment
Start Date/ 
Start Time 
of Dose
Dose Form 
TQ dose 
taken with 
food?
Dose 
vomited 
within 60 
minutes?
Subject
observed 
taking 
medication?
<TQ+DHA-PQP>  xxxxx  xxxx    <TQ>
YYYY-MM-DD/
HH:MM 
<Tablet>
<N/Y>
<N/Y>
<N/Y>
   
<DHA-PQP>
YYYY-MM-DD/
HH:MM 
<Tablet>
<N/Y>
<N/Y>
<N/Y>
<PQ 
Placebo>
YYYY-MM-DD/
HH:MM 
<Tablet>
<N/Y>
<N/Y>
<N/Y>
<PQ+DHA-PQP>  xxxxx  xxxx    <PQ>
YYYY-MM-DD/
HH:MM 
<Tablet>
<N/Y>
<N/Y>
<N/Y>
   
<DHA-PQP>
YYYY-MM-DD/
HH:MM 
<Tablet>
<N/Y>
<N/Y>
<N/Y>
<TQ 
Placebo>
YYYY-MM-DD/
HH:MM 
<Tablet>
<N/Y>
<N/Y>
<N/Y>
…


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Population: Safety
                                                POP_L1
                                   Listing of Malarial Signs and Symptoms
  Treatment   Site ID/ 
Start date of                                              Severity of
              Unique    first malaria    Study                                     malaria
              Subj.      symptoms         Day     Signs and symptoms   symptoms
--------------------------------------------------------------------------------------
  TQ+DHA-PQP  xxxxxx/     DDMMMYYYY           1    Chills and rigors    xxx
              xxx
                                                   Headache             xxx
                                                   Dizziness            xxx
                                                   Abdominal Pain       xxx
                                                   Anorexia             xxx
                                                   Nausea               xxx
                                                   Vomiting             xxx
                                                   Diarrhoea            xxx
                                                   Pruritis/itching     xxx
                                                   Coughing             xxx
                                                   Other ACHES          xxx
Etc.


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Population: Safety                             
                                                POP_L2
                                  Listing of Diagnostic Test Results
  
  Treatment   Site ID/  
Fluorescent
G6PD Enzyme
              
              Unique Subj.   
Spot Test
Activity
  TQ+DHA-PQP  xxxxxx/
<Normal/
x.xx
              
              Xxx
Deficient/
Other>
    
    
    
Etc.


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Population: Safety
                                                
POP_L3
Listing of Compliance Data
Treatment
Site ID Unique 
Subj.   
Number of 
compliant 
doses of 
DHA-PQP
Compliant with 
TQ / TQ 
Placebo
Number of 
compliant doses of 
PQ / PQ Placebo
PQ/ PQ Placebo 
Compliance (%)
Compliant with 
blinded study 
treatment dosing*
<TQ+DHA-
PQP>  
xxxxx  
xxxx    Xx
<N/Y>
Xx
Xx%
<N/Y>
xxxx    xx
<N/Y>
xx
Xx%
<N/Y>
…
*A subject is considered compliant with dosing if they successfully administered 12 or more doses of PQ or PQ 
matched placebo and a single dose of TQ or TQ matched placebo.


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Population: Microbiologic-Intent-to-Treat
                                                
EFF_L1
                                  Listing of Results of Efficacy Endpoints
Treatment: <TQ+DHA-PQP / PQ+DHA-PQP / DHA-PQP only>
Site                                           Time to
ID/      Age(y)/                                Event
Unique
Sex/                                   (Days)            Reason For Outcome       
Subj.
Race           Endpoint                [1]     Outcome  [1]                      
------------------------------------------------------------------------------------------------------------
xxxxxx/  xx/            Relapse-free efficacy at xxx     Success  <Subjects with           
xxx      xxxx/          six months                                relapse-free efficacy at
         xxxx                                                     6 months (primary 
     analysis)
                        Relapse-free efficacy at         Success                            
                        six months (missing at 
                        D180= failure)
                        Recrudescence (blood       xxx   Success  Subjects with no
                        stage treatment failure)                  recrudescence (blood
                                                                  stage treatment failure)
...
[1] Time to Event and Reason for Outcome are only given where appropriate


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Population: Microbiologic-Intent-to-Treat
                                                EFF_L2
                                    Listing of Malarial Parasite Counts
Treatment: <TQ+DHA-PQP / PQ+DHA-PQP / DHA-PQP only>
Site ID/                     Sample                                           -Parasite Count
Unique                       Date/       Study                                  (/microL)-
Subj.       Timepoint        Time        Day    Parasite                     Asexual  Gametocyte
-----------------------------------------------------------------------------------------------------------
xxxxxx/     Day 1            DDMMMYYYY/    x    P. vivax                       xxx        xxx
xxx         Assessment 1     HH:MM
                                                P. falciparum  
                                                Other: P.ovale,                                                           
                                                P.malariae
            Day 2            DDMMMYYYY/    x    P. vivax                       xxx        xxx
            Assessment 1     HH:MM
                                                P. falciparum                                                             
                                                Other: P.ovale,                                                           
                                                P.malariae
            Day 2            DDMMMYYYY/    x    P. vivax                      xxx        xxx
            Assessment 2    HH:MM
                                                P. falciparum                                                             
                                                Other: P.ovale,                                                           
                                               P.malariae
            Day 3            DDMMMYYYY/    x    P. vivax                       xxx        xxx
            Assessment 1     HH:MM
                                                P. falciparum                                                            
                                                Other: P.ovale,                                                           
                                                P.malariae
...


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Population: Microbiologic-Intent-to-Treat
                                                EFF_L3
                                  Listing of Time to Fever Clearance data
Treatment: <TQ+DHA-PQP / PQ+DHA-PQP / DHA-PQP only>
                               Site     Age(y)/                           Time to
                               ID/
  Sex/                              Clearance
                               Unique   Race                              (Hours) [1]     Outcome
                               Subj.
                               ----------------------------------------------------------------------
                               xxxxxx/  xx/                               xxh xxm      <Censored/success>
                               xxx
  xxxx/
                               
  xxxx
                                        
                               xxxxxx/  xx/                               xxh xxm      <Censored/success>
                               xxx
  xxxx/
                              
  xxxx
                               xxxxxx/  xx/                               xxh xxm      <Censored/success>
                               xxx
  xxxx/
                               
  xxxx
                               xxxxxx/  xx/                               xxh xxm      <Censored/success>
                               xxx
  xxxx/
                               
  xxxx
                               xxxxxx/  xx/                               xxh xxm      <Censored/success>
                               xxx
  xxxx/
                               
  xxxx
....
[1] Time to Clearance of zero and outcome of Censored denotes a subject who did not have fever at baseline


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Population: Safety
                                                SAFE_L2
                                      Listing of Blood Transfusions
Treatment
Site ID
Unique 
Subj.
Age
Sex
Race
Visit
Visit Date
TQ + DHA-PQP
XXXX
XXXX
XX
M/F
XXXXXX
XXXX
XXXXX
Note: Visit is the visit at which the check box was ticked to state the subject had a blood transfusion since 
their previous visit. Details of the transfusion itself should have been reported as a concomitant medication.