An Open Label, Non-comparative, Multicenter Study to Assess the Pharmacokinetics, Safety and Efficacy of Tafenoquine (SB-252263, WR238605) in the Treatment of Pediatric Subjects With Plasmodium Vivax Malaria
Phase: PHASE2
Conditions: Malaria, Vivax
Sponsor: GlaxoSmithKline

2014N207627_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
TAF113577
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An Open Label, Non-comparative, Multicenter Study to Assess 
the Pharmacokinetics, Safety and Efficacy of Tafenoquine (SB-
252263, WR238605) in the Treatment of Pediatric Subjects with 
Plasmodium vivax Malaria
Compound Number:
SB252263
Development Phase:
II B
Effective Date:
06-NOV-2018
Protocol Amendment Number:  3
Author (s):
 
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

2014N207627_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
TAF113577
2
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N207627_00
2015-MAR-02
Original
2014N207627_01
2016-SEP-02
Amendment No. 1/SS-1 
(218704)
Amendment No. 1 is a site-specific amendment, and applies to one site in Thailand:  
center 
  At this center, the following changes will be implemented:
An inclusion criterion will be added to state that the subject is of Thai nationality 
(Section 5.1; Inclusion Criteria).
Vital signs will be measured and a physical examination will be conducted at every visit.  
The appropriate revisions have been made to Section 7.1 (Time and Events Table), 
Section 7.5.3 (Physical Exams) and Section 7.5.4 (Vital Signs) of the protocol.
GlaxoSmithKline
Document Number
Date
Version
2014N207627_02
2017-SEP-20
Amendment No. 2
Amendment No. 2 is a global amendment.  The information contained applies to all 
centers with the exception that the site-specific information in the previous local 
amendment will be carried over into this amendment and text added to identify site 
applicability, thus superseding Amendment No. 1.  The following new changes were 
implemented:
Based on results from cohort 1, changes were made to the tafenoquine dose banding 
scheme (Section 6.1; Treatment Assignment).
Change of Secondary Medical Monitor
A newly-described risk, Nervous System & Psychiatric Disorders, was added to the Risk 
Assessment Table (Section 4.6.1; Risk Assessment)
A typographical error was corrected in the inclusion criteria regarding approved methods 
of contraception (Section 5.1; Inclusion Criteria).
PPD

2014N207627_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
TAF113577
3
GlaxoSmithKline
Document Number
Date
Version
2014N207627_03
2018-NOV-06
Amendment No. 3
Amendment No. 3 is a site-specific amendment, and applies to one center in Brazil 
(Center
; Manaus, Brazil).  Revisions to the protocol were made for this center to 
conduct ophthalmic assessments of subjects at screening and prior to randomization, at 
the Day 120 visit, and at withdrawal as applicable.
PPD

PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
5
MEDICAL 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:  IND Number 101471
PPD
PPD
PPD
PPD
PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
6
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol TAF113577
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

2014N207627_03
CONFIDENTIAL
TAF113577
7
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY TAF113577 ...............................................10
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.1.1.
Pediatric P. vivax Malaria.............................................................14
2.1.2.
Adult Tafenoquine Program and Design Rationale ......................15
2.2.
Brief Background ........................................................................................16
3.
OBJECTIVES AND ENDPOINTS...........................................................................17
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................19
4.2.
Treatment Arms and Duration.....................................................................21
4.3.
Type and Number of Subjects.....................................................................22
4.4.
Design Justification.....................................................................................22
4.4.1.
Dose Justification in Cohort Aged <2 years .................................24
4.5.
Dose Justification........................................................................................24
4.6.
Benefit:Risk Assessment ............................................................................25
4.6.1.
Risk Assessment .........................................................................26
4.6.2.
Benefit Assessment.....................................................................30
4.6.3.
Overall Benefit:Risk Conclusion...................................................30
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................31
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screen Failures...........................................................................................33
5.4.
Withdrawal/Stopping Criteria.......................................................................33
5.4.1.
Liver Chemistry Increased Monitoring Criteria .............................34
5.4.2.
QTc Stopping Criteria ..................................................................35
5.5.
Subject and Study Completion....................................................................35
6.
STUDY TREATMENT ............................................................................................36
6.1.
Treatment Assignment................................................................................36
6.2.
Planned Dose Adjustments.........................................................................37
6.3.
Blinding.......................................................................................................37
6.4.
Packaging and Labeling..............................................................................38
6.5.
Preparation/Handling/Storage/Accountability..............................................38
6.6.
Compliance with Study Treatment Administration.......................................38
6.7.
Treatment of Study Treatment Overdose....................................................38
6.8.
Treatment after the End of the Study ..........................................................39
6.9.
Concomitant Medications and Non-Drug Therapies....................................40
6.9.1.
Permitted Medications and Non-Drug Therapies..........................40
6.9.1.1.
Concomitant Medications ...........................................40
6.9.1.2.
Rescue Medication.....................................................40
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................40
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................42
7.1.
Time and Events Table...............................................................................43

2014N207627_03
CONFIDENTIAL
TAF113577
8
7.2.
Screening and Critical Baseline Assessments ............................................46
7.3.
Unscheduled Visits .....................................................................................47
7.4.
Efficacy.......................................................................................................47
7.5.
Safety .........................................................................................................48
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........48
7.5.1.1.
Protocol-Defined SAE.................................................48
7.5.1.2.
Time period and Frequency for collecting AE 
and SAE information...................................................49
7.5.1.3.
Method of Detecting AEs and SAEs ...........................49
7.5.1.4.
Follow-up of AEs and SAEs........................................49
7.5.1.5.
Cardiovascular and Death Events ..............................50
7.5.1.6.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................50
7.5.1.7.
Regulatory Reporting Requirements for SAEs............51
7.5.2.
Pregnancy ...................................................................................51
7.5.3.
Physical Exams ...........................................................................51
7.5.4.
Vital Signs....................................................................................52
7.5.5.
Concomitant Medications.............................................................52
7.5.6.
Clinical Safety Laboratory Assessments ......................................52
7.5.7.
Ophthalmic Assessments (Center 
 Only)..........................53
7.6.
Pharmacokinetics .......................................................................................53
7.6.1.
Sample Analysis ..........................................................................54
7.7.
Genetics .....................................................................................................54
8.
DATA MANAGEMENT ...........................................................................................55
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................55
9.1.
Hypotheses.................................................................................................55
9.2.
Sample Size Considerations.......................................................................55
9.2.1.
Sample Size Assumptions ...........................................................55
9.2.2.
Sample Size Sensitivity................................................................56
9.2.3.
Sample Size Re-estimation or Adjustment...................................56
9.3.
Data Analysis Considerations .....................................................................56
9.3.1.
Key Analysis Populations.............................................................56
9.3.2.
Interim Analysis ...........................................................................56
9.4.
Key Elements of Analysis Plan ...................................................................57
9.4.1.
Primary Analyses.........................................................................57
9.4.2.
Secondary Analyses ....................................................................58
10. STUDY GOVERNANCE CONSIDERATIONS........................................................58
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............58
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................58
10.3.
Quality Control (Study Monitoring) ..............................................................59
10.4.
Quality Assurance.......................................................................................59
10.5.
Study and Site Closure ...............................................................................60
10.6.
Records Retention......................................................................................60
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................61
11. REFERENCES.......................................................................................................62
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
9
12. APPENDICES........................................................................................................65
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................65
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................67
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................70
12.3.1.
Definition of Adverse Events........................................................70
12.3.2.
Definition of Serious Adverse Events...........................................71
12.3.3.
Definition of Cardiovascular Events .............................................73
12.3.4.
Recording of AEs and SAEs ........................................................73
12.3.5.
Evaluating AEs and SAEs............................................................74
12.3.6.
Reporting of SAEs to GSK...........................................................75
12.4.
Appendix 4: Collection of Pregnancy Information........................................77
12.5.
Appendix 5 - Country Specific Requirements..............................................78
12.6.
Appendix 6 - WHO Definition of Severe Malaria..........................................79
12.7.
Appendix 7 – Prohibited Medications for Study Entry..................................80
12.8.
Appendix 8 – Tafenoquine Pediatric Dose Extrapolation.............................82
12.9.
Appendix 9 - Tafenoquine Pediatric Population-PK Trial Simulation ...........90
12.10. Appendix 10:  Protocol Amendment Changes...........................................106

2014N207627_03
CONFIDENTIAL
TAF113577
10
1.
PROTOCOL SYNOPSIS FOR STUDY TAF113577
Rationale
Infants, children and adolescents account for a significant proportion of P. vivax
infections worldwide. In regions with high intensity of transmission, the incidence of 
P. vivax malaria peaks in subjects before the age of 2 years while in low intensity 
transmission areas P. vivax infection and disease occurs in all pediatric age groups.
Many similarities exist in the clinical manifestations of P. vivax infection among adult 
and pediatric populations. In India, fever and chills were the most commonly reported 
clinical symptoms in both populations. Tender splenomegaly and anemia are also 
common findings in patients with chronic or recurrent disease caused by P. vivax. As in 
adults, relapses frequently occur months to years after the initial infection unless 
appropriate treatment to eradicate the hepatic phase of the parasite is administered.  Since 
severe anemia is a relatively common consequence of P. vivax infection in younger 
children, pediatric P. vivax patients are at risk of blood transfusion-associated infections 
(e.g., HIV, hepatitis B and C) and are at an increased probability of death from the 
clinical consequences of the anemia.
A strong exposure-efficacy response relationship has been identified for tafenoquine 
(TQ) in adult patients in part 1 of Study TAF112582.  A clinically relevant systemic 
exposure (AUC) of TQ, 56.4 µg.h/mL, was derived using a Classification and Regression 
Tree (CART) analysis.  Subjects with TQ exposure ≥ 56.4 µg.h/mL were likely to have 
significantly lower relapses compared to subjects with < 56.4 µg.h/mL. Based on 
simulations, the probability of being recurrence-free at 6 months was 52% (95% CI: 44% 
to 61%) in subjects with a TQ AUC < 56.4 μg.h/mL compared to 85% (95% CI: 80% to 
90%) in subjects with a TQ AUC ≥ 56.4 µg.h/mL. Additionally, 93% of subjects on the 
300mg dose had a predicted AUC that exceeded 56.4 μg.h/mL. 
The currently proposed doses for the pediatric study are derived from a population 
pharmacokinetic (PK) model built using the systemic TQ exposure data from adults in 
part 1 of Study TAF112582. The population PK model incorporated allometric scaling 
for bodyweight. Based on this population PK model, a 60 kg adult on 300mg dose will 
have a median AUC(0-∞) of 96 μg.h/mL (95% prediction interval 55-162 μg.h/mL). The 
proposed starting doses for this pediatric study are predicted to achieve a similar target 
exposure after accounting for the subjects’ bodyweight. The lower prediction limit 
AUC(0-∞)  of 55 μg.h/mL from the model is also consistent with the cut-off obtained 
from the CART analysis (AUC(0-∞) of 56.4 μg.h/mL) and therefore provides a high 
degree of confidence in the efficacy in the pediatric population using this PK bridging 
approach.
Therefore the primary objective of this study is to generate systemic exposure data to 
enable the modelling of the pharmacokinetics of TQ in infants, children and adolescents 
with P. vivax to identify and recommend doses for pediatric subjects that achieve similar 
TQ AUC (0-∞) to the selected adult dose of 300 mg.  If achieved, this will provide a 
bridge for dose selection with extrapolation of the adult efficacy data to infants, children
and adolescents aged 6 months to <16 years.  In addition, the safety and the clinical and 

2014N207627_03
CONFIDENTIAL
TAF113577
11
parasitological efficacy of TQ will be studied in pediatric subjects receiving TQ and 
chloroquine (CQ).
Objectives/Endpoints
Objectives
Endpoints
Primary

To evaluate the pharmacokinetics (PK) 
of tafenoquine in children and 
adolescents aged ≥2 years to <16 years 
(weighing ≥5 kg) with P. vivax in order 
to identify appropriate doses that 
achieve a similar exposure to that of the 
tafenoquine adult dose of 300 mg.

AUC(0-∞) of TQ by weight band from 
a population PK model in pediatric 
subjects aged ≥2 years to <16 years 
(weighing ≥5 kg).
Secondary

To assess the safety of tafenoquine 
when administered to pediatric 
subjects with P. vivax malaria.

Description of key safety data in the 
study population.

To assess the clinical and 
parasitological efficacy of tafenoquine 
as a radical cure for pediatric subjects 
with P. vivax malaria when co-
administered with chloroquine.

Recurrence-free efficacy at four 
months post-dosing.

To assess the PK of tafenoquine in 
infants aged ≥6 months to <2 years 
(weighing ≥5 kg) with P. vivax (if data 
permit)

AUC(0-∞) of TQ by weight band from 
a population PK model in infants aged 
≥6 months to <2 years (weighing ≥5
kg).
Overall Design

TAF113577 is a prospective, open-label, multicenter, non-comparative, single-
arm study. All subjects will receive CQ and open-label TQ.

Potential subjects can be identified, pre-screened, and begin off-study treatment 
with CQ, after which sites will have up to 48 hours to obtain full consent/assent, 
as applicable.  Upon consent, subjects will be treated with tafenoquine on Day 1, 
then attend seven follow-up visits (Days 3, 8, 15, 29, 60, 90 and 120). The total 
follow-up period will be 120 days.

Subjects must have a blood smear that is positive for P. vivax at pre-screening.  
Blood smears will be taken at Day 1 (screening) and at Day 8 to confirm the 
parasite has cleared.  Additional parasitological assessments will be conducted on 
visit Days 29, 60, 90 and 120.

At the Day 1 visit subjects will be screened for G6PD deficiency by a quantitative 
assay and the result will be determined as a percentage of the predetermined 

2014N207627_03
CONFIDENTIAL
TAF113577
12
median enzyme activity of the site.  All subjects must have a minimum G6PD 
assay value of 70% to be enrolled.

A subject is considered to have completed the study if they attend all treatment 
and follow-up visits. A PK evaluable subject is defined as one with a minimum of 
one PK sample from Days 3, 15, 29 and 60.

The final safety analysis will take place when all 60 enrolled subjects have 
completed the study. 

Safety data will be collected on all subjects who receive a dose of TQ.
Treatment Arms and Duration
In this single-arm study, potential subjects who are slide-positive for P. vivax will be 
started by the site on CQ per local/national guidelines.  Sites will have up to 48 hours to 
obtain consent.  Once full consent is provided, all subjects will be screened and, if 
eligible, receive TQ, given as a single dose on Day 1.  All study medication should be 
taken with food.  After the treatment period, subjects will attend up to 7 follow-up visits 
through Day 120.
Type and Number of Subjects
Approximately 240 subjects aged <16 years with P. vivax malaria will be screened to 
achieve 60 completed subjects.  A subject is considered to have completed the study if 
they attend all treatment and follow-up visits. A PK evaluable subject is defined as one 
with a minimum of one PK sample from Days 3, 15, 29 and 60, with accurate dosing and
sample time histories.
Initially, subjects ≥2 years to <16 years of age will be enrolled into the study.  
Recruitment to an additional cohort of infants aged ≥6 months to <2 years (weighing ≥5 
kg) may begin following completion of the first interim analysis.  This lower age cohort 
are included as part of the 60 completed subjects.
Analysis
There are no hypotheses tested in this study.  The study is designed to characterize TQ 
exposures in pediatric subjects.  A population PK modelling and simulations-based 
approach was utilized to support appropriate study sample size and PK sampling times 
for the proposed population PK bridging study.  Based on these simulations, a sample 
size of 16 subjects and a sparse sampling scheme of four time points per subject are 
considered sufficient for the evaluation of the primary PK objective of estimating TQ 
apparent systemic clearance (CL) and thus exposure [AUC(0-∞) = Dose/CL] within each 
weight band in pediatric subjects aged ≥2 years to <16 years.  Up to two interim analyses 
(at 16 and 32 subjects) have been planned so that sparse PK sampling may be stopped at 
the earliest opportunity, although all remaining subjects recruited into the study will have 
a minimum of two PK samples taken. Recruitment will continue for safety data 
accumulation.

2014N207627_03
CONFIDENTIAL
TAF113577
13
The primary population PK model-based analysis to be performed will borrow some 
information from the adult model as appropriate. The sparse sampling in pediatric 
subjects is insufficient to independently characterize the absorption phase. Consequently 
the information about absorption from the adult model will be used as prior information 
to feed into the pediatric PK model with the assumption that the absorption processes are 
similar in adults and pediatric subjects.  The pediatric population PK model will aim to 
reliably estimate the TQ clearance and thus the exposures in pediatric population.  The 
clearance estimate for each subject generated from the model-based analysis will be used 
to determine the subject’s TQ AUC(0-∞) [AUC(0-∞) = Dose/CL].

2014N207627_03
CONFIDENTIAL
TAF113577
14
2.
INTRODUCTION
Tafenoquine (TQ; SB-252263 and WR238605) is a novel 8-aminoquinoline anti-malarial 
drug being co-developed by GlaxoSmithKline and the Medicines for Malaria Venture 
with the assistance and historic support of the Walter Reed Army Institute of Research.  It 
is a synthetic analogue of primaquine (PQ) and is currently being developed for the 
radical cure of acute Plasmodium vivax malaria, to be administered as a single dose along 
with standard doses of the anti-malarial chloroquine (CQ).  Of note, TQ possesses 
activity against all stages of the Plasmodium lifecycle, including the dormant P. vivax
hypnozoite.
2.1.
Study Rationale
2.1.1.
Pediatric P. vivax Malaria
Infants, children and adolescents account for a significant proportion of P. vivax
infections worldwide. In regions with high intensity of transmission, the incidence of 
P. vivax malaria peaks in subjects before the age of 2 years while in low intensity 
transmission areas P. vivax infection and disease occurs equally in all pediatric age 
groups [World Global Malaria Programme, 2013; Anstey, 2012].  Congenital P. vivax
infection does not require treatment with radical cure drugs, apparently because
sporozoites do not enter the fetal circulation, preventing the development of hypnozoites 
in the fetus [Menendez, 2007]. By contrast, vector-borne P. vivax infections in the 
pediatric population behave broadly similarly to adults and thus treatment is required to 
prevent relapses from hypnozoites. 
As transmission rates are low in most regions where P. vivax is prevalent, affected 
populations do not achieve high levels of immunity (or premunition) to this parasite and 
people of all ages are at risk of infection [Crawley, 2010]. Many similarities exist in the 
clinical manifestations of P. vivax infection among adult and pediatric populations. For 
example, in a study of adult and pediatric patients with vivax malaria in India, fever and 
chills were the most commonly reported clinical symptoms in both populations [Singh,
2013a]. Tender splenomegaly and anemia are also common findings in patients with 
chronic or recurrent disease caused by P. vivax. As in adults, relapses frequently occur 
months to years after the initial infection unless appropriate treatment to eradicate the 
hepatic phase of the parasite is administered [Summer, 2005]. 
Among patients with severe disease, the most frequent manifestations for both adults and 
children are severe anemia and acute respiratory distress. Less commonly, cerebral 
malaria, kidney injury, shock, and coagulopathy have also been reported [Baird, 2012].  
P. vivax infection may also present with thrombocytopenia, which is a well-documented 
and frequent complication in both adult and pediatric patients with vivax malaria 
[Rodriguez-Morales, 2014], occurring with similar frequency in both age groups. In a 
review of 9 studies of patients with vivax malaria, thrombocytopenia was reported in 
22.5% to 93.3% of adults [George, 2010; Kashinkunti, 2013; Kochar, 2009; Srivastava, 
2011], and 22.2% to 95.6% of children [Mahgoub, 2012; Rodriguez-Morales, 2006; 
Bhattacharjee, 2013; Singh, 2011; Singh, 2013b].

2014N207627_03
CONFIDENTIAL
TAF113577
15
Since severe anemia is a relatively common consequence of P. vivax infection in younger 
children, pediatric P. vivax patients are at risk of blood transfusion-associated infections 
(e.g., HIV, hepatitis B and C) and are at an increased probability of death from the 
clinical consequences of the anemia itself; however, the risks of severe disease and case 
fatality rates for P. vivax infection varies and have not been firmly established. In 
addition, there is accumulating evidence that P. vivax malaria impairs weight gain and 
growth as well as school performance, underlying the chronic, insidious impact that 
repeated relapses have on individuals and communities.
Besides parasite and host-related factors, severe anemia and acute renal failure could 
result from severe hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient 
children being treated with PQ.  Although this is rarely described in the literature under-
reporting is likely to occur.  Fortunately diagnosis of G6PD deficiency in the pediatric 
population is identical to that in adults. Normal G6PD activity has been found to be 
higher in newborns (<7 days) than in adults but this does not affect diagnosis of complete 
G6PD deficiency, as G6PD deficient newborns show identical low levels to those of 
deficient adults but further complicates identification of heterozygote individuals.
2.1.2.
Adult Tafenoquine Program and Design Rationale
A phase III program is ongoing to study TQ in adult subjects (≥16 years of age) with 
P. vivax malaria.  This program is comprised of two studies:
1. Study TAF112582 [GlaxoSmithKline Document Number RM2010/00052/04] is a 
seamless phase II/III study in which the phase II portion has completed and an 
efficacious dose of TQ with a clinically acceptable safety profile has been 
selected; a single 300 mg dose. The phase III portion of TAF112582 will test the 
efficacy and safety of the selected TQ/CQ regimen in the radical cure of P. vivax
malaria.
2. Study TAF116564 [GlaxoSmithKline Document Number 2012N152563_01] will 
characterize the incidence of hemolysis with TQ/CQ, and compare this to the 
incidence of hemolysis with PQ/CQ. In particular, a subset of adult female 
subjects will be enrolled that display a moderate deficiency in G6PD activity 
(G6PD heterozygous deficiency; susceptible to being misclassified as having 
“normal” G6PD activity by G6PD tests) so that the potential for hemolysis can be 
studied using the selected TQ/CQ regimen.
A strong exposure-efficacy response relationship has been identified for TQ in adult 
patients in part 1 of Study TAF112582.  A clinically relevant systemic exposure (AUC) 
of TQ, 56.4 µg.h/mL, was derived using a Classification and Regression Tree (CART) 
analysis.  Subjects with TQ exposure ≥ 56.4 µg.h/mL were likely to have significantly 
lower relapses compared to subjects with < 56.4 µg.h/mL. Based on simulations, the 
probability of being recurrence-free at 6 months was 52% (95% CI: 44% to 61%) in 
subjects with a TQ AUC < 56.4 μg.h/mL compared to 85% (95% CI: 80% to 90%) in 
subjects with a TQ AUC ≥ 56.4 µg.h/mL. Additionally, 93% of subjects on the 300mg 
dose had a predicted AUC that exceeded 56.4 μg.h/mL.

2014N207627_03
CONFIDENTIAL
TAF113577
16
Therefore the primary objective of this study is to generate systemic exposure data to 
enable the modelling of the PK of TQ in infants, children and adolescents with P. vivax to 
identify and recommend doses for pediatric subjects that achieve similar TQ AUC (0-∞) 
to the selected adult 300 mg dose.  If achieved, this will provide a bridge for dose 
selection with extrapolation of the adult efficacy data to children.  In addition, the safety 
and the clinical and parasitological efficacy of TQ will be studied in pediatric subjects 
receiving TQ/CQ.
2.2.
Brief Background
Tafenoquine 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 subjects aged ≥16 years old.
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.  Tafenoquine is thus being 
developed for treatment of patients with sufficient levels of G6PD enzyme activity.  
Tafenoquine has a long half-life, and as such can be administered as a single oral dose.  
This is in contrast to PQ, which requires 14 days dosing.  It must be determined if 
improved compliance with TQ could also lead to improved clinical outcomes.  
Tafenoquine should have no clinically significant side effects that will restrict its use as a 
first line agent in treatment of P. vivax malaria when used in combination with a G6PD 
test and recommended therapies to treat the blood stages of infection.

2014N207627_03
CONFIDENTIAL
TAF113577
17
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the pharmacokinetics (PK) 
of tafenoquine in children and 
adolescents aged ≥2 years to <16 years 
(weighing ≥5 kg) with P. vivax in order 
to identify appropriate doses that 
achieve a similar exposure to that of the 
tafenoquine adult dose of 300 mg.

AUC(0-∞) of TQ by weight band from 
a population PK model in pediatric 
subjects aged ≥2 years to <16 years 
(weighing ≥5 kg).
Secondary

To assess the safety of tafenoquine 
when administered to pediatric 
subjects with P. vivax malaria.

Description of safety data in the study 
population. Key safety endpoints of 
interest are:
Gastrointestinal tolerability, and
Clinically relevant drops in 
hemoglobin.
Additionally, the incidence and 
severity of adverse events and 
abnormal laboratory observations.

To assess the clinical and 
parasitological efficacy of tafenoquine 
as a radical cure for pediatric subjects 
with P. vivax malaria when co-
administered with chloroquine.

Recurrence-free efficacy at four 
months post-dosing.

To assess the PK of tafenoquine in 
infants aged ≥6 months to <2 years 
(weighing ≥5 kg) with P. vivax (if data 
permit)

AUC(0-∞) of TQ by weight band from 
a population PK model in infants aged 
≥6 months to <2 years (weighing ≥5
kg).
With regard to the secondary efficacy endpoint, it should be noted that it is not possible 
to determine if a subject's recurrence of malaria is a relapse (liver stage treatment failure)
or a re-infection (i.e., new infection), even when using current genetic techniques.  
Likewise, it is not possible to determine if a recurrence is a re-infection or recrudescence 
(blood stage treatment failure).  For the purposes of this protocol, the term ‘recurrence’ 
will be used to represent any type of malaria treatment failure.  Recurrence is defined as a 
positive blood smear with or without vivax malaria symptoms.

2014N207627_03
CONFIDENTIAL
TAF113577
18
4.
STUDY DESIGN

TAF113577 is a prospective, open-label, multicenter, non-comparative, single-
arm study. All subjects will receive CQ and open-label TQ.

Potential subjects can be identified, pre-screened, and begin off-study treatment 
with CQ, after which sites will have up to 48 hours to obtain full consent/assent, 
as applicable.  Upon consent, subjects will be treated with tafenoquine on Day 1, 
then attend seven follow-up visits (Days 3, 8, 15, 29, 60, 90 and 120). The total 
follow-up period will be 120 days.

During the follow-up period, sites have the option of performing non-PK visits 
(Days 8, 90 and 120) at the subject’s home.

Subjects must have a blood smear that is positive for P. vivax at pre-screening.  
Blood smears will be taken at Day 1 (screening) and at Day 8 to confirm the 
parasite has cleared.  Additional parasitological assessments will be conducted on 
visit Days 29, 60, 90 and 120.

At the Day 1 visit subjects will be screened for G6PD deficiency by a quantitative 
assay and the result will be determined as a percentage of the predetermined 
median enzyme activity of the site.  All subjects must have a minimum G6PD 
assay value of 70% to be enrolled.

A total of 60 pediatric subjects will be enrolled.  The main cohort will consist of 
subjects aged ≥2 years to <16 years with no restriction on gender. Subjects will be 
dosed according to four weight bands.

Within the total of 60 enrolled pediatric subjects, a second cohort of up to 6
infants aged ≥6 months to <2 years (weighing ≥5 kg) may be recruited following 
completion of a planned first interim analysis (see below).

An interim analysis will be conducted once sufficient data from 16 subjects is 
available to assess PK and safety parameters.  If needed, a second interim analysis 
may be conducted after a total of 32 subjects have enrolled.  The primary analysis 
population will be the PK evaluable population.

A subject is considered to have completed the study if they attend all treatment 
and follow-up visits. A PK evaluable subject is defined as one with a minimum of 
one PK sample from Days 3, 15, 29 and 60.

The final safety analysis will take place when all 60 enrolled subjects have 
completed the study. 

A population PK model will be used to estimate the clearance and thus exposure 
of TQ for each of the weight bands in the main cohort [AUC(0-∞) = 
Dose/Clearance (CL)].

2014N207627_03
CONFIDENTIAL
TAF113577
19

Safety data will be collected on all subjects who receive their dose of TQ.

A single center 
; Manaus, Brazil) will perform ophthalmic safety 
assessments at selected visits to monitor subjects for changes in the eye.
Hospitalization of subjects is not required for this study; however, subjects may be 
hospitalized as warranted by their condition, and at the discretion of the investigator.
4.1.
Overall Design
Study TAF113577 is a prospective, open-label, single arm, multicenter study enrolling 60 
pediatric subjects aged 6 months  to <16 years of age.  The study schematic (Figure 1) 
summarizes the study visits.
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
20
Figure 1
TAF113577 Study Design Schema

2014N207627_03
CONFIDENTIAL
TAF113577
21
4.2.
Treatment Arms and Duration
In this single-arm study, potential subjects who are slide-positive for P. vivax will be 
started by the site on CQ per local/national guidelines.  Sites will have up to 48 hours to 
obtain consent.  Once full consent is provided, all subjects will be screened and, if 
eligible, receive TQ, given as a single dose on Day 1.  All study medication should be 
taken with food.  After the treatment period, subjects will attend up to 7 follow-up visits 
through Day 120.
Due to the large variation in weight for the same age anticipated across various countries, 
pediatric subjects will have TQ dosed by weight instead of by age. This approach with 
weight based dosing is also more relevant since various enzymatic processes that may be 
involved in drug metabolism generally reach adult maturation levels post 6 months of 
age. The current study does not enrol subjects less than 6 months of age. TQ doses 
within weight bands were selected by using a population PK modelling and simulation 
approach based on adult data and incorporation of allometric scaling (see Appendix 8, 
Section 12.8, Tafenoquine Pediatric Dose Extrapolation). Based on these simulations
there will be four weight bands of ≥5 to ≤10 kg, >10 to ≤20 kg, >20 to ≤35 kg and >35 kg 
with proposed starting doses for pediatrics from 100 to 300 mg TQ (see Section 4.5). 
Enrollment into all weight bands will be conducted in parallel.  Although no minimum 
enrollment is required in any single weight band prior to the interim analyses, efforts will 
be made to enrol subjects across all weight bands.
An interim population PK analysis will be performed once data from 16 subjects is 
obtained (Figure 2).  The TQ clearance estimate (CL) for each subject generated from the 
population model based analysis will be used to determine the subject’s TQ exposure; 
i.e., AUC(0-∞) [AUC(0-∞) = Dose/CL].  The model based pediatric exposure predictions
will be compared to the corresponding adult exposures at the 300mg dose that have been 
shown to be efficacious. If the data is sufficient to make reliable predictions for dose 
recommendations, full PK sampling in the trial will be stopped. If the data are deemed 
insufficient, the PK sampling will continue to collect PK data from another set of 16 
pediatric subjects where after the modelling and simulation activity will be repeated at 
the second interim analysis.  Once the full PK assessments are completed and sufficient 
data is available to reliably characterize pediatric TQ PK, all remaining enrolled subjects 
will provide two PK samples at Day 15 and Day 29 to provide data for the final 
population PK analysis of TQ to be conducted at the end of the study. If during the 
analysis it is realized that exposures are greater than 275 µg.hr/mL, the dosing strategy 
will be revised. Refer to Section 4.6.1 for details.

2014N207627_03
CONFIDENTIAL
TAF113577
22
Figure 2
TAF113577 Recruitment Scheme
4.3.
Type and Number of Subjects
Approximately 240 subjects aged <16 years with P. vivax malaria will be screened to 
achieve 60 enrolled subjects.  Initially, subjects ≥2 years to <16 years of age will be 
enrolled into the study.  Recruitment to an additional cohort of infants aged ≥6 months to 
<2 years (weighing ≥5 kg) may begin following completion of the first interim analysis.
A subject is considered to have completed the study if they attend all treatment and 
follow-up visits. A PK evaluable subject is defined as one with a minimum of one PK 
sample from Days 3, 15, 29 and 60, with accurate dosing and sample time histories. The 
key PK parameter to be estimated is the drug’s clearance.
4.4.
Design Justification
Study TAF113577 is an open-label single-arm study and will not include a control arm. 
This pediatric PK bridging and safety study will test appropriate doses of TQ in pediatric 
subjects selected to achieve similar levels of exposure observed in adults treated with 
300mg TQ.  The dosing regimen in the pediatric population is based on allometric scaling 
and targeting a systemic exposure comparable to the 300 mg exposures in adults. Given 
the evidence suggests that the disease process in adults and children is similar, it is 
appropriate to draw conclusions from our emerging adult data set to inform our pediatric 
study design. This assumption allows the use of this pharmacokinetic bridging study to 
support the dose selection in infants, children and adolescents aged 6 months to <16 
years.  
The study will recruit a target of 60 subjects. Safety data will be collected for the entire 
study (up to 120 days, as the half-life of TQ is 2–3 weeks).  With regard to efficacy, the 
study is being conducted in areas with known high recurrence rates in adults.  Therefore, 
high efficacy in this study is not indicative of low background recurrence rates.
Pharmacokinetic samples will be collected in order to achieve the primary objective of 
the study. However, in order to minimize distress in this pediatric population, a sparse 
sampling scheme will be used to reduce the frequency and volume of blood collected and 
a population PK modelling and simulation approach will be utilized. Small volume 
venous sampling (≤1 mL whole blood) and/or microsampling (70 µL whole blood) will 

2014N207627_03
CONFIDENTIAL
TAF113577
23
be employed to minimize volume of blood taken from subjects.  Furthermore, up to two 
interim analyses have been included in this study, so that full PK sampling can be 
stopped as soon as sufficient data have been collected.  As mentioned in Section 4.1, once 
full PK sampling is stopped, two samples will be collected from each remaining enrolled 
subject at Day 15 and Day 29 to provide data for the final population PK analysis of TQ 
to be conducted at the end of the study.  Simulations were used to identify appropriate 
sampling times and total study sample size (See Appendix 9, Section 12.9, Tafenoquine 
Pediatric Population-PK Trial Simulation). The primary objective of this PK bridging 
study is to adequately characterize the systemic TQ exposure in the pediatric population. 
Consequently, a sparse PK sampling scheme is selected to reliably estimate TQ clearance 
(CL) and thereby characterize exposure, i.e., AUC [AUC (0-∞) = dose/CL]. Other 
information that cannot be obtained from the pediatric data owing to the sparse sampling 
design, e.g. absorption rate, will be obtained from the adult exposure data and population 
PK model.
In the phase 2 adult TQ program, efficacy was measured at 4 months and 6 months
[GlaxoSmithKline Document Number 2013N160035_00]. The majority of the 
recurrences across all treatment groups were observed prior to 4 months and efficacy of 
TQ 300 dose at 4 months was significantly higher than placebo (Figure 3). To allow for a 
shorter follow up period in the pediatric study population, recurrence-free efficacy will be 
measured at four months rather than at four and six months as measured in the adult 
studies.
Figure 3
Kaplan-Meier Survival Curves for Time to P. vivax Recurrence 
(Intent-to-Treat Population)

2014N207627_03
CONFIDENTIAL
TAF113577
24
4.4.1.
Dose Justification in Cohort Aged <2 years
There is no lower age limit below which infants and children are not susceptible to vivax 
malaria. There is, however, a balance to be struck in terms of collecting data sufficient to 
define an appropriate dose for infants, versus limiting the number of study related 
assessments to which this highly vulnerable group are subjected. Where possible, PK data 
from an additional cohort of six infants aged ≥6 months to <2 years (weighing ≥5 kg) will 
be obtained to define dosing in infants down to 6 months. Available data from this cohort 
will be combined with data obtained from the main cohort as part of the final population 
PK analysis.  The lower age of 6 months is based on the age at which G6PD enzyme 
activity reaches maturity.  The pediatric population PK model used for dose prediction 
has been developed based on adult patient data and includes an allometric function for 
weight-based dosing. Allometric scaling accounts for size differences only and not age-
related changes in metabolizing enzymes or renal function. However, the generalized 
functional immaturity in metabolizing enzyme activity and renal function approach adult 
levels about 6 months after birth [Kearns, 2003].  Thus, the model is appropriate for dose 
prediction in this cohort.
The decision to enrol subjects aged ≥6 months - <2 years will be based on a review of 
exposure data as well as of safety results from the first interim analysis.  Particular 
attention will be paid to the reporting of adverse events related to decreases in 
hemoglobin (Hb), methemoglobin (metHb) levels, increases in creatinine, and any reports 
of phototoxicity.
4.5.
Dose Justification
As mentioned above, subjects will be dosed based on weight (see Section 6.1).  The 
pediatric dose rationale is based on achieving a target median TQ exposure AUC(0-∞) of  
96 µg.h/mL. The term AUC listed throughout this document refers to the AUC(0-∞) 
unless specified otherwise and is estimated based on model predicted post hoc CL 
estimates [AUC (0-∞) = dose/CL].
The currently proposed doses for the pediatric study are derived from a population PK 
model built using the systemic TQ exposure data from adults in part 1 of Study 
TAF112582. The population PK model incorporated allometric scaling for bodyweight. 
Based on this population PK model, a 60 kg adult on 300mg dose will have a median 
AUC(0-∞) of 96 μg.h/mL (95% prediction interval 55-162 μg.h/mL). The proposed 
starting doses for this pediatric study are predicted to achieve a similar target exposure 
after accounting for the subjects’ bodyweight. 
The lower prediction limit of AUC(0-∞) of 55 μg.h/mL from the population PK model is 
consistent with the cut-off obtained from the CART analysis (AUC(0-∞) of 56.4 
μg.h/mL). The CART analysis conducted with exposure – efficacy/response data from 
part 1 in Study TAF112582 identified a clinically relevant TQ AUC of 56.4 ug.hr/mL. 
Subjects with TQ AUC ≥ 56.4 ug.hr/mL  were likely to have significantly lower relapses 
compared to subjects with < 56.4 ug.hr/mL TQ AUC. This population PK model based 
dose rationale therefore provides a high degree of confidence in the efficacy in the 
pediatric population using such PK bridging approach.

2014N207627_03
CONFIDENTIAL
TAF113577
25
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with TQ 
(SB-252263) can be found in the Investigator’s Brochure The following section outlines 
the risk assessment and mitigation strategy for this protocol:  

2014N207627_03
CONFIDENTIAL
TAF113577
26
4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) – SB-252263
Hemolysis in G6PD-deficient subjects
(PRIMARY RISK)
Tafenoquine is an 8-aminoquinoline, a class of 
drug known to exert oxidative effects on Hb. In 
patients with G6PD deficiency (or other 
disorders of erythrocytic pentose phosphate 
pathway of glucose metabolism) hemolysis is 
expected due to 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 with <70% G6PD activity will 
be excluded. Subjects with Hb levels <8
g/dL will also be excluded.

Protocol-defined SAE criteria will be 
adopted; defined as, ≥ 3.0 g/dL or 30% 
decline in Hb from the baseline value, or a 
Hb value <6 g/dL, to aid in safety 
monitoring.  

Recommendations for clinical management 
of hemolysis will be provided as part of
investigator training.
Methemoglobinemia (metHb)
Methemoglobinemia has been observed in 
previous studies associated with larger total 
doses of TQ than are being considered for 
clinical investigation.  Risk factors have been 
assessed and include a strong relationship 
between MetHb development, TQ dose, and 
body surface area.
The doses recommended for this study, 
designed to achieve similar levels of exposure 
observed in adults treated with 300mg TQ, 
should pose minimal risk of causing elevations 
of metHb of clinical concern.

Methemoglobin percentage will be 
monitored non-invasively at selected times 
throughout the study.
High Systemic Exposure to TQ
In a cohort of patients taking 600 mg TQ (first 
part of Study TAF112582) the highest AUC(0-∞) 
observed was 275 μg.h/mL.

The presence of an observed AUC(0-∞) in 
any subject of >275 μg.h/mL will trigger a 
review of dosing in the study.
Liver Transaminase Elevations
Preclinical repeat dose toxicology studies 
observed liver changes that were fully or 
partially reversible.
During the TQ thorough QT study (TAF114582) 

Conduct liver function tests – baseline and 
Day 8.

TQ dose limited to 300mg total dose 
equivalent in pediatric subjects.

2014N207627_03
CONFIDENTIAL
TAF113577
27
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
two adult subjects receiving 1200 mg TQ 
experienced transient elevations in liver 
transaminases. It was concluded that high 
doses of TQ appeared to be associated with 
transient increases in transaminases. However, 
based on data from TAF112582 Part 1 there is 
no safety signal for hepatoxicity for doses of 
600mg and 300mg.  
Keratopathy
No ophthalmological changes were observed in 
preclincial species. 
Reversible vortex keratopathy was observed in 
clinical trials at higher doses and/or longer 
duration of treatment than are being studied 
here. 
Keratopathy was not observed in a limited 
number of adult patients (n=15) who underwent 
ophthalmological exams at 300mg dose in 
TAF112582 Part 1 study.

This risk will be mitigated in other studies 
within the tafenoquine program

Appropriate training will be provided at 
investigator meetings on these potential 
ophthalmological changes
Retinal Toxicity
No ophthalmological changes have been 
observed in preclinical species. Previous clinical 
studies (057, 058 and TAF 106491) have 
included substantive ophthalmic assessments. 
No evidence of retinal toxicity associated with 
TQ was observed in any of the TQ-treated 
subjects in these studies as per conclusion of 
Ophthalmic Advisory board Nov ’09. 
Irreversible retinopathy has been reported with a 
potential combination partner - CQ (and 
hydroxychloroquine). Effects with CQ are dose 
related and have been observed following 
cumulative total doses of >1g base/kg body 
weight. CQ dose used in treatment of P. vivax is 
a total of 25mg/kg over 3 days. Retinopathy 
associated with severe falciparum malaria is 
reported in the literature but rare in vivax.

This risk will be mitigated in other studies 
within the tafenoquine program

Appropriate training will be provided at 
investigator meetings on these potential 
ophthalmological changes

2014N207627_03
CONFIDENTIAL
TAF113577
28
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Renal Function
Transient increases in serum creatinine have 
been observed in clinical studies in adults. A 
renal safety study was conducted and 
concluded that TQ, when given as 200 mg x 3 
days loading dose followed by weekly 200 mg 
dosing for 6 months was non-inferior to placebo 
when comparing mean change from baseline 
glomerular filtration rate.
In TAF112582 study part 1 outliers were 
characterized by isolated transient rises in 
creatinine with rapid recovery and no consistent 
time to onset at a particular dose for the outliers.
A preclinical assessment of inhibition of renal 
transporters has demonstrated that TQ inhibits 
organic cation transporter 2 (OCT2), multidrug 
and toxin extrusion 1 transporter (MATE1) and 
multidrug and toxin extrusion 2K transporter 
(MATE-2K). The changes in serum creatinine 
are thought to be related to this tubular 
transporter interaction.

Conduct renal function testing in the 
proposed pediatric study – baseline and 
Day 8. 

Include drugs that are excreted via these 
transporters in the list of prohibited 
medications.
Nervous system & psychiatric disorders
Phase 3 results in adult patients showed mild to 
moderate self-limiting nervous system & 
psychiatric disorders including dizziness, anxiety 
& insomnia.

Consider excluding patients with a history 
of serious psychiatric disorders such as 
psychosis, depression and suicidal 
ideation.
Use in Pregnancy and Lactation
Preclinical data reported no adverse effects on 
fertility, embryofetal development or on post-
natal survival.
No clinical studies have been conducted in 
humans during pregnancy.  There may be 
concern about risk to a fetus who is G6PDd and 
risk to breastfed infants whose G6PD status 
may be unknown.

Pregnant or lactating women are excluded 
from the study.
Phototoxicity
Pre-clinical studies concluded that there was a 
possibility that TQ was phototoxic.  However, 

Routine AE information will be collected 
and the incidence and frequency of rash 

2014N207627_03
CONFIDENTIAL
TAF113577
29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
this information was superseded by safety data 
collected in clinical trials in which over 4000 
subjects were exposed to TQ, some of them for 
a long time period. The clinical data indicated 
that there was no pattern in incidence of rash 
associated with TQ treatment and this risk is 
considered to be low.
will continue to be reviewed for signs of 
photoirritancy in this patient population.
Study Procedures
Volume of Blood Draws from Pediatric Subjects
A plasma assay has been used to analyze PK 
samples (preclinical and clinical) throughout the 
development of TQ.  Blood collection to obtain 
the plasma has been via venipuncture.

Small volume venous sampling (≤1 mL 
whole blood) and/or microsampling (70 
µL whole blood) will be employed to 
minimize volume of blood taken from 
subjects.

2014N207627_03
CONFIDENTIAL
TAF113577
30
4.6.2.
Benefit Assessment
In the absence of radical cure treatment, a percentage of patients with P. vivax malaria 
will relapse due to the liver being infected with hypnozoites (the dormant form of the 
parasite).  P. vivax malaria is most prevalent primarily in Asia, Asia-Pacific and Latin 
American countries and frequency of relapse rates may impact product use.  Relapse rates 
vary with strain and are difficult to measure due to confounding by re-infection. The 
WHO has generalized relapse rates in the following countries as: India (15-20%), 
Indonesia (30%) and South East Asia (50-60%).  P. vivax can cause a debilitating fever 
and, as it preferentially invades reticulocytes as well as causing bystander hemolysis, 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, especially in children. Consequences are loss of work or school days (e.g., 5.4 
days school absenteeism per episode) and hospitalization (especially children) due to 
vomiting, dehydration and asymptomatic anemia (resulting in transfusion). 
Due to its long half life, TQ can be administered as a single oral dose and is therefore a 
more convenient treatment regimen with the potential to improve patient compliance. 
Improved compliance could also lead to improved clinical outcomes for patients with 
P. vivax malaria by further reducing recurrence rates.
4.6.3.
Overall Benefit:Risk Conclusion
Tafenoquine is being developed with the aim of a benefit:risk profile which is at least as 
good as the current gold standard therapy PQ. Our intent is to evaluate whether improved 
compliance could also lead to improved clinical outcomes for patients. Tafenoquine 
should have no clinically significant side effects that will restrict its use as a first line 
agent in treatment of P. vivax malaria when used in combination with a G6PD test and 
recommended therapies to treat the blood stages of infection.  With specific regard to this 
study, the overall benefit:risk is favorable to all subjects, given that all are receiving 
active treatment.
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 Tafenoquine Investigator 
Brochure [GlaxoSmithKline Document Number GM2007/00152/08], and the locally-
approved label for chloroquine.
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.

2014N207627_03
CONFIDENTIAL
TAF113577
31
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
[1] AGE
1. Subject is ≥2 years to <16 years of age at the time of signing of the assent and/or 
informed consent. An additional cohort of subjects aged ≥6 months to <2 years may
be recruited following the first interim analysis.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. The subject is of Thai nationality (applicable only to subjects at center
).
3. The subject has a positive malarial smear for P. vivax.
4. The subject has a history of fever within 48 hours prior to enrollment.
5. The subject has a glucose 6-phosphate dehydrogenase (G6PD) value (measured by a 
quantitative spectrophotometric phenotype assay) ≥70% of the site median value for 
G6PD normal adult males.
6. The subject has a screening hemoglobin (Hb) value ≥8 g/dL.
[3] WEIGHT
7. The subject has a body weight ≥5 kg.
[4] SEX
8. Males and females are eligible to enter the study.  A female is eligible to enter and 
participate in this study if she is non-pregnant, non-lactating and if she is of:
a.
Non-childbearing potential (i.e., premenstrual); or,
b. Child-bearing potential, has a negative pregnancy test at screening, and agrees 
to comply with one of the following during the treatment stage of the study 
and for a period of 90 days after stopping study medication:
i. Use of oral contraceptive, either combined or progestogen alone used in 
conjunction with double barrier method as defined below.
ii. Use of an intrauterine device with a documented failure rate of <1% per 
year.
iii. Use of depo provera injection
iv. Double barrier method consisting of spermicide with either condom or 
diaphragm
v. Male partner who is sterile prior to the female subject’s entry into the 
study and is the sole sexual partner for that female.
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
32
vi. Complete abstinence from intercourse for 2 weeks prior to administration 
of study medication, throughout the study and for a period of 90 days 
after stopping study medication.
[5] INFORMED CONSENT
9. The subject and/or the subject’s parent(s)/legal guardian(s) agree to G6PD genotyping 
in the context of a subsequent hemolytic anemia adverse event.
10. The subject and parent(s)/legal guardian(s) are willing and able to comply with the 
study protocol.
11. In accordance with regional/local laws and regulations, the parent(s)/legal guardian(s) 
has given written informed, dated consent; and the subject has given written assent, if 
applicable, to participate in the study.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL)
1. The subject has a mixed malaria infection (identified by a malarial smear or rapid 
diagnostic test).
2. The subject has a condition that may affect absorption of study medication, such as 
severe vomiting (no food or inability to take food during the previous 8 hours).
3. The subject has a liver ALT >2 time the upper limit of normal (ULN).
4. The subject has a clinically significant concurrent illness (e.g., pneumonia, 
meningitis, septicaemia, coagulopathy, severe hemorrhage), pre-existing condition 
(e.g., renal disease, malignancy, malnutrition, known pre-existing HIV), febrile 
convulsions prior to consent, or clinical signs and symptoms of severe cardiovascular 
disease (e.g., congenital heart disease).
5. The subject has a history of porphyria, psoriasis, or epilepsy.
[2] CONCOMITANT MEDICATIONS
6. The subject has taken anti-malarials (e.g., artemisinin-based combination therapies, 
mefloquine, primaquine, or any other 4- or 8-aminoquinoline) or drugs with 
antimalarial activity within 30 days prior to study entry.
7. The subject has received treatment with any investigational drug within 30 days of 
study entry, or within 5 half-lives, whichever is longer.
8. The subject has taken or will likely require during the study the use of:

histamine-2 blockers

antacids

anti-diabetic drugs of the biguanide class (i.e., phenformin, buformin)

2014N207627_03
CONFIDENTIAL
TAF113577
33

anti-arrhythmic agents dofetilide, procainamide, pilsicainide 
9. The subject has a serum creatinine above the upper limit of normal and is currently 
taking metformin.
[3]  CONTRAINDICATIONS 
10. The subject has a history of allergy or intolerance to chloroquine, mefloquine, 
tafenoquine, primaquine, or to any other 4- or 8-aminoquinoline.
11. The subject has previously enrolled in this study.
[4] DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
12. The subject has severe P. vivax malaria as defined by WHO criteria (see Appendix 6, 
Section 12.6).
13. The subject has any retinal abnormality in the macular region, either pre-existing or 
identified at the baseline visit (Center 
 only).
5.3.
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but
are never subsequently dosed. 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 will be reported including Demography, Screen Failure details 
(including G6PD results), Eligibility Criteria, and any Serious Adverse Events.
5.4.
Withdrawal/Stopping Criteria

Adverse event

Protocol deviation

Study closed/terminated

Loss to follow-up

Consent/Assent withdrawal

Subject or investigator non-compliance

At the request of the subject, investigator, or sponsor

Pregnancy
A subject or their parent/legal guardian(s) may voluntarily discontinue participation in 
this study at any time. The investigator may also, at their discretion, discontinue the 
subject from participating in this study at any time.  A subject is considered to be 
withdrawn prematurely from the study if they do not complete the Day 120 assessment.  
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
34
A subject may withdraw or be prematurely withdrawn for any of the reasons presented in 
the list above. If a subject withdraws consent the site should offer to conduct safety 
assessments through Day 120.
Subjects and/or their parent/legal guardian 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 must make every effort to perform the study evaluations as 
specified for the Withdrawal visit as applicable.
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 parent/legal guardian of the subject and re-
schedule the missed visit as soon as possible. 

The site must counsel the subject and/or parent/legal guardian 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 and parent/legal guardian
(where possible, three 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 Increased Monitoring 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
Figure 4 below presents the algorithm for evaluating and monitoring liver chemistry data.  
It should be noted that, given TQ is administered as a single dose, there will be no 
opportunity to discontinue study treatment.  However, liver event follow-up assessments 
would still apply if liver increased monitoring criteria are met.

2014N207627_03
CONFIDENTIAL
TAF113577
35
Figure 4
Phase II 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≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
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*
For further details, refer to the Liver Safety Required Actions and Follow up Assessments 
Section in Appendix 2 (Section 12.2).
5.4.2.
QTc Stopping Criteria
QTc stopping criteria will not be employed in this study.
A TQ definitive QTc study, Study TAF114582 [GlaxoSmithKline Document Number 
2012N145359_00], demonstrated a lack of effect on QTcF elongation at adult clinical 
doses (300 and 600mg). CQ does have a propensity to cause QTc prolongation; however, 
in TQ drug-drug interaction (DDI) Study TAF106491 [GlaxoSmithKline Document 
Number WD2009/01503/00] no difference was seen in PK and QTcF changes between 
CQ/TQ groups with all groups showing the same pattern of elongation as with CQ alone, 
for both frequency and magnitude of changes.
The DDI study concluded that there was no trend over time for increased QTc intervals in 
those treated with TQ alone.  Therefore, no ECG monitoring is planned for this study.
5.5.
Subject and Study Completion
A completed subject is one who attends all treatment and follow-up visits.
The end of the study is defined as the last subject’s last visit.

2014N207627_03
CONFIDENTIAL
TAF113577
36
6.
STUDY TREATMENT
Chloroquine will be provided to subjects outside the parameters of this study, and 
according to local/national treatment guidelines.  Potential subjects who are slide-positive 
for P. vivax will begin CQ treatment and sites will have 48 hours to obtain full subject 
consent and assent, as applicable.  Consented subjects will be screened, randomized and 
dosed with TQ on Day 1.  Two formulations of TQ will be made available; a 150 mg 
film-coated tablet (TQ adult tablet), and a 50mg fast-dispersing film coated tablet (TQ 
pediatric tablet; Table 1).  Instructions for preparation and administration of the TQ 
formulations will be provided in the SRM.
Table 1
Study Treatments
Study Treatment
Product name:
tafenoquine
adult tablet
tafenoquine pediatric tablet
Formulation description:
Film-coated tablet
Fast-dispersing film coated 
tablet
Dosage form:
Tablet
Tablet
Unit dose strength(s)/Dosage 
level(s):
150 mg
50 mg
Route of Administration:
Oral
Oral
Dosing instructions:
Single dose on Day 1
Single dose on Day 1
Physical description:
Dark pink capsule-shaped
Round normal concave-
shaped
Method for individualizing dosage:
Subject weight
Subject weight
6.1.
Treatment Assignment
This is an open-label, single arm study, and all subjects will receive CQ and TQ.  
Subjects will be dosed based on weight, with the goal to achieve a median TQ exposure 
of 96 µg.h/mL, the median exposure observed in adults following administration of a 300 
mg dose of TQ.  The TQ doses presented in Table 2 below were selected using a 
population PK model based on adult data and incorporation of allometric scaling.

2014N207627_03
CONFIDENTIAL
TAF113577
37
Table 2
Tafenoquine Dosing
Weights
Tafenoquine Dosea
Dosing Regimen
>45 kg
300 mg
2 × 150 mg
or
6 × 50 mg
>40–≤45 kg
300 mg
2 × 150 mg
or
6 × 50 mg
>35–≤40kg
300 mg
2 × 150 mg
or
6 × 50 mg
>30–≤35kg
200 mg
4 × 50 mg
>25–≤30 kg
200 mg
4 × 50 mg
>20–≤25 kg
200 mg
4 × 50 mg
>15–≤20 kg
100 mg
2 × 50 mg
>10–≤15 kg
100 mg
2 × 50 mg
≥5–≤10 kg
50 mg
1 × 50 mg
a.  The TQ dose is based on achieving a target AUC(0–∞) of 96 μg.h/ml.
The single dose of TQ will be administered at the investigator site.  Subjects >35 kg have 
the choice of taking the TQ adult tablet or the TQ pediatric tablet.  All study medication 
should be administered with food. If the subject vomits within 1 hour following dosing, a 
repeat dose should be given. If a subject sequentially vomits two doses of study 
medication he/she will be considered intolerant to study medication. These subjects will 
be withdrawn from study medication and be given appropriate rescue medication as 
outlined in Section 6.9.1.2.
6.2.
Planned Dose Adjustments
The TQ doses and weight banding may be refined after a planned interim analysis of at 
least 16 subjects and based on safety and predicted exposures for the pediatric population. 
The observed pediatric exposure data will be compared with corresponding adult 
exposures that have been shown to be efficacious in order to help inform the need for any 
dose adjustments.
6.3.
Blinding
This will be an open-label study and investigators have direct access to the subject’s 
individual study treatment. 

2014N207627_03
CONFIDENTIAL
TAF113577
38
6.4.
Packaging and Labeling
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 Study Reference Manual (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) or 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.
Precautions will be taken to avoid direct contact with the study treatment.  A Material 
Safety Data Sheet (MSDS) describing occupational hazards and recommended handling 
precautions will be provided to the investigator. In the case of unintentional occupational 
exposure notify the monitor, Medical Monitor and/or GSK study contact.
6.6.
Compliance with Study Treatment Administration
Compliance with TQ will be assessed in all subjects by directly observing the taking of 
medication while at the investigator center.  Despite being administered outside of this 
study, CQ compliance should be monitored by the site and recorded in the subject’s 
source documentation.
6.7.
Treatment of Study Treatment Overdose
An overdose for this study will be considered as any dose of study medication that is 
more than the planned dose on each dosing occasion.  
Tafenoquine
No specific antidote for tafenoquine has been identified.  In the event that overdose or 
toxicity does occur, individuals should be managed with appropriate supportive measures 

2014N207627_03
CONFIDENTIAL
TAF113577
39
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.
Chloroquine 
No specific antidote for chloroquine 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.
Drowsiness, blurred vision, diplopia, blindness, tinnitus, convulsions and coma can occur 
with overdose. Chloroquine is a known cardiovascular toxin thus cardiac monitoring and 
resuscitation facilities are essential. Thus in addition to dizziness, nausea, vomiting, 
diarrhea and headache hypotension, cardiogenic shock and cardiac arrest may occur. The 
12 lead ECG may demonstrate decreased T waves, widening of the QRS complex, which 
may lead to ventricular tachycardia and/or fibrillation.
In the event of an overdose the investigator should:
1.
contact the Medical Monitor immediately
2.
closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until TQ and/or CQ can no longer be detected 
systemically (at least 90 days for TQ and 28 days for CQ)
3.
document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
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
There is no extension study planned and thus no post study treatment will be offered 
except for subjects diagnosed with malaria at the end of the study who will receive rescue 
medication outlined in Section 6.9.1.2.
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.

2014N207627_03
CONFIDENTIAL
TAF113577
40
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 during the study but administration time must be 
recorded in the eCRF. Allowable antibiotics are penicillins, cephalosporins, carbapenems 
and aminoglycosides.
All concomitant medications (prescription and non-prescription) taken during the study 
should be recorded in the eCRF. The minimum requirement is drug name and date of 
administration.
6.9.1.2.
Rescue Medication
Subjects requiring rescue medication will be given appropriate medication in accordance 
with site (local) or national treatment guidelines for P. vivax malaria or; e.g., 
P. falciparum malaria, whichever is applicable.  Subjects offered rescue medication 
should be followed up for safety assessment through the Day 120 visit to ensure
resolution of the malaria infection.  Details of rescue medication including reason for the 
rescue medication offered (e.g., withdrawal from study, treatment failure) should be 
recorded in the eCRF.
6.9.2.
Prohibited Medications and Non-Drug Therapies
The following drugs are prohibited for use from 30 days prior to entry in the study 
through Day 120:

Anti-malarials and other medicines with known anti-malarial activity (with the 
exception of CQ being given to potential subjects prior to randomization).
Results from an in vitro renal transporters study showed that TQ 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 prohibited for a period of 21 days immediately 
following the blinded dose of TQ.

Anti-diabetic drugs of the biguanide class:
o
Phenformin
o
Buformin

Anti-arrhythmic drugs:
o
Dofetilide
o
Procainamide
o
Pilsicainide

2014N207627_03
CONFIDENTIAL
TAF113577
41
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 is to be avoided. However, if 
taken this should be recorded in the eCRF under concomitant medication. 
See Appendix 7 in Section 12.7 for a non-exhaustive list of prohibited medicines for 
guidance.

2014N207627_03
CONFIDENTIAL
TAF113577
42
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).

2014N207627_03
CONFIDENTIAL
TAF113577
43
7.1.
Time and Events Table
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence Visita
Withdrawal Visitb
Day 1c
Day 3
day 8 
Day 15 
Day 29
Day 60 
Day 90
Day 120
Recurrence
Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d
-/+10d
-/+10d
-/+10d
Informed Consent 
Process 
X
Demographic Information 
X
Initial History Only d
X
Physician Assess. 
Malaria Signs & 
Symptoms 
X
Inclusion/Exclusion 
Criteria 
X
Efficacy Assessments 
Parasitological 
Assessment (blood 
smear) 
X
X
X
X
X
X
X
X
Plasmodium PCR 
genotyping
X
X
Safety Assessments 
Review Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
X
Vital Signs e,f
X
X
X
X
X
X
X
Brief Physical 
Examination f
X
X
X
X
X
X
X
X
X
Adverse Events 
Assessment g
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events h
X
X
X
X
X
X
X
X
X
X
G6PD (phenotyping) i
X
G6PD (genotyping)
X j
Ophthalmological Exam 
(qualified site only)
X
X
X

2014N207627_03
CONFIDENTIAL
TAF113577
44
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence Visita
Withdrawal Visitb
Day 1c
Day 3
day 8 
Day 15 
Day 29
Day 60 
Day 90
Day 120
Recurrence
Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d
-/+10d
-/+10d
-/+10d
Laboratory Assessments 
Hematology k
X
X
X
Clinical Chemistry l
X
X
Methemoglobin 
X
X
Pregnancy Test m
X
X
X
X
X
X
Pharmacokinetic Assessments 
Pharmacokinetic
Sampling
Xn
Xo
Xo
X
X
Investigational Product 
Dispense Open Label 
tafenoquine
X
Treatment Compliance 
Int. - Invest. 
X
IVRS Registration 
X

2014N207627_03
CONFIDENTIAL
TAF113577
45
a.
Subjects who have a recurrence will continue to be monitored for safety and efficacy at all scheduled visits through day 120. Recurrence is defined by a positive blood smear 
with or without vivax malaria symptoms.
b.
If a subject withdraws, the site should offer to conduct safety assessments through Day 120.
c.
Visit Day 1 includes all screening procedures and treatment with tafenoquine.
d.
Includes medical, disease and therapy histories.
e.
Vital signs include height and weight (screening only), blood pressure, temperature, heart rate and respiratory rate.  Refer to Section 7.5.4 for additional details.
f.
At Center
, Vital Signs and Brief Physical Examination will be performed at every visit.
g.
Adverse events are recorded from the time of the first dose of study medication.
h.
Serious adverse events are recorded from the time of consent in order to fulfil international regulatory requirements.
i.
G6PD phenotyping to be performed by quantitative spectrophotometric analysis. One or more G6PD rapid point of care tests may be performed at baseline (Day 1) only.
j.
A blood sample for G6PD genotyping will be collected only from subjects who experience a SAE due to hemoglobin decline.  Subjects with hemoglobin decline should 
continue to attend all visits through Day 120 to monitor Hb status.
k.
Hematology includes hemoglobin, hematocrit, red blood cell/white blood cell/platelet counts, mean cell volume, white blood cell differential and reticulocyte count.
l.
Clinical Chemistry includes CPK, BUN, serum creatinine, total and indirect bilirubin and liver clinical chemistry.
m.
Pregnancy testing is only for females of child-bearing potential. Use a urine pregnancy test that is routinely used at the site with a test sensitivity for human chorionic 
gonadotropin (hCG) level ≤ 25 mIU/mL.
n.
Day 3 PK sample must be taken 24-96 hours post TQ dose.
o.
Once full PK sampling has completed, remaining enrolled subjects will provide two PK samples at Day 15 and Day 29.
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
46
7.2.
Screening and Critical Baseline Assessments
Study site personnel must obtain written, dated informed consent from the parent(s) or 
legal guardian(s) of the subject, as well as assent from the subject, if applicable, prior to 
the initiation of any screening procedures. 
The following clinical and laboratory assessments will be conducted at screening (prior to 
the dose of TQ) as detailed in the Time and Events (Section 7.1):

Demographic data will be collected to include details of date of birth, gender, race 
and ethnicity

Medical history will be collected, including medical, disease and therapy 
histories; and, cardiovascular history and associated risk factors

A brief physical examination will be conducted including:
o
Cardiovascular examination
o
Abdominal examination including assessment of splenomegaly
o
Respiratory examination

Vital signs will be assessed. These include height, weight, temperature (oral, 
axillary or tympanic), heart rate, respiratory rate, systolic and diastolic blood 
pressure

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 rigors, 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 
the presence of Plasmodium species asexual parasites and gametocytes (see 
Section 7.4 and the SRM for further details).  Given the subject may have already 
received one or more doses of CQ, the parasitological assessment at Day 1 may 
be negative.

A blood sample will be collected on filter paper and stored for future plasmodium 
genotyping analysis.

Current and prior medications will be reviewed including any anti-malarial 
medication that has been used.

G6PD status will be assessed using quantitative spectrophotometric analysis 
(further instructions can be found in the SRM). The quantitative analysis will be 
used to determine the subject's eligibility for the study. One or more G6PD rapid 
point of care tests may also be performed at baseline.

2014N207627_03
CONFIDENTIAL
TAF113577
47
o
Periodic external quality assurance testing will be performed to ensure 
high quality G6PD assay data.  Procedures for quality assurance will be 
described in detail in the SRM.

The following laboratory assessments will be performed by local laboratories at 
screening and prior to dosing TQ:
o
Hematology analysis will include: Hb, hematocrit (Hct), red blood cells 
(RBC), white blood cells (WBC), mean cell volume (MCV), differentiated 
WBC, platelets and reticulocytes (for conversion to absolute).
o
Clinical chemistry evaluations will include: blood urea nitrogen (BUN), 
serum creatinine, total and indirect bilirubin and liver chemistries (alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP) and creatine phosphokinase (CPK)).

A urine pregnancy test will be performed on females of childbearing potential that 
is routinely used at the site, provided the test has sensitivity for human chorionic 
gonadotropin (hCG) of ≤ 25 mIU/mL.

Methemoglobin levels will be assessed using a non-invasive signal extraction CO-
Oximeter handheld machine.

Center
 (Manuas, Brazil) only will perform the following ophthalmic 
assessments prior to randomization:
o
Visual acuity will be assessed by standard methods
o
Slit lamp examination of the cornea to evaluate for vortex keratopathy 
o
Retinal digital imaging (color photographs, fundus autofluorescence and 
OCT)
7.3.
Unscheduled Visits
Subjects who have one or more visits outside the allowable time window defined for each 
scheduled visit will undergo all the procedures and assessments described in the Time 
and Events Table (Section 7.1) with the exception of assessments performed only at 
screening and the PK assessments. Subjects should be able and/or encouraged to return to 
the clinic for unscheduled visits at anytime during the 120-day study period. In addition, 
subjects must return to the clinic anytime they are experiencing a recurrence of malaria 
symptoms.
7.4.
Efficacy
The study is not powered to produce precise estimates of efficacy. However, the 
estimates of recurrence-free efficacy at Day 120 will be reviewed at each interim and at 
the final analysis of the study. The doses in the pediatric study (Section 6.1) have been 
selected to match the exposure following an efficacious dose of TQ (300 mg) in adults, 
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
48
and are therefore expected to provide similar levels of efficacy in the pediatric 
population.
Parasitology
Microscope blood slides will be prepared pre-dose at screening on Day 1 to confirm the 
presence (positive or negative) of P. vivax malaria (asexual parasites and gametocytes), 
and on Day 8 to confirm the parasite has cleared.  Blood films will also be prepared 
during follow-up on Days 29, 60, 90 and 120.  In addition, blood films should be 
obtained at the recurrence visit or withdrawal visit as applicable. At each time point two 
thick and one thin film slides should be prepared on separate slides and one additional 
unstained slide with both thick and thin films retained for quality control.  For detailed 
instructions on the methodology for staining please refer to the SRM.
Parasite Genotyping
Two drops of peripheral blood will be collected onto pre-printed filter paper for 
subsequent DNA extraction and genetic analysis of Plasmodium species on all subjects 
on Day 1, prior to TQ dose and; if necessary, at the time of the first recurrence.
Analysis 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.
External quality control
External quality control of slide readings will be conducted by an independent laboratory. 
They will examine a proportion of slides from each study site. The procedure for quality 
control will be described in the SRM.
7.5.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional details on specific assessments are provided below.  Safety 
information will be reviewed on a monthly basis by a GSK/MMV safety review team.
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 12.3.1 and Section
12.3.2).  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
Hemoglobin decreases of ≥30% of >3 g/dL from baseline; or, an overall drop in Hb 
below 6.0 g/dL in the first 15 days of the study should be reported as an SAE.

2014N207627_03
CONFIDENTIAL
TAF113577
49
7.5.1.2.
Time period and Frequency for collecting AE and SAE information

AEs will be collected from the start of Study Treatment and SAEs will be collected 
from the time of consent.  AEs and SAEs will continue to be collected 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 may 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 
Appendix 3 (Section 12.3.4 and Section 12.3.6).

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 
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 
Appendix 3 (Section 12.3).
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 and/or the parent/legal guardian is the 
preferred method to inquire about AE occurrence.  Appropriate questions include:

“How does your child seem to feel?”

“Has your child had any (other) medical problems or seem to act differently in any 
way since his/her last visit/contact?”

“Has your child needed to take any medicines, other than those provided in this 
study, since his/her 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 
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 12.3.5).

2014N207627_03
CONFIDENTIAL
TAF113577
50
7.5.1.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 (Section 12.3.3) 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.
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 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/recurrence 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.”

2014N207627_03
CONFIDENTIAL
TAF113577
51
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 12.3.6) 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 of SAEs and non-serious AEs 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 
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.
Pregnancy
Information on the occurrence of new pregnancies will be collected over the period 
starting at screening (Day 1) and ending at the Day 120 follow-up assessment.  Only 
those pregnancies that occur following the first dose of study medication will be reported 
to GSK.  Follow-up information will be collected for pregnancies occurring throughout 
the study.
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4
(Section 12.4).
7.5.3.
Physical Exams
Physical examinations will be performed during the treatment period (Day 1), the follow-
up period on Days 3, 8, 29, 60, 90 and 120 and if there is a relapse or premature 
withdrawal visit.  (At center 
 physical examinations are required at all follow-up 
visits.)  When conducting the exam, please note:

A brief physical examination will include, at a minimum, assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen).
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
52

Investigators should pay special attention to clinical signs related to previous serious 
illnesses
7.5.4.
Vital Signs
Vital signs will be performed on the day of TQ treatment (Day 1), immediately prior to 
pharmacokinetic (PK) measurements, and if there is a recurrence or premature 
withdrawal visit.  (At center
 vital signs are to be performed at all follow-up 
visits.)  Vital signs include height and weight (screening only), blood pressure, 
temperature, heart rate and respiratory rate.
7.5.5.
Concomitant Medications
Information on concomitant medications will be collected at all scheduled treatment and 
follow-up visits, and if there is a recurrence or premature withdrawal visit.
7.5.6.
Clinical Safety Laboratory Assessments
Clinical chemistry and hematology samples will be analyzed by local laboratories.  All 
protocol required laboratory assessments must be conducted in accordance with the 
Laboratory Manual, and Protocol Time and Events Schedule (Section 7.1).
Hematology tests will be conducted on the Day 1, 3 and 8 visits.  Clinical chemistry tests 
will be conducted on the Day 1 and Day 8 visits.  In addition, laboratory tests may be 
conducted at any time during the study, as warranted by the condition of the subject and 
at the investigator’s discretion.  All laboratory results that are considered clinically 
significant should be recorded as AEs.  The panel of tests to be analyzed are detailed 
below in Table 3 and Table 4.  All laboratory data will be used for the purpose of safety 
analysis and reporting for this study.
Table 3
Hematology Tests
Hemoglobin
Hematocrit
Platelets
MCV
WBC
RBC
Reticulocyte
WBC Differential
Table 4
Clinical Chemistry Tests
Creatinine
BUN
Total bilirubin
Indirect bilirubin
AST
ALT
ALP
CPK
Hemoglobin and/or Hct measurements that deviate substantially from previous readings 
should be immediately repeated via venous sampling.  If a significant drop in Hb or Hct 
is observed, all additional hematology and clinical chemistry labs should be obtained 
immediately.  In addition, a blood sample should be drawn for G6PD genotyping (see 
Section 7.7).
Methemoglobin status will be assessed at Day 1 and Day 8.  Subjects with anemia may 
have symptomatic methemoglobinemia (e.g., blue discoloration of skin and lips, 
shortness of breath) at levels lower than subjects with normal hemoglobin levels 
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
53
(symptoms typically do NOT occur with MetHb values <20% in subjects with normal 
hemoglobin levels).
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be 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.
7.5.7.
Ophthalmic Assessments (Center 
Only)
Ophthalmic assessments will be performed at Center 
(Manaus, Brazil) at 
screening and prior to randomization, at Day 120 and at the withdrawal visit, if 
applicable. The Principal Investigator and site ophthalmologist will determine if the child 
is able to comply with the assessments, based on their malaria status and ability to 
reasonably cooperate with the assessments.  Subjects who do not complete the
ophthalmic examination at baseline, including interpretable retinal imaging, should not 
complete ophthalmic exams at follow-up or withdrawal.  If a subject completes a portion 
of the ophthalmic exams at baseline, only those same exams should be completed at 
follow-up.
7.6.
Pharmacokinetics
Blood samples for PK analysis of TQ will be collected at the time points indicated in the 
Time and Events Table (Section 7.1).  The Day 3 sample should be taken 24-96 hours 
after TQ dosing and a concurrent set of vital signs should also be obtained.  Sample(s) of 
1 mL blood will be collected (via venipuncture) into blood tubes and/or 70 µL blood (via 
finger or heel prick) will be collected into capillary tubes. Each sample will be 
centrifuged to produce plasma and the plasma transferred into a tube for shipping to a 
central laboratory for analysis.  The actual date and time of each blood sample collection 
will be recorded. The timing and collection of PK samples may be altered and/or PK
samples may be obtained at additional time points to ensure sufficient PK monitoring. In 
addition, concentrations of CQ will be determined.  Details of the PK blood sample 
collection (both venipuncture and microsampling), processing, storage and shipping 
procedures are provided in the SRM.
Evaluation of correlation between venous and microsampling data will be made at each 
interim analysis. If microsampling data is deemed adequately representative of venous 
blood samples, any further PK sampling will switch predominantly to microsampling. 
However, up to two out of the four planned PK samples per subject may still be collected 
by both venous and microsampling methods. This will be as a back-up  given the primary 
objective of this study is to adequately characterize the PK of TQ in the pediatric 
population. The PK data hence is of critical value. In the event that microsampling data is 
deemed an inadequate representation of venous samples, any further PK sampling will be 
only by venous sampling. 
The sampling strategy of four PK samples per subject is designed to be sparse but 
adequately characterize the PK of TQ in the pediatric population. These four samples per 
subject will be reduced to two samples per subject at the earliest interim analysis once 
reliable characterization of TQ PK has been achieved.
PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
54
7.6.1.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SRM.  Concentrations of 
TQ will be determined using approved analytical methodology. Raw data will be 
archived at the bioanalytical site (detailed in the SRM).
7.7.
Genetics
A 1 mL blood sample will be obtained from all subjects who experience hemoglobin 
decline during the study (see Section 7.5.6).  Genetic research will be limited to G6PD 
genotyping.

2014N207627_03
CONFIDENTIAL
TAF113577
55
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 and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

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
There are no hypotheses tested in this study.  The study is designed to characterize the 
TQ exposures in pediatric subjects.
9.2.
Sample Size Considerations
A minimum of 16 subjects are required to assess the clearance and hence exposures of 
TQ in pediatric subjects. However, a total of 60 subjects based on feasibility is required 
to assess overall safety in the pediatric population.
9.2.1.
Sample Size Assumptions
A population PK modelling and simulations-based approach was utilized to support 
appropriate study sample size and PK sampling times for the proposed population PK 
bridging study.  Based on these simulations, a sample size of 16 subjects and a sparse 
sampling scheme of four time points per subject (Day 3 (24 to 96 hours post TQ dose), 
Day 15, Day 29, and Day 60) are considered sufficient for the evaluation of the primary 
PK objective of estimating exposure within each weight band in pediatric subjects aged 
≥2 years to <16 years.
Assuming that the rates of absorption and distribution in this population will be similar to 
the adult population, this sparse sampling scheme allows for adequate estimation of TQ 
clearance (coefficient of variation < 40% within each weight band as per regulatory 
recommendation) and thereby exposure within each weight band while obtaining a 
minimum number of samples for each subject (Appendix 9, Section 12.9).

2014N207627_03
CONFIDENTIAL
TAF113577
56
9.2.2.
Sample Size Sensitivity
Population PK simulations were performed to assess the adequacy of study sample sizes 
of 4, 8, 16, 32, 64 subjects and different sampling schemes to determine exposure with 
sufficient precision. With sparse sampling of 3-4 time points per subject, a minimum of 
n=16 subjects are deemed adequate. However, if the variability is higher than expected at 
the interim analysis, the PK sampling may be continued with a larger sample size to 
provide exposure assessments across weight bands with sufficient precision (Appendix 9, 
Section 12.9).
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
9.3.1.
Key Analysis Populations
Safety Population: 
This population includes all subjects who received at least one dose of study medication. 
Primary PK Population:
This population will include all subjects with at least one PK sample taken at Days 3, 15, 
29 and 60.  The primary PK analysis to evaluate TQ exposure will be carried out using 
this population.
9.3.2.
Interim Analysis
Up to two interim analyses have been planned so that serial but sparse (i.e., 4 PK 
timepoints) PK sampling may be stopped at the earliest opportunity.  The first interim 
analysis will take place after a total of at least 16 subjects in the main cohort have PK 
evaluable data or 12 months post study initiation, whichever comes first. The second 
interim analysis will take place after a total of at least 32 subjects in the main cohort have 
evaluable PK data or at 24 months post study initiation, whichever comes first. The 
second interim analysis will take place only if serial but sparse PK sampling is continued 
after the first interim analysis.
At every interim analysis, the 95% prediction interval of AUCs based on the simulation 
with the population pharmacokinetic model will be generated for the mid-point of each 
weight band (at a population level). The population PK model predicted individual 
clearance estimates will be utilized to calculate exposure [AUC(0-∞) = Dose/CL]. If this 
interval lies within the 55-162 µg.hr/mL for the mid-point of each weight band, serial 
(but sparse) sampling can be stopped for any subjects enrolled further. These bounds 
were chosen because 95% of adult subjects dosed with the efficacious dose of 300 mg 
TQ in part 1 of Study TAF112582 had an AUC that fell within this range and the lower 
bound is consistent with the clinically relevant breakpoint of 56.4 μg.h/mL for the adult 

2014N207627_03
CONFIDENTIAL
TAF113577
57
Phase IIb data (TAF112582 Part1). Recruitment will continue for safety data 
accumulation with these subjects having a PK assessment at two timepoints.
If it is found that due to insufficient number of children being enrolled in the lowest 
weight band(s) the prediction intervals are wider in that lowest weight band, then further 
serial (but sparse) sampling may be limited to the children being enrolled in the lowest 
weight band. The analyses will then be repeated after next set of 4 subjects and so on 
until the 95% prediction intervals based on the population PK model simulations for that 
weight band are within the targeted 55-162 µg.hr/mL. Additionally, based on the 
available data post the two planned interim analyses, up to two samples will be collected 
in all children enrolled to provide data for the final population PK analysis of TQ to be 
conducted at the end of the study.
Although the volume of blood required for PK sampling is expected to be small, this 
study assessment does not form part of the routine standard-of-care for vivax malaria. It 
is therefore important that serial PK sampling not continue past the point when sufficient 
data have been collected to answer the primary study question. Recruitment to the 
additional cohort of infants aged ≥6 months to <2 years may begin following completion 
of the first interim analysis.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
The primary population PK model based analysis to be performed at the end of the study 
will borrow some information from the adult model. The sparse sampling in pediatric 
subjects is insufficient to independently characterize the absorption phase. Consequently 
the information about absorption from the adult model will be used as prior information 
to feed into the pediatric PK model with the assumption that the absorption processes are 
similar in adults and pediatric subjects. Similarly, other information from the adult PK 
model may also be borrowed in the pediatric model (e.g., distribution). The pediatric 
population PK model will aim to reliably estimate the TQ clearance and thus the 
exposures in the pediatric population [AUC(0-∞) = Dose/CL]. If data permit, other PK 
parameters such as apparent volume of distribution may also be estimated based on 
pediatric data; otherwise, the information will be borrowed from available adult data.
Such model based analyses utilizing prior information from the adult model may be 
implemented using one of the various options available within routinely used population 
PK software such as NONMEM [Beal, 2013] (ICON PLC, USA). The exposures in 
pediatric subjects across various weight bands will be simulated based on the population 
PK model developed from the pediatric PK data. The doses that provide target median 
exposures of 96 µg.hr/mL in each weight band with relevant precision (see Section 9.3.2) 
will be estimated using the population PK model. The details of the approach will be 
described in the study reporting and analysis plan.
The final analysis of the data will include modeling and simulation activity in order to 
provide dosing recommendations for pediatric subjects across different weight bands. 
The weight bands and doses may or may not be similar to the weight bands and doses 
currently proposed in the study. The final recommended dosing schedule across any 

2014N207627_03
CONFIDENTIAL
TAF113577
58
weight band will aim to provide the average target exposure of 96 µg.hr/mL and will take 
into account the safety and efficacy data from the pediatric study.
9.4.2.
Secondary Analyses
The overall safety and particularly of key endpoints such as gastrointestinal tolerability, 
clinically relevant drops in hemoglobin and incidence of AEs will be assessed.  The 
ophthalmic assessments of visual acuity, keratopathy and retinopathy will be 
summarized.
The recurrence-free efficacy at 4 months will be estimated at the interim and final 
analyses.  The targeted exposure in the pediatric study population is expected to match 
the high level of recurrence free efficacy observed in adults. Although there is no control 
group to compare the background recurrence rates, the overall estimate of recurrence 
rates will help compare the exposure-efficacy response in this study to the observed 
response in the efficacy studies in adults.
If data has been acquired in infants aged ≥6 months to <2 years, it will be included in the 
main PK model and will contribute to the overall assessment of TQ exposure by weight 
band and dose setting in this age band.
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 initiation of a site, 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

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

2014N207627_03
CONFIDENTIAL
TAF113577
59

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.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors 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 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 
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 

2014N207627_03
CONFIDENTIAL
TAF113577
60
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. For multicenter studies, this can occur at one or more or at all sites.  

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 
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.

2014N207627_03
CONFIDENTIAL
TAF113577
61

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements. 

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.
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.

2014N207627_03
CONFIDENTIAL
TAF113577
62
11.
REFERENCES
Anstey NM, Douglas NM, Poespoprodjo JR, Price RN. Plasmodium vivax: clinical 
spectrum, risk factors and pathogenesis. Adv Parasitol 2012;80:151-201.
Baird JK, Maguire JD, Price RN. Chapter Four - Diagnosis and Treatment of 
Plasmodium vivax Malaria. In: Advances in Parasitology, vol. 80, 2012, pp 203-270.
Beal S, Sheiner LB, Boeckmann A, Bauer RJ.  NONMEM User's Guides. (1989-2013), 
Icon Development Solutions, Ellicott City, MD, USA, 2013.
Bhattacharjee P, Dubey S, Gupta VK, Agarwal P, Mahato MP. The clinicopathologic 
manifestations of Plasmodium vivax malaria in children: A growing menace. J Clin 
Diagn Res 2013; 7(5):861-867.
Crawley J, Chu C, Mtove G, Nosten F. Malaria in children. The Lancet 2010; 
375(9724):1468-1481.
Doherty AN, Kring EA, Posey YF, Maisels MJ.  Glucose-6-phosphate dehydrogenase 
activity levels in white newborn infants.  J Pediatr 2014;164:1416-1420.
George P, Alexander LM: A study on the clinical profile of complicated Plasmodium 
vivax mono-infections. Asian Pac J Trop Med 2010;3(7):560-562.
GlaxoSmithKline Document Number 2012N145359_00.  Study TAF114582.  A 
randomized, placebo-controlled study to evaluate the effect of tafenoquine (SB252263) 
on the electrocardiogram (ECG) with focus on cardiac repolarization (QTc duration) in 
healthy subjects.  Effective date: 8 April 2013.
GlaxoSmithKline Document Number 2012N152563_01.  Study ID TAF116564.  A 
Randomized, Double-Blind, Double Dummy, Comparative, Multicenter Study to Assess 
the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB-252263, 
WR238605) versus Primaquine in the Treatment of Subjects with Plasmodium vivax
Malaria.  Effective Date:  20 February 2014.
GlaxoSmithKline Document Number 2013N160035_00.  Study ID TAF112582 Part 1 
(clinical study report).  A multi-centre, double-blind, randomised, parallel-group, active-
controlled study to evaluate the efficacy, safety and tolerability of tafenoquine (SB-
252263, WR238605) in subjects with Plasmodium vivax malaria.  Effective Date:  14 
November 2013.
GlaxoSmithKline Document Number GM2007/00152/08.  SB-252263 Investigator's 
Brochure.  Effective Date:  10 October 2014.
GlaxoSmithKline Document Number RM2010/00052/04.  Study ID TAF112582.  A 
multi-centre, double-blind, randomised, parallel-group, active controlled study to 
evaluate the efficacy, safety and tolerability of tafenoquine (SB-252263, WR238605) in 
subjects with Plasmodium vivax malaria.  Effective Date:  25 November 2013.

2014N207627_03
CONFIDENTIAL
TAF113577
63
GlaxoSmithKline Document Number WD2009/01503/00. Study ID TAF106491.  
Safety, tolerability and pharmacokinetic study of concomitant chloroquine and 
tafenoquine in healthy volunteers. Effective Date: 16th October 2009.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.
Kashinkunti M, Gundikeri S, Dhananjaya M. Clinical profile of severe Plasmodium vivax
malaria in a tertiary care centre of North Karnataka. Int J Sci Res Pub 3[7]. 2013.
Kearns G, Abdel-Rahman S, Alander S et al. Developmental Pharmacology – drug 
disposition, action, and therapy in infants and children. N Engl J Med 2003;349:1157-
1167.
Kochar DK, Das A, Kochar SK et al.: Severe Plasmodium vivax Malaria: A Report on 
Serial Cases from Bikaner in Northwestern India. Am J Trop Med Hyg 2009; 80(2):194-
198.
Koepfli C, Colborn KL, Kiniboro B et al. A high force of Plasmodium vivax blood-stage 
infection drives the rapid acquisition of immunity in Papua New Guinean children. PLoS 
Negl Trop Dis 2013;7:e2403.
Lança EF, Magalhães BM, Vitor-Silva S et al. Risk factors and characterization of 
Plasmodium vivax-associated admissions to pediatric intensive care units in the Brazilian 
Amazon. PLoS One 2012;7:e35406.
Luxemburger C, Nosten F, Kyle DE, Kiricharoen L, Chongsuphajaisiddhi T, White NJ. 
Clinical features cannot predict a diagnosis of malaria or differentiate the infecting 
species in children living in an area of low transmission. Trans R Soc Trop Med Hyg 
1998;92:45-49.
Mahgoub H, Gasim G, Musa I, Adam I: Severe Plasmodium vivax malaria among 
sudanese children at New Halfa Hospital, Eastern Sudan. Parasites & Vectors 2012; 
5(1):154.
Maitland K, Williams TN, Bennett S et al. The interaction between Plasmodium 
falciparum and P. vivax in children on Espiritu Santo island, Vanuatu. Trans R Soc Trop 
Med Hyg 1996;90:614-620.
Marcsisin SR, Sousa JC, Reichard GA, et al.  Tafenoquine and NPC-1161B require CYP
2D metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of 
anti-malarial compounds.  Mal J 2014;13:2.
Menendez C, Mayor A. Congenital malaria: The least known consequence of malaria in 
pregnancy. Semin Fetal Neonat Med 2007;12:207-213.

2014N207627_03
CONFIDENTIAL
TAF113577
64
Michon P, Cole-Tobian JL, Dabod E et al. The risk of malarial infections and disease in 
Papua New Guinean children. Am J Trop Med Hyg 2007;76: 997-1008.
Rhodin MM, Anderson BJ, Peters AM et al. Human renal function maturation: a 
quantitative description using weight and postmenstrual age. Pediatr Nephrol 2009;24:67-
76.
Rodriguez-Morales AJ, Giselle-Badillo Al, Manrique-Casta+¦o S, Yepes MaC: Anemia 
and thrombocytopenia in Plasmodium vivax malaria is not unusual in patients from 
endemic and non-endemic settings. Travel Medicine and Infectious Disease 2014;(0).
Rodriguez-Morales AJ, Sínchez E, Vargas M et al.  Anemia and Thrombocytopenia in 
Children with Plasmodium vivax Malaria. Journal of Tropical Pediatrics 2006; 52(1):49-
51.
Singh H, Parakh A, Basu S, Rath B.  Plasmodium vivax malaria: Is it actually benign? 
Journal of Infection and Public Health 2011; 4(2):91-95.
Singh J, Purohit B, Desai A et al.  Clinical manifestations, treatment, and outcome of 
hospitalized patients with Plasmodium vivax malaria in two Indian states: A retrospective 
study. Malar Res Treat 2013; 2013a.
Singh R, Kumar S, Rana SK, Thakur B, Singh SP.  A comparative study of clinical 
profiles of vivax and falciparum malaria in children at a tertiary care centre in 
Uttarakhand. J Clin Diagn Res 2013b; 7(10):2234-2237.
Srivastava S, Ahmad S, Shirazi N, Kumar Verma S, Puri P: Retrospective analysis of 
vivax malaria patients presenting to tertiary referral centre of Uttarakhand. Acta Trop 
2011; 117(2):82-85.
Summer AP, Stauffer WM, Fischer PR.  Pediatric malaria in the developing world. 
Seminars in Pediatric Infectious Diseases 2005; 16(2):105-115.
Wildt SN. Profound changes in drug metabolism enzymes and possible effects on drug 
therapy in neonates and children. Expert Opin Drug Metab Toxicol 2011:7(8);935-947.
World Global Malaria Programme, 2013. World Malaria Report. World Health 
Organization, ed. Geneva, Switzerland.

2014N207627_03
CONFIDENTIAL
TAF113577
65
12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
µg.h/mL
Microgram Hours per milliliter
µL
Microliters
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BUN
Blood Urea Nitrogen
CL
Clearance
CPK
Creatine Phosphokinase
CQ
Chloroquine
CRF
Case Report Form
CV
Cardiovascular
DDI
Drug-drug Interaction
DRE
Disease-Related Event
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration
g
Grams
g/dL
Grams per Deciliter
G6PD
Glucose-6-phosphate Dehydrogenase
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
Hb
Hemoglobin
hCG
Human Chorionic Gonadotropin
Hct
Hematocrit
HIV
Human Immunodeficiency Virus
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
kg
Kilograms
LDH
Lactate Dehydrogenase
MCV
Mean Cell Volume
MetHb
Methemoglobin
mg
Milligrams
mL
Milliliters
MMV
Medicines for Malaria Venture
MSDS
Material Safety Data Sheet
PK
Pharmacokinetics

2014N207627_03
CONFIDENTIAL
TAF113577
66
PQ
Primaquine
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
None

2014N207627_03
CONFIDENTIAL
TAF113577
67
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN 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 3xULN 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
(i.e., screening) (see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 
for any protocol specified follow up assessments 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained as soon as possible 
and within 24 hours after last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

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

2014N207627_03
CONFIDENTIAL
TAF113577
68
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
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)
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.
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.

2014N207627_03
CONFIDENTIAL
TAF113577
69
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
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 (i.e., screening)

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

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.

2014N207627_03
CONFIDENTIAL
TAF113577
70
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.

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.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.

2014N207627_03
CONFIDENTIAL
TAF113577
71
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 
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.

2014N207627_03
CONFIDENTIAL
TAF113577
72
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
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

2014N207627_03
CONFIDENTIAL
TAF113577
73
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

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.

2014N207627_03
CONFIDENTIAL
TAF113577
74

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
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 

2014N207627_03
CONFIDENTIAL
TAF113577
75
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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.

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.

2014N207627_03
CONFIDENTIAL
TAF113577
76
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.
SAE reporting to GSK via PIMS

Facsimile transmission of the following PIMS listings for the corresponding subject 
is the preferred method to transmit SAE information to the protocol contact:
SAE listing
Demographic listing
Study treatment listing

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight 
mail.

If the PIMS system is unavailable when the SAE occurs, the site will use the paper 
SAE form and fax that to the protocol contact. The site will enter the SAE data into 
PIMS as soon as the system becomes available.

2014N207627_03
CONFIDENTIAL
TAF113577
77
12.4.
Appendix 4: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK 
within 2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will 
be forwarded to GSK.  Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to 
GSK as described above. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.

2014N207627_03
CONFIDENTIAL
TAF113577
78
12.5.
Appendix 5 - Country Specific Requirements
No country-specific requirements exist.

2014N207627_03
CONFIDENTIAL
TAF113577
79
12.6.
Appendix 6 - 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.

2014N207627_03
CONFIDENTIAL
TAF113577
80
12.7.
Appendix 7 – Prohibited Medications for Study Entry
Acetylsalicylic acid. (Paracetamol is the recommended antipyretic agent due to FDA 
requirement to record times antipyretics are given).
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
Drugs with antimalarial activity:
This list serves to provide examples of more commonly used drugs with antimalarial 
activity, but is not exhaustive. 

Allopurinol 

Clindamycin 

Diamidines (e.g., Pentamidine)

Fluroquinolones e.g. ciprofloxacin, Nalidixic acid sparfloxacin 

Glibenclamide 

Indinavir, Saquinavir and Ritonavir 

Isoniazid 

Probenecid

Rifampicin

Sulfadiazine, Sulfadoxine or Sulfalene/pyrimethamine, 
Sulfamethoxazole/trimethoprim,  Sulfasalazine (and other sulfonamides) 

Sulfacetamide

2014N207627_03
CONFIDENTIAL
TAF113577
81
Drugs Contraindicated in G6PD deficiency:

Melarsoprol 

Menadiol

Methyl dopa-

Methylthioninium chloride (i.e., Methylene Blue) 

Nalidixic acid

Niridazole 

Nitrofurantoin 
Drugs excreted via the renal transporters MATE1, MATE2-K AND OCT2:

Phenformin

Buformin

Dofetilide

Procainamide

Pilsicainide
Others-miscellaneous:

Phenazopyridine 

Phenylhydrazine 

Chloramphenicol
CQ interactions (source eMC):

Amiodarone

Antacids (Al, Ca, Mg salts) may cause reduced absorption of CQ. If required 
therapy must be taken well separated from CQ (at least four hours apart).

Cimetidine inhibits metabolism of CQ (increases plasma concentration)

Cyclosporin (CQ interaction)
In addition, refer to locally approved prescribing information.

2014N207627_03
CONFIDENTIAL
TAF113577
82
12.8.
Appendix 8 – Tafenoquine Pediatric Dose Extrapolation
Document Number: 2014N199461_03
Division: Worldwide Development
Retention Category: GRS019
Information Type: Clinical Pharmacology Modelling Report
____________________________________________________________
Title:
Tafenoquine Paediatric Dose Extrapolation
____________________________________________________________
Compound Number: SB-252263, Tafenoquine
Effective Date: 23/04/2014
Description:
Extrapolation of the adult population-PK modelling to paediatric dosing. 
Identification of doses and weight bands using random-space sampling with 
optimality.
Subject: Tafenoquine, paediatric, allometry, dose selection
Author's Name and Functional Area:
 & 
Clinical Pharmacology Modelling & Simulation
Clinical Statistics
Approved by:
____________________________________________________________
Clinical Pharmacology Modelling & Simulation
PPD
PPD
PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
83
Tafenoquine Paediatric Dose Extrapolation
____________________________________________________________
23/04/2014
1. Introduction
Tafenoquine has been dosed in a Phase 2b dose-ranging study in adults with extensive 
pharmacokinetic data for single adult doses of 50, 100, 300 and 600 mg. A population PK 
analysis (to be reported) using a two-compartment model with first order absorption and 
random effects on volume and terminal phase half-life (beta) identified bodyweight to be a 
significant determinant of exposure. The allometric power for clearance was approximately 0.5, 
in contrast to traditional estimates of 0.75. The inclusion of bodyweight allometry into the 
model was highly statistically significant.
Assuming a target exposure equivalent to the adult dose of 300 mg, we propose using 
allometry to optimally select doses and weight bands that provide the best matching of 
paediatric AUC(0-inf) to that of adults. The justification for the selection of 300 mg will be 
discussed elsewhere. The proposal is to use the parameters for the adult model, and assume 
that there are no developmental effects on the apparent clearance of tafenoquine for the age 
(and weight) ranges to be treated.
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
84
2. Methods
The adult population pharmacokinetic model used to describe the Phase 2b dose ranging study 
was the standard two-compartment model with first order absorption. Bodyweight is part of 
the model and the full equation takes the form;
(t) = Dose*((BWT/60)**-pBWT)*(A*exp(-Alpha*t) + B*exp(-Beta*t) - (A+B)*exp(-KA*t)).
Bodyweight was centred on 60 kg in accordance with observation from the trial. The dose-
normalized AUC(0-inf) for a 60 kg adult is therefore given by DNAUC(0-inf) = A/Alpha+B/Beta-
(A+B)/KA = 0.316 ug.hr/ml/mg. The only other parameter required to extrapolate AUC(0-inf) 
for other doses and bodyweights is the allometric power, pBWT = 0.5217.
The pharmacokinetic model estimates between-subject variability for parameters A and B, and 
this can be used to derive 95% confidence limits for adult exposure and hence a target 
exposure to be maintained in children. Moreover, the variability in children is solely assumed 
to result from bodyweight, and hence 95% limits for children can also be derived.
We propose up to four weight bands with cut-off points and doses for each weight band. For 
each scenario, we can calculate AUC(0-inf) with 95% confidence limits across the weight range 
0-100 kg. For each scenario, we derive the square error (deviation) from the idealized 300 mg
adult exposure (for a 60 kg subject), then evaluate the root mean square error for the range 0-
100 kg.
In order to evaluate scenarios, we begin with a proposal that has been optimized by trial and 
error. Doses are assumed to be 50, 100, 200 and 300 mg and weight bands are 0-4, 4-16, 16-40 
and >40 kg. In the Phase 2b trials, the lowest recorded weight was 32kg. A cut-off of 30-40 kg is 
therefore reasonable.
To evaluate optimality we could, in principle, minimise the RMSE by changing weight bands and 
doses. In practice this is a hard optimization, so we propose an alternative. Four weight classes 
are defined and generated from uniform random distributions. The lowest dose range is 
defined randomly from 0-100 mg and subsequent doses selected using linear: 150*rand[0,1], 
and multiplicative: 4**rand[0,1] escalations. 100,000 scenarios are simulated and the RMSE 
calculated for each scenario. Optimization is performed manually by selecting the extreme 
(low) RMSE scenarios and comparing with the trial and error proposal. Finally a pseudo-optimal 
solution is presented graphically with a recommendation for dose strengths.
In principle, the full solution is soluble in closed form with integration of the RMSE function by 
dose and weight band in an eight dimensional phase space. The random sampling algorithm, 
whilst not the most efficient, is robust and should therefore be capable of finding very good 
solutions.

2014N207627_03
CONFIDENTIAL
TAF113577
85
3. Results
3.1. Trial and Error
We begin by assuming that a 50 mg dose might be possible for the smallest children, and that 
we should try and avoid dosing on a mg/kg basis greater than 10 mg/kg. Doses are fixed to 50, 
100, 200 and 300 mg, and weight bands were chosen manually and are 0-4, 4-16, 16-40 and 
>40 kg. The predicted AUC(0-inf), complete with dose bands and adult 300 mg target (for a 60 
kg subject) are plotted below. The RMSE for this scenario is an impressive 14.6 ug.hr/ml, 
compared with a target of 95 ug.hr/ml, implying an over/under dosing of approximately 15%.
Figure 5
First Guess Paediatric AUC (0-inf) as a Function of Bodyweight and 
Dose 
3.2. Simulations
We now conduct a simulation of 100,000 scenarios, selected at random with some structural 
components. First, the lowest dose is deemed to be between 0 and 100 mg and is uniformly 
distributed (i.e., the mean will be 50 mg). Second, the increment in dose for each weight band is 
4**rand[0,1] (i.e., the mean fold increase will be two-fold). Finally we assume four uniform 
random weight bands of widths 10, 20, 30 and 20 kg, implying mean cut-offs of 0-5, 5-15, 15-30 
and 30-40 kg, in keeping with the first proposal. These can be varied at will, as can the fold 
changes in dose per weight band.
The histogram below shows the RMSE for AUC(0-inf) compared with target. The dashed red line 
shows the RMSE for the first proposal and it is clearly close to optimal. Some selections will 
clearly under- or over-dose paediatric patients hugely!

2014N207627_03
CONFIDENTIAL
TAF113577
86
Figure 6
Histogram of RMSE for Predicted Exposure
3.3. Optimality
Having simulated 100,000 scenarios, the histogram shows the distribution of RMSEs. The 
multiplicative dose escalation tended to produce many scenarios with large over- or under-
dosing, when presented on a semi-log plot (not shown). The additive escalations show a log-
normal distribution. We select the five smallest as a measure of optimality and compare with 
the trial proposal (Scenario 0). The table below shows original proposal compares well, but that 
a smaller RMSE available by tuning doses and weight bands accordingly. It is however entirely 
possible that the small difference in RMSE is of little clinical significance, and this can be tested 
with the exposure-relapse response logistic regression model we have used to analyse the 
efficacy data (not shown).
Table 5
Table of Scenarios with Lowest RMSE
Scenario
Lowest 
Value
Weight1
Weight2
Weight3
Weight4
Dose1 Dose2 Dose3
Dose4
0
14.6
4.0
16.0
40.0
40.0
50.0
100.0
200.0
300.0
6692
13.0
6.2
14.8
28.6
49.8
65.1
127.1
173.8
236.1
21313
13.2
2.5
9.1
21.2
49.4
46.9
72.7
140.3
223.8
87977
13.3
7.1
19.0
33.2
50.2
57.2
129.0
194.4
264.0
9445
13.3
6.3
16.6
23.1
46.3
62.3
123.0
156.0
208.3
88153
13.4
6.1
10.4
19.5
45.4
61.9
102.6
147.2
197.4

2014N207627_03
CONFIDENTIAL
TAF113577
87
3.4. Optimal Exposure Prediction
Selecting the scenario with the lowest RMSE from the table and using the weight bands and 
doses for a final simulation of the predicted exposures. This is compared with the target AUC(0-
inf) and range in adults in the Figure below.
Figure 7
Optimal Paediatric AUC (0-inf) as a Function of Bodyweight and 
Dose
3.5. Proposed Paediatric Dose and Weight Bands
We assume that the paediatric formulation is only to be made available in one tablet strength, 
and that selection of dose and weight bands should be close to optimal. Table 5 suggests that a 
low dose of 50 mg and a low weight range of 0-5 kg is optimal. We therefore propose a tablet 
strength of 50 mg that provides for doses of 50, 100, 150, 200 and 250 mg, combined with the 
adult dosage form of 300 mg. Using the weight bands 0-5, 5-10, 10-20, 20-35 and >35 kg, we 
present a near optimal one-tablet dosing nomogram with RMSE 14.0 ug/day/ml (15% error). 
Subjects >35 kg receive the adult dosage form.

2014N207627_03
CONFIDENTIAL
TAF113577
88
Figure 8
Paediatric AUC (0-inf) for Doses 50, 100, 150, 200, 300 mg, and 
Weight Bands 0-5, 5-10, 10-20, 20-35 and >35 kg
Bodyweight has been used as a covariate to predict exposure with an exponent estimated 
from the adult data.  The lowest weight in the adult study was 32 kg, and it is possible the 
exponent, pBWT, although estimated with good precision, may be an underestimate.  The 
conventional value for metabolic processes is 0.75, and we now consider model 
misspecification, should the true value (estimated from paediatric data) fall closer to the 
conventional value.
With all other parameters fixed, the RMSE for the conventional exponent of 0.75 increases to 34 
ug.hr/ml ().  Much of this error is, however, in the 0-5 kg weight range, which will not be treated 
in the proposed study.  Once data is acquired, estimation of exposure in the treated subjects 
using the established population pharmacokinetic model in the first instance, will provide a 
better estimation of the allometric exponent down to 5 kg. 
Table 6
RMSE for Proposed Nomogram with Estimated and Conventional 
Allometry
Scenario
pBWT
RMSE
Estimated
0.522
14.0
Theoretical
0.750
34.8

2014N207627_03
CONFIDENTIAL
TAF113577
89
Figure 9
Paediatric AUC (0-inf) for the Proposed Dosing Nomogram 
Assuming a Conventional Allometric Exponent of 0.75
4. Conclusion
A simple closed-form solution that describes the effect of bodyweight on Tafenoquine exposure, 
which has in turn been related to the probability of relapse, has been used to extrapolate adult 
exposure down to paediatric populations. It is assumed that the only determinants of exposure 
are dose and bodyweight, and that the effects of bodyweight scale allometrically from 60 kg 
down to 1kg.
A range of weight bands and doses have been investigated, and these have been optimized 
using random phase space exploration. Simulation of 100,000 possible scenarios shows that a 
weight band of 0-5 kg is prudent, and that a low dose of 50 mg is optimal. If one tablet strength 
is desired for paediatric formulation, we propose 50, with four weight bands. This nomogram is 
very close to optimal, with a RMSE of less than 15% of the target exposure in adults.
Evaluation of model mis-specification shows that the proposed nomogram is robust, with a 
maximum RMSE of 36%. Since most of this error is in the smallest weight band that will not be 
treated in the proposed paediatric trial, and evaluation of exposure is planned after 
approximately 20 subjects have been dosed, the proposal is deemed to be sufficiently robust for 
evaulation in a clinical setting.

2014N207627_03
CONFIDENTIAL
TAF113577
90
12.9.
Appendix 9 - Tafenoquine Pediatric Population-PK Trial 
Simulation
Document Number: 2014N201728_01
Division: Worldwide Development
Retention Category: GRS019
Information Type: Clinical Pharmacology Modelling Report
____________________________________________________________
Title:
Tafenoquine Paediatric Population-PK Trial Simulation
____________________________________________________________
Compound Number: SB-252263, Tafenoquine
Effective Date: 27/04/2014
Description:
Simulation of paediatric trial and re-estimation of exposure using population-PK 
methods to evaluate different trial designs and sampling schemes.
Subject: Tafenoquine, paediatric, allometry, dose selection
Author's Name and Functional Area:
Clinical Pharmacology Modelling & Simulation
Clinical Statistics
Approved by:
____________________________________________________________
Clinical Pharmacology Modelling & Simulation
PPD
PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
91
Tafenoquine Paediatric Population-PK Trial 
Simulation
____________________________________________________________
27/04/2014
1.Introduction
The pharmacokinetics of tafenoquine have been evaluated in adults in a Phase 2b dose-
ranging study. A population PK analysis was used to extrapolate exposure to paediatric cases 
and a weight-based dosing nomogram proposed for the paediatric trial (see Appendix 8).
Having evaluated suitable doses and weight bands, the purpose of this report is to consider 
how the paediatric trial should be designed to best evaluate exposure in a much small 
population whilst still maintain precision in estimation methods.
For the paediatric population we have proposed five weight bands; 0-5, 5-10, 10-20, 20-35 and 
>35 kg, with corresponding doses of 50, 100, 150, 200 and 300 mg. Analysis showed that this is 
a near optimal nomogram for maintaining predicted exposure within 15% of that of adults. 
Design parameters for the paediatric trial to confirm the suitability of this nomogram are; 
number of subjects in each weight band, total number of subjects and sample times.
In the adult study five pharmacokinetic samples were taken over 60 days. This scheme, 
coupled with the large number of subjects, meant that a two-compartment model with first-
order absorption was well-estimated and described the observed data. Allometry was 
integrated into the model allowing for  full paediatric extrapolation.
In this report we consider the effects of sparse sampling and reduced sample sizes. These 
restrictions are necessary on the grounds of practicality; minimising data collection in children 
is an important aim of paediatric extrapolation, but at the same time reduce the ability to 
estimate exposure accurately. Any finalised design should aim to balance sample size, 
sampling scheme and precision of estimation.
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
92
2. Methods
To conduct the trial simulation we begin from the adult population PK model incorporating 
allometry. We draw random samples from a distribution of bodyweight and categorise 
according to pre-established weight bands and corresponding doses. Full PK profiles, including 
residual, are generated for each subject. For each design scenario 1000 trial replicates are 
simulated. This superset of data forms the basis for analysis. A variety of sampling schemes can 
then be subsampled and a population PK model fitted to the data for each sampling scheme. 
Once a model is fitted, post-hoc individual estimates of exposure are calculated and compared 
with the true value for each subject. Deviation (Observed - Predicted) is calculated. Finally, the 
Root Mean Square Error (RMSE) is used to summarise the precision of each trial replicate. The 
overall outcome is a distribution of 1000 estimated of RMSEs for each trial design scenario, from 
which a sampling recommendation can be made.
In the Phase 2b analysis, the model used to describe the data was fully parameterised and all 
parameters were estimated with very good precision. In the paediatric trial we are concerned 
with estimation of exposure for the smallest number of subjects (as opposed to evaluation of 
efficacy). This means that the much smaller sample size, say 20 subjects compared with 200, 
may make estimation of all pharmacokinetic parameters challenging. Moreover, sparse 
sampling, particularly when there is no sampling during the absorption phase, makes estimation 
of a fully parametrised model impossible. A number of techniques are possible to overcome this 
challenge ranging from no parameter estimation (assume the adult model is a perfect 
description of paediatric subjects) to a Bayesian analysis with informative priors (using proc 
mcmc) and estimating posterior pharmacokinetic parameters after incorporating the paediatric 
data. For the purposes of this analysis, we will use full estimation for the full dataset and fix 
parameters as necessary for sparse sampled datasets. The final trial analysis may additionally 
make use of Bayesian techniques, but those will not be tested here.

2014N207627_03
CONFIDENTIAL
TAF113577
93
3. Model Simulation
3.1. Pharmacokinetic Model
The Phase 2b adult data was described using a two-compartment model with first-order 
absorption and integral allometry that incorporated weight as a determinant of exposure. 
The model was parameterised in terms of macroconstants, A, B, Alpha and Beta and the full 
equation takes the form;
(t) = Dose*((BWT/60)**-pBWT)*(A*exp(-Alpha*t) + B*exp(-Beta*t) - (A+B)*exp(-KA*t)) + s2.
where s2 is the residual. Parameters A and B are random effects and share the same log-
normal distribution with inter-subject variance s2b1. The terminal elimination rate, Beta, is 
also a random effect with variance s2b2 with no correlation to A and B. The final parameter 
estimates from the adult model are given in the table below. AUC(0-inf) was estimated from 
the macroconstant parameterisation as Dose*((BWT/60)**-pBWT)*(A/alpha + B/Beta -
(A+B)/KA), and clearance calculated from AUC for both population and individual subjects.
Table 7
Pharmacokinetic Parameters for the Model (above)
Parameter
Value
Units
Notes
A
0.8586 ng/ml/mg
Macroconstant with V2/F
B
0.4813 ng/ml/mg
Macroconstant with V2/F
Alpha
0.4380 /day
Distribution half-life
Beta
0.0415 /day
Elimination half-life
KA
3.3073 /day
Absorption Rate
pBWT
0.5217 NA
Scaling power for BWT
s2b1
0.2766 NA
SDLOG(A,B) variability
s2b2
0.1695 NA
SDLOG(Beta) variability
s2
0.2657 NA
SDLOG(Resid) residual

2014N207627_03
CONFIDENTIAL
TAF113577
94
A population of 1000 paediatric subjects is simulated for each of 1000 trials based on a log-
normal weight distribution with mean 3.36 and log standard deviation 0.66. This gives a mean 
bodyweight of 28.9 kg and probabilities of <1%, 5%, 23%, 33% and 36% of being in weight bands 
0-5, 5-10, 10-20, 20-35 and >35 kg respectively (see Figure 10 below). From this population 
subjects are then drawn with or without stratification. Since subjects of less than 5 kg will not be 
recruited, stratification only impacts the proportions in bands 2-5. Without stratification, bands 
2 and 5 will be under-represented, which may have consequences for the estimation of 
allometric scaling and hence patient exposure at bodyweight extremes.
Figure 10
Cumulative Probability Distributions for Recruitment by Weight 
Band (above)

2014N207627_03
CONFIDENTIAL
TAF113577
95
Having sampled a suitable population of subjects, the second trial design parameter is sampling 
times. A dense sampling scheme of twelve PK samples; 0.25, 0.5, 1, 2, 3, 4, 7, 15, 21, 29, 60 and 
84 days forms the superset of all possible times. One of the aims of paediatric studies is to 
balance sampling of subjects with precision of exposure estimation. A number of sample 
schemes can be tested ranging from all twelve samples (the base case) down to as few as two or 
three samples (very sparse).
After simulating 1000 trials from the sampled population and PK sampling scheme, non-linear 
mixed-effects modelling can be used to estimate exposure. We use the same adult 
pharmacokinetic model; a two-compartment linear model with first-order absorption. Paediatric 
sparse sampling will typically mean that there are fewer subjects and sparser sampling than 
adult data. For example, sampling subjects from Day 3 means that there will be very limited 
information on absorption and distribution, hence estimation of the absorption and distribution 
rates, KA and Alpha, will not be possible. The low numbers of subjects means that estimation of 
the magnitude of any random effects may also prove difficult. Instead, we propose fixing these 
nuisance parameters to their adult reference values where necessary, whilst estimating other 
parameters of importance to the paediatric population; relative bioavailability compared with 
adults, allometric scaling power for bodyweight and terminal elimination rate, Beta.
Once the model is fitted and parameters estimated, individual estimates of exposure can be 
calculated and compared with the known value (i.e., known in the sense simulated from the true 
parameters for each subject in the trial); the square of the deviance from true AUC(0-inf) 
calculated and the trial summarised by root mean square error (RMSE). A distribution of RMSE 
values across all 1000 simulated trials is a summary measure of the precision of the trial design 
and allows direct comparison of designs.
The primary objective of the paediatric study is to understand and predict the exposure for each 
weight band and compare with the desired target adult exposure of 96 ug.hr/ml for a 300 mg 
dose in a 60 kg adult. The final model can be used to predict exposure for the midpoint of each 
weight band, complete with propagated uncertainty in precision, using the Estimate statement 
in proc nlmixed. These prediction intervals for the final outcome for each trial and their 
properties can then be summarised over all simulated trials to give confidence that the trial 
design is capable of estimating exposure in a wider population of children.
3.2. A Sample Trial Design
3.2.1. Simulated Data
As an example, we consider a sample trial design of 20 subjects with stratification based on 
weight and five subjects per weight band. The simulated weight distribution, including weight 
bands, coupled with exposures for all 20000 subjects are shown in Figure 11. Note that weight 
stratification distorts the expected log-normal weight distribution and that the proportion in 
each weight band is a constant 25%.

2014N207627_03
CONFIDENTIAL
TAF113577
96
Figure 11
Summary Weight and Exposure Distributions for the Simulated 
Population (above)
3.2.2. Simulated Pharmacokinetic Profiles
We now consider a sparse sampling scheme with pharmacokinetic samples taken on Days 3, 15, 
29. For illustration, we plot data and analysis results from the first nine simulated trials to show 
trial-to-trial variability. Final results and conclusions are drawn from all 1000 simulated clinical 
trials. The full pharmacokinetic profiles for the first nine trials are shown below with sampling 
from 0.5 to 84 days:

2014N207627_03
CONFIDENTIAL
TAF113577
97
Figure 12
Simulated Full Pharmacokinetic Profiles (Trials 1-9) (above)
By way of contrast, with a sampling scheme of only three time points, the analysis dataset for 
this specific trial design looks much less promising, with no data during the absorption and 
distribution phases whatsoever, and a relatively short observation of terminal elimination 
compared with the half-life:
Figure 13
Simulated Sparse Pharmacokinetic Profiles (Trials 1-9) (above)

2014N207627_03
CONFIDENTIAL
TAF113577
98
Since the inter-subject variability for the elimination of tafenoquine is low, the half-life, beta 
looks well-defined on a population basis, despite a truncation of sampling at Day 29. This means 
that sampling beyond one month may not be necessary and this analysis is designed to test that 
hypothesis. Multiple sampling scenarios can be tested, but without data during the absorption 
process, estimation of absorption and distribution rates, KA and Alpha, will not be possible.
3.2.3.Non-linear Mixed-Effects Modelling
We know from the adult data with full pharmacokinetic profiles that tafenoquine 
concentrations are well-described by a two-compartment model with first-order absorption. 
The sparse sampling in this example means that estimation of absorption, distribution and 
possibly inter-subject variability will be challenging. Instead, we fix certain parameters to 
those of adults, whilst allowing the model to estimate others. For this example we estimate 
parameters; A (equivalent to an intercept in a linear model), Beta, allometric power pBWT 
and the residual s2. We fix Alpha and the ratio A/B (equivalent to the overall shape of the 
two-compartment profile), and the inter-subject variability s2b1. For simplicity, only a single 
random effect is used in the model to describe variability on A and B equally (as would be 
expected for volume of distribution, V/F). In this model all subjects will have the same 
terminal-phase elimination rate, Beta, despite the data being simulated with variability in this 
parameter, but each subject will have an individual clearance, CL/F and AUC(0-inf) due to the 
random effect. Starting values for estimated parameters are the adult values.
A conventional model diagnostic plot of observed vs. individual predicted (Log) concentration 
(DV vs. iPRED in NONMEM) is shown in the plots below. The first plot shows a representative 
trial, with prediction intervals from proc nlmixed for each data point. The dashed line is the 
line of equality, the solid line a regression of DV vs. iPRED and the shaded region the prediction 
interval for the linear regression. Notice the prediction interval for almost every data point 
includes the line of unity (this interval diagnostoc is not available in NONMEM).
Figure 14
Diagnostic Plot of DV vs. iPRED With Prediction Interval Bars (Trial 
1) (above)
Removing the prediction interval error bars for clarity, we can show the same diagnostic plot for 
the first nine trials. By fixing some of the parameters, the model is able to provide excellent 
predictions in spite of the sparse sampling scheme.

2014N207627_03
CONFIDENTIAL
TAF113577
99
Figure 15
Diagnostic Plot of DV vs. iPRED (Trials 1-9) (above)
3.2.4. Predicted Exposures
Having estimated the model parameters, proc nlmixed can provide population estimates of 
exposure calculated from the fixed effects. Using the mid-points for each weight band; 2.5, 7.5, 
15, 27.5 and 47.5 kg, and the closed-form expression for AUC(0-inf) given earlier, the predicted 
population mean AUC(0-inf) for the first nine trials by weight class are shown below, complete 
with target 96 ug.hr/ml and the interval 77-120 which represents traditional bounds for 
bioequivalence, complete with 55-162 which is the prediction interval for a 60 kg adult.
Figure 16
Predicted AUC (0-inf) by Weight Class (Trials 1-9) (above)

2014N207627_03
CONFIDENTIAL
TAF113577
100
Summarising all 1000 simulated trials, shows that the point estimate AUC by weight class for all 
weight bands falls within the 80-125 conventional bounds for bioequivalence. Confidence limits 
for weight bands 10-20 and 20-35 kg may additionally fall within the same bands for some trial 
replicates, which means that formal bioequivalence could be declared (Figure 17) based on 
model predicted exposure. For other weight bands, formal bioequivalence is unlikely without a 
larger sample size.
Figure 17
Predicted AUC (0-inf) Mean and 95% CLs by Weight Class (All Trials) 
(above)
One measure of precision is the coefficient of variation (CV) of a predicted parameter. The 
parameterisation used in this modelling requires clearance to be calculated from the 
macroconstants. The CV can however be calculated and summarised over all clinical trials to 
measure trial design performance. The FDA have proposed a target CV of 0.4 as a guide to 
sample size in paediatric trials. This target does not, however, factor in the effects of 
bodyweight on clearance, nor does it take into account the fact that the actual trial replicate will 
have a trial-specific distribution of bodyweights and the model predicted clearance will be a
function of bodyweight; hence predictions of clearance (but not AUC) are required across the 
weight range of a wider population. In the plot below we present the CV distribution by weight 
class. Although this example uses stratifcation by bodyweight, even in the weight class 0-5 kg, 
who were explicitly excluded from the trial, the sample trial design provides acceptable 
precision.
Figure 18
Predicted Coefficient of Variation for Clearance by Weight Class (All 
Trials) (above)

2014N207627_03
CONFIDENTIAL
TAF113577
101
A further method of evaluating the performance of a trial, and one that is much less arbitrary 
than a nominal target CV of 0.4, is to consider how well the post-hoc individual exposure 
estimates compare with the (true) exposure for each subject. The root mean square error for 
AUC(0-inf) provides an objective measure of the precision of any trial design, independent of 
bodyweight.
Figure 19
Histogram of RMSE for Predicted AUC (0-inf) (above)
Table 8
RMSE (ug.hr/ml) for Sample Trial (above)
Scenario
Subjects
Stratified
Times
Fixed
Median
Lower
Upper
Sample 
Trial
20
Yes
3,15,29 B,Alpha,KA,s2b2
16.4
12.0
21.9
These results show that for the sample trial design the median RMSE for AUC(0-inf) is only 16 
ug.hr/ml (18%), with 90% (5-95th percentiles) of all trials falling in the range 12.1-21.9 ug.hr/ml. 
By fixing suitable parameters to their adult values, even 20 subjects with only three samples per 
subject can give a reasonable estimate of individual and population exposure with less that 20% 
error.
4. Results
We consider the following scenarios; fixed or weight-based stratification; full, sparse or very 
sparse pharmacokinetic sampling; and sample sizes ranging from 4 to 64 subjects in doubling 
steps. The trial design space therefore has multiple dimensions than can be explored. The 
measure of trial performance is RMSE AUC(0-inf), with a lower value being a higher performing 
trial. The goal is not, however, one of optimisation, but evaluation of adequacy. The full trial 
design without stratification, all twelve samples and 64 subjects can be thought of as the 
reference, and all other trial designs considered in this context. In each sampling scenario, the 
number of parameters estimated is set depending on sampling scheme (but not sample size).

2014N207627_03
CONFIDENTIAL
TAF113577
102
Figure 20
Summary Plot of RMSE for All Trial Scenarios (above)
Looking at the plot of RMSE for AUC(0-inf) and the listing of trial results (Table 9), we note the 
effects of sample size are relatively modest, provided we are prepared to fix parameters from 
the adult model. Increasing sample size reduces the trial-to-trial variability, but the median 
RMSE is relatively constant for any given sampling and parameter estimation scheme. Weight 
stratification was tested for all scenarios and has a smaller effect than might be anticipated 
unless the sample size is very small (4-8 subjects), largely because the weight range included is 
still wide and able to demonstrate allometry (estimation of pBWT). Prediction of AUC(0-inf) at 
the lowest weight class 0-5 kg may, however, be improved. Number of PK samples and durations 
of sampling is not significant provided that the terminal phase elimination is sampled 
appropriately. The low variability in terminal half-life means that no random effect is needed to 
describe this data (despite it being simulated with variability).

2014N207627_03
CONFIDENTIAL
TAF113577
103
5.Conclusions
Any paediatric clinical trial with a primary objective of characterising pharmacokinetics should 
aim to balance sample size, precision and extrapolation from adult data. Tafenoquine 
pharmacokinetics in adults are well-characterised which means that extrapolation to children 
should focus on the allometric aspects of bodyweight and relative bioavailability, rather than 
assuming nothing is known. From an estimation perspective, this means that any sampling can 
borrow information from adults effectively, the question being what information to borrow. In 
this analysis we have shown using simulated paediatric clinical trials, that a relatively small 
sample size is sufficient to characterise the exposure of tafenoquine in children provided some 
parameters are fixed to adult values. Moreover, stratification by previously defined weight 
bands during the clinical trial does not appear to offer additional precision, except for very small 
sample sizes.
Fixing some aspects of the model from adults; namely absorption and distribution, allows the 
trial to focus on clearance and exposure. We find that even very sparse sampling with three or 
four plasma samples will be sufficient to estimate exposure in paediatric subjects. In all events, 
this trial simulation exercise shows that the expected precision for reasonable designs will give 
an estimate of paediatric exposure within 15% of the true value, and well below the 40% 
proposed by the FDA. Once approximately 20 subjects have been recruited, an interim analysis 
can be used to make predictions of AUC(0-inf) by weight class and the need for re-estimation of 
the dosing nomogram considered.

2014N207627_03
CONFIDENTIAL
TAF113577
104
6. Appendix
Table 9
RMSE (ug.hr/ml) for All Trial Scenarios
Subject
s
Stratifie
d
Times
Fixed
Media
n
Lowe
r
Uppe
r
64
No 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
9.8
8.0
12.2
32
No 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
9.8
7.5
13.6
16
No 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
9.9
6.4
15.0
8
No 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
9.8
5.3
16.9
4
No 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
10.4
4.4
20.4
64
No 1,3,15,29,60,84
B,Alpha,KA
10.9
9.1
13.0
32
No 1,3,15,29,60,84
B,Alpha,KA
11.0
8.6
14.2
16
No 1,3,15,29,60,84
B,Alpha,KA
11.2
7.7
16.1
8
No 1,3,15,29,60,84
B,Alpha,KA
11.8
6.6
20.2
4
No 1,3,15,29,60,84
B,Alpha,KA
12.7
5.5
25.5
64
No 3,15,29,60
B,Alpha,KA
12.7
10.6
15.4
32
No 3,15,29,60
B,Alpha,KA
12.9
10.0
17.0
16
No 3,15,29,60
B,Alpha,KA
13.2
8.8
19.5
8
No 3,15,29,60
B,Alpha,KA
13.9
7.9
23.1
4
No 3,15,29,60
B,Alpha,KA
14.4
6.3
28.8
64
No 3,15,29
B,Alpha,KA,s2
b1
16.0
13.3
19.1
32
No 3,15,29
B,Alpha,KA,s2
b1
15.9
12.6
20.7
16
No 3,15,29
B,Alpha,KA,s2
b1
15.8
11.1
22.5
8
No 3,15,29
B,Alpha,KA,s2
b1
15.8
9.4
25.0
4
No 3,15,29
B,Alpha,KA,s2
b1
16.0
6.5
31.8
64
Yes 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
9.7
7.9
12.0

2014N207627_03
CONFIDENTIAL
TAF113577
105
Subject
s
Stratifie
d
Times
Fixed
Media
n
Lowe
r
Uppe
r
32
Yes 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
9.7
7.2
13.1
16
Yes 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
9.7
6.3
14.2
8
Yes 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
9.5
5.3
15.5
4
Yes 0.25,0.5,1,2,3,4,7,15,21,29,60,
84
No Parameters
9.7
4.1
19.6
64
Yes 1,3,15,29,60,84
B,Alpha,KA
10.7
9.0
12.6
32
Yes 1,3,15,29,60,84
B,Alpha,KA
10.7
8.3
13.9
16
Yes 1,3,15,29,60,84
B,Alpha,KA
10.9
7.4
15.4
8
Yes 1,3,15,29,60,84
B,Alpha,KA
11.3
6.4
18.1
4
Yes 1,3,15,29,60,84
B,Alpha,KA
12.3
5.5
23.7
64
Yes 3,15,29,60
B,Alpha,KA
12.4
10.2
15.2
32
Yes 3,15,29,60
B,Alpha,KA
12.7
9.6
16.5
16
Yes 3,15,29,60
B,Alpha,KA
13.0
8.7
18.7
8
Yes 3,15,29,60
B,Alpha,KA
13.6
7.8
22.0
4
Yes 3,15,29,60
B,Alpha,KA
14.1
6.2
27.0
64
Yes 3,15,29
B,Alpha,KA,s2
b1
15.8
12.9
19.1
32
Yes 3,15,29
B,Alpha,KA,s2
b1
15.7
12.3
20.4
16
Yes 3,15,29
B,Alpha,KA,s2
b1
15.7
10.8
22.0
8
Yes 3,15,29
B,Alpha,KA,s2
b1
15.5
8.9
24.6
4
Yes 3,15,29
B,Alpha,KA,s2
b1
15.6
7.1
31.0

2014N207627_03
CONFIDENTIAL
TAF113577
106
12.10.
Appendix 10:  Protocol Amendment Changes
Amendment 1
This amendment is site-specific and applies to one center in Thailand (center
).  
The primary reason for this amendment is to add an inclusion criterion stating that only 
subjects of Thai nationality can be enrolled in the study.  In addition, vital signs and the 
physical examination will be conducted at all visits of the study.
5.1 Inclusion Criteria
PREVIOUS TEXT
Not applicable.
ADDED TEXT
2. The subject is of Thai nationality.
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
107
7.1
Time and Events Table
PREVIOUS TEXT
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120 Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Informed Consent 
Process 
X
Demographic 
Information 
X
Initial History 
Only d
X
Physician Assess. 
Malaria Signs & 
Symptoms 
X
Inclusion/Exclusion 
Criteria 
X
Efficacy Assessments 
Parasitological 
Assessment (blood 
smear) 
X
X
X
X
X
X
X
X
Plasmodium PCR 
genotyping
X
X
Safety Assessments 
Review 
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
X
Vital Signs e
X
X
X
X
X
X
X
Brief Physical 
Examination 
X
X
X
X
X
X
X
X
X
Adverse Events 
Assessment f
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Events g
X
X
X
X
X
X
X
X
X
X
G6PD 
(phenotyping) h
X
G6PD (genotyping)
X i
Laboratory Assessments 
Hematology j
X
X
X
Clinical 
Chemistry k
X
X
Methemoglobin 
X
X
Pregnancy Test l
X
X
X
X
X
X
Pharmacokinetic Assessments 
Pharmacokinetic
Sampling
Xm
Xn
Xn
X
X
Investigational Product 
Dispense Open 
Label tafenoquine
X

2014N207627_03
CONFIDENTIAL
TAF113577
108
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120 Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Treatment 
Compliance Int. -
Invest. 
X
IVRS Registration 
X
a.
Subjects who have a recurrence will continue to be monitored for safety and efficacy at all scheduled visits 
through day 120. Recurrence is defined by a positive blood smear with or without vivax malaria symptoms.
b.
If a subject withdraws, the site should offer to conduct safety assessments through Day 120.
c.
Visit Day 1 includes all screening procedures and treatment with tafenoquine.
d.
Includes medical, disease and therapy histories.
e.
Vital signs include height and weight (screening only), blood pressure, temperature, heart rate and respiratory 
rate. Vital signs are to be performed on Day 1, and immediately prior to all pharmacokinetic sampling.
f.
Adverse events are recorded from the time of the first dose of study medication.
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 quantitative spectrophotometric analysis. One or more G6PD rapid 
point of care tests may be performed at baseline (Day 1) only.
i.
A blood sample for G6PD genotyping will be collected only from subjects who experience a SAE due to
hemoglobin decline.  Subjects with hemoglobin decline should continue to attend all visits through Day 120 to 
monitor Hb status.
j.
Hematology includes hemoglobin, hematocrit, red blood cell/white blood cell/platelet counts, mean cell 
volume, white blood cell differential and reticulocyte count.
k.
Clinical Chemistry includes CPK, BUN, serum creatinine, total and indirect bilirubin and liver clinical 
chemistry.
l.
Pregnancy testing is only for females of child-bearing potential. Use a urine pregnancy test that is routinely 
used at the site with a test sensitivity for human chorionic gonadotropin (hCG) level ≤ 25 mIU/mL.
m.
Day 3 PK sample must be taken 24-96 hours post TQ dose.
n.
Once full PK sampling has completed, remaining enrolled subjects will provide two PK samples at Day 15 and 
Day 29.
REVISED TEXT
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120
Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Informed Consent 
Process 
X
Demographic 
Information 
X
Initial History 
Only d
X
Physician Assess. 
Malaria Signs & 
Symptoms 
X
Inclusion/Exclusion 
Criteria 
X

2014N207627_03
CONFIDENTIAL
TAF113577
109
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120
Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Efficacy Assessments 
Parasitological 
Assessment (blood 
smear) 
X
X
X
X
X
X
X
X
Plasmodium PCR 
genotyping
X
X
Safety Assessments 
Review 
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
X
Vital Signs e
X
X
X
X
X
X
X
X
X
X
Brief Physical 
Examination 
X
X
X
X
X
X
X
X
X
X
Adverse Events 
Assessment f
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Events g
X
X
X
X
X
X
X
X
X
X
G6PD 
(phenotyping) h
X
G6PD (genotyping)
X i
Laboratory Assessments 
Hematology j
X
X
X
Clinical 
Chemistry k
X
X
Methemoglobin 
X
X
Pregnancy Test l
X
X
X
X
X
X
Pharmacokinetic Assessments 
Pharmacokinetic
Sampling
Xm
Xn
Xn
X
X
Investigational Product 
Dispense Open 
Label tafenoquine
X
Treatment 
Compliance Int. -
Invest. 
X
IVRS Registration 
X
a.
Subjects who have a recurrence will continue to be monitored for safety and efficacy at all scheduled visits 
through day 120. Recurrence is defined by a positive blood smear with or without vivax malaria symptoms.
b.
If a subject withdraws, the site should offer to conduct safety assessments through Day 120.
c.
Visit Day 1 includes all screening procedures and treatment with tafenoquine.
d.
Includes medical, disease and therapy histories.
e.
Vital signs include height and weight (screening only), blood pressure, temperature, heart rate and respiratory 
rate.  Refer to Section 7.5.4 for additional details.
f.
Adverse events are recorded from the time of the first dose of study medication.
g.
Serious adverse events are recorded from the time of consent in order to fulfil international regulatory 
requirements.

2014N207627_03
CONFIDENTIAL
TAF113577
110
h.
G6PD phenotyping to be performed by quantitative spectrophotometric analysis. One or more G6PD rapid 
point of care tests may be performed at baseline (Day 1) only.
i.
A blood sample for G6PD genotyping will be collected only from subjects who experience a SAE due to 
hemoglobin decline.  Subjects with hemoglobin decline should continue to attend all visits through Day 120 to 
monitor Hb status.
j.
Hematology includes hemoglobin, hematocrit, red blood cell/white blood cell/platelet counts, mean cell 
volume, white blood cell differential and reticulocyte count.
k.
Clinical Chemistry includes CPK, BUN, serum creatinine, total and indirect bilirubin and liver clinical 
chemistry.
l.
Pregnancy testing is only for females of child-bearing potential. Use a urine pregnancy test that is routinely 
used at the site with a test sensitivity for human chorionic gonadotropin (hCG) level ≤ 25 mIU/mL.
m.
Day 3 PK sample must be taken 24-96 hours post TQ dose.
n.
Once full PK sampling has completed, remaining enrolled subjects will provide two PK samples at Day 15 and 
Day 29.
Amendment 2
This amendment is global and applies to all centers.  In this amendment a newly-
described risk was added to the Risk Assessment Table, a typographical error was 
corrected in the inclusion criteria regarding approved methods of contraception, and, 
based on results from cohort 1, changes were made to the tafenoquine dose banding 
scheme.  A change was made to the secondary medical monitor.
In addition, the site-specific information in the previous amendment will be carried over 
into this amendment, thus superseding Amendment No. 1.  
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
PREVIOUS TEXT
Role
Name
Day Time Phone 
Number and email 
address
After-hours Cell
Number
Site Address
Secondary 
Medical 
Monitor
GlaxoSmithKline 
Research & 
Development 
Limited
Iron Bridge Road 
Stockley Park 
West, Uxbridge, 
Middlesex, UB11 
1BT, UK
PPD
PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
111
REVISED TEXT
Role
Name
Day Time Phone Number 
and email address
After-hours Cell
Number
Site Address
Secondary 
Medical 
Monitor
GlaxoSmithKline 
Research & 
Development 
Limited
Iron Bridge Road 
Stockley Park 
West, Uxbridge, 
Middlesex, UB11 
1BT, UK
4.6.1. Risk Assessment
PREVIOUS TEXT
Not applicable.
ADDED TEXT (to Risk Assessment Table)
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Nervous system & psychiatric 
disorders
Phase 3 results in adult 
patients showed mild to 
moderate self-limiting nervous 
system & psychiatric disorders 
including dizziness, anxiety & 
insomnia. See Investigator 
Brochure addendum for more 
details. 

Consider excluding 
patients with a history of 
serious psychiatric 
disorders such as 
psychosis, depression 
and suicidal ideation.
5.1.
Inclusion Criteria
PREVIOUS TEXT
2.
The subject is of Thai nationality.
REVISED TEXT
2.
The subject is of Thai nationality (applicable only to subjects at center
.
PPD
PPD
PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
112
PREVIOUS TEXT
[4] SEX

Males and females are eligible to enter the study.  A female is eligible to enter and 
participate in this study if she is non-pregnant, non-lactating and if she is of:
a.
Non-childbearing potential (i.e., premenstrual); or,
b. Child-bearing potential, has a negative pregnancy test at screening, and agrees 
to comply with one of the following during the treatment stage of the study 
and for a period of 90 days after stopping study medication:
i. Complete abstinence from intercourse for 2 weeks prior to administration 
of study medication, throughout the study and for a period of 90 days 
after stopping study medication.
ii. Use of combined oral contraceptive consisting of spermicide with either 
condom or diaphragm
iii. Use of intrauterine device with a documented failure rate of <1% per year
iv. Use of depo provera injection
v. Male partner who is sterile prior to the female subject's entry into the 
study and is the sole sexual partner for that female.
REVISED TEXT
[4] SEX
8. Males and females are eligible to enter the study.  A female is eligible to enter and 
participate in this study if she is non-pregnant, non-lactating and if she is of:
a.
Non-childbearing potential (i.e., premenstrual); or,
b. Child-bearing potential, has a negative pregnancy test at screening, and agrees 
to comply with one of the following during the treatment stage of the study 
and for a period of 90 days after stopping study medication:
i. Use of oral contraceptive, either combined or progestogen alone used in 
conjunction with double barrier method as defined below.
ii. Use of an intrauterine device with a documented failure rate of <1% per 
year.
iii. Use of depo provera injection
iv. Double barrier method consisting of spermicide with either condom or 
diaphragm
v. Male partner who is sterile prior to the female subject’s entry into the 
study and is the sole sexual partner for that female.
vi. Complete abstinence from intercourse for 2 weeks prior to administration 
of study medication, throughout the study and for a period of 90 days 
after stopping study medication.

2014N207627_03
CONFIDENTIAL
TAF113577
113
6.1.
Treatment Assignment
PREVIOUS TEXT
Table 10
Tafenoquine Dosing
Tafenoquine Dosea
Dosing Regimen
Weights
>45 kg
300 mg
2 × 150 mg
>40–≤45 kg
300 mg
2 × 150 mg
>35–≤40kg
300 mg
2 × 150 mg
>30–≤35kg
200 mg
4 × 50 mg
>25–≤30 kg
200 mg
4 × 50 mg
>20–≤25 kg
200 mg
4 × 50 mg
>15–≤20 kg
150 mg
3 × 50 mg
>10–≤15 kg
150 mg
3 × 50 mg
≥5–≤10 kg
100 mg
2 × 50 mg
a.  The TQ dose is based on achieving a target AUC(0–∞) of 96 μg.h/ml.
The single dose of TQ will be administered at the investigator site.  Subjects >35 kg will 
take the TQ adult tablet.  All study medication should be administered with food. If the 
subject vomits within 1 hour following dosing, a repeat dose should be given. If a subject 
sequentially vomits two doses of study medication he/she will be considered intolerant to 
study medication. These subjects will be withdrawn from study medication and be given 
appropriate rescue medication as outlined in Section 6.9.1.2.
REVISED TEXT

2014N207627_03
CONFIDENTIAL
TAF113577
114
Table 11
Tafenoquine Dosing
Weights
Tafenoquine Dosea
Dosing Regimen
>45 kg
300 mg
2 × 150 mg
or
6 × 50 mg
>40–≤45 kg
300 mg
2 × 150 mg
or
6 × 50 mg
>35–≤40kg
300 mg
2 × 150 mg
or
6 × 50 mg
>30–≤35kg
200 mg
4 × 50 mg
>25–≤30 kg
200 mg
4 × 50 mg
>20–≤25 kg
200 mg
4 × 50 mg
>15–≤20 kg
100 mg
2 × 50 mg
>10–≤15 kg
100 mg
2 × 50 mg
≥5–≤10 kg
50 mg
1 × 50 mg
a.  The TQ dose is based on achieving a target AUC(0–∞) of 96 μg.h/ml.
The single dose of TQ will be administered at the investigator site.  Subjects >35 kg have 
the choice of taking the TQ adult tablet or the TQ pediatric tablet.  All study medication 
should be administered with food. If the subject vomits within 1 hour following dosing, a 
repeat dose should be given. If a subject sequentially vomits two doses of study 
medication he/she will be considered intolerant to study medication. These subjects will 
be withdrawn from study medication and be given appropriate rescue medication as 
outlined in Section 6.9.1.2.
7.1.
Time and Events Table
PREVIOUS TEXT
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120
Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Informed Consent 
Process 
X
Demographic 
Information 
X

2014N207627_03
CONFIDENTIAL
TAF113577
115
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120
Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Initial History 
Only d
X
Physician Assess. 
Malaria Signs & 
Symptoms 
X
Inclusion/Exclusion 
Criteria 
X
Efficacy Assessments 
Parasitological 
Assessment (blood 
smear) 
X
X
X
X
X
X
X
X
Plasmodium PCR 
genotyping
X
X
Safety Assessments 
Review 
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
X
Vital Signs e
X
X
X
X
X
X
X
X
X
X
Brief Physical 
Examination 
X
X
X
X
X
X
X
X
X
X
Adverse Events 
Assessment f
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Events g
X
X
X
X
X
X
X
X
X
X
G6PD 
(phenotyping) h
X
G6PD (genotyping)
X i
Laboratory Assessments 
Hematology j
X
X
X
Clinical 
Chemistry k
X
X
Methemoglobin 
X
X
Pregnancy Test l
X
X
X
X
X
X
Pharmacokinetic Assessments 
Pharmacokinetic
Sampling
Xm
Xn
Xn
X
X
Investigational Product 
Dispense Open 
Label tafenoquine
X
Treatment 
Compliance Int. -
Invest. 
X
IVRS Registration 
X
a.
Subjects who have a recurrence will continue to be monitored for safety and efficacy at all scheduled visits 
through day 120. Recurrence is defined by a positive blood smear with or without vivax malaria symptoms.
b.
If a subject withdraws, the site should offer to conduct safety assessments through Day 120.
c.
Visit Day 1 includes all screening procedures and treatment with tafenoquine.

2014N207627_03
CONFIDENTIAL
TAF113577
116
d.
Includes medical, disease and therapy histories.
e.
Vital signs include height and weight (screening only), blood pressure, temperature, heart rate and respiratory 
rate.  Refer to Section 7.5.4 for additional details.
f.
Adverse events are recorded from the time of the first dose of study medication.
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 quantitative spectrophotometric analysis. One or more G6PD rapid 
point of care tests may be performed at baseline (Day 1) only.
i.
A blood sample for G6PD genotyping will be collected only from subjects who experience a SAE due to 
hemoglobin decline.  Subjects with hemoglobin decline should continue to attend all visits through Day 120 to 
monitor Hb status.
j.
Hematology includes hemoglobin, hematocrit, red blood cell/white blood cell/platelet counts, mean cell 
volume, white blood cell differential and reticulocyte count.
k.
Clinical Chemistry includes CPK, BUN, serum creatinine, total and indirect bilirubin and liver clinical 
chemistry.
l.
Pregnancy testing is only for females of child-bearing potential. Use a urine pregnancy test that is routinely 
used at the site with a test sensitivity for human chorionic gonadotropin (hCG) level ≤ 25 mIU/mL.
m.
Day 3 PK sample must be taken 24-96 hours post TQ dose.
n.
Once full PK sampling has completed, remaining enrolled subjects will provide two PK samples at Day 15 and 
Day 29.
REVISED TEXT
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120 Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Informed Consent 
Process 
X
Demographic 
Information 
X
Initial History 
Only d
X
Physician Assess. 
Malaria Signs & 
Symptoms 
X
Inclusion/Exclusion 
Criteria 
X
Efficacy Assessments 
Parasitological 
Assessment (blood 
smear) 
X
X
X
X
X
X
X
X
Plasmodium PCR 
genotyping
X
X
Safety Assessments 
Review 
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
X
Vital Signs e,f
X
X
X
X
X
X
X
Brief Physical 
Examination f
X
X
X
X
X
X
X
X
X

2014N207627_03
CONFIDENTIAL
TAF113577
117
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120 Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Adverse Events 
Assessment g
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Events h
X
X
X
X
X
X
X
X
X
X
G6PD 
(phenotyping) i
X
G6PD (genotyping)
X j
Laboratory Assessments 
Hematology k
X
X
X
Clinical Chemistry l
X
X
Methemoglobin 
X
X
Pregnancy Test m
X
X
X
X
X
X
Pharmacokinetic Assessments 
Pharmacokinetic
Sampling
Xn
Xo
Xo
X
X
Investigational Product 
Dispense Open 
Label tafenoquine
X
Treatment 
Compliance Int. -
Invest. 
X
IVRS Registration 
X
a.
Subjects who have a recurrence will continue to be monitored for safety and efficacy at all scheduled visits 
through day 120. Recurrence is defined by a positive blood smear with or without vivax malaria symptoms.
b.
If a subject withdraws, the site should offer to conduct safety assessments through Day 120.
c.
Visit Day 1 includes all screening procedures and treatment with tafenoquine.
d.
Includes medical, disease and therapy histories.
e.
Vital signs include height and weight (screening only), blood pressure, temperature, heart rate and respiratory 
rate.  Refer to Section 7.5.4 for additional details.
f.
At Center
, Vital Signs and Brief Physical Examination will be performed at every visit.
g.
Adverse events are recorded from the time of the first dose of study medication.
h.
Serious adverse events are recorded from the time of consent in order to fulfil international regulatory 
requirements.
i.
G6PD phenotyping to be performed by quantitative spectrophotometric analysis. One or more G6PD rapid 
point of care tests may be performed at baseline (Day 1) only.
j.
A blood sample for G6PD genotyping will be collected only from subjects who experience a SAE due to 
hemoglobin decline.  Subjects with hemoglobin decline should continue to attend all visits through Day 120 to 
monitor Hb status.
k.
Hematology includes hemoglobin, hematocrit, red blood cell/white blood cell/platelet counts, mean cell 
volume, white blood cell differential and reticulocyte count.
l.
Clinical Chemistry includes CPK, BUN, serum creatinine, total and indirect bilirubin and liver clinical 
chemistry.
m.
Pregnancy testing is only for females of child-bearing potential. Use a urine pregnancy test that is routinely 
used at the site with a test sensitivity for human chorionic gonadotropin (hCG) level ≤ 25 mIU/mL.
n.
Day 3 PK sample must be taken 24-96 hours post TQ dose.
o.
Once full PK sampling has completed, remaining enrolled subjects will provide two PK samples at Day 15 and 
Day 29.
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
118
7.5.3. Physical Exams
PREVIOUS TEXT
Physical examinations will be performed during the treatment period (Day 1), at all 
follow-up visits, and if there is a relapse or premature withdrawal visit.
REVISED TEXT
Physical examinations will be performed during the treatment period (Day 1), the follow-
up period on Days 3, 8, 29, 60, 90 and 120 and if there is a relapse or premature 
withdrawal visit.  (At center 
physical examinations are required at all follow-up 
visits.)  
7.5.4. Vital Signs
PREVIOUS TEXT
Vital signs will be performed on the day of TQ treatment (Day 1), at all follow-up visits, 
and if there is a recurrence or premature withdrawal visit.  At visits where a 
pharmacokinetic (PK) sample is taken, vital signs should be conducted immediately prior 
to the PK sample collection.  
REVISED TEXT
Vital signs will be performed on the day of TQ treatment (Day 1), immediately prior to 
pharmacokinetic (PK) measurements, and if there is a recurrence or premature 
withdrawal visit.  (At center 
vital signs are to be performed at all follow-up 
visits.)  
Amendment 3
Amendment No. 3 is a site-specific amendment, and applies to one center in Brazil 
(Center 
; Manaus, Brazil).  Revisions to the protocol were made for this center to 
conduct ophthalmic assessments of subjects at screening and prior to randomization, at 
the Day 120 visit, and at withdrawal as applicable.
4. STUDY DESIGN
PREVIOUS TEXT
Not applicable.
ADDED TEXT
PPD
PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
119

A single center (
; Manaus, Brazil) will perform ophthalmic safety 
assessments at selected visits to monitor subjects for changes in the eye.
5.2. Exclusion Criteria
PREVIOUS TEXT
Not applicable.
ADDED TEXT
13.
The subject has any retinal abnormality in the macular region, either pre-existing or 
identified at the baseline visit (Center 
only).
7.1 Time and Events Table
PREVIOUS TEXT
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120
Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Informed Consent 
Process 
X
Demographic 
Information 
X
Initial History 
Only d
X
Physician Assess. 
Malaria Signs & 
Symptoms 
X
Inclusion/Exclusion 
Criteria 
X
Efficacy Assessments 
Parasitological 
Assessment (blood 
smear) 
X
X
X
X
X
X
X
X
Plasmodium PCR 
genotyping
X
X
Safety Assessments 
Review 
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
X
Vital Signs e,f
X
X
X
X
X
X
X
Brief Physical 
Examination f
X
X
X
X
X
X
X
X
X
Adverse Events 
Assessment g
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Events h
X
X
X
X
X
X
X
X
X
X
PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
120
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120
Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
G6PD 
(phenotyping) i
X
G6PD (genotyping)
X j
Laboratory Assessments 
Hematology k
X
X
X
Clinical Chemistry l
X
X
Methemoglobin 
X
X
Pregnancy Test m
X
X
X
X
X
X
Pharmacokinetic Assessments 
Pharmacokinetic
Sampling
Xn
Xo
Xo
X
X
Investigational Product 
Dispense Open 
Label tafenoquine
X
Treatment 
Compliance Int. -
Invest. 
X
IVRS Registration 
X
a.
Subjects who have a recurrence will continue to be monitored for safety and efficacy at all scheduled visits 
through day 120. Recurrence is defined by a positive blood smear with or without vivax malaria symptoms.
b.
If a subject withdraws, the site should offer to conduct safety assessments through Day 120.
c.
Visit Day 1 includes all screening procedures and treatment with tafenoquine.
d.
Includes medical, disease and therapy histories.
e.
Vital signs include height and weight (screening only), blood pressure, temperature, heart rate and respiratory 
rate.  Refer to Section 7.5.4 for additional details.
f.
At Center 
, Vital Signs and Brief Physical Examination will be performed at every visit.
g.
Adverse events are recorded from the time of the first dose of study medication.
h.
Serious adverse events are recorded from the time of consent in order to fulfil international regulatory 
requirements.
i.
G6PD phenotyping to be performed by quantitative spectrophotometric analysis. One or more G6PD rapid 
point of care tests may be performed at baseline (Day 1) only.
j.
A blood sample for G6PD genotyping will be collected only from subjects who experience a SAE due to 
hemoglobin decline.  Subjects with hemoglobin decline should continue to attend all visits through Day 120 to 
monitor Hb status.
k.
Hematology includes hemoglobin, hematocrit, red blood cell/white blood cell/platelet counts, mean cell 
volume, white blood cell differential and reticulocyte count.
l.
Clinical Chemistry includes CPK, BUN, serum creatinine, total and indirect bilirubin and liver clinical 
chemistry.
m.
Pregnancy testing is only for females of child-bearing potential. Use a urine pregnancy test that is routinely 
used at the site with a test sensitivity for human chorionic gonadotropin (hCG) level ≤ 25 mIU/mL.
n.
Day 3 PK sample must be taken 24-96 hours post TQ dose.
o.
Once full PK sampling has completed, remaining enrolled subjects will provide two PK samples at Day 15 and 
Day 29.
REVISED TEXT
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
121
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120 Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
Informed Consent 
Process 
X
Demographic 
Information 
X
Initial History 
Only d
X
Physician Assess. 
Malaria Signs & 
Symptoms 
X
Inclusion/Exclusion 
Criteria 
X
Efficacy Assessments 
Parasitological 
Assessment (blood 
smear) 
X
X
X
X
X
X
X
X
Plasmodium PCR 
genotyping
X
X
Safety Assessments 
Review 
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
X
Vital Signs e,f
X
X
X
X
X
X
X
Brief Physical 
Examination f
X
X
X
X
X
X
X
X
X
Adverse Events 
Assessment g
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Events h
X
X
X
X
X
X
X
X
X
X
G6PD 
(phenotyping) i
X
G6PD (genotyping)
X j
Ophthalmological 
Exam (qualified 
site only)
X
X
X
Laboratory Assessments 
Hematology k
X
X
X
Clinical Chemistry l
X
X
Methemoglobin 
X
X
Pregnancy Test m
X
X
X
X
X
X
Pharmacokinetic Assessments 
Pharmacokinetic
Sampling
Xn
Xo
Xo
X
X
Investigational Product 
Dispense Open 
Label tafenoquine
X
Treatment 
Compliance Int. -
Invest. 
X

2014N207627_03
CONFIDENTIAL
TAF113577
122
Protocol Activity
Visit Day 
Screen & Treat
Follow-Up Period
Recurrence
Visita
Withdrawal 
Visitb
Day 1c
Day 3 day 8 Day 15 Day 
29
Day 
60 Day 90 Day 
120 Recurrence Withdrawal 
Window
+2d
-/+2d
-/+3d
-/+5d -/+10d -/+10d -/+10d
IVRS Registration 
X
a.
Subjects who have a recurrence will continue to be monitored for safety and efficacy at all scheduled visits 
through day 120. Recurrence is defined by a positive blood smear with or without vivax malaria symptoms.
b.
If a subject withdraws, the site should offer to conduct safety assessments through Day 120.
c.
Visit Day 1 includes all screening procedures and treatment with tafenoquine.
d.
Includes medical, disease and therapy histories.
e.
Vital signs include height and weight (screening only), blood pressure, temperature, heart rate and respiratory 
rate.  Refer to Section 7.5.4 for additional details.
f.
At Center 
 Vital Signs and Brief Physical Examination will be performed at every visit.
g.
Adverse events are recorded from the time of the first dose of study medication.
h.
Serious adverse events are recorded from the time of consent in order to fulfil international regulatory 
requirements.
i.
G6PD phenotyping to be performed by quantitative spectrophotometric analysis. One or more G6PD rapid 
point of care tests may be performed at baseline (Day 1) only.
j.
A blood sample for G6PD genotyping will be collected only from subjects who experience a SAE due to 
hemoglobin decline.  Subjects with hemoglobin decline should continue to attend all visits through Day 120 to 
monitor Hb status.
k.
Hematology includes hemoglobin, hematocrit, red blood cell/white blood cell/platelet counts, mean cell 
volume, white blood cell differential and reticulocyte count.
l.
Clinical Chemistry includes CPK, BUN, serum creatinine, total and indirect bilirubin and liver clinical 
chemistry.
m.
Pregnancy testing is only for females of child-bearing potential. Use a urine pregnancy test that is routinely 
used at the site with a test sensitivity for human chorionic gonadotropin (hCG) level ≤ 25 mIU/mL.
n.
Day 3 PK sample must be taken 24-96 hours post TQ dose.
o.
Once full PK sampling has completed, remaining enrolled subjects will provide two PK samples at Day 15 and 
Day 29.
7.2. Screening and Critical Baseline Assessments
PREVIOUS TEXT
Not applicable.
ADDED TEXT

Center
 (Manuas, Brazil) only will perform the following ophthalmic 
assessments prior to randomization:
o
Visual acuity will be assessed by standard methods
o
Slit lamp examination of the cornea to evaluate for vortex keratopathy 
o
Retinal digital imaging (color photographs, fundus autofluorescence and 
OCT)
PPD
PPD

2014N207627_03
CONFIDENTIAL
TAF113577
123
7.5.7. Ophthalmic Assessments (Center
 Only)
PREVIOUS TEXT
Not applicable.
ADDED TEXT
Ophthalmic assessments will be performed at Center
(Manaus, Brazil) at 
screening and prior to randomization, at Day 120 and at the withdrawal visit, if 
applicable. The Principal Investigator and site ophthalmologist will determine if the child 
is able to comply with the assessments, based on their malaria status and ability to 
reasonably cooperate with the assessments.  Subjects who do not complete the 
ophthalmic examination at baseline, including interpretable retinal imaging, should not 
complete ophthalmic exams at follow-up or withdrawal.  If a subject completes a portion 
of the ophthalmic exams at baseline, only those same exams should be completed at 
follow-up.
9.4.2. Secondary Analyses
PREVIOUS TEXT
The overall safety and particularly of key endpoints such as gastrointestinal tolerability, 
clinically relevant drops in hemoglobin and incidence of AEs will be assessed.
REVISED TEXT
The overall safety and particularly of key endpoints such as gastrointestinal tolerability, 
clinically relevant drops in hemoglobin and incidence of AEs will be assessed.  The 
ophthalmic assessments of visual acuity, keratopathy and retinopathy will be 
summarized.
PPD
PPD