Clinical trial NCT02563496
Conditions: Malaria, Vivax
Keywords: pharmacokinetic pediatric Tafenoquine Plasmodium vivax Malaria G6PD deficiency
Sponsor: GlaxoSmithKline
Start date: 2017-02-06; Completion date: 2020-02-17
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, open-label, multicenter, non-comparative, single arm study of pediatric subjects with Plasmodium vivax (P. vivax) malaria, aged 6 months to \<16 years of age. A total of 60 subjects will be enrolled. Potential subjects who are slide-positive for P. vivax will be started by the site on chloroquine (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 Tafenoquine (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 (Days 3, 8, 15, 29, 60, 90 and 120). 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 kilogram \[kg\]) will be recruited following completion of a planned first interim analysis. An interim analysis will be conducted once sufficient data from 16 subjects is available to assess pharmacokinetic (PK) and safety parameters. If needed, a second interim analysis will be conducted after a total of 32 subjects have enrolled. The primary objective of this PK bridging study is to adequately characterize the systemic TQ exposure in the pediatric population in order to identify appropriate doses that achieve a similar exposure to that of the TQ adult dose of 300 milligram (mg).

Detailed description:

Arms: arm 1: Subjects with weight band of \>=5 to \<=10 kilogram (kg) will receive 50 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines. arm 2: Subjects with weight band of \>10 to \<=20 kg will receive 100 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines. arm 3: Subjects with weight band of \>10 to \<=20 kg will receive 150 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines. arm 4: Subjects with weight band of \>20 to \<=35 kg will receive 200 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines. arm 5: Subjects with weight band of \>35 kg will receive 300 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines.
Interventions: intervention 1: Tafenoquine intervention 2: Chloroquine
Intervention descriptions: intervention 1: Tafenoquine tablet is supplied as film-coated tablet (100 mg, 150 mg, 200 mg and 300 mg) and fast-dispersing film coated tablet (50 mg). intervention 2: Subjects may receive chloroquine according to local/national treatment guidelines.

Protocol documents:
Prot_000.pdf: 
2014N207627_03
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The GlaxoSmithKline group of companies
TAF113577
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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.
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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).
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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.
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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
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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


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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


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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
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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


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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 


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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 


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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.


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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].


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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].


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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.


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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.


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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.


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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)].


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
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


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Figure 1
TAF113577 Study Design Schema


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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.


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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 


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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)


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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.


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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:  


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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.


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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


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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 


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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.


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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.


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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.
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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)


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
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.  
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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.


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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.


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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.


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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. 


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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 


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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.


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6.9.
Concomitant Medications and Non-Drug Therapies
6.9.1.
Permitted Medications and Non-Drug Therapies
6.9.1.1.
Concomitant Medications
All subjects can be given paracetamol 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


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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.


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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table (Section 7.1).


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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


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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


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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


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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.


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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, 
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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.


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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).


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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 
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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).
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
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 
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(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.
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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 
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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).


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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 


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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 


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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 
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
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 


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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.


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
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.


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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.


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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.


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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.


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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


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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


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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


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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.


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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.


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


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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.


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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


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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.


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
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 


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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.


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


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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.


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12.5.
Appendix 5 - Country Specific Requirements
No country-specific requirements exist.


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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.


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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


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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.


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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


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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


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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.


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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!


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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


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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.


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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


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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.


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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


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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


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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.


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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


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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)


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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%.


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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:


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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)


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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.


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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)


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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)


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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).


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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).


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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.


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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


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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


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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


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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


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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


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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.


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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


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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
.
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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.


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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


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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


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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.


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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


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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.
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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
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
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
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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
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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


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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)
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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
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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
TAF113577
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 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
Effective Date 
:
17 January 2020
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol TAF113577

This RAP is intended to describe the interim and final analyses required for the 
study. 

This version includes amendments to the originally approved RAP.

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.


CONFIDENTIAL
The GlaxoSmithKline group of companies
TAF113577
2
RAP Author(s): 
Approver
Date
Approval 
Method
Director Clinical Pharmacology (CPMS)
09Dec2019
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Author for 
Final RAP and 
Amendment 1
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Author for 
Amendment 2
RAP Team Approvals: 
Approver
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Global Clinical Development Manager, (GCSD
09Jan2020
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Global Health Physician (Global Health 
Clinical)
09Dec2019
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Manager (Clinical Data Management)
09Jan2020
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Medical Director (SERM, SMG Pharma Safety)
06Dec2019
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Director (Global Regulatory Affairs)
08Jan2020
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Programming Manager (Biostatistics)
09Dec2019
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Clinical Statistics and Clinical Programming Line Approvals: 
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Director (Biostatistics)
17Jan2020
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TAF113577
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................6
1.1.
RAP Amendments ........................................................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................9
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................9
2.2.
Study Objective(s) and Endpoint(s)...............................................................9
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses.................................................................................11
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................13
4.
ANALYSIS POPULATIONS ...................................................................................14
4.1.
Protocol Deviations.....................................................................................14
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................16
6.1.
Overview of Planned Analyses ...................................................................16
6.2.
Subject Disposition .....................................................................................16
6.3.
Protocol Deviations.....................................................................................16
6.4.
Demography and Baseline Characteristics .................................................16
6.5.
Prior and Concomitant Medications and Conditions....................................17
6.6.
Treatment Compliance and Exposure.........................................................17
7.
PRIMARY PK AND STATISTICAL ANALYSES......................................................18
7.1.
PK Analyses ...............................................................................................18
7.1.1.
Overview of Planned PK Analyses...............................................18
7.1.2.
Planned PK Statistical Analyses ..................................................19
8.
SECONDARY STATISTICAL ANALYSES .............................................................20
8.1.
Efficacy Analyses........................................................................................20
8.1.1.
Overview of Planned Efficacy Analyses .......................................20
8.2.
Safety Analyses..........................................................................................20
8.2.1.
Overview of Planned Analyses ....................................................20
8.2.1.1.
Adverse Events ..........................................................21
8.3.
Vital Signs...................................................................................................23
8.4.
Clinical Laboratory Parameters...................................................................23
8.4.1.
Overview of Planned Clinical Laboratory Analyses ......................23
8.4.2.
Hemoglobin Declines and Related Laboratory Parameters..........25
8.5.
Pharmacokinetic Analyses..........................................................................25
8.5.1.
Overview of Planned Pharmacokinetic Analyses .........................25
8.5.2.
Drug Concentration Measures .....................................................25
8.5.3.
Pharmacokinetic Parameters.......................................................25
8.5.4.
Population Pharmacokinetic (PopPK) Analyses...........................25
8.6.
Pharmacodynamic Analyses.......................................................................26
8.7.
Pharmacokinetic / Pharmacodynamic Analyses..........................................26


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8.8.
Evaluation of Microsampling .......................................................................26
9.
REFERENCES.......................................................................................................27
10. APPENDICES........................................................................................................28
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................29
10.1.1.
Exclusions from Per Protocol Population .....................................29
10.2.
Appendix 2: Time & Events.........................................................................30
10.2.1.
Protocol Defined Time & Events ..................................................30
10.3.
Appendix 3: Assessment Windows .............................................................33
10.3.1.
Definitions of Assessment Windows for Analyses........................33
10.4.
Appendix 4: Treatment States and Phases.................................................34
10.4.1.
Treatment States .........................................................................34
10.4.1.1.
Treatment States for AE Data.....................................34
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................35
10.5.1.
Study Treatment & Sub-group Display Descriptors......................35
10.5.2.
Baseline Definition & Derivations .................................................35
10.5.2.1.
Baseline Definitions....................................................35
10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................35
10.5.3.
Reporting Process & Standards...................................................36
10.6.
Appendix 6: Derived and Transformed Data ...............................................38
10.6.1.
General........................................................................................38
10.6.2.
Study Population..........................................................................38
10.6.3.
Safety ..........................................................................................40
10.6.4.
Efficacy........................................................................................42
10.6.5.
Pharmacokinetic ..........................................................................43
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............44
10.7.1.
Premature Withdrawals................................................................44
10.7.2.
Handling of Missing Data.............................................................44
10.7.2.1.
Handling of Missing Dates..........................................44
10.7.2.2.
Handling of Partial Dates............................................45
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................46
10.8.1.
Laboratory Values........................................................................46
10.9.
Appendix 9: Multicenter Studies..................................................................48
10.9.1.
Methods for Handling Centres .....................................................48
10.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata..........49
10.10.1. Handling of Covariates, Subgroups & Other Strata......................49
10.10.1.1. Footnote Regarding Dose Groups..............................49
10.11. Appendix 11: Multiple Comparisons & Multiplicity .......................................50
10.11.1. Handling of Multiple Comparisons & Multiplicity...........................50
10.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................51
10.12.1. Statistical Analysis Assumptions..................................................51
10.13. Appendix 13: Population Pharmacokinetic Analyses...................................52
10.13.1. Introduction..................................................................................52
10.13.2. General Considerations For Data Analyses and Handling ...........52
10.13.2.1. Software.....................................................................52
10.13.2.2. Data Set Preparation..................................................52
10.13.2.3. TQ Population PK dataset ..........................................53
10.13.2.4. Archival Of Data Sets .................................................53


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10.13.3. Handling of Missing Data.............................................................53
10.13.3.1. PK Data......................................................................53
10.13.3.2. Subject Demographics ...............................................53
10.13.3.3. Handling of Data Below the Lower Limit of 
Quantification .............................................................53
10.13.3.4. Handling of Outliers....................................................54
10.13.4. Population PK Modelling..............................................................54
10.13.4.1. TQ Population PK Analysis.........................................54
10.13.4.1.1. Base Model ............................................54
10.13.4.1.2. Covariate Inclusion .................................55
10.13.4.1.3. Final Model.............................................55
10.13.4.2. Interim TQ POP PK Analysis......................................55
10.13.4.3. Final TQ POP PK Analysis .........................................57
10.13.5. References ..................................................................................57
10.13.6. POP PK File Specification ...........................................................58
10.13.6.1. Pop PK Dataset File Structure....................................58
10.13.7. Output..........................................................................................62
10.13.7.1. Tables ........................................................................62
10.13.7.2. Figures .......................................................................62
10.13.7.3. Data listings................................................................62
10.13.7.4. Interim Analysis Outputs.............................................62
10.14. Appendix 14: Abbreviations & Trade Marks ................................................63
10.14.1. Abbreviations...............................................................................63
10.14.2. Trademarks .................................................................................64
10.15. Appendix 15: List of Data Displays..............................................................65
10.15.1. Data Display Numbering..............................................................65
10.15.2. Deliverable...................................................................................65
10.15.3. Study Population Tables..............................................................66
10.15.4. Efficacy Tables ............................................................................69
10.15.5. Efficacy Figures ...........................................................................69
10.15.6. Safety Tables...............................................................................70
10.15.7. Safety Figures .............................................................................75
10.15.8. Pharmacokinetic Figures .............................................................78
10.15.9. Pharmacogenetic Tables .............................................................78
10.15.10.ICH Listings .................................................................................79
10.15.11.Non-ICH Listings..........................................................................82
10.16. Appendix 16: Example Mock Shells for Data Displays ................................84


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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this Reporting and Analysis Plan (RAP) is to describe the 
analyses to be included in the Clinical Study Report for Protocol TAF113577. 
This document will be provided to the study team members to convey the 
content of the interim analyses and Statistical Analysis Complete (SAC) 
deliverables.
Protocol

This RAP is based on the amended protocol [(Dated: 06-Nov-2018) of study 
TAF113577 [GSK Document Number 2014N207627_03, 2018] and eCRF 
Version 1.
Primary 
Objective

To evaluate the pharmacokinetics (PK) of tafenoquine (TQ) 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.
Primary 
Endpoint

AUC(0-∞) of TQ by weight band from a population PK model in pediatric 
subjects aged ≥2 years to <16 years (weighing ≥5 kg).
Study 
Design

TAF113577 is a prospective, open-label, multicenter, non-comparative, single-
arm study. All subjects will receive Chloroquine (CQ) and open-label TQ.

Potential subjects who are slide-positive for P. vivax will be started by the site on 
off-study CQ per local/national guidelines.  Eligible subjects will also 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.

Approximately 240 subjects aged <16 years with P. vivax malaria will be 
screened to achieve 60 enrolled subjects.  

A subject is considered to have completed the study if they attend all treatment 
and follow-up visits.

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.

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.
Planned 
Analyses

Up to two interim analyses (at 16 and 32 subjects) have been planned so that
the initially planned four PK samples per subject can be reduced to a minimum 
of two PK samples. 

Recruitment will continue for safety data accumulation until 60 subjects are 


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Overview
Key Elements of the RAP
enrolled.

All decisions regarding final analysis, as defined in this RAP document, will be 
made prior to Database Freeze of the study data. 
Analysis 
Populations

Safety Population: all subjects who received at least one dose of study 
medication. 

Primary PK Population: all subjects with at least one PK sample taken at Days 
3, 15, 29 or 60. This population will be used for the primary PK analysis to 
evaluate TQ exposure.

Microbiologic-Intent-To-Treat (mITT) population: All subjects who received a 
dose of study treatment (tafenoquine) and have microscopically-confirmed vivax 
parasitemia at baseline.
Hypothesis

There are no hypotheses tested in this study
Primary 
Analyses

The primary population PK model-based analysis to be performed may borrow 
some information from the adult model as appropriate. For example, the sparse 
sampling in a limited number of pediatric subjects may be insufficient to 
independently characterize all the population PK parameters e.g. the absorption 
phase. Consequently the information about absorption from the adult model may 
be used as prior information to feed into the pediatric PK model with the 
assumption that these 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].”
Secondary 
Analyses

Relapse-free efficacy will be summarized descriptively. 

Safety data, including data related to gastrointestinal tolerability, clinically 
relevant drops in hemoglobin and incidence and severity of AEs, will be 
presented in tabular format and summarized descriptively according to GSK’s 
Integrated Data Standards Library (IDSL) standards.
1.1.
RAP Amendments
RAP Section
Amendment Details
Reporting and Analysis Plan_TAF113577_Final [11-APR-2017]
Reporting and Analysis Plan_TAF113577_Amendment1_Final
Section 2.3, 
Appendix 5.1
and Appendix 
Dosing amended as per Protocol TAF113577 Amendment 2 (GSK Document 
number: 2014N207627_02)


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15
Section 4
Addition of Microbiological ITT population.
Appendix 2
Time and Events table amended as per Protocol TAF113577 Amendment 2 
(GSK Document number: 2014N207627_02)
Appendix 3
Extended window for Study Day 1 to allow for screening procedures performed 
prior to Day 1. 
Appendix 6.4
Updated censoring rule for subjects who demonstrated initial clearance to align 
with other studies in the project.
Appendix 
10.12.7
Updated Pop PK file specification to align with current project standards.
Various
Minor typographical errors.
Reporting and Analysis Plan_TAF113577_Amendment2_Final
Section 2.1 and 
Section 4
Addition of 2 analysis populations, the Screened and Enrolled populations.
Section 8.2.1,
Section 10.6.3,
Appendix 
10.15.6 and 
Appendix 
10.15.7
Amended definition for common AEs to those occurring in ≥10% subjects 
(previously ≥5%)
Various
Minor clarifications and amendments.


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Three additional analysis populations have been defined in this RAP:
o
Screened
o
Enrolled
o
Microbiological ITT (MITT)
The definitions are provided in Section 4. 
The efficacy endpoint was called recurrence free efficacy in the protocol, to keep in line with other 
GSK studies in the project this will be referred to as relapse free efficacy throughout this document. 
The window in which to confirm parasite clearance has been extended from the Day 8 visit to on or 
before the Day 29 visit to allow for missed and unscheduled visits which would represent 
clearance. 
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

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 Objectives
Secondary Endpoints

To assess the safety of tafenoquine 
when administered to pediatric subjects 
with P. vivax malaria.

Key safety data (gastrointestinal tolerability, 
clinically relevant drops in hemoglobin, 
incidence and severity of adverse events and 
abnormal laboratory observations) 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.

Relapse-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).


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

An open-label, multicentre, non-comparative, single-arm study. 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 study will recruit a target of 60 subjects. The duration of the study is 
120 days; study treatment on Day 1, followed by seven follow-up visits on 
Days 3, 8, 15, 29, 60, 90 and 120. 

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. Furthermore, up to two interim 
analyses have been included in this study, so that full PK sampling can be 
reduced as soon as sufficient data have been collected. 
Dosing
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.  The doses prior to Protocol Amendment 1 are given which 
relate to the first interim analysis, together with the doses post Protocol 
Amendment 1 used in the second interim and final analyses.


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Overview of Study Design and Key Features
Weights
Tafenoquine 
Dosea prior to 
Protocol 
Amendment 2
Tafenoquine 
Dosea post 
Protocol 
Amendment 2
Dosing Regimen
post Protocol 
Amendment 2
>35 kg
300 mg
300 mg
2 × 150 mg
or
6 x 50 mg
>20–≤35 kg
200 mg
200 mg
4 × 50 mg
>10–≤20 kg
150 mg
100 mg
2 × 50 mg
≥5–≤10 kg
100 mg
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.
Treatment 
Assignment

This is an open label study. All subjects will receive TQ dose according to the 
baseline weight.
Interim 
Analysis
Up to two interim analyses have been planned so that serial but sparse PK 
sampling (i.e., 4 PK timepoints) may be reduced at the earliest opportunity.  
2.4.
Statistical Hypotheses
There are no hypotheses tested in this study.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
Up to two main interim analyses have been planned so that serial but sparse PK sampling (i.e., 4 
PK timepoints) may be reduced 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.
The interim analyses will be performed after the completion of the following sequential steps:
1.
All required subjects (i.e. 16 or 32 subjects) have PK evaluable data as defined in the protocol
(or 12/24 months post study initiation).
2.
All required database cleaning activities have been completed and interim database release 
and database freeze has been declared by Data Management.
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 TQ PK for that weight band are 
adequately characterized and the 95% interval within the targeted 55-162 µg.hr/mL. 
See Appendix 12 for details about the population pharmacokinetic analysis.
The correlation between TQ PK data from venous sampling and capillary microsampling will be 
evaluated. Based on the emerging data, if deemed appropriate, further PK sampling of TQ in 
pediatric subjects will be limited predominantly to capillary microsampling to reduce the PK 
sampling burden on this highly vulnerable population. Agreement will be evaluated based on 
correlation and Bland-Altman analyses. Further details will be documented in the TAF113577 
Interim Analysis Charter.
The decision to enroll 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 and increases in key laboratory parameters. The review and decision-making process for 
inclusion of the ≥6 months - <2 years cohort will be outlined in detail in the TAF113577 Interim 
Analysis Charter.
At each interim analysis a review of all available outputs will be performed and decisions made 
regarding the continuation of the study as pre-planned. Potential changes to the study could 
include stopping the study based on safety concerns or adjusting dosing regimens. Further details 
will be documented in the TAF113577 Interim Analysis Charter.


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3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the following 
sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database release and 
database freeze has been declared by Data Management.


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4.
ANALYSIS POPULATIONS
Table 1
Analysis Populations
Population
Definition / Criteria
Analyses Evaluated
Screened

All participants who were screened for 
eligibility.

Study Population
Enrolled

All participants who passed screening and 
entered the study.

Study Population
Safety

All subjects who received the dose of study 
treatment (tafenoquine).

Study Population

Safety
PK

All subjects with at least one PK sample taken 
at Days 3, 15, 29 or 60, with accurate dosing 
and sample time histories.

PK
MITT

All subjects who received a dose of study 
treatment (tafenoquine) and have 
microscopically-confirmed vivax parasitemia at 
baseline.

Efficacy
NOTES: 

Please refer to Appendix 15: List of Data Displays which details the population to be used for each display being 
generated.
4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study inclusion/exclusion criteria, 
conduct of the trial, patient management or patient assessment) will be summarised and 
listed.

Protocol deviations will be tracked by the study team throughout the conduct of the study in 
accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important deviations are 
captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion page of 
the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 2 provides an overview of appendices within the RAP for outlining general considerations for 
data analyses and data handling conventions. 
Table 2
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Treatment States and Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
10.9
Appendix 9: Multicenter Studies
10.10
Appendix 10: Examination of Covariates, Subgroups & Other Strata
10.11
Appendix 11: Multiple Comparisons & Multiplicity
10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
10.13
Appendix 13: Population Pharmacokinetic Analyses


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the Safety population, unless otherwise specified.
All summaries will be presented by dose group.
The precise format and content of Study Population tables are shown in Appendix 15.
All data will be listed as presented in Appendix 15. 
6.2.
Subject Disposition
For screen failed subjects, a summary displaying the reasons for screen failure as number and 
percentage of subjects will be presented.
A summary of the number of subjects in the analysis populations will be provided.
For subjects in the safety population, the following summaries will be presented:
-
The number and percentage of subjects who violated any inclusion or exclusion criteria 
along with the number and percentage for each criterion which was violated.
-
Subject disposition, including the number of subjects who withdrew and the reasons for 
withdrawal will be presented.
-
The number of subjects recruited into the study by country and centre.
6.3.
Protocol Deviations
Important protocol deviations will be determined by the clinical investigators (and reviewed by the 
study team prior to DBF) and will be tabulated within the Clinical Study Report (CSR). 
6.4.
Demography and Baseline Characteristics
Demography and other baseline characteristics (age, gender, ethnicity, height, weight, 
methemoglobin (%), G6PD enzyme activity and enzyme activity as a percentage of the site’s 
median) will be summarized for the safety population and the primary PK population.
Summaries of race and racial combinations and race and racial combination details will be 
produced.
Malaria signs and symptoms, splenomegaly status at baseline and previous episodes of malaria
will be summarized. 
No formal comparisons of baseline variables will be performed.


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6.5.
Prior and Concomitant Medications and Conditions
Summaries of prior medications (excluding prior chloroquine usage)and current (concomitant) 
medications will be produced. Additionally, a summary of the number (%) of subjects taking 
chloroquine prior to the start of study treatment will be produced.
Medical conditions by body system will be summarized separately for past medical conditions and 
current medical conditions. In addition, there will be summaries of past specific medical conditions 
and current specific medical conditions. 
Subjects who take concomitant medications during the study will be listed. Concomitant medication 
text will be coded and classified by the Generic Term and the preferred term using the 
standardized GSK coding system (GSK DRUG). 
6.6.
Treatment Compliance and Exposure
A summary of the number and percentage of subjects who were successfully dosed with TQ will be 
produced, the summary will also display the number and percentage of subjects who had to be re-
dosed. 


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7.
PRIMARY PK AND STATISTICAL ANALYSES
7.1.
PK Analyses
7.1.1.
Overview of Planned PK Analyses
The primary efficacy analyses will be based on the primary PK population, unless otherwise 
specified.
The primary population PK model based analysis to be performed at the end of the study may
borrow some information from the POP PK model developed from the systemic TQ PK data from 
the dose ranging Phase 2B study (TAF112582). For example, the sparse sampling scheme in 
pediatric subjects is likely to be insufficient to independently characterize all the population PK 
parameters e.g. 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). Additionally, any impact of formulation differences from Phase 2B study (TAF112582) 
and emerging data from the Part 2 of TAF112582 and TAF116564 may be utilized to inform model 
development. 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, 2009] (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 will be 
estimated using the population PK model. The details of the approach are described in Appendix 
12 of this study reporting and analysis plan.
The final analysis of the data will include modelling 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 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.
Full details of data displays being presented are provided in Appendix 12.


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7.1.2.
Planned PK Statistical Analyses
A population pharmacokinetic (POP PK) model based approach will be utilized to analyse the TQ 
exposure data from this study. The POP PK model based on adult TQ systemic exposure data was 
utilized to predict pediatric doses with allometric scaling.  Interim analyses will be conducted to 
estimate the systemic exposure in pediatric subjects across different weight bands. Based on that 
outcome, doses across weight bands may be modified or continued as is. The serial but sparse 
sampling may be further reduced post confirmation of exposure across weight groups as 
appropriate. The final analysis of all exposure data from this study will be conducted to formulate a 
final dosing recommendation for TQ in pediatric population. The technical details of the POP PK 
analysis are described in detail in Appendix 12.


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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Efficacy Analyses
8.1.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the mITT population, unless otherwise specified.
Secondary Statistical Analyses
Endpoint(s)

Relapse-free efficacy four months post-dosing. See Section 10.6.4 for derivations including 
censoring. 
Specification
mITT population
Kaplan-Meier estimates
Results Presentation

Summary of the proportion of subjects with relapse-free efficacy at four months as n (%) (Table 
2.2) by dose group and overall.  

Analysis table will show:

Number of subjects with an observed relapse and numbers of subjects censored 
(censored prior to 4 months, and censored relapse-free at 4 months, see Section 
10.6.4 for censoring derivations)

Point estimate and 95% confidence interval of the relapse-free efficacy rate across all 
the dose groups combined.

A Kaplan-Meier survival curve will also be produced).
Additional Efficacy Summaries

Summary of parasite presence (parasitological assessment, to include P.vivax and 
P.falciparum asexual parasites), mITT population.

Summary of subjects with P. falciparum asexual parasite emergence post baseline (n, %) 
Efficacy Listings

Efficacy data will be listed as presented in Appendix 15: List of Data Displays
8.2.
Safety Analyses
8.2.1.
Overview of Planned Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.
Safety data will be presented in tabular and/or graphical format and summarized descriptively 
according to GSK’s Integrated Data Standards Library (IDSL) standards. 


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Details of the mock-ups that describe the precise format and content of Safety figures, tables and 
listings are shown in Appendix 16.
8.2.1.1.
Adverse Events
Counting of Adverse Events (AEs) will be based on the number of subjects – not the number of 
AEs. For example, if a subject reports the same AE on three occasions within the relevant time 
interval, that AE will only be counted once.   If a subject experiences the same AE (i.e. same 
preferred term (PT)) more than once, they are counted only once under the count for the preferred 
term.  If a subject experiences more than one AE in a particular System Organ Class (SOC), they 
will only be included once in the count for the SOC, but will appear in the count for each 
appropriate preferred term within the SOC.  Therefore, the sum of the numbers of subjects with 
each preferred term event within a SOC may exceed the total number of subjects with at least one 
event.  For the summary of AEs by maximum intensity, subjects who experience the same event 
several times with different intensity will only be counted once with the maximum intensity. 
Only treatment emergent AEs (TEAEs) will be presented as all subjects receive study medication 
on Study Day 1.  TEAEs are defined as AEs with an onset date and time on or after that of the start 
of first dose of study medication (including CQ).
The recurrence of P. vivax malaria and any associated signs and symptoms are recorded as 
Disease Related Events (DREs) and will not be included in the AE data displays, but will be listed 
separately.
Adverse Events will be summarized by dose group and overall as specified below and in Appendix 
15: List of Data Displays, and presented in order of descending frequency. Table 3 provides an 
overview of the planned analyses, with further details of data displays being presented in Appendix 
15: List of Data Displays.


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Table 3
Overview of Planned Adverse Event Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AEs
Y1
All TEAEs by SOC
Y
All TEAEs by PT
Y
Drug-related TEAE by PT
Y
TEAEs by maximum grade or intensity
Y
Common (≥10% in any treatment group) TEAEs by PT
Y
Y2
Common (≥10% in any treatment group) Non-serious TEAEs by SOC and PT –
number of subjects and occurrences
Y
TEAEs by week and month of onset
Y
Subject numbers for individual AEs
Y
Relationship between AE SOCs, PTs and verbatim text
Y
All drug-related TEAEs by SOC and maximum grade or intensity4
Y
Serious and Other Significant AEs
Fatal TEAEs by PT
Y
Y
Serious TEAEs3
Y
Y
Drug related serious TEAEs by PT
Y
Drug related fatal serious TEAEs by PT
Y
TEAEs leading to withdrawal from the study
Y
Y
AEs that are considered to be potentially hematologically-related (i.e. clinically 
relevant drops in Hb or Hct or other complications)
Y
Grade 3 and Grade 4 AEs by PT
Y
Disease Related Events
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data. 

TEAEs (SAEs) are defined as AEs (SAEs) with an onset date and time on or after that of the start of first dose of 
study medication (including CQ).

AEs which have missing onset dates and any with an onset date equal to that of medication, but where onset time 
is unknown, will be considered to be treatment emergent. 

For each preferred term counting will be done by subject and not event.

AEs related to drug will be selected based on where the 'Relationship to Investigational Product' flag on the eCRF 
has been marked 'Yes'.

See Section 10.6.3 for additional information on the derivations and definitions of AEs

Additional information on any deaths will be provided by Global Clinical Safety and Pharmacovigilance (GCSP) as 
part of the SAE reconciliation process. 

Events will be sorted based on Total incidence unless otherwise noted in Section 10.15.6

1 TEAEs will be flagged

2 Plot of common AEs will be generated. Note that since there is no control arm, relative risks won’t be calculated

3 By SOC, by PT, by overall frequency and by SOC – number of subjects and occurrences

4Interim analyses only


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8.3.
Vital Signs
Vital sign measurements include systolic and diastolic blood pressure, temperature, heart rate and 
respiratory rate. Vital signs are to be performed on Day 1, and prior to all PK sampling. 
These measurements are summarised and summary statistics of the measurements by visit and 
change from baseline will be presented by dose group and overall.
8.4.
Clinical Laboratory Parameters
8.4.1.
Overview of Planned Clinical Laboratory Analyses
Clinical safety laboratory assessments including hematology, clinical chemistry, methemoglobin 
and additional parameters and screening tests are reported before the first dose of study drug and 
at Day 8 (and additionally at Day 3 for hematology).
Summaries of laboratory results and changes from baseline will be provided by visit. A listing 
displaying clinically relevant drops in hemoglobin by dose group will also be provided.
Table 4 provides an overview of the planned analyses, with further details of data displays being 
presented in Appendix 15: List of Data Displays.


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Table 4
Overview of Planned Clinical Laboratory Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Chemistry Data by Time 
Y
Y3
Chemistry Changes from Baseline 
Y
Chemistry Laboratory Abnormalities1
Y
Y
Clinical Chemistry Profile Plots
Y2
Hematology
Hematology Data by Time and Sex
Y
Y3
Hematology Changes from Baseline by Time and Sex 
Y
Y3
Hematology Laboratory Abnormalities1
Y
Y
Hemoglobin Categories4 of Change from Baseline by Time
Y
Hemoglobin Categories4 of Change from Baseline by Time 
and Sex
Y
Maximum Fall in Hemoglobin Over First 10 Days
Y
Mean Change in Hemoglobin Over First 10 Days4
Y
Hematology Profile Plots5
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Y
Liver Biopsy Details
Y
Liver Imaging Details
Y
Y
Medical Conditions for Subjects with Liver Stopping Events
Y
LFT Profile Plots6
Y
LFT Abnormalities
Y
Maximum LFTs 
Y
LFT Changes from Baseline
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

1Abnormalities refer to values outside of the clinical concern range (F3) for the tables, and either outside of the 
clinical concern range (F3) or with a change from baseline of clinical concern (F2) for the listings, as defined in 
Section 10.8.1.  

2Only for subjects with >3 ULN in ALT or AST or change from baseline in urea or creatinine >50%. 

3 Boxplots for Hemoglobin, WCC, Platelets, ALT, AST and Creatinine. Change from baseline boxplot for 
Hemoglobin only. 

4Categories defined as <=20 g/L, >20 g/L to <=30 g/L, > 30 g/L 5 See Section 8.4.2

5 Individual plots for all subjects at each interim analysis. At SAC, only for subjects with a >30g/L decline from 
baseline hemoglobin or and found to be G6PD deficient; see Section 8.4.2.

6 Individual plots for all subjects at each interim analysis. At SAC, only for subjects with >3 ULN in ALT or AST 

All scheduled visits should be included in the tables and figures.

Data recorded at unscheduled assessments will not be included in tables and figures (with the exception of being 
used in establishing maximum/minimum changes post baseline) but will be listed.


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
Change from baseline is defined in Section 10.5.2.
8.4.2.
Hemoglobin Declines and Related Laboratory Parameters
For all subjects with a drop in hemoglobin >30 g/L or ≥30%, G6PD enzyme activity will be plotted 
against maximum drop in hemoglobin up to and including the Day 8 visit, with separate pages for 
each dose group. Within the plot, different symbols will be used for the following categories:

subjects who were G6PD genotyped and had a mutation classified as World Health 
Organization (WHO) class 1

subjects who were G6PD genotyped and had a mutation classified as WHO class 2 or 3

subjects who were G6PD genotyped and had a mutation of unknown significance

subjects who were G6PD genotypically normal or had a mutation classified as a normal 
variant (WHO class 4)

subjects who were not G6PD genotyped or did not have an evaluable genotyping result
Individual profile plots for all subjects at each interim analysis. For SAC, if a subject has a >30g/L
or ≥30% decline from baseline hemoglobin or is found to be G6PD deficient, a hematological
profile plot will be produced for the subject. This will display their hemoglobin, absolute reticulocyte, 
methemoglobin and bilirubin results (total and indirect bilirubin on same plot) at each visit.  The 
subject ID, treatment group, sex, age, weight and G6PD status should be included as a header for 
each subject’s plot.
8.5.
Pharmacokinetic Analyses
8.5.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the Pharmacokinetic population, unless 
otherwise specified.
8.5.2.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3 Reporting 
Process & Standards).
8.5.3.
Pharmacokinetic Parameters
PK parameters will be estimated based on POP PK model. See Appendix 12 for more details.
8.5.4.
Population Pharmacokinetic (PopPK) Analyses

The primary goal of this analysis is to characterize the population pharmacokinetics of 
tafenoquine (TQ) administered orally in subjects with P. vivax malaria.


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o
The influence of subject demographics, baseline characteristics, including disease activity, 
and co-medication on the pharmacokinetics of TQ in this population will be investigated. 

A summary of the planned population pharmacokinetic analyses are outlined below:
o
Drug plasma concentration-time data will be subjected to nonlinear mixed effects 
modelling using the program NONMEM to develop a population PK model.  
o
Individual post-hoc estimated PK parameters will be summarised descriptively.  
o
To support this analysis a NONMEM data file will be generated.  
o
The details for the dataset specifications are provided in Appendix 13: Population 
Pharmacokinetic Analyses with detailed methodology for the analysis.
8.6.
Pharmacodynamic Analyses
Not applicable
8.7.
Pharmacokinetic / Pharmacodynamic Analyses
Not applicable
8.8.
Evaluation of Microsampling
The relationship between venous blood sampling concentrations and capillary microsampling 
concentrations will be explored using the PK population. 
A scatterplot comparing the venous blood plasma concentrations and the microsampling blood 
concentrations for all subjects, at all timepoints will be produced. In addition, the correlation 
between the methods will be calculated and presented in the same plot. The correlation will be 
calculated separately for each quartile, according to the concentration range observed. 
To quantify the level of agreement between the blood sampling methods, a Bland-Altman plot will 
be produced [Bland, 1999]. The plot will display average concentration (x-axis) versus the 
concentration ratio (microsampling concentration/venous concentration) (y-axis). The following 
reference lines will be included in the plot
-
Mean concentration ratio (bias)
-
Mean concentration ratio ± 5% (interim analysis 1 only)
-
Mean concentration ratio ± 15% (interim analysis 2 and SAC only)
-
Limits of agreement calculated as: mean concentration ratio ± 1.96 x SD


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9.
REFERENCES
Beal, S., Sheiner, L.B., Boeckmann, A., & Bauer, R.J., NONMEM User's Guides. (1989-
2009), Icon Development Solutions, Ellicott City, MD, USA, 2009.
Bland, M., Altman, D., Measuring agreement in method comparison studies, Statistical 
Methods in Medical Research, 1999
FDA, Population Pharmacokinetics, Guidance for Industry, 1999
GlaxoSmithKline Document Number 2014N207627_00 Study ID TAF113577. An Open 
Label, Non-comparative, Multicentre Study to Assess the Pharmacokinetics, Safety and 
Efficacy of Tafenoquine (SB252263, WR238605) in the Treatment of Pediatric Subjects 
with Plasmodium vivax Malaria. 2015.
GUI_137354, Information for Authors: Reporting and Analysis Plan (RAP), Global
SOP_54838, Development, Review & Approval of Reporting & Analysis Plan (RAP), 
Global
Supportive Templates (for RAP), IMMS Example: Reporting and Analysis Plan (RAP) 
Template_Core Safety Reporting Standards


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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Treatment States & Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacokinetic

Pharmacodynamic and or Biomarkers
Section 10.7
Appendix 7 Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.8
Appendix 8: Values of Potential Clinical Importance
Section 10.9
Appendix 9: Multicentre Studies
Section 10.10
Appendix 10: Examination of Covariates and Subgroups
Section 10.11
Appendix 11: Multiple Comparisons and Multiplicity
Section 10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Section 10.3
Appendix 13: Population Pharmacokinetic Analyses
Other RAP Appendices
Section 10.14
Appendix 14: Abbreviations & Trade Marks
Section 10.15
Appendix 15: List of Data Displays
Section 10.16
Appendix 16: Example Mock Shells for Data Displays


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10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
10.1.1.
Exclusions from Per Protocol Population
No per protocol population has been defined for this study. 


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10.2.
Appendix 2: Time & Events
10.2.1.
Protocol Defined Time & Events
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


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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 (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.  
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.
PPD


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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.


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10.3.
Appendix 3: Assessment Windows
10.3.1.
Definitions of Assessment Windows for Analyses
Domain
Parameter      
(if applicable)
Target 
Analysis Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
Safety, PK, 
Efficacy
All
Day 1
Day -2
Day 1
Day 1
Safety, Efficacy
All except PK
Day 3
Day 3
Day 5
Day 3
Safety, PK, 
Efficacy
All
Day 8
Day 6
Day 10
Day 8
Safety, PK, 
Efficacy
All
Day 15
Day 12
Day 18
Day 15
Safety, PK, 
Efficacy
All
Day 29
Day 24
Day 34
Day 29
Safety, PK, 
Efficacy
All
Day 60
Day 50
Day 70
Day 60
Safety, PK, 
Efficacy
All
Day 90
Day 80
Day 100
Day 90
Safety, PK, 
Efficacy
All
Day 120
Day 110
Day 130
Day 120
For all data summarised by visit, the nominal visit description will be used. Unscheduled and 
withdrawal visit data will be slotted into a scheduled visit window, but the data will only be included 
in summaries and figures if no scheduled visit exists within the window. If there are multiple 
assessments within the same window which are not unscheduled visits, the earliest results will be 
used in the summaries. If only unscheduled visits are included in the same window, the earliest of 
these results will be used in summaries and figures.
For derivations of the maximum/minimum value/change post-baseline, then all data will be 
considered, regardless of whether or not it slotted to a scheduled window.


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10.4.
Appendix 4: Treatment States and Phases
10.4.1.
Treatment States
Adverse events will be classified according to time of occurrence relative to the start of the study 
treatment. No other treatment states are required for this study. 
10.4.1.1.
Treatment States for AE Data
Treatment State
Definition
Onset Time Since 
1st Dose (Days)
If Treatment Start Date ˃  AE Onset Date = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on eCRF OR value is missing.
Onset before Day 7
AE Start Date ≤ Study Day 7
Onset on days 8-15
Study Day 8 ≤ AE Start Date < Study Day 16
Onset on days 16-
29
Study Day 16 ≤ AE Start Date < Study Day 30
Onset in Months 2 
or 3
Study Day 30 ≤ AE Start Date < Study Day 91
Onset after Month 
3
AE Start Date ≥ Study Day 91


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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
Data Displays for Reporting 
Description
Description – Interim 1
Description – Interim 2 and 
Final
Order [1]
≥ 5 kg to ≤ 10 kg
TQ 50mg
1
> 10 kg to ≤ 20 
kg[2]
TQ 100mg
2
> 10 kg to ≤ 20 
kg[3]
TQ 150mg
TQ 150mg
3
> 20 kg to ≤ 35 kg
TQ 200mg
TQ 200mg
4
> 35 kg
TQ 300mg
TQ 300mg
5
Tafenoquine
Total
Total
6
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
2.
Subjects from Cohorts 2 and 3
3.
Subjects from Cohort 1
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
For all endpoints the baseline value will be the latest pre-Tafenoquine dose assessment on Day 1. 
Asexual parasite and gametocyte counts
If there are multiple pre-treatment assessments, a subject will be considered to have a positive 
(non-zero) baseline assessment if any of the assessments are positive.  They will only be 
considered to have a zero baseline count if all of the pre-treatment assessments are slide negative.
10.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.5.2 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.


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10.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
: /arenv/arprod/sb252263/taf113577/internal_01
: /arenv/arprod/sb252263/taf113577/internal_02
  /arenv/arprod/sb252263/taf113577/final_01
QC Spreadsheet
: /arenv/arprod/sb252263/taf113577/final_01/qc
Analysis Datasets 

Interim analysis datasets will be created according to legacy GSK IDSL A&R dataset
standards. Final analysis datasets will be created according to CDISC standards (SDTM IG 
Version 3.1.3 & AdaM IG Version 1.0.

For creation of ADaM datasets (ADCM, ADC1 and ADAE), the same version of dictionary 
datasets will be implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for interim and final analyses. 
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.


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Reporting Standards

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings.
Unscheduled Visits

Unscheduled visits will not be included in summary tables, unless slotted to a scheduled visit 
(Section 10.3.1). The exception is when maximum/minimum values/changes post baseline are 
summarised, in which case, all data will be considered.

Unscheduled visits will not be included in figures, unless slotted to a scheduled visit (Section 
10.3.1). The exception is when maximum/minimum values/changes post baseline are plotted, 
in which case, all data will be considered.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Time Point

If there are multiple assessments within the same window which are not unscheduled visits, 
the earliest results will be used in the summaries. All values will be listed. 

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Study Day 1 is defined as the day the dose of study medication was taken. 

Study Day >1 calculated as the number of days from study Day 1 date:

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Study Day 1 date   → Study Day = Ref Date – study Day 1 date

Ref Data ≥ Study Day 1 date   → Study Day = Ref Date – (study Day 1 date) + 1    
Cohort

A subject’s cohort can be determined based on the date of study medication as follows:

Cohort 1 – Date of study medication <05-Jan-2018

Cohort 2 – Date of study medication ≥05-Jan-2018 and <26-Feb-2019

Cohort 3 – Date of study medication ≥26-Feb-2019
10.6.2.
Study Population
Demographics
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)]2
Prior and Concomitant Medications

Medications will be coded using the latest version of GSK Drug.

Prior medications = medications taken up to 30 days before the date and time of the first dose 
of study medication.

Any medications with stop dates earlier than 30 days will not be reported in tables and listings.

Concomitant medications = medications with start date and time on or after the start date and 
time of the dose of study medication (Study Day 1). Medications, with the exception of 
chloroquine, taken prior to the study and continuing during the study will be summarised as both 
prior medications and concomitant medications.

All subjects were expected to take chloroquine prior to the start of study medication, and often
continuing after the start date of study medication. The number and percent of subjects taking 
prior chloroquine will be summarised separately to other prior medications. If chloroquine 
treatment is started after the start of study medication, e.g. to treat a relapse, this should be 
reported in the same way as other concomitant medications. All chloroquine data (prior and 


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Prior and Concomitant Medications
concomitant) will be included in the listing of prior and concomitant medications.

See Section 10.7.2 for the handling of missing and partial dates.
Treatment Compliance and Exposure

All study medication will be administered at the investigator centre in the presence of the 
Investigator or study nurse, and ingestion confirmed. 

On the day of dosing, a subject will be classified as compliant with daily administered dose if 
they do not vomit the initial dose or if they are successfully re-dosed.

A subject is considered to be compliant in clinic if they retain all study medication given to them.

Subjects who were entered but did not report a treatment start date will be categorised as 
having zero doses.

Study treatment consists of a single dose so duration of exposure will not be calculated.
G6PD enzyme activity as a percentage of site median

Each site has a median G6PD enzyme value for healthy G6PD-normal subjects, determined 
from G6PD-normal males in study TAF115226:
Region
Country
Site
Investigator
Centre ID
G6PD 
median 
value 
(IU/g Hb)
South 
America
Brazil
Fundação de 
Medicina Tropical 
do Amazonas, 
Amazonas
De Lacerda
7.92
Colombia
Oncomedica SA, 
Monteria
Velez
8.32
Peru
Asociacion Civil 
Selva Amazonica, 
Iquitos
Llanos
9.01
Asia
Thailand
Mea Sot General 
Hospital, Tak
Kluabwang
7.79
Thailand
Hospital for 
Tropical Disease, 
Bangkok
Chokejindachai
7.40
Vietnam
National Institute 
of Malariology, 
parasitology and 
entomology
(NIMPE), Hanoi
Bui
10.51
Vietnam
Oxford University 
Clinical Research 
Unit, Ho Chi Minh 
City
Tran
8.38
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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G6PD enzyme activity as a percentage of site median
Vietnam
OUCRU-Phuoc 
Long Medical 
Center, Ho Chi 
Minh City
Tran
8.38

Enzyme activity as percentage of site median = (absolute enzyme activity / site median) x 100%

G6PD deficient subjects are defined as those with a G6PD enzyme activity <70% of the site 
median.
10.6.3.
Safety
Adverse Events

All AEs reported up to and including the Day 120 visit following enrolment of a subject into the 
study will be documented.

These will be recorded and coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA). All terms applied will be reviewed by a GSK physician prior to database 
freeze. If any malaria related coded terms are considered to have lost useful information in the 
coding step (e.g., if a verbatim term of ‘Plasmodium vivax malaria’ is mapped to ‘malaria’), 
he/she will recommend a study-specific code, which will be documented.

Treatment emergent AEs are defined as AEs with an onset date and time on or after that of the 
start of first dose of study medication (including CQ).

AEs with entirely missing or unknown start dates will be assumed to be treatment emergent for 
reporting. AEs where the start date is equal to that of study medication, but where the start time 
is unknown will also be assumed to be treatment emergent. AEs with missing end dates are not 
anticipated to affect reporting.

If the grade/intensity is missing for an AE, it will be considered severe/Grade 3 if an AE, or 
Grade 4 if an SAE and the subject is alive, or Grade 5 if an SAE and the subject dies (i.e. the 
highest intensity possible) for the summary of AEs by maximum intensity.

See Section 10.7.2 for more information on missing and partial dates.

Common AEs are those occurring in ≥10% of subjects in any treatment group.

The recurrence of malaria and any associated signs and symptoms are recorded as Disease 
Related Events (DREs) and will not be classified as AEs.

The GSK clinical team will review terms that qualify as potentially hematologically related.
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ is present, the number of decimal places of x will be 
used to determine how much to add or subtract in order to impute the corresponding numeric 
PPD


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Laboratory Parameters
value. 

Example 1: 2 decimal place =  ‘< x ‘ becomes x – 0.01

Example 2: 1 decimal place   =  ‘> x’ becomes x + 0.1

Example 3: 0 decimal places = ‘< x’ becomes x – 1    
Vital Signs – Mean Arterial Blood Pressure

To be calculated (to 1 decimal place) where systolic and diastolic blood pressure are both 
present at the same timepoint:


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10.6.4.
Efficacy
Relapse free efficacy at 4 months

Relapse is defined below based on a positive blood smear with or without vivax malaria 
symptoms. 

A subject will be considered to have demonstrated relapse free efficacy for the purpose of the 
efficacy analysis if all of the following are true (also described in Figure 1):

Subject is slide positive for P. vivax (per slide or source documents) at baseline. 

Subject demonstrated initial clearance of P. vivax parasitemia. This is defined as a negative 
slide at or before the Day 29 visit. Subjects who do not meet this criteria will be censored, 
with time to relapse = 0 days.

Subject is not slide-positive for P. vivax at any assessment prior to or on Study Day 130
following initial parasite clearance. Subjects who are slide-positive for P. vivax will be 
classified as relapses, with time to relapse = (date of first positive slide) – (date of Study 
Day 1) days.

Subject did not take a concomitant medication with anti-malarial activity at any point 
between Study Day 1 and their last parasite assessment (up to and including Study Day 
130). A list of all concomitant medications will be reviewed by a GSK clinician prior to 
unblinding the study, and classified accordingly. Subjects who did take a drug with anti-
malarial activity but never had a positive asexual P. vivax parasite slide after initial 
clearance will be censored, with time to relapse censored at (date of last negative parasite 
assessment prior to concomitant medication start) – (date of Study Day 1). If a subject has 
not had a negative assessment prior to the concomitant medication start date, they will be 
censored at 0 days.

Subject is parasite-free at 4 months. This is defined as a negative asexual P. vivax parasite 
slide at the first parasite assessment performed on or after Study Day 110 (up to and 
including Study Day 130).   

Subjects who do not have a positive asexual P. vivax parasite slide following initial clearance 
but where the final parasite assessment occurred before Study Day 110 will not have been 
classified by the preceding rules.  These subjects will be considered to be censored, with time 
to relapse censored at (Date of final parasite assessment) – (date of Study Day 1).

If a subject has a relapse outcome and a censored outcome, they will be considered to be a 
relapse, even if the time point of the relapse is later than the time point of censoring. For 
example, a subject who took a medication with anti-malarial activity at Study Day 32, but 
remained parasite-free after initial clearance until Study Day 68 will be treated as a relapse at 
Study Day 68.


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Figure 1
Flowchart of algorithm for relapse-free efficacy at 4 months
10.6.5.
Pharmacokinetic
See Appendix 13.


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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) is defined as a 
subject who attends all treatment and follow-up visits. 

Withdrawn subjects will not be replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument :
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses due to 
outlying data will be documented along with the reason for exclusion in the 
clinical study report.
10.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
Adverse 
Events

It is not possible to record partial dates in the eCRF for AEs. 

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

AEs with entirely missing or unknown start dates will be assumed to be 
treatment emergent for reporting. 

AEs with missing end dates are not anticipated to affect reporting. 
Concomitant 
medications

Where the start or stop date of a concomitant medication record is entirely 
missing or unknown, the eCRF flags 'Taken prior to study?' and 'Ongoing 
medication?' will be used in order to derive whether it is prior or concurrent. 

If these flags are also missing, then it will be assumed that it is concurrent. 

In the event that use of the same medication is recorded at more than one visit 
(and if this has not been collapsed to one record), the eCRF flags will be cross-
checked for both records.


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10.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

It is not possible to record partial dates in the eCRF for AEs. 


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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Element
Reporting Detail
F1 flag

Denotes a value that falls outside the normal range.

Used by the laboratory and provided directly by the site for inclusion on the
database.
F2 flag  

Denotes a value that has increased or decreased from baseline by more than a 
specified amount.

Defined below
F3 flag 

Denotes a value that falls outside an extended normal range. 

This range is independent of any change from baseline or other values.

F3 range is calculated as:

Absolute: pre-specified limits.

Proportional: upper and lower limits are defined by multiplying the normal 
range limits by different factors 

Defined below
General

If a subject has both ‘high’ and ‘low’ values flagged for a parameter during the 
study, they will be reported once under each category.
Hematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hemoglobin
G/L
F2
Max(baseline –
>30 g/L, ≥30% 
decline from 
baseline)
Platelet count
10^9/L
F3
50
Lymphocytes
10^9/L
F3
0.5
4
Eosinophils
10^9/L
F3
1.5
Reticulocytes count
10^12/L
F3
1xULN
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Creatine kinase (CPK) a
IU/L
F3
5x ULN
Creatininea 
mol/L
F2
3x baseline
F3
3x ULN


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Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Urea (BUN) b 
mmol/L
F3
11.067
Alanine aminotransferase
IU/L
F3
3x ULN
Aspartate aminotransferase
IU/L
F3
3x ULN
Total bilirubin
mol/L
F3
1.5x ULN
Indirect bilirubin
mol/L
F3
1.5x ULN
Alkaline phosphatase
IU/L
F3
2.5xULN
a.
CTC AE criteria
b.
FDA industry toxicity grading scale for healthy volunteer adults and adolescents in preventative vaccine trials


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10.9.
Appendix 9: Multicenter Studies
10.9.1.
Methods for Handling Centres

In this multicentre global study, enrolment will be presented by investigator site and country.


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10.10.
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata
10.10.1.
Handling of Covariates, Subgroups & Other Strata

Summaries will be presented by dose group, if the percentage of subjects within a particular 
dose group is small then the groups may be refined prior to final reporting.  
10.10.1.1. Footnote Regarding Dose Groups

For all data displays presented by dose group, the following footnote should be added: 
Weight bands were: TQ 50mg = ≥5-≤10kg; TQ 100mg = >10-≤20kg (Cohort 2 and 3); TQ 
150mg = >10-≤20kg (Cohort 1); TQ 200mg = >20kg-≤35kg; TQ 300mg = >35kg


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10.11.
Appendix 11: Multiple Comparisons & Multiplicity
10.11.1.
Handling of Multiple Comparisons & Multiplicity
No hypothesis testing will be performed in this study, all analyses are exploratory and so no 
adjustments for multiplicity are required. 


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10.12.
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses
10.12.1.
Statistical Analysis Assumptions
No statistical modelling is being performed. Kaplan-Meier curves are being fitted which assume 
that censored subjects have the same prospect of relapse as those being followed, however, it is 
not possible to test this assumption. All other data is being summarised only. 


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10.13.
Appendix 13: Population Pharmacokinetic Analyses
10.13.1.
Introduction
The purpose of the data analyses outlined in this document is to characterise the systemic 
exposure of Tafenoquine (TQ) administered as a single dose to pediatric subjects with P. vivax
malaria with a model based population pharmacokinetic (POP PK) approach. The influence of 
subject demographics, baseline characteristics and any other relevant covariate on the PK of TQ in 
pediatric subjects with malaria will be investigated to identify a dose regimen that provides 
systemic TQ exposure across various weight bands in pediatric subjects similar to that in adult 
population.
Given the small subject numbers in this study, and the sparse nature of PK sampling, a model-
based population PK analysis using non-linear mixed effects is a robust approach for assessing the 
PK of TQ in the pediatric population.
10.13.2.
General Considerations For Data Analyses and Handling
10.13.2.1.
Software
Programming will be performed in a HARP™environment using SAS Version 9 or a later release 
and S-Plus Version 7 or later release. The population PK analysis will be completed using 
NONMEM software, Version 7 (ICON Development Solutions). Data set handling, graphical 
analysis and post-processing of table files will be performed with R Version 3 or later. The 
platform(s), operating system(s), Fortran compiler and any other software used will be described in 
the study report. 
10.13.2.2.
Data Set Preparation
POP PK analysis with NONMEM needs the data to be arranged in a specific format along with a 
number of indicator variables integral to the software. A summary of the dataset specifications, 
indicator variables and their description are given in Section 10.13.6. Variables included in the final 
data set will depend upon the best fit population model(s) and influential covariate(s) in this 
population.  Therefore all indicator variables may not be included in the final model. If data sets are 
modified or reformatted over the course of the analysis, the file name of each version of the data 
set will be unique. For each generated data file, the source file and the SAS orR/S-Plus script file 
used for data manipulation will be archived.
The POP PK dataset will be generated on multiple occasions as the study progresses to support 
the planned interim analyses - up to two main interim analyses are currently planned. Any dataset 
generated will include all available evaluable TQ PK data up to that time. The dataset aggregation 
and initial modelling setup work may begin earlier than the planned interim analyses to aid any
pre-programming, preliminary structural model establishment and generation of simulation and 
graphing scripts. 
Any deviations from the analysis plan will be described in detail in the study report.


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10.13.2.3.
TQ Population PK dataset
For the TQ population PK analysis, patient demographic data (e.g. gender, age, weight, body mass 
index (BMI)), treatment, dosing and sampling dates and time will be extracted from the study 
database and merged with TQ plasma concentration data extracted from SMS2000 for the TQ PK 
population. The POP PK analysis compliant data file will be produced by or under the direct 
auspices of the programming support within the Clinical Statistics or Clinical Pharmacology, 
Modelling and Simulation groups, GlaxoSmithKline. 
Due to the small study size and sparse nature of the PK sampling schedule, data from the previous 
adult studies with more extensive sampling (e.g. the Phase 2B dose ranging study TAF112582) 
may be included to stabilise the structural model as deemed appropriate. SAS or R may be used to 
merge the pediatric TQ PK data with adult TQ PK data. All such POP PK dataset processing 
scripts will be archived. 
10.13.2.4.
Archival Of Data Sets
Data sets, R-script used for data manipulation and/or graphics, NONMEM control stream files, 
NONMEM output files, NONMEM output processing programs and files obtained from processing 
of NONMEM output will be archived.
10.13.3.
Handling of Missing Data
10.13.3.1.
PK Data
If dosing and/or sampling times are missing, the relevant concentrations will be deleted from the 
analysis dataset and summarized in a deletion record listing by the programmer. Samples listed as 
having no sample (NS), no result (NR) or insufficient sample (IS) will be excluded from the PK data 
set and also included in the deletion record listing.  
10.13.3.2.
Subject Demographics
Imputations of any continuous covariate value will only be performed if the variable is missing for 
less than 10% of the subjects and the variable is deemed necessary for the modelling effort. For 
continuous covariates, missing values for an individual subject will be imputed as the gender-
specific median value for the study. Any changes to the imputation methods will be justified and 
documented. If the percentage of missing data is greater than 10%, the variable will only be 
evaluated in exploratory graphical displays. There may not be imputation for any missing 
categorical covariate value.
10.13.3.3.
Handling of Data Below the Lower Limit of Quantification
TQ concentrations below the respective lower limit of quantification (LLQ) for the bio-analytical 
assay will be reported as NQ (Below Quantification Limit, BQL). All NQ values will be set to “.”in the 
population PK dataset. Individuals with all plasma concentrations reported as NQ will be included 
in the data set. However, a likelihood estimation method (M3) for these BQL data will not be 
implemented (Ahn et al) and the BQL observation rows will be ignored during model building.


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10.13.3.4.
Handling of Outliers
Concentration results inconsistent with the expected PK behaviour of TQ may be excluded from 
the modelling after investigation about possible sampling/labelling errors.  Outlier detection will be 
based initially on visual examination of individual and pooled PK profiles. However, the final model 
may be retested with and without inclusion of these data points. The exclusions will be listed in the 
report.
10.13.4.
Population PK Modelling
The POP PK analysis will be based on non-linear mixed-effects models. The analysis will be 
performed as recommended by the FDA, Population Pharmacokinetics Guidance for Industry
document [FDA, 1999]. Mixed-effects models describe the influence of both fixed effects and 
random effects on a dependent variable, e.g. concentration or clinical endpoint. Fixed effects, 
THETA () in NONMEM notation, are factors that are either measured or controlled.  Random 
effects include residual error (ERR), epsilon (ε) in NONMEM notation, and between subject random 
effects, ETA () in NONMEM notation.
Population mixed effects models include the basic components:

The structural model, which predicts the plasma concentration as a function of time and 
dose.

The covariate model component, which describes the influence of fixed effects (e.g. 
demography, disease, treatment, concomitant medication) on the PK model population 
parameters.

The between-subject variance component, which describes the inter-individual variation in 
PK parameters (after “correction” for fixed effects).  Inter-individual or between-subject 
variability will be initially modelled using an exponential error model.

The residual error model components describe the underlying distribution of the error in 
the measured PK variable. Various error models are available to choose from based on 
emerging data. The goodness-of-fit plots and any potential biases therein will aid selection 
of an appropriate residual variability model e.g., additive, proportional, additive plus 
proportional or exponential.
A visual predictive check (VPC) method will be utilized to evaluate the adequacy of the final model, 
including the effects of statistically significant covariates. Statistics of interest including mean
derived PK parameter values will be calculated from this model based analysis. 
10.13.4.1.
TQ Population PK Analysis
10.13.4.1.1.
Base Model
A structural model for the available TQ PK data from pediatric population will be built first, including 
error models. Initial selection of the simplest structural POP PK model, to be used as a valid base 
model, will be based on but not limited to the minimum objective function value, plausibility of 
parameter estimates, goodness-of-fit plots and VPC plots.  The most appropriate between-subjects 


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variability and residual error model, will be identified and the resulting model called a BASE model. 
If needed different estimation methods available in recent NONMEM versions may be tested to 
characterize the sparse PK data.
Due to the sparse PK sampling and few subjects, only key parameters of interest may be 
estimated (e.g. clearance – TQ CL) as data permit. Other PK parameters (e.g. absorption rate –
TQ KA) may be fixed to the population estimates obtained from the TQ POP PK analysis of data 
from the dose ranging Phase 2B study in adult population (TAF112582). The random effect on 
these parameters may be estimated as data permit. If needed, the TQ PK data from those studies 
may also be included in the analyses dataset to provide stability to the POP PK structural model.
Any deviations from such planned analysis will be described in detail in the study report.
10.13.4.1.2.
Covariate Inclusion
Once a BASE model has been identified, covariates will be added as necessary, using predefined 
strategy.  Currently, the doses selected for the TEACH study are based on allometric scaling of 
clearance based on weight. Thus while not mandatory, patient weight is likely to be included as a 
significant component of the structural model and will be primarily guided by emerging pediatric PK 
data. While unlikely that other covariates will be included in the model due to small study size, the 
effects of subject demographic characteristics (e.g. age, body mass index (BMI)) may be examined 
as data permit. The final model shall have no redundant factor but the strategy shall ensure that no 
significant factor is missing. 
Covariate model building may be undertaken once data from all pediatric patients is available at 
the end of the study. The covariate modelling approach will consider the step-wise process 
consisting of a forward and a backward selection procedure as appropriate based on emerging 
data. 
10.13.4.1.3.
Final Model
The model that has evaluated the impact of any key clinically relevant covariates (weight and other 
covariates) and adequately describes the observed data will be called the FINAL model and used 
for simulations. 
The FINAL TQ POP PK model will be used to predict the systemic TQ exposure across various 
weight bands in pediatric population. The POP PK model based individual post-hoc TQ CL 
estimates will be utilized to calculate the individual TQ exposure [AUC(0-∞) = Dose/CL].  At every 
interim analysis, the 95% prediction interval of AUCs based on the simulation with the population 
pharmacokinetic model will also be generated for the mid-point of each weight band (at a 
population level). See details in Section 3.1. 
10.13.4.2.
Interim TQ POP PK Analysis
Based on the data from the dose finding Phase 2B study in adult subjects with P. vivax malaria 
(TAF112582), initial POP PK modelling and simulation (M&S) exercise suggested that 
approximately 16 pediatric subjects would provide sufficient information to adequately characterize 
the TQ PK in this population. Hence the POP PK M&S activity will be undertaken after a total of at 
least 16 subjects have evaluable PK data or 12 months post study start whichever comes first. In 


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case these data are insufficient to adequately characterize the POP PK in the pediatric population, 
the sparse serial PK sampling will continue and the next M&S exercise will be performed after a 
total of at least 32 subjects have evaluable PK data or 24 months post study initiation, whichever 
comes first. 
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).  If this interval lies within the AUC range of 55-162 µg.hr/mL for the mid-point of 
each weight band, serial (but sparse) sampling can be reduced 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 Phase IIb data 
(TAF112582 Part1). Recruitment will continue for safety data accumulation with these subjects 
having a PK assessment at two timepoints.
The first set of 16 subjects to be enrolled in the study will be 2 or more years old. Based on the 
interim analyses of data from these 16 subjects, if TQ is well tolerated without any significant safety 
concern the enrolment will be opened to infants 6 months and older. If the 95% prediction interval 
of AUCs based on the simulation with the population pharmacokinetic model lies within the AUC 
range of 55-162 µg.hr/mL for the mid-point of each weight band, the dose strengths to be 
administered for the lower weight band subjects i.e. for infants 6 months to 2 years will be as listed 
in the protocol. Further original serial (but sparse) sampling may be limited to the subjects 6 
months to 2 years.  
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 with serial  PK sampling and so on until the TQ PK for 
that weight band are adequately characterized and the 95%  interval 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.
The second interim analysis will take place only if serial but sparse PK sampling is continued after 
the first interim analysis. At the end of any interim analysis, if the data and the M&S outcome 
reliably confirm the previously predicted TQ doses across various pediatric weight bands, or allow 
reliable estimation of TQ PK in the pediatric population, the PK sampling scheme in the subjects to 
be enrolled next may be modified or reduced as deemed appropriate.  
At the end of any interim analysis, in the unlikely event of the data and the M&S outcome 
suggesting that the previously predicted TQ doses across various pediatric weight bands are 
grossly incorrect e.g. >2-3 fold off targeted exposure, existing pediatric PK data may be utilized to 
estimate a new dosing regimen. Exposure will be confirmed by continuing the sparse but serial PK 
sampling in the next set of 16 subjects with the new dosing scheme as deemed appropriate and 
necessary. One way to achieve this will be to modify the weight bands and TQ doses across the 
weight bands based on dose strengths. If the M&S outcome suggests that the previously predicted 
TQ doses across various pediatric weight bands are slightly off targeted exposure (e.g. <1.5 fold), 
the dosing may be continued as is, unless there are any safety concerns based on emerging data. 


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After study completion, the Final POP PK analysis will be performed to determine an appropriate 
dosing regimen across various weight bands in this population.
Any deviations from the analysis plan will be described in detail in the study report.
10.13.4.3.
Final TQ POP PK Analysis
Upon completion of the study, final POP PK analysis will be undertaken. All PK evaluable data will 
be utilized for this analysis to confirm the dose regimen in the pediatric population across various 
weight bands. If the interim analysis demonstrate that the TQ PK was slightly different than 
previously predicted, M&S with the full dataset will be conducted to define the new dosage regimen 
across weight bands to ensure that the systemic TQ exposure across various weight bands in 
pediatric population is comparable to that in adult population. The simplest approach will be to 
modify the previously defined weight bands and the doses across these weight bands. The dosing 
scheme will be recommended in the study report. 
Analysis of the TQ PK data from the pediatric study may also guide formulation of different dose 
strengths i.e. having fewer, more or different dose strengths than those used in the current 
pediatric study to support the TQ pediatric indication post approval. M&S will be undertaken to 
recommend the dose regimen with any new dose strengths across various pediatric population 
weight bands that provides exposure similar to that in adult population with the 300 mg TQ dose.
Any deviations from the analysis plan will be described in detail in the study report.
10.13.5.
References
FDA, Population Pharmacokinetics, Guidance for Industry, 1999
Ahn JE, Karlsson MO, Dunne A, Ludden TM, J Pharmacokinet Pharmacodyn. 2008 
Aug;35(4):401-21


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10.13.6.
POP PK File Specification
10.13.6.1. Pop PK Dataset File Structure
The PME compliant file structure for pop PK is a space-delimited file with each row containing the 
following columns of information. This file will be provided within 5 days of DBF.
Records with CONC value of NS, IS or NR will be excluded from the dataset
Item Name
Description
Code
Derivation/Comments
Dataset
ID
NONMEM sequential 
number starting at 1 
identifying each 
subject
00001 – 99999
Sequential identifier for 
each subject starting at 1.
CENT
Centre Identification
1= Thailand -
2= Madagascar -
3= Peru –
4= Thailand –
, 
5= Vietnam -
6= Brazil -
7= Colombia -
8= Thailand -
9= Thailand -
10= Vietnam –
11=USA –
12= India-
 
13= Philippines-
14= Brazil-
15=Ethiopia-
16= Ethiopia-
17=Cambodia
18=Brazil-
19=Peru
20=SMIU Thailand-
21=Thailand-
22=Vietnam-
23=Colombia-
24=Colombia
Additional centre 
numbers to be added 
based on where patients 
are recruited
PT
Patient Identification 
Number
As per randomization;
Retain all subjects with at 
least one measurable PK 
sample for the TQ 
analyte(s)
STUDY
6= TAF113577
TRTGRP
Treatment group for 
each study
24: TAF113577 arm
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Item Name
Description
Code
Derivation/Comments
Dataset
HEALTHY
Healthy volunteer or 
patient
1: Healthy volunteer
2: Patient
Studies 200951, 201780 
and TAF114582 are all in 
Healthy volunteers (i.e., 
HEALTHY=1)
DOSE
Dose amount (mg) for 
tafenoquine (TQ, 
SB252263)
Fill in the intended dose 
amount (mg) in all cells 
for each patient.
TQ
AMT
Dose amount (mcg) 
for tafenoquine
If EVID=1, AMT= Dose amt in 
mcg for tafenoquine
If EVID=0, AMT= 0
TQ
DAY
Study day relative to 
the start of study
Day = day of study 
relative to the TQ dose
DATE
Date of dose or 
sample collected. 
MM/DD/YYYY
TIME
Time of dose sample 
collected.
HH:MM (24 hr)
RTLD
Relative time of 
sample from most 
recent TQ dose (hr)
Numeric
If negative assign 0
RTFD
Relative time of 
sample from first TQ 
dose (hr)
Numeric
If negative assign 0
TQ
Plasma TQ 
concentrations 
(ng/mL)
Numeric
If EVID = 1, DV = “.” 
If CODE > 0 then DV = “.”
Else DV= conc. Value
Where ADPC .AVAL ne “”or 
ADPC.ANL01FL=”Y”
Then TQ=ADPC.AVAL
3 decimal places.
TQ
LNTQ
Ln transformed 
Plasma TQ 
concentrations 
Numeric
6 decimal places.
TQ
CODE
Drug concentration 
result code
0 = Measurable conc.
0 when EVID=1
1 = NQ/BQL
2 = NA/NR/NS/IS
MDV
Missing Data Value 
(drug concentration)
1 = Yes, 0 = No
If EVID = 1, MDV = 1
If EVID = 0 and CODE>0, 
MDV = 1 , otherwise MDV =0
EVID
Event indicator (flag 
for NONMEM)
1 = Dose
0 = PK Sample
VOMIT
Vomit within 60 min of 
dose 
1 = Yes, vomited
0 = No
0 = PK observations
-99=missing
-99 if missing in datasets


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Item Name
Description
Code
Derivation/Comments
Dataset
CNTY
Country
1=Brazil
2=Peru
3=Thailand
4=Colombia
5=Vietnam
6= India
7=USA
8=Ethiopia
9=Cambodia
10=Philippines
Other countries to be 
added where subjects 
recruited
For the 114582, all 
are in the USA (as 
per the IB).
AGE
Baseline Age of 
subject (yr)
GEN
Gender of the Subject 
(1=M,2=F)
1=Male, 
2 =Female
RACE
Race of the Subject
1=White,  
2=Black or african american,  
3=Oriental or asian, 
4= Hispanic,
5=Other
6= American indian or Alaska 
native
7= Multiple
-99 =Missing
WT
Baseline Weight of 
Subject (kg)
BMI
Baseline Body mass 
Index (kg/m2)
1 decimal
PARA
Baseline parasitemia
1=Yes
0=No
-99 for all of these studies
CONMEDS
Concomitant 
medications
Add if available as
1=Yes
0=No
-99= Missing
1 – for subjects who 
have medications 
identified as being 
concomitant (could 
include subjects taking 
medications that are 
identified as starting 
prior and becoming 
concomitant)
0 – for subjects who do 
not take any 
concomitant 
medications (they may 
have had prior 
medications recorded 
only or no medications 
recorded at all)
-99 is used when 


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Item Name
Description
Code
Derivation/Comments
Dataset
concomitant medication 
data is not collected in 
a study
FORMU
Formulation
1= Tablet150
3 = Tablet50
1 = Tablet150 (150mg 
tablet strength) – only 
300mg dose was 
administered with the 
150mg tablet
3 = Tablet50 (50mg tablet 
strength) – all doses 
200mg or less were 
administered 50mg 
tablets
DUPLI
Duplicate records
DUPLI =1 for all 
concentrations 
DUPLI =2 for the duplicate 
concentration records for a 
specific date and time
DUPLI=3 for samples with 
missing DATE/TIME records 
(but concentration is 
available)
DUPLI=4 for a duplicate 
(second) dosing record 
where no vomiting of any 
doses occur
This variable is only 
provided for Study 582 
Part 2 and Study 564 
files. 
If no concentrations 
and time record, then 
we can exclude the 
records


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10.13.7.
Output
Note, results will be displayed by age group (6m-<2years and ≥2-16 years). 
10.13.7.1.
Tables
The following tables may be presented (not necessarily in this order) in the report:

Summary of Demographics in PK population

Parameter Estimates and Standard Errors for Base Structural PK Model 

Parameter Estimates and Standard Errors from Final PK Model, Including Covariate 
Effects

Summary of TQ AUC across weight bands
10.13.7.2.
Figures
The following graphs may be presented (not necessarily in this order) in the report:

Goodness of fit plots of basic and final PK model (observed TQ PK versus population 
predictions, observed TQ PK versus individual predictions, weighted residuals vs time, 
weighted residuals vs population predictions) 

Plots of base model PK parameter estimates versus influential covariates, if applicable.
Visual Predictive Check (VPC) Plots for base and final model as applicable
10.13.7.3.
Data listings
The following data listings may be presented (not necessarily in this order) in the report:

Key of all the variables used in the model development dataset.

Listing of the primary model development datasets.

NONMEM output files from the base and final models

Listing of control files used for selection of PK model as applicable (base model,
intermediate model and final control file)
10.13.7.4.
Interim Analysis Outputs

Population PK Model predicted AUCs [Mean (95% PI)] across weight bands


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10.14.
Appendix 14: Abbreviations & Trade Marks
10.14.1.
Abbreviations
Abbreviation
Description
A&R
Analysis and Reporting
ADaM
Analysis Data Model
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
AUC(0-∞)
Area Under the Concentration-time Curve Extrapolated to Infinity
BUN
Blood Urea Nitrogen
bpm
beats per minute
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL
Apparent Systemic Clearance
CPK
Creatine kinase
CPMS
Clinical Pharmacology Modelling and Simulation
CQ
Chloroquine
CSR
Clinical Study Report
CS
Clinical Statistics
CTR
Clinical Trial Register
DP
Decimal Places
DRE
Disease Related Events
eCRF
Electronic Case Record Form
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
G6PD
Glucose-6-phosphate Dehydrogenase
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
GUI
Guidance
HARP
Harmonisation of Analysis and Reporting Project
Hb
Hemoglobin
Hcg
Human Chorionic Gonadotropin
Hct
Hematocrit
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
INR
International Normalised Ratio
IP
Investigational Product
IVRS
Interactive Voice Response System
MCV
Mean Cell Volume
mITT
Microbiologic-Intent-To-Treat
PD
Pharmacodynamic


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Abbreviation
Description
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PT
Preferred Term
QC
Quality Control
RBC
Red Blood Count
RAP
Reporting & Analysis Plan
RTF
Revisable Form Text
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SDTM
Study Data Tabulation Model
SOC
System Organ Class
SOP
Standard Operation Procedure
TEAE
Treatment Emergent Adverse Event
TFL
Tables, Figures & Listings 
TQ
Tafenoquine
WCC
White Blood Cell Count
10.14.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
NONMEM
R
SAS
S-PLUS


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10.15.
Appendix 15: List of Data Displays
10.15.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays for the interim analyses:
Section
Tables
Figures
Study Population
1.1 to 1.7
None
Efficacy
2.1 to 2.2^
2.1
Safety
3.1 to 3.15
3.1 to 3.5
Pharmacokinetic*
None
4.1 to 4.2
Pharmacogenetic
None
None
Section
Listings
ICH Listings
1
Other Listings
2 to 3
^Table 2.2 produced for interim analysis 2 only.
*PK outputs produced by CPMS are detailed separately in Section 10.13.7.
The following numbering will be applied for RAP generated displays for the final analysis:
Section
Tables
Figures
Study Population
1.1 to 1.22
None
Efficacy
2.1 to 2.4
2.1
Safety
3.1 to 3.37
3.1 to 3.15
Pharmacokinetic*
None
4.1 to 4.2
Pharmacogenetic
5.1
None
Section
Listings
ICH Listings
1 to 18
Other Listings
19 to 31
*PK outputs are detailed separately in Section 10.13.7.
10.15.2.
Deliverable
Delivery
Description
IA1
Interim Analysis 1
IA2
Interim Analysis 2
SAC
Final Statistical Analysis Complete


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10.15.3.
Study Population Tables
Study Population Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
Populations Analysed
1.1.
1.1
Screened
SA1
Summary of Analysis Populations
IDSL
.
IA1, IA2, SAC
Subject Disposition
1.2.
1.2
Safety
IE1
Summary of Inclusion/Exclusion Criteria Deviations
IA1, IA2, SAC
1.3.
1.3
Safety
ES1
Summary of Subject Disposition
ICH E3, GSK CTR, FDAAA, 
EudraCT
Include footnote stating the weight 
band for each dose (see SA1).
IA1, IA2, SAC
1.4.
Safety
NS1
Summary of Number of Subjects Enrolled by Country and 
Site ID
EudraCT
.
SAC
1.5.
Screened
ES6
Summary of Reasons for Screen Failure
.
SAC
Protocol Deviations
1.6.
1.4
Safety
DV1
Summary of Important Protocol Deviations
ICH E3
IA1, IA2, SAC
Demographic and Baseline Characteristics
1.7.
1.5
Safety
DM1
Summary of Demographic Characteristics
Include age, sex, ethnicity, race 
detail, weight, height and BMI,
Present age as continuous variable 
only, do not categorise. 
IA1, IA2, SAC


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Study Population Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
1.8.
1.6
PK
DM1
Summary of Demographic Characteristics
Include age, sex, ethnicity, race 
detail, weight, height and BMI,
Present age as continuous variable 
only, do not categorise. 
IA1, IA2, SAC
1.9.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, GSK CTR, FDA, FDAAA, 
EudraCT
SAC
1.10.
Safety
DM6
Summary of Race and Racial Combination Details
ICH E3, FDA
SAC
1.11.
Safety
DM1
Summary of Baseline Characteristics
Include G6PD enzyme activity 
(IU/gHb) and G6PD as a % of site 
median.
SAC
1.12.
Safety
SA4
Summary of Malarial Signs and Symptoms
SAC
1.13.
Safety
SA5
Summary of Splenomegaly at Baseline
SAC
1.14.
Safety
SA6
Summary of Previous Episodes of Malaria
SAC
Prior and Concomitant Medications and Conditions
1.15.
Safety
CM1
Summary of Prior Medications (Excluding Chloroquine)
Add footnote ‘Only medications 
taken prior to the start date and time 
of first dose of study medication, 
and within 30 days of Study Day 1 
are included.’
ICH E3
SAC
1.16.
Safety
SA15
Summary of the Number (%) of Subjects Taking Prior 
Chloroquine
SAC


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Study Population Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
1.17.
Safety
CM1
Summary of Concomitant Medications
ICH E3
Add footnote ‘Subjects were 
expected to take chloroquine prior 
to starting study treatment, but the 
course could be ongoing at the time 
that the subject took their first dose 
of study medication. This ongoing 
chloroquine usage is excluded from 
this summary. Any subsequent 
doses of chloroquine (e.g. to treat a 
P.vivax a malaria relapse) are 
included in this summary. 
SAC
1.18.
Safety
MH1
Summary of Current Medical Conditions by Body System
ICH E3
SAC
1.19.
Safety
MH1
Summary of Past Medical Conditions by Body System
ICH E3
SAC
1.20.
Safety
MH4
Summary of Current Specific Medical Conditions
SAC
1.21.
Safety
MH4
Summary of Past Specific Medical Conditions
SAC
Treatment Compliance
1.22.
1.7
Safety
SA7
Summary of Treatment Compliance
ICH E3
IA1, IA2, SAC


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10.15.4.
Efficacy Tables
Efficacy: Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
Parasite counts
2.1.
Safety
SA8
Summary of Parasite Presence at all Timepoints
SAC
Relapse-free efficacy
2.2.
2.1
mITT
SA9
Summary of Relapse-Free Efficacy at 4 months
IA1, IA2, SAC
2.3.
2.2
mITT
TTE6
Survival Analysis of Relapse-Free Efficacy over 4 months 
IA2, SAC
Other Efficacy endpoints
2.4.
mITT
SA10
Summary of P. falciparum Asexual Parasite Emergence
Change display to a listing if 5 or 
fewer subjects in total
SAC
10.15.5.
Efficacy Figures
Efficacy: Figures
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
Relapse-free efficacy
2.1.
2.1
mITT
TTE10
Kaplan-Meier Survival Curve for Relapse-Free Efficacy 
over 4 Months
IA1, IA2, SAC


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10.15.6.
Safety Tables
Safety: Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
Adverse Events (AEs)
3.1.
3.1
Safety
AE1
Summary of All Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term
ICH E3
Add footnote: ‘Events are ordered 
based on Total incidence’.
Please check data to determine 
how many subjects had events of 
vomiting occurring on day 1, and 
add a footnote to provide this 
information, e.g. ”Of the X subjects 
with AEs of vomiting, Y experience 
vomiting on Day 1”’.
IA1, IA2, SAC
3.2.
Safety
AE3
Summary of Common Treatment Emergent Adverse 
Events (>=10% in Any Treatment Group) by Preferred 
Term
ICH E3, GSK CTR
Order events in descending order. 
SAC
3.3.
Safety
AE15
Summary of Common (>=10% in Any Treatment Group) 
Non-serious Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
FDAAA, EudraCT
SAC


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Safety: Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
3.4.
3.2
Safety
AE3
Summary of All Drug-Related Treatment Emergent 
Adverse Events by Preferred Term
GSK CTR
Order events in descending order.
Please check data to determine 
how many drug-related events of 
vomiting occurred on day 1, and 
add a footnote to provide this 
information, e.g. ‘All drug-related 
AEs of vomiting occurred on day 1’, 
or ‘9 of the 10 drug-related AEs of 
vomiting occurred on day 1’.
IA1, IA2, SAC
3.5.
3.3
Safety
AE5B
Summary of All Drug-related Treatment Emergent Adverse 
Events by System Organ Class and Maximum Grade or 
Intensity
The following AE grades should be 
displayed: 1, 2, 1+2, 3, 4, All 
Grades. Output should be displayed 
for all subjects combined only (not 
by dose group).
IA1, IA2, SAC
3.6.
Safety
AE5A
Summary of Treatment Emergent Adverse Events by 
Maximum Grade or Intensity
Add footnote: ‘Events are ordered 
based on Total incidence’
SAC
3.7.
Safety
AE3
Summary of All Treatment Emergent Adverse Events by 
Preferred Term
Order events in descending order.
SAC
3.8.
3.4
Safety
AE3
Summary of Treatment Emergent Adverse Events with 
Onset on or Prior to Study Day 7
Add footnote: ‘Events are ordered 
based on Total incidence’
IA1, IA2, SAC
3.9.
3.5
Safety
AE3
Summary of Treatment Emergent Adverse Events with 
Onset Date on Study Days 8-15
Add footnote: ‘Events are ordered 
based on Total incidence’
IA1, IA2, SAC
3.10.
3.6
Safety
AE3
Summary of Treatment Emergent Adverse Events with 
Onset on Study Days 16-29
Add footnote: ‘Events are ordered 
based on Total incidence’
IA1, IA2, SAC
3.11.
3.7
Safety
AE3
Summary of Treatment Emergent Adverse Events with 
Onset Date in Month 2 or 3
Add footnote: ‘Events are ordered 
based on Total incidence’
IA1, IA2, SAC


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Safety: Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
3.12.
3.8
Safety
AE3
Summary of Treatment Emergent Adverse Events with 
Onset After Month 3
Add footnote: ‘Events are ordered 
based on Total incidence’
IA1, IA2, SAC
Serious and Other Significant Adverse Events
3.13.
Safety
AE3
Summary of Fatal Serious Treatment Emergent Adverse 
Events
GSK CTR
Order events in descending order.
SAC
3.14.
Safety
AE1
Summary of Serious Treatment Emergent Adverse Events 
by System Organ Class
GSK CTR, IDSL
Add footnote: ‘Events are ordered 
based on Total incidence’
SAC
3.15.
3.9
Safety
AE3
Summary of Serious Treatment Emergent Adverse Events 
by Preferred Term
GSK CTR
Order events in descending order.
IA1, IA2, SAC
3.16.
Safety
AE3
Summary of Drug-Related Treatment Emergent Serious 
Adverse Events by Preferred Term
GSK CTR
Order events in descending order.
SAC
3.17.
Safety
AE3
Summary of Drug-Related Fatal Serious Treatment 
Emergent Adverse Events by Preferred Term
GSK CTR
Order events in descending order.
SAC
3.18.
Safety
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences)
FDAA, EudraCT
SAC
3.19.
Safety
AE3
Summary of Treatment Emergent Adverse Events Leading 
to Withdrawal from the Study
IDSL
Order events in descending order.
SAC
3.20.
Safety
AE1
Summary of Treatment Emergent Adverse Events 
Considered to be Potentially Hematologically-Related
Add footnote: ‘Events are ordered 
based on Total incidence’
SAC
3.21.
Safety
AE3
Summary of Grade 3 and Grade 4 Treatment-Emergent 
Adverse Events by Preferred Term
Include Grade 3 and Grade 4 
events only.
Order events in descending order.
SAC


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Safety: Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
Laboratory: Chemistry
3.22.
3.10
Safety
SA11
Summary of Clinical Chemistry Data by Time 
IA1, IA2, SAC
3.23.
3.11
Safety
SA12
Summary of Change from Baseline in Clinical Chemistry 
Data by Time 
ICH E3
IA1, IA2, SAC
3.24.
Safety
LB2
Summary of Worst Case Chemistry Results Relative 
to Potential Clinical Importance (PCI) Criteria Post-
Baseline Relative to Baseline
SAC
Laboratory: Hematology
3.25.
3.12
Safety
SA11
Summary of Hematology Data by Time and Sex 
Add sex column
IA1, IA2, SAC
3.26.
3.13
Safety
SA12
Summary of Change from Baseline in Hematology Data by 
Time and Sex
ICH E3
Add sex column
IA1, IA2, SAC
3.27.
Safety
LB17
Summary of Worst Case Hematology Results 
Relative to Potential Clinical Importance (PCI) Criteria 
Post-Baseline Relative to Baseline
ICH E3
SAC
3.28.
Safety
SA13
Summary of Categories of Change from Baseline 
Hemoglobin (G/L) Data by Time
SAC
3.29.
3.14
Safety
SA13
Summary of Categories of Change from Baseline 
Hemoglobin (G/L) Data by Time and Sex
Add sex column
IA1, IA2, SAC
3.30.
Safety
SA14
Summary of Hemoglobin Declines over First 10 Days
SAC
3.31.
Safety
SA14
Summary of Hemoglobin Declines over First 10 Days by 
Sex
Add sex column
SAC
Hepatobiliary (Liver)
3.32.
Safety
LIVER1
Summary of Liver Events Assessment
IDSL
SAC


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Safety: Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
3.33.
Safety
LIVER2
Summary of Time on Treatment Before Liver Event
SAC
3.34.
Safety
LIVER3
Summary of Liver Biopsy Details
SAC
3.35.
Safety
LIVER4
Summary of Liver Imaging Details
SAC
3.15
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
Only include rows for:
-
ALT≥5xULN
-
ALT≥3xULN
-
ALT≥3xULN and Bilirubin 
≥2xULN (>35% direct) or 
INR>1.5, if measured.
IA1, IA2
Vital signs
3.36.
Safety
VS1
Summary of Absolute Values in Vital Signs by Visit
ICHE3
Include Systolic Blood Pressure,
Diastolic Blood Pressure, Mean 
Arterial Blood Pressure, Heart Rate, 
Respiratory Rate and Temperature
SAC
3.37.
Safety
VS1
Summary of Change From Baseline in Vital Signs by Visit
ICHE3
Include Systolic Blood Pressure, 
Diastolic Blood Pressure, Mean 
Arterial Blood Pressure, Heart Rate, 
Respiratory Rate and Temperature
SAC


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10.15.7.
Safety Figures
Safety: Figures
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
Adverse Events
3.1.
Safety
AE10
Plot for Common Adverse Events (>=10% in Any 
Treatment Group) by Overall Frequency
IDSL
SAC
Clinical laboratory endpoints
3.2.
3.1
Safety
LB9
Boxplot of Hematological Parameters by Visit and Dose 
Group – Hemoglobin
Include all subjects in the figure. For 
min section, use nadir up to Day 8 
visit.. Use result/LLN  on the Y-axis 
IA1, IA2, SAC
3.3.
3.2
Safety
LB9
Boxplot of Hematological Parameters by Visit and Dose 
Group – Hemoglobin change from Baseline
For max section, include maximum 
decline for all subjects, including 
where this is actually an increase. 
Use result on the y-axis
IA1, IA2, SAC
3.4.
Safety
LB9
Boxplot of Hematological Parameters by Visit and Dose 
Group – WCC
Use result on the y-axis
SAC
3.5.
Safety
LB9
Boxplot of Hematological Parameters by Visit and Dose 
Group – Platelets
Use result on the y-axis
SAC
3.6.
Safety
LB9
Boxplot of Clinical Chemistry Parameters by Visit and 
Dose Group – ALT
Use result/ULN on the y-axis
SAC
3.7.
Safety
LB9
Boxplot of Clinical Chemistry Parameters by Visit and 
Dose Group – AST
Use result/ULN on the y-axis
SAC
3.8.
Safety
LB9
Boxplot of Clinical Chemistry Parameters by Visit and 
Dose Group – Creatinine
Use result/ULN on the y-axis
SAC
3.9.
3.3
Safety
SF1
Maximum Fall in Hemoglobin over First 10 Days by 
Enzyme Activity 
Subjects with decline of >30g/L or 
≥30% in hemoglobin only
IA1, IA2, SAC


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Safety: Figures
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
3.10.
3.4
Safety
LB11
LFT Profile Plots
Individual plots for all subjects at 
each interim analysis. Only for 
subjects with >3 ULN in ALT or 
AST at SAC.  
Add footnote to this effect.
Parameters to include are Alkaline 
phosphatase, ALT, AST and Total 
Bilirubin.
The subject ID, dose, sex, age and 
race should be included as a 
header for each subject’s plot.
IA1, IA2, SAC
3.11.
3.5
Safety
LB11
Hematology Profile Plots
Individual plots for all subjects at 
each interim analysis. Only for 
subjects with a >30g/L or ≥30% 
decline from baseline hemoglobin
or found to be G6PD deficient at 
SAC.
Add footnote to this effect.
Parameters to include are 
hemoglobin, absolute reticulocyte, 
methemoglobin and bilirubin results 
(total and indirect bilirubin on same 
plot).
The subject ID, dose, sex, age, 
weight and G6PD status should be 
included as a header for each 
subject’s plot.
IA1, IA2, SAC


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Safety: Figures
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
3.12.
Safety
LB11
Clinical Chemistry Profile Plots
Only for subjects with >3 ULN in 
ALT or AST or change from 
baseline in urea or creatinine > 
50%
Add footnote to this effect.
Parameters to include are 
creatinine, creatine kinase and 
urea.
The subject ID, dose, sex, age and 
race should be included as a 
header for each subject’s plot.
SAC
3.13.
Safety
LB10
Distribution of Maximum LFTs 
SAC
3.14.
Safety
LB7
LFT Shift from Baseline to Maximum Value
SAC
3.15.
Safety
LB8
Matrix Display of Maximum LFT Values
SAC


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10.15.8.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
IA No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable
Blood Sampling Comparison
4.1
4.1
PK
SF2
Correlation Between Venous Blood Sampling and 
Microsampling Concentrations
IA1, IA2, SAC
4.2
4.2
PK
SF3
Bland-Altman Plot of Agreement Between Venous Blood 
Sampling and Microsampling Concentrations
IA1, IA2, SAC
10.15.9.
Pharmacogenetic Tables
Pharmacogenetic: Tables
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
PGx General Summaries
5.1
Enrolled
GN1
Summary of Subject Accountability for PGx
SAC


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10.15.10.
ICH Listings
ICH: Listings
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
Study Population - Subject Disposition
1.
Safety
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC
Study Population - Protocol Deviations
2.
Safety
DV2
Listing of Important Protocol Deviations
ICH E3
SAC
3.
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC
Study Population - Populations Analysed
4.
Safety
LA1
Listing of Subjects Excluded from Any Population
ICH E3
SAC
Study Population - Demographic and Baseline Characteristics
5.
Safety
DM2
Listing of Demographic Characteristics
ICH E3
SAC
6.
Safety
DM9
Listing of Race
ICH E3
SAC
Study Population – Exposure
7.
Safety
LA2
Listing of Exposure Data
ICH E3
SAC
Safety - Adverse Events
8.
1
Safety
AE8
Listing of All Adverse Events
ICH E3
Include flag for treatment emergent
IA1, IA2, SAC
9.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
Safety - Serious and Other Significant Adverse Events
10.
Safety
AE8
Listing of Fatal Serious Adverse Events
ICH E3
Include reasons for considering AE 
to be serious
SAC


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ICH: Listings
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
11.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Include reasons for considering AE 
to be serious
SAC
12.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal From 
Study
ICH E3
SAC
13.
Safety
AE8
Listing of Disease Related Events
ICH E3
SAC
Safety - All Laboratory endpoints
14.
Safety
LB5
Listing of Laboratory Data with Abnormalities of Potential 
Clinical Importance
ICH E3
Include footnotes similar to the 
following (as appropriate): 
NR flags are determined based on 
the original values and ranges 
provided by the laboratory (i.e. 
based on non-converted values not 
shown in this standard display).
For WBC absolute differentials and 
absolute reticulocytes, the normal 
ranges are not available. The NR 
flag for these absolute parameters 
are based on the corresponding 
percentages.
SAC


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ICH: Listings
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
15.
Safety
LB5
Listing of Laboratory Data for Subjects with Abnormalities 
of Potential Clinical Importance
ICH E3
Include footnotes similar to the 
following (as appropriate): 
NR flags are determined based on 
the original values and ranges 
provided by the laboratory (i.e. 
based on non-converted values not 
shown in this standard display).
For WBC absolute differentials and 
absolute reticulocytes, the normal 
ranges are not available. The NR 
flag for these absolute parameters 
are based on the corresponding 
percentages.
SAC
16.
Safety
UR2a
Listing of Urinalysis Data 
ICH E3
All subjects
SAC
Safety - Hepatobiliary (Liver)
17.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver 
Stopping Criteria
IDSL
SAC
Safety - Vital Signs
18.
Safety
VS4
Listing of Vital Signs
Include mean arterial BP
SAC


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10.15.11.
Non-ICH Listings
Non-ICH: Listings
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
Study Population - Subject Disposition
19.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
20.
Safety
TA1
Listing of Planned and Actual Treatments
IDSL
SAC
Study Population - Demographic and Baseline Characteristics 
21.
Safety
LA3
Listing of Malaria Signs and Symptoms at Baseline
SAC
22.
Safety
MH2
Listing of Past and Current Medical Conditions
SAC
Study Population - Concomitant Medication
23.
Safety
CM10
Listing of Prior and Concomitant Medications
Include concomitant medications 
and prior medications taken within 
30 days of first dose of study 
medication. 
Add footnote: Includes concomitant 
medications and prior medications 
taken within 30 days of first dose of 
study medication.
SAC
Study Population - Compliance
24.
Safety
LA4
Listing of Compliance Data
SAC
Efficacy
25.
Safety
LA5
Listing of Results of Efficacy Endpoints
SAC
26.
Safety
LA6
Listing of Malarial Slide Readings
SAC


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Non-ICH: Listings
No.
IA No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
Pharmacokinetics
27.
PK
PK07
Listing of PK Concentrations
Change the standard template 
heading from “Planned Time Point” 
to “Planned Sample”.
Remove “Time Deviation” column.
SAC
Safety - Adverse Events
28.
Safety
AE2
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms and Verbatim Text
IDSL
SAC
Safety – Laboratory endpoints
29.
2
Safety
LA7
Listing of Methemoglobin
IA1, IA2, SAC
30.
3
Safety
LA8
Listing of Creatinine
IA1, IA2, SAC
Safety – Hepatobiliary (Liver)
31.
Safety
LIVER8
Listing of Liver Imaging Details
SAC


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10.16.
Appendix 16: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request.