Trial Outcomes & Findings for Ph 2B/3 Tafenoquine (TFQ) Study in Prevention of Vivax Relapse (NCT NCT01376167)

Results Overview

A participant was considered to have demonstrated recurrence-free efficacy at 6 months if: a) Participant had non-zero P vivax asexual parasite count at Baseline. b) Participant showed initial clearance of P vivax parasitemia defined as two negative asexual P vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the interval. c) Participant had no positive asexual P vivax parasite count at any assessment prior to or on Study Day 201 following initial parasite clearance. d) Participant did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment. e) Participant is parasite-free at 6 months. Participants were censored if they did not have P.vivax at Baseline, or took a drug with anti-malarial action despite not having malaria parasites, or did not have a 6 month assessment. The number of participants with recurrence-free efficacy at 6 months has been summarized.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

851 participants

Primary outcome timeframe

6 months post dose

Results posted on

2018-04-23

Participant Flow

This was a multi-centre, double-blind, randomized, parallel-group, active-controlled study to evaluate the efficacy, safety and tolerability of tafenoquine (TQ) in participants with Plasmodium vivax (P vivax) malaria. TAF112582 consisted of two parts-Part 1 (Phase 2 dose ranging) and Part 2 (Phase 3 pivotal). Results have been presented for Part 2.

A total of 683 participants were screened of which 161 failed screening and 522 participants were randomized to receive chloroquine (CQ) + 300 milligrams (mg) TQ, CQ + 15 mg primaquine (PQ) and CQ alone regimen in a ratio of 2:1:1.

Participant milestones

Participant milestones
Measure	CQ Only Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Overall Study STARTED	133	260	129
Overall Study COMPLETED	129	250	123
Overall Study NOT COMPLETED	4	10	6

Reasons for withdrawal

Reasons for withdrawal
Measure	CQ Only Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Overall Study Lost to Follow-up	2	4	2
Overall Study Physician Decision	1	1	0
Overall Study Withdrawal by Subject	1	5	4

Baseline Characteristics

Ph 2B/3 Tafenoquine (TFQ) Study in Prevention of Vivax Relapse

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.	Total n=522 Participants Total of all reporting groups
Age, Continuous	35.3 Years STANDARD_DEVIATION 14.23 • n=5 Participants	35.0 Years STANDARD_DEVIATION 14.39 • n=7 Participants	34.7 Years STANDARD_DEVIATION 14.26 • n=5 Participants	35.0 Years STANDARD_DEVIATION 14.29 • n=4 Participants
Sex: Female, Male Female	36 Participants n=5 Participants	64 Participants n=7 Participants	30 Participants n=5 Participants	130 Participants n=4 Participants
Sex: Female, Male Male	97 Participants n=5 Participants	196 Participants n=7 Participants	99 Participants n=5 Participants	392 Participants n=4 Participants
Race/Ethnicity, Customized American(Amer) Indian(Ind) or Alaska(Al) Native(N)	43 Participants n=5 Participants	81 Participants n=7 Participants	41 Participants n=5 Participants	165 Participants n=4 Participants
Race/Ethnicity, Customized Asian-South East Asian (A) Heritage (Her)	26 Participants n=5 Participants	50 Participants n=7 Participants	26 Participants n=5 Participants	102 Participants n=4 Participants
Race/Ethnicity, Customized Black or African (Afr) Amer	14 Participants n=5 Participants	28 Participants n=7 Participants	13 Participants n=5 Participants	55 Participants n=4 Participants
Race/Ethnicity, Customized White-White/Caucasian(Cau)/European(Eur) Her	3 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	9 Participants n=4 Participants
Race/Ethnicity, Customized Multiple-Afr Amer/Afr Her/Amer Ind or Al N	47 Participants n=5 Participants	95 Participants n=7 Participants	47 Participants n=5 Participants	189 Participants n=4 Participants
Race/Ethnicity, Customized Multiple-Afr Amer/Afr Her/White-White/Cau/Eur Her	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Multiple-Amer Ind or Al N/A-Central/South A Her	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: 6 months post dose

Population: Microbiologic intent to treat (mITT) Population-all randomized participants who received at least one dose of study medication, who have at least one P vivax parasite assessment after randomization, and who have a positive parasite smear for P vivax at Baseline.

A participant was considered to have demonstrated recurrence-free efficacy at 6 months if: a) Participant had non-zero P vivax asexual parasite count at Baseline. b) Participant showed initial clearance of P vivax parasitemia defined as two negative asexual P vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the interval. c) Participant had no positive asexual P vivax parasite count at any assessment prior to or on Study Day 201 following initial parasite clearance. d) Participant did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment. e) Participant is parasite-free at 6 months. Participants were censored if they did not have P.vivax at Baseline, or took a drug with anti-malarial action despite not having malaria parasites, or did not have a 6 month assessment. The number of participants with recurrence-free efficacy at 6 months has been summarized.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Recurrence-free Efficacy at 6 Months Post Dose	35 Participants	155 Participants	83 Participants

SECONDARY outcome

Timeframe: 4 months post dose

Population: mITT Population

A participant (par) was considered to have demonstrated recurrence-free efficacy at 4 months if: a) Par had non-zero P vivax asexual parasite count at Baseline. b) Par showed initial clearance of P vivax parasitemia. c) Par had no positive asexual P vivax parasite count at any assessment prior to or on Study Day 130 following initial parasite clearance. d) Par did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment after Study Day 109 (up to and including Study Day 130). e) Par is parasite-free at 4 months defined as a negative asexual P vivax parasite count at the first parasite assessment performed after Study Day 109 (up to and including Study Day 130). Par were censored if they did not have P.vivax at Baseline, or took a drug with anti-malarial action despite not having malaria parasites or did not have a 4 month assessment. The number of par with recurrence-free efficacy at 4 months has been summarized.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Recurrence-free Efficacy at 4 Months Post Dose	47 Participants	177 Participants	90 Participants

SECONDARY outcome

Timeframe: Up to Day 180

Population: mITT Population

Recurrence was defined as the first confirmed presence of P vivax asexual stage parasites after clearance of initial parasitemia following CQ treatment. Time to recurrence was defined as the time (in days) from initial parasite clearance to recurrence. The time to recurrence was analyzed by the Kaplan-Meier method. NA indicates data was not available due to insufficient number of participants with events during the follow up period in the study. The median number of days to recurrence along with 95% confidence interval has been presented for each treatment group.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Time to Recurrence of P Vivax Malaria	86 Days Interval 63.0 to 109.0	NA Days Insufficient number of participants with events during the follow up period in the study.	NA Days Insufficient number of participants with events during the follow up period in the study.

SECONDARY outcome

Timeframe: Up to Day 180

Population: mITT Population

Parasite clearance time was defined as time needed to clear asexual parasite from the blood that is, parasite numbers falling below the limit of detection in the thick blood smear and remaining undetectable after 6 to 12 hours. The time taken to achieve parasite clearance was analyzed using Kaplan Meier Methodology. The median parasite clearance time along with 95% confidence interval has been presented for each treatment group.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Time to Parasite Clearance	43 Hours Interval 41.0 to 48.0	45 Hours Interval 42.0 to 47.0	42 Hours Interval 39.0 to 45.0

SECONDARY outcome

Timeframe: Up to Day 180

Population: mITT Population

Fever clearance time was defined as time from first dose of treatment to the time when body temperature falls to normal within Study Days 1-4 and remains normal for at least 48 hours up to the Day 8 visit. Fever clearance was considered to have been achieved once an initial temperature of more than 37.40 degree Celsius is reduced to a value less than or equal to 37.40 degree Celsius and in the absence of value more than 37.40 degree Celsius in the following 48 hours up to the Day 8 visit. The time taken to achieve fever clearance was analyzed using Kaplan Meier Methodology. The median fever clearance time along with 95% confidence interval has been presented for each treatment group.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Time to Fever Clearance	7 Hours Interval 5.0 to 14.0	7 Hours Interval 5.0 to 12.0	8 Hours Interval 6.0 to 18.0

SECONDARY outcome

Timeframe: Baseline and up to Day 29

Population: Safety Population

Glucose-6-phosphate dehydrogenase deficiency (G6PD) deficiency is known to be a risk factor for hemolysis in participants treated with 8-aminoquinolines. Blood samples were collected for the evaluation of hemoglobin levels. Hemoglobin decreases of \>=30% or \>3 grams/deciliter (g/dL) from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL in the first 15 days of the study were considered as protocol defined serious adverse events (SAEs). Number of participants with maximum hemoglobin decline from Baseline over first 29 days of study has been summarized. Safety Population consisted of all randomized participants who received at least one dose of study medication.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=259 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Hemoglobin Decline From Baseline Over First 29 Days <=20 grams/liter (g/L)	120 Participants	214 Participants	114 Participants
Number of Participants With Hemoglobin Decline From Baseline Over First 29 Days >20g/L to <=30 g/L	11 Participants	31 Participants	12 Participants
Number of Participants With Hemoglobin Decline From Baseline Over First 29 Days >30 g/L or >=30%	2 Participants	14 Participants	3 Participants

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

TEAEs are defined as adverse events (AEs) with an onset date and time on or after that of the start of first dose of study medication (including CQ). The number of participants with TEAEs potentially related to hemoglobin decrease has been presented.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Potentially Related to Hemoglobin Decrease Haemoglobin decreased	2 Participants	14 Participants	2 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Potentially Related to Hemoglobin Decrease Fatigue	2 Participants	1 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Potentially Related to Hemoglobin Decrease Hyperbilirubinaemia	1 Participants	0 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Potentially Related to Hemoglobin Decrease Pallor	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

The number of participants who received blood transfusion as a result of hemoglobin decline has been summarized.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants Who Received Blood Transfusion	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

There were no participants with acute renal failure in the study.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Acute Renal Failure	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline and up to Day 120

Population: Safety Population

Methemoglobin assessment was made with the aid of a non-invasive signal extraction pulse CO-Oximeter handheld machine (Masimo). The change from Baseline in percent methemoglobin by treatment, time and sex has been summarized. The last assessment performed prior to the first dose of study medication (CQ or randomized treatment) was considered as Baseline. Change from Baseline was calculated as the post baseline assessment minus the Baseline assessment for percent methemoglobin. Only those participants with data available at the specified data points were analyzed.

Outcome measures

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

Gastrointestinal tolerability was analyzed by the number of par experiencing gastrointestinal disorders such as abdominal pain, heartburn, diarrhea, constipation, nausea, and vomiting. The number of participants with gastrointestinal disorders for each treatment group has been summarized.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Gastrointestinal Disorders Nausea	12 Participants	21 Participants	9 Participants
Number of Participants With Gastrointestinal Disorders Vomiting	9 Participants	22 Participants	11 Participants
Number of Participants With Gastrointestinal Disorders Abdominal pain upper	13 Participants	11 Participants	7 Participants
Number of Participants With Gastrointestinal Disorders Diarrhoea	6 Participants	15 Participants	5 Participants
Number of Participants With Gastrointestinal Disorders Abdominal pain	5 Participants	8 Participants	6 Participants
Number of Participants With Gastrointestinal Disorders Dyspepsia	5 Participants	6 Participants	2 Participants

SECONDARY outcome

Timeframe: Up to Day 180

Population: Ophthalmic Safety Population. Day 180 was not a required follow up assessment, hence, data was not collected for most participants.

Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. The number of participants displaying keratopathy in each eye was summarized for each visit. The number of participants with new keratopathy at any time post Baseline was also reported. Ophthalmic Safety Population comprised of all participants in the Safety Population who have results from any eye assessments. Only those participants with data available at the specified data points were analyzed.

Outcome measures

Outcome measures
Measure	CQ Only n=29 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=65 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=31 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Keratopathy Baseline; right eye	0 Participants	0 Participants	0 Participants
Number of Participants With Keratopathy Baseline; left eye	0 Participants	0 Participants	0 Participants
Number of Participants With Keratopathy Day 1; right eye	0 Participants	0 Participants	0 Participants
Number of Participants With Keratopathy Day 1; left eye	0 Participants	0 Participants	0 Participants
Number of Participants With Keratopathy Day 29; right eye	0 Participants	0 Participants	0 Participants
Number of Participants With Keratopathy Day 29; left eye	0 Participants	0 Participants	0 Participants
Number of Participants With Keratopathy Day 90; right eye	0 Participants	1 Participants	0 Participants
Number of Participants With Keratopathy Day 90; left eye	0 Participants	0 Participants	0 Participants
Number of Participants With Keratopathy Day 180; right eye	—	0 Participants	0 Participants
Number of Participants With Keratopathy Day 180; left eye	—	0 Participants	0 Participants
Number of Participants With Keratopathy Any time post Baseline; right eye	0 Participants	1 Participants	0 Participants
Number of Participants With Keratopathy Any time post Baseline; left eye	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to Day 180

Population: Ophthalmic Safety Population. Day 180 was not a required follow up assessment, hence, data was not collected for most participants.

Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Best corrected visual acuity was assessed individually for each eye. Scores were recorded as a ratio. The values were used to derive a logMAR score for statistical analysis where logMAR=-1x log10 (ratio score). The mean and standard deviation of logMAR score for each treatment group has been summarized. High scores were associated with worse vision, and low scores with better vision. Only those participants with data available at the specified data points were analyzed.

Outcome measures

Outcome measures
Measure	CQ Only n=29 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=65 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=31 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores Baseline; right eye	0.041 logMAR scores Standard Deviation 0.0825	0.046 logMAR scores Standard Deviation 0.1045	0.029 logMAR scores Standard Deviation 0.0461
Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores Baseline; left eye	0.048 logMAR scores Standard Deviation 0.0859	0.039 logMAR scores Standard Deviation 0.0652	0.048 logMAR scores Standard Deviation 0.1306
Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores Day 29; right eye	0.039 logMAR scores Standard Deviation 0.0906	0.049 logMAR scores Standard Deviation 0.1159	0.021 logMAR scores Standard Deviation 0.0412
Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores Day 29; left eye	0.032 logMAR scores Standard Deviation 0.0580	0.032 logMAR scores Standard Deviation 0.0565	0.045 logMAR scores Standard Deviation 0.1325
Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores Day 90; right eye	0.044 logMAR scores Standard Deviation 0.0928	0.038 logMAR scores Standard Deviation 0.1083	0.016 logMAR scores Standard Deviation 0.0374
Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores Day 90; left eye	0.041 logMAR scores Standard Deviation 0.0599	0.028 logMAR scores Standard Deviation 0.0971	0.041 logMAR scores Standard Deviation 0.1303
Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores Day 180; right eye	—	0.033 logMAR scores Standard Deviation 0.0577	0.000 logMAR scores Standard Deviation NA Standard Deviation not calculable because data were only collected for 1 participant
Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores Day 180; left eye	—	0.033 logMAR scores Standard Deviation 0.0577	0.000 logMAR scores Standard Deviation NA Standard Deviation not calculable because data were only collected for 1 participant

SECONDARY outcome

Timeframe: Baseline and up to Day 180

Population: Ophthalmic Safety Population. Day 180 was not a required follow up assessment, hence, data was not collected for most participants.

Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment. The number of participants with definite retinal change and questionable (ques) retinal change from Baseline was presented. Only those participants with data available at the specified data points were analyzed.

Outcome measures

Outcome measures
Measure	CQ Only n=29 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=65 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=31 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Retinal Changes From Baseline Day 29, Definite change, right eye	1 Participants	0 Participants	0 Participants
Number of Participants With Retinal Changes From Baseline Day 29, Ques change, right eye	0 Participants	0 Participants	0 Participants
Number of Participants With Retinal Changes From Baseline Day 29, Definite change, left eye	1 Participants	0 Participants	0 Participants
Number of Participants With Retinal Changes From Baseline Day 29, Ques change, left eye	0 Participants	0 Participants	0 Participants
Number of Participants With Retinal Changes From Baseline Day 90, Definite change, right eye	1 Participants	1 Participants	1 Participants
Number of Participants With Retinal Changes From Baseline Day 90, Ques change, right eye	0 Participants	0 Participants	1 Participants
Number of Participants With Retinal Changes From Baseline Day 90, Definite change, left eye	1 Participants	1 Participants	0 Participants
Number of Participants With Retinal Changes From Baseline Day 90, Ques change, left eye	0 Participants	1 Participants	2 Participants
Number of Participants With Retinal Changes From Baseline Day 180, Definite change, right eye	0 Participants	0 Participants	—
Number of Participants With Retinal Changes From Baseline Day 180, Ques change, right eye	0 Participants	0 Participants	—
Number of Participants With Retinal Changes From Baseline Day 180, Definite change, left eye	0 Participants	0 Participants	—
Number of Participants With Retinal Changes From Baseline Day 180, Ques change, left eye	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/ birth defect, other situations and is associated with possible drug induced liver injury with hyperbilirubinemia. TEAEs is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with TEAEs and serious TEAEs have been presented.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With TEAEs and Serious TEAEs TEAEs	86 Participants	164 Participants	76 Participants
Number of Participants With TEAEs and Serious TEAEs Serious TEAEs	6 Participants	21 Participants	4 Participants

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with AEs based on severity has been presented.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=65 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=31 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With TEAEs by Maximum Intensity Mild or Grade 1	30 Participants	70 Participants	38 Participants
Number of Participants With TEAEs by Maximum Intensity Moderate or Grade 2	52 Participants	89 Participants	37 Participants
Number of Participants With TEAEs by Maximum Intensity Severe or Grade 3	3 Participants	2 Participants	1 Participants
Number of Participants With TEAEs by Maximum Intensity Grade 4	1 Participants	0 Participants	0 Participants
Number of Participants With TEAEs by Maximum Intensity Grade 5	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to Day 120

Population: Safety Population

Blood samples were collected for the evaluation of hematology parameters including eosinophils, leukocytes, lymphocytes, neutrophils, platelets, reticulocytes and methemoglobin. The number of participants with hematology laboratory data outside the extended normal range (F3) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Hematology Laboratory Data Outside the Reference Range Blood lymphocytes, Low	7 Participants	4 Participants	0 Participants
Number of Participants With Hematology Laboratory Data Outside the Reference Range Blood lymphocytes, High	23 Participants	32 Participants	13 Participants
Number of Participants With Hematology Laboratory Data Outside the Reference Range Blood neutrophils, Low	2 Participants	5 Participants	7 Participants
Number of Participants With Hematology Laboratory Data Outside the Reference Range Blood platelets, Low	14 Participants	35 Participants	15 Participants
Number of Participants With Hematology Laboratory Data Outside the Reference Range Blood reticulocytes, High	72 Participants	141 Participants	85 Participants
Number of Participants With Hematology Laboratory Data Outside the Reference Range Methemoglobin, High	4 Participants	5 Participants	11 Participants
Number of Participants With Hematology Laboratory Data Outside the Reference Range Blood eosinophils, High	18 Participants	38 Participants	28 Participants
Number of Participants With Hematology Laboratory Data Outside the Reference Range Blood leukocytes, Low	0 Participants	3 Participants	2 Participants

SECONDARY outcome

Timeframe: Up to Day 120

Population: Safety Population

Blood samples were collected for the evaluation of clinical chemistry parameters including Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk. Phos), Aspartate Aminotransferase (AST), bilirubin, creatine kinase, creatinine, glomerular filtration rate (GFR), indirect bilirubin and urea. The number of participants with clinical chemistry laboratory data outside the extended normal range (F3) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.

Outcome measures

Outcome measures
Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=259 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range ALT, High	11 Participants	10 Participants	5 Participants
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range Alk Phos, High	3 Participants	1 Participants	1 Participants
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range AST, High	5 Participants	7 Participants	2 Participants
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range Bilirubin, High	18 Participants	23 Participants	12 Participants
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range Creatine kinase, High	8 Participants	5 Participants	8 Participants
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range Creatinine, High	0 Participants	1 Participants	0 Participants
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range GFR, Low	0 Participants	1 Participants	0 Participants
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range Indirect bilirubin	11 Participants	22 Participants	8 Participants
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range Urea, High	42 Participants	85 Participants	46 Participants

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

Health outcomes were evaluated based on the total costs spent on treatment, transport, medication and tests. The cost was summarized according to the place at which the participant went to for care (drug shop, trial clinic, other clinic, hospital (inpatient/outpatient), traditional healer, other). The reported costs by type and by site has been summarized. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.

Outcome measures

Outcome measures
Measure	CQ Only n=193 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=193 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Cost Associated With Recurrence Episode of P Vivax Malaria Brazil (Drug shop for care)	4.76 US Dollars (USD) Standard Deviation 3.24	—	—
Cost Associated With Recurrence Episode of P Vivax Malaria Brazil (Enrollment clinic for care)	6.17 US Dollars (USD) Standard Deviation 2.39	6.15 US Dollars (USD) Standard Deviation 2.14	—
Cost Associated With Recurrence Episode of P Vivax Malaria Brazil (other location for care)	4.23 US Dollars (USD) Standard Deviation 0	—	—
Cost Associated With Recurrence Episode of P Vivax Malaria Peru (Drug shop for care)	1.47 US Dollars (USD) Standard Deviation 1.30	—	—
Cost Associated With Recurrence Episode of P Vivax Malaria Peru (Enrollment clinic for care)	8.78 US Dollars (USD) Standard Deviation 7.94	8.54 US Dollars (USD) Standard Deviation 8.52	—
Cost Associated With Recurrence Episode of P Vivax Malaria Peru (Attended another clinic)	2.71 US Dollars (USD) Standard Deviation 4.69	3.94 US Dollars (USD) Standard Deviation 1.42	—
Cost Associated With Recurrence Episode of P Vivax Malaria Peru (Other location for care)	0.72 US Dollars (USD) Standard Deviation 0.41	1.30 US Dollars (USD) Standard Deviation 0	—
Cost Associated With Recurrence Episode of P Vivax Malaria Thailand (Drug shop for care)	4.60 US Dollars (USD) Standard Deviation 0	—	—
Cost Associated With Recurrence Episode of P Vivax Malaria Thailand (Enrollment clinic for care)	19.15 US Dollars (USD) Standard Deviation 10.60	—	—
Cost Associated With Recurrence Episode of P Vivax Malaria Thailand (In-hospital care)	6.13 US Dollars (USD) Standard Deviation 0	—	—

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

Health outcomes were evaluated based on the cost of medications purchased. The reported total medication cost for paracetamol associated with recurrence episode of P vivax malaria has been reported by site. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Medications recorded as "Other" and medications without costs are excluded from the analysis. Only those participants with data available at the specified data points were analyzed.

Outcome measures

Outcome measures
Measure	CQ Only n=29 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=3 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Cost Incurred With Purchase of Medications Associated With Recurrence Episode of Malaria Peru, n=23, 3	0.49 USD Standard Deviation 0.1941	0.32 USD Standard Deviation 1	—
Cost Incurred With Purchase of Medications Associated With Recurrence Episode of Malaria Brazil, n=6, 0	1.70 USD Standard Deviation 0.144	—	—

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

Health outcomes were evaluated based on total time lost by participants or care givers due to an episode of malaria. The reported time lost due to recurrence episode of P vivax malaria has been summarized by category and by site. Where categories by site have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.

Outcome measures

Outcome measures
Measure	CQ Only n=193 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=188 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Time Lost by Participants or Care Givers From Normal Occupation Brazil, Housework	1 Days	0 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Brazil, Farming	8 Days	0 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Brazil, paid employment	8 Days	0 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Brazil, Other	3 Days	5 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Cambodia, Farming	17 Days	24 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Ethiopia, Housework	4 Days	3 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Ethiopia, Farming	2.5 Days	3 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Ethiopia, Student	3 Days	0 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Ethiopia, Paid employment	2 Days	4 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Ethiopia, Other	1 Days	7 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Peru, Housework	24 Days	29 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Peru, Farming	19 Days	28 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Peru, Student	1 Days	6 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Peru, Paid employment	6 Days	8.5 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Peru, Other	26 Days	32 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Philippines, Farming	0 Days	—	—
Time Lost by Participants or Care Givers From Normal Occupation Thailand, paid employment	20 Days	0 Days	—
Time Lost by Participants or Care Givers From Normal Occupation Thailand, Other	1 Days	0 Days	—

SECONDARY outcome

Timeframe: Up to Day 180

Population: Safety Population

Health outcomes were evaluated based on the actions taken by the participants to treat recurrence episode of P vivax malaria. The reported action taken by site is summarized. Where no action by site have been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.

Outcome measures

Outcome measures
Measure	CQ Only n=193 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=188 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Brazil, Nothing	21 Participants	5 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Brazil, Drug shop	2 Participants	0 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Brazil, Trial clinic	62 Participants	76 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Brazil, Other	2 Participants	0 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Cambodia, Nothing	13 Participants	14 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Ethiopia, Nothing	12 Participants	13 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Ethiopia, Another clinic	1 Participants	0 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Ethiopia, Other	1 Participants	0 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Ethiopia, Trial clinic	0 Participants	1 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Peru, Nothing	1 Participants	0 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Peru, Drug shop	8 Participants	0 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Peru, Trial clinic	61 Participants	63 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Peru, Another clinic	10 Participants	54 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Peru, Other	15 Participants	1 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Philippines, Nothing	1 Participants	—	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Thailand, Nothing	1 Participants	16 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Thailand, Drug shop	1 Participants	0 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Thailand, Trial clinic	13 Participants	0 Participants	—
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria Thailand, In hospital	1 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Day 2, Day 8, Day 15, Day 29 and Day 60

Population: Safety Population

Apparent population oral clearance of TQ

Outcome measures

Outcome measures
Measure	CQ Only n=259 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Oral Clearance (CL/F) of TQ	2.96 Liters per hour Interval 2.87 to 3.05	—	—

SECONDARY outcome

Timeframe: Day 2, Day 8, Day 15, Day 29 and Day 60

Population: Safety Population

Apparent population central volume of distribution of TQ

Outcome measures

Outcome measures
Measure	CQ Only n=259 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Volume of Distribution (Vc/F) of TQ	915 Liters Interval 879.0 to 956.0	—	—

Adverse Events

CQ Only

Serious events: 6 serious events

Other events: 72 other events

Deaths: 0 deaths

TQ + CQ

Serious events: 21 serious events

Other events: 119 other events

Deaths: 0 deaths

PQ + CQ

Serious events: 4 serious events

Other events: 56 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	CQ Only n=133 participants at risk Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 participants at risk Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 participants at risk Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Investigations Haemoglobin decreased	1.5% 2/133 • Number of events 2 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	5.4% 14/260 • Number of events 14 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	1.6% 2/129 • Number of events 2 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Investigations Electrocardiogram QT prolonged	2.3% 3/133 • Number of events 3 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/260 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/129 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Infections and infestations Abscess limb	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.38% 1/260 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/129 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Infections and infestations Gastroenteritis	0.75% 1/133 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/260 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/129 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Infections and infestations Hepatitis E	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.38% 1/260 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/129 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Infections and infestations Urinary tract infection	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.38% 1/260 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/129 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Gastrointestinal disorders Diarrhoea	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.38% 1/260 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.78% 1/129 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Gastrointestinal disorders Nausea	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/260 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.78% 1/129 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Gastrointestinal disorders Vomiting	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/260 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.78% 1/129 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Hepatobiliary disorders Drug-induced liver injury	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.38% 1/260 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/129 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Metabolism and nutrition disorders Dehydration	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/260 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.78% 1/129 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.38% 1/260 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/129 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Reproductive system and breast disorders Menorrhagia	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.38% 1/260 • Number of events 1 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	0.00% 0/129 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.

Other adverse events

Other adverse events
Measure	CQ Only n=133 participants at risk Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 participants at risk Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 participants at risk Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Gastrointestinal disorders Nausea	9.0% 12/133 • Number of events 13 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	8.1% 21/260 • Number of events 22 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	6.2% 8/129 • Number of events 8 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Gastrointestinal disorders Vomiting	6.8% 9/133 • Number of events 10 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	8.5% 22/260 • Number of events 22 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	7.8% 10/129 • Number of events 10 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Gastrointestinal disorders Abdominal pain upper	9.8% 13/133 • Number of events 13 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	4.2% 11/260 • Number of events 14 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	5.4% 7/129 • Number of events 9 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Gastrointestinal disorders Diarrhoea	4.5% 6/133 • Number of events 6 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	5.4% 14/260 • Number of events 14 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	3.1% 4/129 • Number of events 4 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Nervous system disorders Headache	14.3% 19/133 • Number of events 23 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	10.4% 27/260 • Number of events 34 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	7.8% 10/129 • Number of events 13 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Nervous system disorders Dizziness	8.3% 11/133 • Number of events 13 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	9.6% 25/260 • Number of events 30 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	7.0% 9/129 • Number of events 9 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Skin and subcutaneous tissue disorders Pruritus	15.0% 20/133 • Number of events 23 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	13.1% 34/260 • Number of events 35 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	10.9% 14/129 • Number of events 14 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Infections and infestations Nasopharyngitis	5.3% 7/133 • Number of events 7 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	7.3% 19/260 • Number of events 19 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	7.0% 9/129 • Number of events 11 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Infections and infestations Pharyngitis	3.0% 4/133 • Number of events 4 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	5.0% 13/260 • Number of events 14 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	6.2% 8/129 • Number of events 8 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Myalgia	14.3% 19/133 • Number of events 24 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	5.8% 15/260 • Number of events 15 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	7.8% 10/129 • Number of events 11 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Investigations Blood creatine phosphokinase increased	6.0% 8/133 • Number of events 9 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	3.8% 10/260 • Number of events 10 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	5.4% 7/129 • Number of events 7 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.
Investigations Alanine aminotransferase increased	6.0% 8/133 • Number of events 8 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	2.3% 6/260 • Number of events 6 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.	2.3% 3/129 • Number of events 3 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180) Safety Population comprised of all randomized participants who received at least one dose of study medication.

Additional Information

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Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	CQ Only n=133 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	TQ + CQ n=260 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	PQ + CQ n=129 Participants Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Change From Baseline in Percent Methemoglobin Day 120, Female	0.10 Percent Methemoglobin Standard Deviation 1.332	-0.03 Percent Methemoglobin Standard Deviation 0.906	0.37 Percent Methemoglobin Standard Deviation 1.552
Change From Baseline in Percent Methemoglobin Day 2, Male	-0.18 Percent Methemoglobin Standard Deviation 1.525	-0.03 Percent Methemoglobin Standard Deviation 1.246	-0.10 Percent Methemoglobin Standard Deviation 1.372
Change From Baseline in Percent Methemoglobin Day 2, Female	-0.22 Percent Methemoglobin Standard Deviation 0.895	0.10 Percent Methemoglobin Standard Deviation 0.830	-0.01 Percent Methemoglobin Standard Deviation 0.438
Change From Baseline in Percent Methemoglobin Day 3, Male	-0.15 Percent Methemoglobin Standard Deviation 1.256	-0.01 Percent Methemoglobin Standard Deviation 1.254	-0.02 Percent Methemoglobin Standard Deviation 1.454
Change From Baseline in Percent Methemoglobin Day 3, Female	-0.20 Percent Methemoglobin Standard Deviation 0.902	0.26 Percent Methemoglobin Standard Deviation 0.781	0.11 Percent Methemoglobin Standard Deviation 0.443
Change From Baseline in Percent Methemoglobin Day 5, Male	-0.28 Percent Methemoglobin Standard Deviation 1.329	0.42 Percent Methemoglobin Standard Deviation 1.633	1.28 Percent Methemoglobin Standard Deviation 2.619
Change From Baseline in Percent Methemoglobin Day 5, Female	-0.20 Percent Methemoglobin Standard Deviation 0.789	1.37 Percent Methemoglobin Standard Deviation 1.263	0.90 Percent Methemoglobin Standard Deviation 0.885
Change From Baseline in Percent Methemoglobin Day 8, Male	-0.12 Percent Methemoglobin Standard Deviation 1.135	0.98 Percent Methemoglobin Standard Deviation 1.870	3.01 Percent Methemoglobin Standard Deviation 3.214
Change From Baseline in Percent Methemoglobin Day 8, Female	-0.16 Percent Methemoglobin Standard Deviation 0.857	2.04 Percent Methemoglobin Standard Deviation 1.716	2.58 Percent Methemoglobin Standard Deviation 2.565
Change From Baseline in Percent Methemoglobin Day 11, Male	-0.07 Percent Methemoglobin Standard Deviation 1.348	1.17 Percent Methemoglobin Standard Deviation 2.074	3.61 Percent Methemoglobin Standard Deviation 3.498
Change From Baseline in Percent Methemoglobin Day 11, Female	-0.13 Percent Methemoglobin Standard Deviation 0.676	2.13 Percent Methemoglobin Standard Deviation 1.667	3.41 Percent Methemoglobin Standard Deviation 2.659
Change From Baseline in Percent Methemoglobin Day 15, Male	0.12 Percent Methemoglobin Standard Deviation 1.404	0.94 Percent Methemoglobin Standard Deviation 1.963	3.51 Percent Methemoglobin Standard Deviation 3.369
Change From Baseline in Percent Methemoglobin Day 15, Female	-0.08 Percent Methemoglobin Standard Deviation 0.684	1.67 Percent Methemoglobin Standard Deviation 1.349	3.63 Percent Methemoglobin Standard Deviation 2.678
Change From Baseline in Percent Methemoglobin Day 22, Male	0.07 Percent Methemoglobin Standard Deviation 1.211	0.54 Percent Methemoglobin Standard Deviation 1.431	1.96 Percent Methemoglobin Standard Deviation 2.401
Change From Baseline in Percent Methemoglobin Day 22, Female	-0.05 Percent Methemoglobin Standard Deviation 0.467	0.93 Percent Methemoglobin Standard Deviation 1.042	1.86 Percent Methemoglobin Standard Deviation 1.494
Change From Baseline in Percent Methemoglobin Day 29, Male	-0.10 Percent Methemoglobin Standard Deviation 1.428	0.23 Percent Methemoglobin Standard Deviation 1.350	0.58 Percent Methemoglobin Standard Deviation 1.835
Change From Baseline in Percent Methemoglobin Day 29, Female	-0.18 Percent Methemoglobin Standard Deviation 0.927	0.24 Percent Methemoglobin Standard Deviation 0.717	0.49 Percent Methemoglobin Standard Deviation 0.502
Change From Baseline in Percent Methemoglobin Day 60, Male	0.44 Percent Methemoglobin Standard Deviation 1.925	-0.10 Percent Methemoglobin Standard Deviation 1.362	0.20 Percent Methemoglobin Standard Deviation 1.940
Change From Baseline in Percent Methemoglobin Day 60, Female	0.19 Percent Methemoglobin Standard Deviation 1.080	0.03 Percent Methemoglobin Standard Deviation 0.700	0.16 Percent Methemoglobin Standard Deviation 0.620
Change From Baseline in Percent Methemoglobin Day 120, Male	0.20 Percent Methemoglobin Standard Deviation 1.783	0.07 Percent Methemoglobin Standard Deviation 1.503	0.37 Percent Methemoglobin Standard Deviation 2.153