Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB-252263, WR238605) Versus Primaquine in Subjects With Plasmodium Vivax Malaria

• Sponsor: GlaxoSmithKline
• Collaborator: Medicines for Malaria Venture
• Information provided by (Responsible Party): GlaxoSmithKline

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Malaria, Vivax
Interventions	Drug: Tafenoquine; Drug: Tafenoquine Placebo; Drug: Chloroquine; Drug: Primaquine; Drug: Primaquine Placebo
Enrollment	251

Participant Flow

Recruitment Details	This is a randomized, double-blind, double-dummy, comparative, multicenter study to assess the incidence of hemolysis, safety and efficacy of Tafenoquine (TQ) versus Primaquine (PQ) in treatment of participants with Plasmodium vivax (P. vivax) malaria.
Pre-assignment Details	A total of 369 participants were screened of which 118 failed screening and 251 participants were randomized to receive either TQ+chloroquine (CQ) or PQ+CQ in a ratio of 2:1.

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Period Title: Overall Study
Started	166	85
Completed	160	83
Not Completed	6	2
Reason Not Completed
Lost to Follow-up	4	2
Withdrawal by Subject	2	0

Baseline Characteristics

Arm/Group Title		TQ+CQ	PQ+CQ	Total
Arm/Group Description		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.	Total of all reporting groups
Overall Number of Baseline Participants		166	85	251
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	166 participants	85 participants	251 participants
		37.5 (14.28)	37.7 (14.69)	37.6 (14.39)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	166 participants	85 participants	251 participants
	Female	52 31.3%	32 37.6%	84 33.5%
	Male	114 68.7%	53 62.4%	167 66.5%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Count of Participants	Number Analyzed	166 participants	85 participants	251 participants
American (Amer) Indian (Ind) or Alaska Native (N)		87	43	130
Asian-East Asian Heritage		6	3	9
Asian-South East Asian Heritage		35	20	55
Black or African Amer		2	0	2
African Amer/African Heritage/Amer Ind or Alaska N		36	19	55

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Clinically Relevant Hemolysis.
Description	Clinically relevant hemolysis is defined as a decrease in hemoglobin of >=30% or >3 grams per deciliter (g/dL) from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL at any visit after the first dose of study medication. The percentage of participants with clinically relevant hemolysis has been summarized. Safety Population comprised of all randomized participants who received at least one dose of blinded study medication.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	2.41; (0.941 to 6.031)	1.18; (0.208 to 6.367)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TQ+CQ, PQ+CQ
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; -4.161 to 4.982
	Estimation Comments	Confidence interval for the treatment difference was based on the Newcombe method. Percent treatment difference (TQ+CQ-PQ+CQ) has been presented.

2. Primary Outcome

Title	Percentage of Female Participants With Moderate Glucose-6 Phosphate Dehydrogenase (G6PD) Deficiency Experiencing Clinically Relevant Hemolysis.
Description	Clinically relevant hemolysis is defined as a decrease in hemoglobin of >=30% or >3 g/dL from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL at any visit after the first dose of study medication. Despite additional efforts, no females with moderate G6PD-deficiency were enrolled that experienced clinically-significant hemolysis during the study; hence, the end point could not be estimated.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

3. Secondary Outcome

Title	Rate of Relapse-free Efficacy at Six Months Post Dose
Description	A participant was considered to have demonstrated relapse-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. The rate of relapse-free efficacy was estimated by Kaplan-Meier methodology. The percentage of participants who were relapse-free at 6 months post dose has been presented along with 95% confidence interval.
Time Frame	6 months post dose

Outcome Measure Data

Analysis Population Description

Microbiologic-Intent-To-Treat (mITT) Population comprised of all randomized participants who received at least one dose of blinded study medication and had microscopically-confimed P. vivax parasitemia at Baseline.

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	72.7; (64.8 to 79.2)	75.1; (64.2 to 83.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TQ+CQ, PQ+CQ
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.984
	Confidence Interval	95%; 0.577 to 1.678
	Estimation Comments	Hazards ratio was estimated from Cox Proportional Hazards Model with treatment and region as covariates. A hazard ratio <1 indicates a lower chance of relapse with TQ+CQ compared to PQ+CQ.

4. Secondary Outcome

Title	Rate of Relapse-free Efficacy at Four Months Post Dose
Description	A participant was considered to have demonstrated recurrence-free efficacy at 4 months if: a) Participant had non-zero P. vivax asexual parasite count at Baseline. b) Participant showed initial clearance of P. vivax parasitemia. c) Participant had no positive asexual P. vivax parasite count at any assessment prior to or on Study Day 130 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 after Study Day 109 (up to and including Study Day 130). e) Participant is parasite-free at 4 months. The rate of relapse-free efficacy was estimated by Kaplan-Meier methodology. The percentage of participants who were relapse-free at 4 months post dose has been presented along with 95% confidence interval.
Time Frame	4 months post dose

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	82.3; (74.9 to 87.7)	79.7; (68.9 to 87.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TQ+CQ, PQ+CQ
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.815
	Confidence Interval	(2-Sided) 95%; 0.442 to 1.503
	Estimation Comments	Hazard ratio was estimated from Cox Proportional Hazards Model with treatment and region as covariates. A hazard ratio<1 indicates a lower chance of relapse with TQ+CQ compared to PQ+CQ.

5. Secondary Outcome

Title	Time to Relapse of P. Vivax Malaria
Description	Relapse is defined by a positive blood smear with or without vivax symptoms. Relapse is described as any recurrence of malaria that occurred after Day 32 of the study. The time to relapse was analyzed by the Kaplan-Meier method. The median number of days to relapse along with 95% confidence interval has been presented for each treatment group.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Median (95% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

The median estimate for the time to relapse is the time taken (in days) for 50% of participants to relapse. As less than 50% of participants in both treatment arms relapsed during the study, the median times to relapse could not be calculated.

6. Secondary Outcome

Title	Time to Parasite Clearance
Description	Parasite clearance time is 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 later. The time to achieve parasite clearance was analyzed by Kaplan-Meier methodology. The median parasite clearance time along with 95% confidence interval has been presented for each treatment group.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Median (95% Confidence Interval); Unit of Measure: Hours
	41; (38 to 45)	44; (41 to 49)

7. Secondary Outcome

Title	Time to Fever Clearance
Description	Fever clearance time is defined as the 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 37.4 degree Celsius is reduced to a value less than or equal to 37.4 degree Celsius, in the absence of value more than 37.4 degree Celsius in the following 48 hours up to the Day 8 visit. The time taken to achieve fever clearance was analyzed by Kaplan-Meier method.
Time Frame	Up to Day 9

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Median (95% Confidence Interval); Unit of Measure: Hours
	10; (7 to 19)	13; (8 to 22)

8. Secondary Outcome

Title	Time to Gametocyte Clearance
Description	Gametocyte clearance time is defined as time from first dose until the first slide that was gametocyte negative and remained so at the next slide reading. The time taken to achieve gametocyte clearance was analyzed by Kaplan-Meier method.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Median (95% Confidence Interval); Unit of Measure: Hours
	38; (37 to 43)	41; (37 to 48)

9. Secondary Outcome

Title	Number of Participants With Recrudescence
Description	Recrudescence is defined as any P. vivax parasitemia occurring on or before Day 32 (that is, blood stage treatment failure). A participant was considered to have had a recrudescence if both of the following were true: a) Participant had a positive P. vivax asexual parasite count at Baseline and demonstrated clearance (that is, did not have two negative asexual P. vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the interval). b) Participant had a positive genetically homologous asexual P. vivax parasite count, after their zero count in Days 1 to 5, but on or before Study Day 32. The number of participants with recrudescence before Study Day 33 has been presented.
Time Frame	Up to Day 32

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Measure Type: Number; Unit of Measure: Participants
	0	0

10. Secondary Outcome

Title	Number of Participants With Genetically Homologous and Genetically Heterologous P. Vivax Infections
Description	Two drops of peripheral blood were collected onto pre-printed filter paper for subsequent deoxyribonucleic acid (DNA) extraction and polymerase chain reaction (PCR) analysis of Plasmodium species on all participants at screening (Day 1; pre-dose) and; if necessary, at the time of the first recrudescence/relapse or re-infection. PCR of the P. vivax genes, was used to distinguish between genetically homologous and genetically heterologous infection. The number of participants with genetically homologous and genetically heterologous P. vivax infections has been summarized for each treatment group. Only those participants with an infection occuring on or after Study Day 33 were analyzed.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

mITT Population. Only those participants who had a recurrence of infection were included in the analysis.

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	42	20
Measure Type: Number; Unit of Measure: Participants
Heterologous P. vivax	8	9
Homologous P. vivax	29	10
Unknown genetic classification	5	1

11. Secondary Outcome

Title	Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range
Description	Plasma or serum samples were anlalyzed to evaluate clinical chemistry parameters such as alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, creatine kinase, creatinine, glomerular filtration rate (GFR), indirect bilirubin and urea. The number of participants with clinical chemistry laboratory values outside the extended normal range (F3) has been 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. Safety Population consisted of all randomized participants who received at least one dose of blinded study medication.
Time Frame	Up to Day 120

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Measure Type: Number; Unit of Measure: Participants
ALT, High	8	0
ALP, High	0	1
AST, High	6	3
Bilirubin, High	28	18
Creatine kinase, High	3	4
Creatinine, High	0	0
GFR, Low	0	0
Indirect bilirubin, High	36	21
Urea, High	40	19

12. Secondary Outcome

Title	Number of Participants With Hematology Laboratory Data Outside the Reference Range
Description	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) has been 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. Participants having both High and Low values for Normal Ranges at any post-baseline visits for safety parameters were counted in both the High and Low categories.
Time Frame	Up to Day 120

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Measure Type: Number; Unit of Measure: Participants
Blood eosinophils, High	32	15
Blood leukocytes, Low	0	0
Blood lymphocytes, Low	8	1
Blood lymphocytes, High	11	4
Blood neutrophils, Low	5	3
Blood platelets, Low	13	8
Blood reticulocytes, High	80	39
Methemoglobin, High	2	3

13. Secondary Outcome

Title	Number of Participants With Abnormal Urinalysis Dipstick Results
Description	Mid-stream urine was collected and analyzed for bilirubin, glucose, ketones, leukocyte esterase (LE), nitrites, occult blood, proteins and urobilinogen by dipstick method. The number of participants with abnormal urinalysis results (Trace, +, ++, +++, ++++) has been presented. Only those participants with data available at the specified data points were analyzed.
Time Frame	Up to Day 120

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title		TQ+CQ	PQ+CQ
Arm/Group Description:		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed		166	85
Measure Type: Number; Unit of Measure: Participants
Bilirubin, Day 1, Trace	Number Analyzed	166 participants	84 participants
		1	1
Bilirubin, Day 1, +	Number Analyzed	166 participants	84 participants
		9	2
Bilirubin, Day1, ++	Number Analyzed	166 participants	84 participants
		3	0
Bilirubin, Day 3, +	Number Analyzed	165 participants	85 participants
		8	3
Bilirubin, Day 3, ++	Number Analyzed	165 participants	85 participants
		2	0
Bilirubin, Day 5, Trace	Number Analyzed	166 participants	85 participants
		1	0
Bilirubin, Day 5, +	Number Analyzed	166 participants	85 participants
		4	0
Bilirubin, Day 8, +	Number Analyzed	164 participants	84 participants
		0	2
Bilirubin, Day 11, Trace	Number Analyzed	163 participants	84 participants
		1	1
Bilirubin, Day 22, Trace	Number Analyzed	164 participants	84 participants
		0	1
Bilirubin, Day 22, +	Number Analyzed	164 participants	84 participants
		1	0
Bilirubin, Day 60, Trace	Number Analyzed	160 participants	83 participants
		0	1
Bilirubin, Day 60, +	Number Analyzed	160 participants	83 participants
		2	1
Bilirubin, Day 90, +	Number Analyzed	160 participants	82 participants
		0	1
Bilirubin, Day 120, +	Number Analyzed	160 participants	81 participants
		3	2
Glucose, Day 1, +	Number Analyzed	166 participants	84 participants
		2	1
Glucose, Day 1, ++	Number Analyzed	166 participants	84 participants
		0	1
Glucose, Day1, +++	Number Analyzed	166 participants	84 participants
		2	3
Glucose, Day1, ++++	Number Analyzed	166 participants	84 participants
		0	1
Glucose, Day 3, +	Number Analyzed	165 participants	85 participants
		0	1
Glucose, Day 3, ++	Number Analyzed	165 participants	85 participants
		1	1
Glucose, Day 3, +++	Number Analyzed	165 participants	85 participants
		0	2
Glucose, Day 3, ++++	Number Analyzed	165 participants	85 participants
		0	1
Glucose, Day 5, ++	Number Analyzed	166 participants	85 participants
		0	1
Glucose, Day 5, +++	Number Analyzed	166 participants	85 participants
		0	3
Glucose, Day 8, +	Number Analyzed	164 participants	84 participants
		1	1
Glucose, Day 8, ++	Number Analyzed	164 participants	84 participants
		0	1
Glucose, Day 8,+++	Number Analyzed	164 participants	84 participants
		0	1
Glucose, Day 11, Trace	Number Analyzed	163 participants	84 participants
		0	1
Glucose, Day 11, +	Number Analyzed	163 participants	84 participants
		0	2
Glucose, Day 11, ++	Number Analyzed	163 participants	84 participants
		3	0
Glucose, Day 11, +++	Number Analyzed	163 participants	84 participants
		1	1
Glucose, Day 15, ++	Number Analyzed	165 participants	84 participants
		0	1
Glucose, Day 15, +++	Number Analyzed	165 participants	84 participants
		1	0
Glucose, Day 15, ++++	Number Analyzed	165 participants	84 participants
		0	1
Glucose, Day 22, +	Number Analyzed	164 participants	84 participants
		1	2
Glucose, Day 22, +++	Number Analyzed	164 participants	84 participants
		0	1
Glucose, Day 29, Trace	Number Analyzed	162 participants	84 participants
		1	0
Glucose, Day 29, ++	Number Analyzed	162 participants	84 participants
		1	2
Glucose, Day 60, +	Number Analyzed	160 participants	83 participants
		0	4
Glucose, Day 60, ++	Number Analyzed	160 participants	83 participants
		1	1
Glucose, Day 90, +	Number Analyzed	160 participants	82 participants
		0	1
Glucose, Day 90, ++	Number Analyzed	160 participants	82 participants
		0	1
Glucose, Day 90, +++	Number Analyzed	160 participants	82 participants
		1	1
Glucose, Day 120, Trace	Number Analyzed	160 participants	81 participants
		1	0
Glucose, Day 120, +	Number Analyzed	160 participants	81 participants
		1	1
Glucose, Day 120, ++	Number Analyzed	160 participants	81 participants
		0	2
Glucose, Day 120, +++	Number Analyzed	160 participants	81 participants
		0	2
Glucose, Day 120, ++++	Number Analyzed	160 participants	81 participants
		1	0
Ketones, Day 1, Trace	Number Analyzed	166 participants	84 participants
		3	0
Ketones, Day 1, +	Number Analyzed	166 participants	84 participants
		4	2
Ketones, Day1, ++	Number Analyzed	166 participants	84 participants
		4	3
Ketones, Day1, +++	Number Analyzed	166 participants	84 participants
		2	1
Ketones, Day 3, Trace	Number Analyzed	165 participants	85 participants
		0	1
Ketones, Day 3, +	Number Analyzed	165 participants	85 participants
		5	3
Ketones, Day 3, ++	Number Analyzed	165 participants	85 participants
		3	2
Ketones, Day 3, +++	Number Analyzed	165 participants	85 participants
		3	0
Ketones, Day 5, +	Number Analyzed	166 participants	85 participants
		1	0
Ketones, Day 8, +	Number Analyzed	164 participants	84 participants
		1	1
Ketones, Day 11, Trace	Number Analyzed	163 participants	84 participants
		1	0
Ketones, Day 22, Trace	Number Analyzed	164 participants	84 participants
		1	1
Ketones, Day 22, +	Number Analyzed	164 participants	84 participants
		1	0
Ketones, Day 90, Trace	Number Analyzed	160 participants	82 participants
		2	0
Ketones, Day 90, +	Number Analyzed	160 participants	82 participants
		0	1
Ketones, Day 90, ++	Number Analyzed	160 participants	82 participants
		1	0
Ketones, Day 120, Trace	Number Analyzed	160 participants	81 participants
		1	0
Ketones, Day 120, +	Number Analyzed	160 participants	81 participants
		1	0
Ketones, Day 120, ++	Number Analyzed	160 participants	81 participants
		1	0
LE, Day 1, Trace	Number Analyzed	166 participants	84 participants
		3	1
LE, Day 1, +	Number Analyzed	166 participants	84 participants
		19	9
LE, Day1, ++	Number Analyzed	166 participants	84 participants
		5	2
LE, Day1, +++	Number Analyzed	166 participants	84 participants
		1	2
LE, Day 3, Trace	Number Analyzed	165 participants	85 participants
		4	0
LE, Day 3, +	Number Analyzed	165 participants	85 participants
		13	5
LE, Day 3, ++	Number Analyzed	165 participants	85 participants
		2	1
LE, Day 3, +++	Number Analyzed	165 participants	85 participants
		1	0
LE, Day 5, Trace	Number Analyzed	165 participants	85 participants
		3	1
LE, Day 5, +	Number Analyzed	165 participants	85 participants
		11	4
LE, Day 5, ++	Number Analyzed	165 participants	85 participants
		3	2
LE, Day 5, +++	Number Analyzed	165 participants	85 participants
		3	2
LE, Day 8, Trace	Number Analyzed	164 participants	84 participants
		7	3
LE, Day 8, +	Number Analyzed	164 participants	84 participants
		10	4
LE, Day 8, ++	Number Analyzed	164 participants	84 participants
		6	1
LE, Day 8, +++	Number Analyzed	164 participants	84 participants
		2	2
LE, Day 11, Trace	Number Analyzed	163 participants	84 participants
		6	2
LE, Day 11, +	Number Analyzed	163 participants	84 participants
		11	3
LE, Day 11, ++	Number Analyzed	163 participants	84 participants
		3	3
LE, Day 11, +++	Number Analyzed	163 participants	84 participants
		3	1
LE, Day 15, Trace	Number Analyzed	165 participants	84 participants
		8	2
LE, Day 15, +	Number Analyzed	165 participants	84 participants
		4	8
LE, Day 15, ++	Number Analyzed	165 participants	84 participants
		4	3
LE, Day 15, +++	Number Analyzed	165 participants	84 participants
		2	1
LE, Day 22, Trace	Number Analyzed	164 participants	84 participants
		4	2
LE, Day 22, +	Number Analyzed	164 participants	84 participants
		13	4
LE, Day 22, ++	Number Analyzed	164 participants	84 participants
		3	0
LE, Day 22, +++	Number Analyzed	164 participants	84 participants
		1	1
LE, Day 29, Trace	Number Analyzed	162 participants	84 participants
		5	0
LE, Day 29, +	Number Analyzed	162 participants	84 participants
		11	6
LE, Day 29, ++	Number Analyzed	162 participants	84 participants
		1	4
LE, Day 29, +++	Number Analyzed	162 participants	84 participants
		4	0
LE, Day 60, Trace	Number Analyzed	160 participants	83 participants
		8	3
LE, Day 60, +	Number Analyzed	160 participants	83 participants
		8	4
LE, Day 60, ++	Number Analyzed	160 participants	83 participants
		5	2
LE, Day 60, +++	Number Analyzed	160 participants	83 participants
		2	1
LE, Day 90, Trace	Number Analyzed	159 participants	82 participants
		6	1
LE, Day 90, +	Number Analyzed	159 participants	82 participants
		13	7
LE, Day 90, ++	Number Analyzed	159 participants	82 participants
		2	2
LE, Day 90, +++	Number Analyzed	159 participants	82 participants
		0	1
LE, Day 120, Trace	Number Analyzed	160 participants	81 participants
		5	1
LE, Day 120, +	Number Analyzed	160 participants	81 participants
		12	3
LE, Day 120, ++	Number Analyzed	160 participants	81 participants
		5	2
LE, Day 120, +++	Number Analyzed	160 participants	81 participants
		0	1
Nitrite, Day 1, Trace	Number Analyzed	166 participants	84 participants
		1	0
Nitrite, Day 1, +	Number Analyzed	166 participants	84 participants
		4	0
Nitrite, Day 3, +	Number Analyzed	165 participants	85 participants
		1	0
Nitrite, Day 5, +	Number Analyzed	166 participants	85 participants
		1	0
Nitrite, Day 5, +++	Number Analyzed	166 participants	85 participants
		1	0
Nitrite, Day 8, +++	Number Analyzed	164 participants	84 participants
		1	0
Nitrite, Day 11, +	Number Analyzed	163 participants	84 participants
		1	1
Nitrite, Day 15, +	Number Analyzed	165 participants	84 participants
		2	0
Nitrite, Day 22, Trace	Number Analyzed	164 participants	84 participants
		1	0
Nitrite, Day 29, +	Number Analyzed	162 participants	84 participants
		2	0
Nitrite, Day 60, +	Number Analyzed	160 participants	83 participants
		3	0
Nitrite, Day 90, Trace	Number Analyzed	160 participants	82 participants
		0	1
Nitrite, Day 90, +	Number Analyzed	160 participants	82 participants
		2	1
Nitrite, Day 120, +	Number Analyzed	160 participants	81 participants
		2	1
Nitrite, Day 120, ++	Number Analyzed	160 participants	81 participants
		1	0
Occult blood, Day 1, Trace	Number Analyzed	166 participants	85 participants
		2	4
Occult blood, Day 1, +	Number Analyzed	166 participants	85 participants
		18	7
Occult blood, Day 1, ++	Number Analyzed	166 participants	85 participants
		9	4
Occult blood, Day1, +++	Number Analyzed	166 participants	85 participants
		12	2
Occult blood, Day1, ++++	Number Analyzed	166 participants	85 participants
		6	1
Occult blood, Day 3, Trace	Number Analyzed	165 participants	85 participants
		4	3
Occult blood, Day 3, +	Number Analyzed	165 participants	85 participants
		14	6
Occult blood, Day 3, ++	Number Analyzed	165 participants	85 participants
		9	3
Occult blood, Day 3, +++	Number Analyzed	165 participants	85 participants
		5	3
Occult blood, Day 3, ++++	Number Analyzed	165 participants	85 participants
		3	1
Occult blood, Day 5, Trace	Number Analyzed	166 participants	85 participants
		4	1
Occult blood, Day 5, +	Number Analyzed	166 participants	85 participants
		7	3
Occult blood, Day 5, ++	Number Analyzed	166 participants	85 participants
		6	3
Occult blood, Day 5, +++	Number Analyzed	166 participants	85 participants
		4	2
Occult blood, Day 5, ++++	Number Analyzed	166 participants	85 participants
		3	2
Occult blood, Day 8, Trace	Number Analyzed	164 participants	84 participants
		4	4
Occult blood, Day 8, +	Number Analyzed	164 participants	84 participants
		12	4
Occult blood, Day 8, ++	Number Analyzed	164 participants	84 participants
		3	0
Occult blood, Day 8,+++	Number Analyzed	164 participants	84 participants
		3	2
Occult blood, Day 11, Trace	Number Analyzed	163 participants	84 participants
		2	1
Occult blood, Day 11, +	Number Analyzed	163 participants	84 participants
		8	3
Occult blood, Day 11, ++	Number Analyzed	163 participants	84 participants
		3	2
Occult blood, Day 11, +++	Number Analyzed	163 participants	84 participants
		3	0
Occult blood, Day 11, ++++	Number Analyzed	163 participants	84 participants
		1	1
Occult blood, Day 15, Trace	Number Analyzed	165 participants	84 participants
		2	1
Occult blood, Day 15, +	Number Analyzed	165 participants	84 participants
		11	2
Occult blood, Day 15, ++	Number Analyzed	165 participants	84 participants
		3	2
Occult blood, Day 15, +++	Number Analyzed	165 participants	84 participants
		2	1
Occult blood, Day 15, ++++	Number Analyzed	165 participants	84 participants
		0	1
Occult blood, Day 22, Trace	Number Analyzed	164 participants	84 participants
		4	1
Occult blood, Day 22, +	Number Analyzed	164 participants	84 participants
		11	5
Occult blood, Day 22, ++	Number Analyzed	164 participants	84 participants
		4	1
Occult blood, Day 22, +++	Number Analyzed	164 participants	84 participants
		2	1
Occult blood, Day 22, ++++	Number Analyzed	164 participants	84 participants
		1	1
Occult blood, Day 29, Trace	Number Analyzed	162 participants	84 participants
		5	2
Occult blood, Day 29, +	Number Analyzed	162 participants	84 participants
		17	5
Occult blood, Day 29, ++	Number Analyzed	162 participants	84 participants
		3	1
Occult blood, Day 29, +++	Number Analyzed	162 participants	84 participants
		3	4
Occult blood, Day 29, ++++	Number Analyzed	162 participants	84 participants
		1	0
Occult blood, Day 60, Trace	Number Analyzed	160 participants	83 participants
		5	0
Occult blood, Day 60, +	Number Analyzed	160 participants	83 participants
		15	7
Occult blood, Day 60, ++	Number Analyzed	160 participants	83 participants
		2	3
Occult blood, Day 60, +++	Number Analyzed	160 participants	83 participants
		3	0
Occult blood, Day 60, ++++	Number Analyzed	160 participants	83 participants
		1	0
Occult blood, Day 90, Trace	Number Analyzed	160 participants	82 participants
		4	1
Occult blood, Day 90, +	Number Analyzed	160 participants	82 participants
		13	7
Occult blood, Day 90, ++	Number Analyzed	160 participants	82 participants
		7	2
Occult blood, Day 90, +++	Number Analyzed	160 participants	82 participants
		4	3
Occult blood, Day 90, ++++	Number Analyzed	160 participants	82 participants
		2	2
Occult blood, Day 120, Trace	Number Analyzed	160 participants	81 participants
		2	2
Occult blood, Day 120, +	Number Analyzed	160 participants	81 participants
		13	5
Occult blood, Day 120, ++	Number Analyzed	160 participants	81 participants
		3	3
Occult blood, Day 120, +++	Number Analyzed	160 participants	81 participants
		6	0
Occult blood, Day 120, ++++	Number Analyzed	160 participants	81 participants
		0	2
Protein, Day 1, Trace	Number Analyzed	166 participants	85 participants
		15	8
Protein, Day 1, +	Number Analyzed	166 participants	85 participants
		19	8
Protein, Day1, ++	Number Analyzed	166 participants	85 participants
		4	1
Protein, Day 3, Trace	Number Analyzed	165 participants	85 participants
		8	6
Protein, Day 3, +	Number Analyzed	165 participants	85 participants
		21	13
Protein, Day 3, ++	Number Analyzed	165 participants	85 participants
		3	1
Protein, Day 5, Trace	Number Analyzed	166 participants	85 participants
		5	5
Protein, Day 5, +	Number Analyzed	166 participants	85 participants
		4	1
Protein, Day 5, ++	Number Analyzed	166 participants	85 participants
		2	1
Protein, Day 8, Trace	Number Analyzed	164 participants	84 participants
		6	4
Protein, Day 8, +	Number Analyzed	164 participants	84 participants
		6	2
Protein, Day 8,++	Number Analyzed	164 participants	84 participants
		1	0
Protein, Day 11, Trace	Number Analyzed	163 participants	84 participants
		1	3
Protein, Day 11, +	Number Analyzed	163 participants	84 participants
		4	1
Protein, Day 11, ++	Number Analyzed	163 participants	84 participants
		1	0
Protein, Day 15, +	Number Analyzed	165 participants	84 participants
		2	0
Protein, Day 15, ++	Number Analyzed	165 participants	84 participants
		1	0
Protein, Day 22, Trace	Number Analyzed	164 participants	84 participants
		2	1
Protein, Day 22, +	Number Analyzed	164 participants	84 participants
		2	1
Protein, Day 22, ++	Number Analyzed	164 participants	84 participants
		1	0
Protein, Day 29, Trace	Number Analyzed	162 participants	84 participants
		3	1
Protein, Day 29, +	Number Analyzed	162 participants	84 participants
		4	0
Protein, Day 29, ++	Number Analyzed	162 participants	84 participants
		1	0
Protein, Day 60, Trace	Number Analyzed	160 participants	83 participants
		3	1
Protein, Day 60, +	Number Analyzed	160 participants	83 participants
		3	2
Protein, Day 60, ++	Number Analyzed	160 participants	83 participants
		1	0
Protein, Day 90, Trace	Number Analyzed	160 participants	82 participants
		4	1
Protein Day 90, +	Number Analyzed	160 participants	82 participants
		3	0
Protein, Day 120, Trace	Number Analyzed	160 participants	81 participants
		2	1
Protein, Day 120, +	Number Analyzed	160 participants	81 participants
		6	0
Protein, Day 120, ++	Number Analyzed	160 participants	81 participants
		1	0
Urobilinogen, Day 1, Trace	Number Analyzed	166 participants	84 participants
		8	0
Urobilinogen, Day 1, +	Number Analyzed	166 participants	84 participants
		23	5
Urobilinogen, Day1, ++	Number Analyzed	166 participants	84 participants
		10	4
Urobilinogen, Day1, +++	Number Analyzed	166 participants	84 participants
		3	1
Urobilinogen, Day 3, Trace	Number Analyzed	165 participants	85 participants
		6	2
Urobilinogen, Day 3, +	Number Analyzed	165 participants	85 participants
		14	11
Urobilinogen, Day 3, ++	Number Analyzed	165 participants	85 participants
		8	4
Urobilinogen Day 3, +++	Number Analyzed	165 participants	85 participants
		0	3
Urobilinogen, Day 3, ++++	Number Analyzed	165 participants	85 participants
		0	1
Urobilinogen, Day 5, Trace	Number Analyzed	166 participants	85 participants
		3	1
Urobilinogen, Day 5, +	Number Analyzed	166 participants	85 participants
		3	2
Urobilinogen, Day 8, Trace	Number Analyzed	164 participants	84 participants
		2	2
Urobilinogen, Day 8, +	Number Analyzed	164 participants	84 participants
		0	2
Urobilinogen, Day 8, ++	Number Analyzed	164 participants	84 participants
		0	1
Urobilinogen, Day 8,+++	Number Analyzed	164 participants	84 participants
		0	1
Urobilinogen, Day 11, Trace	Number Analyzed	163 participants	84 participants
		1	1
Urobilinogen, Day 11, +	Number Analyzed	163 participants	84 participants
		2	0
Urobilinogen, Day 11, ++	Number Analyzed	163 participants	84 participants
		0	1
Urobilinogen, Day 15, Trace	Number Analyzed	164 participants	84 participants
		3	1
Urobilinogen, Day 15, +	Number Analyzed	164 participants	84 participants
		1	0
Urobilinogen, Day 15, ++	Number Analyzed	164 participants	84 participants
		1	0
Urobilinogen, Day 22, Trace	Number Analyzed	164 participants	84 participants
		3	0
Urobilinogen, Day 29, Trace	Number Analyzed	162 participants	84 participants
		4	1
Urobilinogen, Day 29, +	Number Analyzed	162 participants	84 participants
		2	1
Urobilinogen, Day 60, Trace	Number Analyzed	160 participants	83 participants
		3	1
Urobilinogen, Day 60, +	Number Analyzed	160 participants	83 participants
		1	0
Urobilinogen, Day 90, Trace	Number Analyzed	160 participants	82 participants
		4	1
Urobilinogen, Day 90, +	Number Analyzed	160 participants	82 participants
		3	0
Urobilinogen, Day 120, Trace	Number Analyzed	160 participants	81 participants
		2	0
Urobilinogen, Day 120, +	Number Analyzed	160 participants	81 participants
		2	0
Urobilinogen, Day 120, ++	Number Analyzed	160 participants	81 participants
		0	1

14. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
Description	An adverse event (AE) is defined as any untoward medical occurrence in a participant under clinical investigation, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Serious adverse event (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 such as important medical events and events of possible drug induced liver injury with hyperbilirubinemia. TEAEs are defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with TEAEs and serious TEAEs have been presented.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Measure Type: Number; Unit of Measure: Participants
TEAEs	119	64
Serious TEAEs	6	1

15. Secondary Outcome

Title	Number of Participants With Electrocardiogram (ECG) Findings
Description	12 lead ECG was performed with the participant in a semi-supine position having rested in this position for at least 10 minutes. ECG assessments were performed in triplicate at screening followed by single ECGs 12 hours after the first dose of study medication and at Day 29. The number of participants with abnormal-clinically significant ECG findings have been presented. The 12 Hour Post Randomized Treatment (11.5-12.5 Hours) timepoint included all readings taken between 11.5 and 12.5 hours post randomized treatment. The 12 Hour Post Randomized Treatment (8-72 Hours) timepoint is a sensitivity analysis of the 12 Hour post randomized treatment timepoint, including all readings taken between 8 and 72 hours post randomized treatment. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Up to Day 29

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title		TQ+CQ	PQ+CQ
Arm/Group Description:		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed		166	85
Measure Type: Number; Unit of Measure: Participants
11.5 to 12.5 hours Day 1, Assessment 1; n=143, 75	Number Analyzed	143 participants	75 participants
		0	0
11.5 to 12.5 hours Day 1 Assessment 2; n=6, 6	Number Analyzed	6 participants	6 participants
		0	0
11.5 to 12.5 hours Day 1 Assessment 3; n=5, 5	Number Analyzed	5 participants	5 participants
		0	0
8 to 72 hours Day 1 Assessment 1; n=166, 85	Number Analyzed	166 participants	85 participants
		0	0
8 to 72 hours Day 1 Assessment 2; n=6, 6	Number Analyzed	6 participants	6 participants
		0	0
8 to 72 hours Day 1 Assessment 3; n=5, 5	Number Analyzed	5 participants	5 participants
		0	0
Day 29; n=161, 84	Number Analyzed	161 participants	84 participants
		0	0

16. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP)
Description	Vital signs were measured twice a day on Days 1 through 3, at least 4 hours apart, and immediately prior to pharmacokinetic (PK) measurements. MAP was calculated as the sum of SBP and two times DBP divided by 3. The mean and standard deviation of SBP, DBP and MAP has been presented. The values presented does not include Day 3 assessments for participant number 570. Baseline value is defined as the latest pre-treatment assessment where treatment is their first dose of study medication (CQ/PQ/TQ/Placebo). Change from Baseline is the value at post dose minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Baseline and up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title		TQ+CQ	PQ+CQ
Arm/Group Description:		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed		166	85
Mean (Standard Deviation); Unit of Measure: millimeter of mercury (mmHg)
SBP, Day 1 assessment 4; n=161, 84	Number Analyzed	161 participants	84 participants
		1.2 (10.98)	-0.9 (10.73)
SBP, Day 2 assessment 1; n=166, 85	Number Analyzed	166 participants	85 participants
		0.4 (11.78)	-2.3 (10.91)
SBP, Day 2 assessment 4; n=166, 85	Number Analyzed	166 participants	85 participants
		-0.8 (12.21)	-2.7 (12.46)
SBP, Day 3 assessment 1; n=166, 83	Number Analyzed	166 participants	83 participants
		-0.6 (13.38)	-2.1 (11.69)
SBP, Day 3 assessment 4; n=166, 82	Number Analyzed	166 participants	82 participants
		-2.7 (12.45)	-2.2 (12.66)
SBP, Day 8; n=164, 84	Number Analyzed	164 participants	84 participants
		2.2 (12.00)	0.8 (12.47)
SBP, Day 11; n=163, 84	Number Analyzed	163 participants	84 participants
		1.3 (12.35)	1.2 (14.69)
SBP, Day15; n=165, 84	Number Analyzed	165 participants	84 participants
		3.2 (13.81)	2.5 (12.64)
SBP, Day 22; n=164, 84	Number Analyzed	164 participants	84 participants
		3.3 (13.21)	2.9 (12.55)
SBP, Day 29; n=163, 84	Number Analyzed	163 participants	84 participants
		2.6 (14.08)	4.4 (14.29)
SBP, Day 60; n=160, 83	Number Analyzed	160 participants	83 participants
		4.4 (14.10)	4.3 (15.95)
SBP, Day 90; n=160, 82	Number Analyzed	160 participants	82 participants
		3.8 (14.30)	5.3 (14.91)
SBP, Day 120; n=159, 81	Number Analyzed	159 participants	81 participants
		3.8 (14.05)	3.1 (15.40)
SBP, Day 150; n=161, 82	Number Analyzed	161 participants	82 participants
		4.4 (13.99)	4.9 (12.83)
SBP, Day180; n=160, 83	Number Analyzed	160 participants	83 participants
		3.7 (14.21)	5.7 (13.64)
DBP, Day 1 assessment 4; n=161, 84	Number Analyzed	161 participants	84 participants
		1.1 (7.56)	-1.5 (8.07)
DBP, Day 2 assessment 1; n=166, 85	Number Analyzed	166 participants	85 participants
		-0.1 (8.67)	-2.2 (8.42)
DBP, Day 2 assessment 4; n=166, 85	Number Analyzed	166 participants	85 participants
		-0.8 (9.57)	-2.6 (8.99)
DBP, Day 3 assessment 1; n=166, 83	Number Analyzed	166 participants	83 participants
		-0.2 (10.91)	-1.3 (9.28)
DBP, Day 3 assessment 4; n=166, 82	Number Analyzed	166 participants	82 participants
		-1.9 (9.69)	-1.9 (9.79)
DBP, Day 8; n=164, 84	Number Analyzed	164 participants	84 participants
		0.9 (8.93)	1.1 (9.99)
DBP, Day 11; n=163, 84	Number Analyzed	163 participants	84 participants
		-0.0 (9.42)	-0.5 (9.39)
DBP, Day15; n=165, 84	Number Analyzed	165 participants	84 participants
		1.5 (10.91)	0.4 (9.74)
DBP, Day 22; n=164, 84	Number Analyzed	164 participants	84 participants
		1.2 (10.00)	1.3 (9.25)
DBP, Day 29; n=163, 84	Number Analyzed	163 participants	84 participants
		0.9 (10.58)	1.5 (10.79)
DBP, Day 60; n=160, 83	Number Analyzed	160 participants	83 participants
		3.1 (11.05)	1.9 (10.34)
DBP, Day 90; n=160, 82	Number Analyzed	160 participants	82 participants
		2.7 (11.60)	3.5 (9.32)
DBP, Day 120; n=159, 81	Number Analyzed	159 participants	81 participants
		3.3 (10.99)	2.4 (10.83)
DBP, Day 150; n=161, 82	Number Analyzed	161 participants	82 participants
		3.2 (11.15)	4.1 (10.96)
DBP, Day180; n=160, 83	Number Analyzed	160 participants	83 participants
		2.9 (11.04)	3.7 (10.71)
MAP, Day 1 assessment 4; n=161, 84	Number Analyzed	161 participants	84 participants
		1.1 (7.45)	-1.3 (7.98)
MAP, Day 2 assessment 1; n=166, 85	Number Analyzed	166 participants	85 participants
		0.0 (8.68)	-2.2 (8.08)
MAP, Day 2 assessment 4; n=166, 85	Number Analyzed	166 participants	85 participants
		-0.8 (9.48)	-2.6 (9.14)
MAP, Day 3 assessment 1; n=166, 83	Number Analyzed	166 participants	83 participants
		-0.3 (10.75)	-1.6 (8.98)
MAP, Day 3 assessment 4; n=166, 82	Number Analyzed	166 participants	82 participants
		-2.2 (9.76)	-2.0 (9.91)
MAP, Day 8; n=164, 84	Number Analyzed	164 participants	84 participants
		1.3 (8.98)	1.0 (9.76)
MAP, Day 11; n=163, 84	Number Analyzed	163 participants	84 participants
		0.4 (9.33)	0.1 (9.51)
MAP, Day15; n=165, 84	Number Analyzed	165 participants	84 participants
		2.0 (10.72)	1.1 (9.58)
MAP, Day 22; n=164, 84	Number Analyzed	164 participants	84 participants
		1.9 (9.94)	1.8 (9.06)
MAP, Day 29; n=163, 84	Number Analyzed	163 participants	84 participants
		1.5 (10.58)	2.4 (10.80)
MAP, Day 60; n=160, 83	Number Analyzed	160 participants	83 participants
		3.5 (11.07)	2.7 (10.79)
MAP, Day 90; n=160, 82	Number Analyzed	160 participants	82 participants
		3.1 (11.34)	4.1 (9.76)
MAP, Day 120; n=159, 81	Number Analyzed	159 participants	81 participants
		3.5 (10.66)	2.6 (10.90)
MAP, Day 150; n=161, 82	Number Analyzed	161 participants	82 participants
		3.6 (10.83)	4.4 (10.44)
MAP, Day180; n=160, 83	Number Analyzed	160 participants	83 participants
		3.2 (10.91)	4.4 (9.95)

17. Secondary Outcome

Title	Change From Baseline in Pulse Rate
Description	Vital signs were measured twice a day on Days 1 through 3, at least 4 hours apart, and immediately prior to PK measurements. The mean and standard deviation of pulse rate has been presented. The values presented does not include Day 3 assessments for participant number 570. Baseline value is defined as the latest pre-treatment assessment where treatment is their first dose of study medication (CQ/PQ/TQ/Placebo). Change from Baseline is the value at post dose minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Baseline and up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title		TQ+CQ	PQ+CQ
Arm/Group Description:		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed		166	85
Mean (Standard Deviation); Unit of Measure: beats per minute
Day 1 assessment 4; n=161, 84	Number Analyzed	161 participants	84 participants
		-10.8 (15.24)	-9.3 (15.05)
Day 2 assessment 1; n=166, 85	Number Analyzed	166 participants	85 participants
		-9.9 (17.06)	-9.9 (14.90)
Day 2 assessment 4; n=166, 85	Number Analyzed	166 participants	85 participants
		-11.9 (15.78)	-11.8 (13.74)
Day 3 assessment 1; n=166, 83	Number Analyzed	166 participants	83 participants
		-15.1 (16.62)	-18.2 (16.09)
Day 3 assessment 4; n=166, 82	Number Analyzed	166 participants	82 participants
		-16.5 (17.16)	-17.5 (16.17)
Day 8; n=164, 84	Number Analyzed	164 participants	84 participants
		-12.7 (16.49)	-14.6 (17.91)
Day 11; n=163, 84	Number Analyzed	163 participants	84 participants
		-13.4 (17.83)	-15.5 (17.05)
Day15; n=165, 84	Number Analyzed	165 participants	84 participants
		-13.5 (17.98)	-16.9 (17.77)
Day 22; n=164, 84	Number Analyzed	164 participants	84 participants
		-14.7 (17.72)	-16.8 (17.08)
Day 29; n=163, 84	Number Analyzed	163 participants	84 participants
		-16.9 (16.85)	-17.5 (16.27)
Day 60; n=160, 83	Number Analyzed	160 participants	83 participants
		-16.7 (17.44)	-18.5 (17.51)
Day 90; n=160, 82	Number Analyzed	160 participants	82 participants
		-16.3 (16.87)	-18.6 (17.27)
Day 120; n=159, 81	Number Analyzed	159 participants	81 participants
		-16.7 (17.82)	-19.1 (18.40)
Day 150; n=161, 82	Number Analyzed	161 participants	82 participants
		-16.8 (16.60)	-17.9 (18.32)
Day180; n=160, 83	Number Analyzed	160 participants	83 participants
		-18.0 (18.51)	-18.3 (18.27)

18. Secondary Outcome

Title	Change From Baseline in Temperature
Description	Vital signs were performed twice a day on Days 1 through 3, at least 4 hours apart, and immediately prior to PK measurements. The mean and standard deviation of pulse rate has been presented. The values presented does not include Day 3 assessments for participant number 570. Baseline value is defined as the latest pre-treatment assessment where treatment is their first dose of study medication (CQ/PQ/TQ/Placebo). Change from Baseline is the value at post dose minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Baseline and up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title		TQ+CQ	PQ+CQ
Arm/Group Description:		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed		166	85
Mean (Standard Deviation); Unit of Measure: Celsius
Day 1 assessment 4; n=161, 84	Number Analyzed	161 participants	84 participants
		-0.6 (1.05)	-0.5 (1.29)
Day 2 assessment 1; n=166, 85	Number Analyzed	166 participants	85 participants
		-0.6 (1.20)	-0.6 (1.36)
Day 2 assessment 4; n=166, 85	Number Analyzed	166 participants	85 participants
		-0.6 (1.08)	-0.6 (1.14)
Day 3 assessment 1; n=166, 83	Number Analyzed	166 participants	83 participants
		-1.0 (1.03)	-0.9 (1.10)
Day 3 assessment 4; n=166, 82	Number Analyzed	166 participants	82 participants
		-1.0 (1.02)	-1.0 (1.09)
Day 8; n=164, 84	Number Analyzed	164 participants	84 participants
		-1.0 (1.01)	-0.9 (1.03)
Day 11; n=163, 84	Number Analyzed	163 participants	84 participants
		-1.0 (1.05)	-0.9 (1.05)
Day15; n=165, 84	Number Analyzed	165 participants	84 participants
		-0.9 (1.00)	-1.0 (1.03)
Day 22; n=164, 84	Number Analyzed	164 participants	84 participants
		-1.0 (0.99)	-1.0 (1.03)
Day 29; n=163, 84	Number Analyzed	163 participants	84 participants
		-1.0 (0.97)	-1.0 (1.02)
Day 60; n=160, 83	Number Analyzed	160 participants	83 participants
		-1.0 (1.03)	-1.0 (1.05)
Day 90; n=160, 82	Number Analyzed	160 participants	82 participants
		-1.0 (1.10)	-1.0 (0.96)
Day 120; n=159, 81	Number Analyzed	159 participants	81 participants
		-1.0 (1.05)	-0.9 (1.00)
Day 150; n=161, 82	Number Analyzed	161 participants	82 participants
		-1.0 (1.04)	-1.0 (1.04)
Day180; n=160, 83	Number Analyzed	160 participants	83 participants
		-1.0 (1.04)	-1.0 (0.99)

19. Secondary Outcome

Title	Number of Participants With P. Falciparum
Description	Microscopic blood slides (two thick film and one thin film slide) were prepared and examined for asexual parasite count. The number of participants with positive P. falciparum asexual parasite count post Baseline has been summarized for each treatment arm.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	TQ+CQ	PQ+CQ
Arm/Group Description:	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed	166	85
Measure Type: Number; Unit of Measure: Participants
	4	3

20. Secondary Outcome

Title	Number of Participants With Keratopathy
Description	Ophthalmic assessments were carried out at pre-qualified sites prior to randomization and at Days 29 and 90 and at withdrawal follow-up visit. Assessments were carried out at Day 180 (and up to resolution) 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 has been summarized for each visit. The number of participants with new keratopathy at any time post Baseline is 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 (represented by n=X in category title).
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Ophthalmic Safety Population

Arm/Group Title		TQ+CQ	PQ+CQ
Arm/Group Description:		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed		27	13
Measure Type: Number; Unit of Measure: Participants
Baseline; right eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Baseline; left eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Day 1; right eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Day 1; left eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Day 29; right eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Day 29; left eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Day 90; right eye; n=27, 12	Number Analyzed	27 participants	12 participants
		0	0
Day 90; left eye; n=27, 12	Number Analyzed	27 participants	12 participants
		0	0
Day 180; right eye; n=2, 2	Number Analyzed	2 participants	2 participants
		0	0
Day 180; left eye; n=2, 2	Number Analyzed	2 participants	2 participants
		0	0
Any time post Baseline; right eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Any time post Baseline; left eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0

21. Secondary Outcome

Title	Number of Participants With Change in Best Corrected Visual Acuity Test Scores
Description	Ophthalmic assessments were carried out at pre-qualified sites 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 is the value at post dose visit minus the Baseline value. 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 number of participants with change in Best Corrected Visual Acuity Test Scores from Baseline has been presented where possible change is defined as a change from Baseline >=0.12 to <0.3 and definite change is defined as a change from Baseline >=0.3 logMAR score. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Baseline and up to Day 180

Outcome Measure Data

Analysis Population Description

Ophthalmic Safety Population

Arm/Group Title		TQ+CQ	PQ+CQ
Arm/Group Description:		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed		27	13
Measure Type: Number; Unit of Measure: Participants
Maximum change; possible; right eye; n=27, 13	Number Analyzed	27 participants	13 participants
		1	0
Maximum change; definite; right eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Maximum change; possible; left eye; n=27, 13	Number Analyzed	27 participants	13 participants
		2	0
Maximum change; definite; left eye; n=27, 13	Number Analyzed	27 participants	13 participants
		1	1
Day 29; possible change; right eye; n=27, 13	Number Analyzed	27 participants	13 participants
		1	0
Day 29; definite change; right eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Day 29; possible change; left eye; n=27, 13	Number Analyzed	27 participants	13 participants
		2	0
Day 29; definite change; left eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0
Day 90; possible change; right eye; n=27, 12	Number Analyzed	27 participants	12 participants
		0	0
Day 90; definite change; right eye; n=27, 12	Number Analyzed	27 participants	12 participants
		0	0
Day 90; possible change; left eye; n=27, 12	Number Analyzed	27 participants	12 participants
		2	0
Day 90; definite change; left eye; n=27, 12	Number Analyzed	27 participants	12 participants
		1	0
Day 180; possible change; right eye; n=2, 2	Number Analyzed	2 participants	2 participants
		0	0
Day 180; definite change; right eye; n=2, 2	Number Analyzed	2 participants	2 participants
		0	0
Day 180; possible change; left eye; n=2, 2	Number Analyzed	2 participants	2 participants
		0	0
Day 180; definite change; left eye; n=2, 2	Number Analyzed	2 participants	2 participants
		0	1

22. Secondary Outcome

Title	Number of Participants With Retinal Changes From Baseline
Description	Ophthalmic assessments were carried out at pre-qualified sites prior to randomization and at Days 29 and 90 and at withdrawal follow-up. Assessments were carried out at Day 180 (and up to resolution) 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 value at post dose visit minus the Baseline value. The number of participants with definite retinal change and questionable (ques) retinal change from Baseline has been presented. The number of participants with maximum change post-Baseline (definite when absent or questionable at Baseline) has been presented for either eye. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Baseline and up to Day 180

Outcome Measure Data

Analysis Population Description

Ophthalmic Safety Population

Arm/Group Title		TQ+CQ	PQ+CQ
Arm/Group Description:		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed		27	13
Measure Type: Number; Unit of Measure: Participants
Day 29, Definite change, right eye; n=22, 13	Number Analyzed	22 participants	13 participants
		0	0
Day 29, Ques change, right eye; n=22, 13	Number Analyzed	22 participants	13 participants
		2	0
Day 29, Definite change, left eye; n=22, 13	Number Analyzed	22 participants	13 participants
		0	0
Day 29, Ques change, left eye; n=22, 13	Number Analyzed	22 participants	13 participants
		1	0
Day 90, Definite change, right eye; n=24, 11	Number Analyzed	24 participants	11 participants
		0	0
Day 90, Ques change, right eye; n=24, 11	Number Analyzed	24 participants	11 participants
		2	1
Day 90, Definite change, left eye; n=24, 11	Number Analyzed	24 participants	11 participants
		0	0
Day 90, Ques change, left eye; n=24, 11	Number Analyzed	24 participants	11 participants
		0	0
Day 180, Definite change, right eye; n=3, 2	Number Analyzed	3 participants	2 participants
		0	0
Day 180, Ques change, right eye; n=3, 2	Number Analyzed	3 participants	2 participants
		0	0
Day 180, Definite change, left eye; n=3, 2	Number Analyzed	3 participants	2 participants
		0	0
Day 180, Ques change, left eye; n=3, 2	Number Analyzed	3 participants	2 participants
		0	0
Maximum change post-Baseline; either eye; n=27, 13	Number Analyzed	27 participants	13 participants
		0	0

23. Secondary Outcome

Title	Change From Baseline in Percent Methemoglobin
Description	Methemoglbin is an oxidized and inactive form of hemoglobin. Methemoglobin assessment was made with the aid of a non-invasive signal extraction pulse CO-Oximeter handheld machine. The change from Baseline in percent methemoglobin by treatment, time and sex has been summarized. The latest pre-treatment assessment where treatment is their first dose of study medication (CQ/PQ/TQ/Placebo) was considered as Baseline value. Change from Baseline is the value at post dose visit minus the Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Baseline and up to Day 120

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title		TQ+CQ	PQ+CQ
Arm/Group Description:		Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.	Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
Overall Number of Participants Analyzed		166	85
Mean (Standard Deviation); Unit of Measure: Percent change
Day 2, Male, n=114, 53	Number Analyzed	114 participants	53 participants
		0.02 (0.754)	0.02 (0.406)
Day 2, Female, n=52, 32	Number Analyzed	52 participants	32 participants
		-0.16 (1.168)	-0.06 (0.181)
Day 3, Male, n=114, 53	Number Analyzed	114 participants	53 participants
		0.18 (0.762)	0.03 (0.373)
Day 3, Female, n=52, 32	Number Analyzed	52 participants	32 participants
		0.08 (1.264)	0.17 (0.663)
Day 5, Male, n=113, 53	Number Analyzed	113 participants	53 participants
		0.77 (1.226)	0.89 (1.207)
Day 5, Female, n=52, 32	Number Analyzed	52 participants	32 participants
		0.63 (1.354)	1.32 (1.400)
Day 8, Male, n=112, 52	Number Analyzed	112 participants	52 participants
		1.22 (1.505)	2.63 (2.881)
Day 8, Female, n=52, 32	Number Analyzed	52 participants	32 participants
		1.00 (1.755)	2.81 (2.530)
Day 11, Male, n=112, 52	Number Analyzed	112 participants	52 participants
		1.16 (1.446)	3.30 (3.116)
Day 11, Female, n=51, 32	Number Analyzed	51 participants	32 participants
		1.04 (1.656)	3.44 (2.651)
Day 15, Male, n=113, 52	Number Analyzed	113 participants	52 participants
		1.01 (1.226)	3.26 (2.920)
Day 15, Female, n=52, 32	Number Analyzed	52 participants	32 participants
		0.81 (1.474)	3.61 (2.324)
Day 22, Male, n=112, 52	Number Analyzed	112 participants	52 participants
		0.61 (1.008)	1.58 (1.692)
Day 22, Female, n=52, 32	Number Analyzed	52 participants	32 participants
		0.32 (1.364)	2.30 (1.900)
Day 29, Male, n=111, 52	Number Analyzed	111 participants	52 participants
		0.24 (0.714)	0.46 (0.795)
Day 29, Female, n=52, 32	Number Analyzed	52 participants	32 participants
		-0.02 (1.239)	0.84 (0.842)
Day 60, Male, n=107, 51	Number Analyzed	107 participants	51 participants
		0.05 (0.583)	0.20 (1.220)
Day 60, Female, n=52, 32	Number Analyzed	52 participants	32 participants
		-0.09 (1.202)	0.14 (0.496)
Day 120, Male, n=109, 50	Number Analyzed	109 participants	50 participants
		0.06 (0.389)	-0.01 (0.328)
Day 120, Female, n=50, 31	Number Analyzed	50 participants	31 participants
		0.14 (1.676)	0.04 (0.422)

24. Secondary Outcome

Title	Cost Associated With Relapse Episode of P Vivax Malaria
Description	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 emergency center, other). The costs associated with a relapse episode of P. vivax malaria has been presented. Participants may be represented in more than one category, so the total number of participants may be less than the number quoted. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants who experienced a relapse or who had a follow-up visit for a relapse were included in the analysis.

Arm/Group Title		First Malaria Relapse	First Malaria Relapse Follow-up
Arm/Group Description:		Participants from all treatment arms (CQ+TQ and PQ+TQ) with a relapse episode of malaria were included.	Participants from all treatment arms (CQ+TQ and PQ+TQ) who had a follow-up visit for relapse episode of malaria were included.
Overall Number of Participants Analyzed		72	85
Mean (Standard Deviation); Unit of Measure: US Dollars (USD)
Brazil; enrollment clinic for care; n=19, 17	Number Analyzed	19 participants	17 participants
		8.208 (2.8369)	8.032 (2.2403)
Colombia; enrollment clinic for care; n=1,0	Number Analyzed	1 participants	0 participants
		42.776 (0)
Colombia; attended another clinic; n=1,0	Number Analyzed	1 participants	0 participants
		4.194 (0)
Colombia; hospital emergency center; n=1,1	Number Analyzed	1 participants	1 participants
		16.775 (0)	16.775 (0)
Peru; enrollment clinic for care; n=32, 33	Number Analyzed	32 participants	33 participants
		9.244 (2.8235)	8.815 (1.2803)
Peru; attended another clinic; n=8, 30	Number Analyzed	8 participants	30 participants
		1.677 (0.9807)	3.959 (0.8522)
Peru; Other; n=8, 0	Number Analyzed	8 participants	0 participants
		0.818 (0.4284)
Thailand; enrollment clinic for care; n=0, 1	Number Analyzed	0 participants	1 participants
			1.534 (0)
Vietnam; drug shop for care;n=1, 2	Number Analyzed	1 participants	2 participants
		0.702 (0)	2.809 (2.6483)
Vietnam; Other; n=1, 0	Number Analyzed	1 participants	0 participants
		1.873 (0)
Vietnam; attended another clinic; n=0, 1	Number Analyzed	0 participants	1 participants
			0.936 (0)

25. Secondary Outcome

Title	Cost Associated With a Hemolysis Event
Description	Health outcomes were evaluated based on cost incurred due to clinically relevant hemolysis. The total cost was evaluated based on the amount spent on treatment, transport, medication and test. The costs associated with hemolysis event has been presented. The aim of this outcome measure was to determine the cost to a participant due to an event of hemolysis, regardless of treatment received in the study. It was not expected there would be major cost differences with hemoglobin decrease between the treatment arms. This was pre-specified in the statistical analysis plan.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Participants With Clinically Relevant Hemolysis
Arm/Group Description:	Participants from both treatment arms (TQ + CQ and PQ + CQ) with clinically relevant hemolysis were included.
Overall Number of Participants Analyzed	1
Mean (Standard Deviation); Unit of Measure: USD
	9.174 (0)

26. Secondary Outcome

Title	Cost Incurred With Purchase of Medications Associated With Relapse Episode of P. Vivax Malaria
Description	Health outcomes were evaluated based on the cost of medications purchased. The total medication cost for paracetamol associated with relapse episode of P vivax malaria has been presented. 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 (represented by n=X in category title).
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title		First Malaria Relapse	First Malaria Relapse Follow-up
Arm/Group Description:		Participants from all treatment arms (CQ+TQ and PQ+TQ) with a relapse episode of malaria were included.	Participants from all treatment arms (CQ+TQ and PQ+TQ) who had a follow-up visit for relapse episode of malaria were included.
Overall Number of Participants Analyzed		9	4
Mean (Standard Deviation); Unit of Measure: USD
Colombia; n=2, 1	Number Analyzed	2 participants	1 participants
		2.516 (2.3723)	4.194 (0)
Peru; n=6, 2	Number Analyzed	6 participants	2 participants
		0.491 (0.1792)	0.327 (0.0000)
Vietnam; n=1, 1	Number Analyzed	1 participants	1 participants
		0.468 (0)	2.341 (0)

27. Secondary Outcome

Title	Cost Incurred With Purchase of Medications Associated With Hemolysis Event
Description	Health outcomes were evaluated based on the cost of medications purchased. The total medication cost associated with hemolysis event has been presented. Medications recorded as “Other” and medications without costs are excluded from the analysis. The aim of this outcome measure was to determine the cost to a participant due to an event of hemolysis, regardless of treatment received in the study. It was not expected there would be major cost differences with hemoglobin decrease between the treatment arms. This was pre-specified in the statistical analysis plan.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Participants With Clinically Relevant Hemolysis
Arm/Group Description:	Participants from both treatment arms (TQ + CQ and PQ + CQ) with clinically relevant hemolysis were included.
Overall Number of Participants Analyzed	1
Mean (Standard Deviation); Unit of Measure: USD
	0 (0)

28. Secondary Outcome

Title	Number of Participants or Care Givers Who Had Taken Time Off From Normal Occupation Due to Relapse Episode of Malaria
Description	Health outcomes were evaluated based on total time lost by participants or care givers due to an episode of malaria. The number of participants or care givers who had taken off from their normal occupation due to relapse episode of P vivax malaria has been presented by country. Participants may be represented in more than one category, so the total number of participants may be less than the number quoted. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title		First Malaria Relapse	First Malaria Relapse Follow-up
Arm/Group Description:		Participants from all treatment arms (CQ+TQ and PQ+TQ) with a relapse episode of malaria were included.	Participants from all treatment arms (CQ+TQ and PQ+TQ) who had a follow-up visit for relapse episode of malaria were included.
Overall Number of Participants Analyzed		61	61
Measure Type: Number; Unit of Measure: Participants
Brazil; Housework; n=2, 1	Number Analyzed	2 participants	1 participants
		0	0
Brazil; Farming; n=1, 1	Number Analyzed	1 participants	1 participants
		0	0
Brazil; Student; n=1, 1	Number Analyzed	1 participants	1 participants
		0	0
Brazil; Paid employment; n=7, 7	Number Analyzed	7 participants	7 participants
		0	0
Brazil; Other; n=8, 7	Number Analyzed	8 participants	7 participants
		0	0
Colombia; Housework; n=1, 0	Number Analyzed	1 participants	0 participants
		1
Colombia; Farming; n=2, 2	Number Analyzed	2 participants	2 participants
		0	0
Colombia; Paid employment; n=1, 1	Number Analyzed	1 participants	1 participants
		1	1
Peru; Housework; n=18, 18	Number Analyzed	18 participants	18 participants
		14	15
Peru, Farming; n=4, 4	Number Analyzed	4 participants	4 participants
		4	4
Peru; Student; n=3, 3	Number Analyzed	3 participants	3 participants
		2	2
Peru; Paid employment; n=1, 1	Number Analyzed	1 participants	1 participants
		1	1
Peru; Other; n=7, 7	Number Analyzed	7 participants	7 participants
		7	6
Thailand; Farming; n=1, 1	Number Analyzed	1 participants	1 participants
		1	1
Vietnam; Farming; n=4, 4	Number Analyzed	4 participants	4 participants
		3	1
Vietnam; Paid employment; n=0, 3	Number Analyzed	0 participants	3 participants
			2

29. Secondary Outcome

Title	Number of Participants or Care Givers Who Had Taken Time Off From Normal Occupation Due to a Hemolysis Event
Description	Health outcomes were evaluated based on total time lost by participants or care givers due to a hemolysis event. The number of participants or care givers who took days off from work due to a hemolysis event has been presented based on the normal occupation. The aim of this outcome measure was to determine the time taken off by participants due to an event of hemolysis, regardless of treatment received in the study. It was not expected there would be major differences in time taken off by participants with hemoglobin decrease between the treatment arms. This was pre-specified in the statistical analysis plan.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Participants With Clinically Relevant Hemolysis
Arm/Group Description:	Participants from both treatment arms (TQ + CQ and PQ + CQ) with clinically relevant hemolysis were included.
Overall Number of Participants Analyzed	1
Measure Type: Number; Unit of Measure: Participants
	0

30. Secondary Outcome

Title	Number of Participants With Action Taken to Treat Relapse Episode of P. Vivax Malaria
Description	Health outcomes were evaluated based on the actions taken by the participants to treat relapse episode of P vivax malaria. The number of participants with the type of action taken to treat relapse episode of P vivax malaria has been presented by country. Participants may be represented in more than one category, so the total number of participants may be less than the number quoted. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title		First Malaria Relapse	First Malaria Relapse Follow-up
Arm/Group Description:		Participants from all treatment arms (CQ+TQ and PQ+TQ) with a relapse episode of malaria were included.	Participants from all treatment arms (CQ+TQ and PQ+TQ) who had a follow-up visit for relapse episode of malaria were included.
Overall Number of Participants Analyzed		61	61
Measure Type: Number; Unit of Measure: Participants
Brazil; Trial clinic; n=19, 17	Number Analyzed	19 participants	17 participants
		19	17
Brazil; Other; n=19, 17	Number Analyzed	19 participants	17 participants
		5	0
Colombia; Nothing; n=4, 3	Number Analyzed	4 participants	3 participants
		2	2
Colombia; Trial clinic; n=4, 3	Number Analyzed	4 participants	3 participants
		1	0
Colombia; Another clinic; n=4, 3	Number Analyzed	4 participants	3 participants
		1	0
Colombia; Hospital emergency center; n=4, 3	Number Analyzed	4 participants	3 participants
		1	1
Peru; Trial clinic; n=33, 33	Number Analyzed	33 participants	33 participants
		32	33
Peru; Another clinic; n=33, 33	Number Analyzed	33 participants	33 participants
		8	33
Peru; Other; n=33, 33	Number Analyzed	33 participants	33 participants
		9	0
Thailand; Nothing; n=1, 1	Number Analyzed	1 participants	1 participants
		1	0
Thailand; Trial Clinic; n=1, 1	Number Analyzed	1 participants	1 participants
		0	1
Vietnam; Nothing; n=4, 7	Number Analyzed	4 participants	7 participants
		1	5
Vietnam; Drug Shop; n=4, 7	Number Analyzed	4 participants	7 participants
		2	2
Vietnam; Other; n=4, 7	Number Analyzed	4 participants	7 participants
		1	0
Vietnam; Another clinic; n=4, 7	Number Analyzed	4 participants	7 participants
		0	1

31. Secondary Outcome

Title	Number of Participants With Action Taken to Treat a Hemolysis Event
Description	Health outcomes were evaluated based on the actions taken by the participants to treat hemolysis events. The number of participants in Brazil who attended the trial clinic to treat a hemolysis event has been presented. The aim of this outcome measure was to determine the action taken by a participant due to an event of hemolysis, regardless of treatment received in the study. It was not expected there would be major differences in action taken by the participants with hemoglobin decrease between the treatment arms. This was pre-specified in the statistical analysis plan.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Participants With Clinically Relevant Hemolysis
Arm/Group Description:	Participants from both treatment arms (TQ + CQ and PQ + CQ) with clinically relevant hemolysis were included.
Overall Number of Participants Analyzed	1
Measure Type: Number; Unit of Measure: Participants
	1

32. Secondary Outcome

Title	Oral Clearance (CL/F) of TQ
Description	Apparent population oral clearance of TQ
Time Frame	Day 2, Day 3, Day 8, Day 15, Day 29, Day 60 and Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Participants in TQ Only Arms
Arm/Group Description:	TQ only arms
Overall Number of Participants Analyzed	166
Median (90% Confidence Interval); Unit of Measure: Liters per hour
	2.96; (2.87 to 3.05)

33. Secondary Outcome

Title	Volume of Distribution (Vc/F) of TQ
Description	Apparent population central volume of distribution of TQ
Time Frame	Day 2, Day 3, Day 8, Day 15, Day 29, Day 60 and Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Participants in TQ Only Arms
Arm/Group Description:	TQ only arms
Overall Number of Participants Analyzed	166
Median (90% Confidence Interval); Unit of Measure: Liters
	915; (879 to 956)

Adverse Events

Time Frame	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)
Adverse Event Reporting Description	Safety Population comprised of all randomized participants who received at least one dose of study medication.
Arm/Group Title	TQ+CQ		PQ+CQ
Arm/Group Description	Participants were administered CQ 600 milligram (mg) once daily on Days 1 and 2 and CQ 300 mg on Day 3. A single dose of TQ 300 mg was administered orally on Day 1 or Day 2. PQ placebo capsules were administered orally once daily for 14 days starting on the same day as TQ administration.		Participants were administered CQ 600 mg tablet once daily on Days 1 and 2 and CQ 300 mg on Day 3. Participants received a single TQ placebo tablet orally on Day 1 or Day 2. PQ 15 mg was administered orally once daily for 14 days starting on the same day as TQ placebo administration.
All-Cause Mortality
	TQ+CQ		PQ+CQ
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/166 (0.00%)		0/85 (0.00%)
Serious Adverse Events
	TQ+CQ		PQ+CQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/166 (3.61%)		1/85 (1.18%)
General disorders
Pyrexia † 1	1/166 (0.60%)	1	0/85 (0.00%)	0
Infections and infestations
Pneumonia † 1	1/166 (0.60%)	1	0/85 (0.00%)	0
Investigations
Haemoglobin decreased † 1	4/166 (2.41%)	4	1/85 (1.18%)	1
1 Term from vocabulary, MedDRA 20.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	TQ+CQ		PQ+CQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	97/166 (58.43%)		50/85 (58.82%)
Gastrointestinal disorders
Nausea † 1	21/166 (12.65%)	23	7/85 (8.24%)	12
Vomiting † 1	15/166 (9.04%)	15	8/85 (9.41%)	8
Diarrhoea † 1	12/166 (7.23%)	12	3/85 (3.53%)	3
Abdominal pain upper † 1	10/166 (6.02%)	13	1/85 (1.18%)	1
General disorders
Pyrexia † 1	6/166 (3.61%)	7	6/85 (7.06%)	7
Asthenia † 1	5/166 (3.01%)	5	5/85 (5.88%)	7
Infections and infestations
Nasopharyngitis † 1	14/166 (8.43%)	15	5/85 (5.88%)	5
Urinary tract infection † 1	9/166 (5.42%)	11	9/85 (10.59%)	10
Pharyngitis † 1	5/166 (3.01%)	5	6/85 (7.06%)	6
Musculoskeletal and connective tissue disorders
Myalgia † 1	15/166 (9.04%)	16	11/85 (12.94%)	13
Back pain † 1	9/166 (5.42%)	11	3/85 (3.53%)	4
Nervous system disorders
Dizziness † 1	29/166 (17.47%)	35	16/85 (18.82%)	22
Headache † 1	27/166 (16.27%)	34	16/85 (18.82%)	22
Skin and subcutaneous tissue disorders
Pruritus † 1	21/166 (12.65%)	23	19/85 (22.35%)	19
1 Term from vocabulary, MedDRA 20.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

Name/Title: GSK Response Center

Organization: GlaxoSmithKline

Phone: 866-435-7343

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Llanos-Cuentas A, Lacerda MVG, Hien TT, Vélez ID, Namaik-Larp C, Chu CS, Villegas MF, Val F, Monteiro WM, Brito MAM, Costa MRF, Chuquiyauri R, Casapía M, Nguyen CH, Aruachan S, Papwijitsil R, Nosten FH, Bancone G, Angus B, Duparc S, Craig G, Rousell VM, Jones SW, Hardaker E, Clover DD, Kendall L, Mohamed K, Koh GCKW, Wilches VM, Breton JJ, Green JA. Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria. N Engl J Med. 2019 Jan 17;380(3):229-241. doi: 10.1056/NEJMoa1802537.

Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT02216123 History of Changes
Other Study ID Numbers:	116564
First Submitted:	June 19, 2014
First Posted:	August 13, 2014
Results First Submitted:	November 1, 2017
Results First Posted:	May 16, 2018
Last Update Posted:	May 16, 2018