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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01376167
• Collaborator: Medicines for Malaria Venture (Other)
• Enrollment: 851
• Locations: 14
• Arms: 9
• Actual Duration (Months): 30.9
• Patients Per Site: 60.8
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

The purpose of this two part study is to test the safety and efficacy of Tafenoquine (with Cholorquine) as a radical cure for Plasmodium vivax (P.vivax) malaria relative to the control Chloroquine.Part 1 aims to select an efficacious and well tolerated dose that can be co-administered with Chloroquine. Part 2 will investigate the safety and efficacy of the selected dose (300 mg tafenoquine) in the treatment and radical cure of Plasmodium Vivax Malaria.

Condition or Disease	Intervention/Treatment	Phase
Malaria, Vivax	Drug: Chloroquine 600mg; Drug: Chloroquine 300mg; Drug: Tafenoquine 50mg; Drug: Tafenoquine 100mg; Drug: Tafenoquine 300mg; Drug: Tafenoquine 600mg; Drug: Primaquine 15mg; Drug: Chloroquine 600mg (Part 2 ); Drug: Chloroquine 300mg (Part 2 ); Drug: Tafenoquine 300mg (Part 2); Drug: Primaquine 15mg (Part2 )	Phase 2

Detailed Description

Plasmodium vivax represents 50-80% of all malarial cases in Latin America and South East Asia. It is able to establish a dormant liver stage called the hypnozoite. Hypnozoite activation after initial infection can cause a relapse. Currently the only widely available drug is primaquine which requires administration over 14 days, resulting in poor compliance and treatment failure. Tafenoquine (an 8-aminoquinoline anti-malarial drug) has been shown to possess activity against all stages of the plasmodium life cycle, including the dormant stage in the liver. This is a multi-centre, double dummy, double blind, parallel group, randomized, active control study which is conducted in two parts. For both parts, subjects are treated with Chloroquine on days 1 to 3 (600mg, 600mg, and 300mg) to treat the blood stage vivax malaria. Part 1 will include at least 324 subjects and part 2 at least 600 subjects. Part 1 has 6 treatment arms, arms 1 to 4 contain different doses of Tafenoquine (50mg, 100mg, 300mg, and 600mg) dosed on day 1 or 2, arm 5 contains primaquine (15mg) dosing over 14 days (days 2-15 (15mg)) and arm 6 contains chloroquine only. The aim of this is to find a dose of Tafenoquine which meets the defined dose criteria. Based on Part 1 efficacy and safety, a single Tafenoquine dose (300 mg) will be studied in the pivotal Part 2. Part 2 contains 3 treatment arms one with the selected Tafenoquine dose (300 mg), the second arm will be 15mg Primaquine which will again be dosed over 14 days and the final arm contains chloroquine only dosed days 1-3 (600mg, 600mg, 300mg). Therefore as with Part 1, in Part 2 all subjects will receive Chloroquine. The aim of Part 2 is to investigate the safety and efficacy of the selected Tafenoquine/Chloroquine dose in the treatment and radical cure of Plasmodium vivax malaria. In addition to the Primary and Secondary endpoints stated below we will also be collecting; other efficacy endpoints (gametocyte clearance time, Recrudescence defined as any Plasmodium vivax parasitemia occurring on or before Day 29 (blood stage treatment failure), Incidence of Plasmodium falciparum malaria and Incidence of recrudescence and new Plasmodium vivax infection, determined by Polymerase Chain Reaction (PCR), safety endpoints (clinically relevant haemolysis leading to drops in haemoglobin / haematocrit or complications thereof (required transfusions, acute renal failure), changes in methaemoglobin, gastrointestinal (GI) tolerability - incidence of abdominal pain, heartburn, diarrhoea, constipation, nausea and vomiting and ophthalmic safety - incidence of corneal deposits, retinal and visual field abnormalities. Data collected at up to four centres . Additionally, the incidence and severity of adverse events and abnormal laboratory observations will be presented).Pharmacokinetic endpoints (Population pharmacokinetic parameters for tafenoquine including but not limited to oral clearance (CL/F) and volume of distribution (V/F)and Pharmacokinetic/Pharmacodynamic endpoints (e.g. tafenoquine plasma concentrations) and selected Pharmacodynamic endpoints (e.g. relapse efficacy, change in methaemoglobin) if appropriate, will be explored.

Study Design

• Study Type: Interventional
• Actual Enrollment: 851 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-centre, Double-blind, Randomised, Parallel-group, Active Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Tafenoquine (SB-252263, WR238605) in Subjects With Plasmodium Vivax Malaria.
• Actual Study Start Date: Apr 24, 2014
• Actual Primary Completion Date: Nov 18, 2016
• Actual Study Completion Date: Nov 18, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tafenoquine 50mg On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 50mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.	Drug: Chloroquine 600mg; 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial; Drug: Chloroquine 300mg; 300mg Chloroquine given to each subject on Day 3 of the trial; Drug: Tafenoquine 50mg; single dose 50mg Tafenoquine given to subject on treatment arm 1 on Days 1 or 2
Experimental: Tafenoquine 100mg On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 100mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.	Drug: Chloroquine 600mg; 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial; Drug: Chloroquine 300mg; 300mg Chloroquine given to each subject on Day 3 of the trial; Drug: Tafenoquine 100mg; single dose 100mg Tafenoquine given to subject on treatment arm 2 on Days 1 or 2
Experimental: Tafenoquine 300mg On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 300mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.	Drug: Chloroquine 600mg; 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial; Drug: Chloroquine 300mg; 300mg Chloroquine given to each subject on Day 3 of the trial; Drug: Tafenoquine 300mg; single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2
Experimental: Tafenoquine 600mg On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 600mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.	Drug: Chloroquine 600mg; 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial; Drug: Chloroquine 300mg; 300mg Chloroquine given to each subject on Day 3 of the trial; Drug: Tafenoquine 600mg; single dose 600mg Tafenoquine given to subject on treatment arm 4 on Days 1 or 2
Active Comparator: Primaquine 15mg On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 15mg Primaquine once daily Days 2-15.	Drug: Chloroquine 600mg; 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial; Drug: Chloroquine 300mg; 300mg Chloroquine given to each subject on Day 3 of the trial; Drug: Primaquine 15mg; 15mg Primaquine given once daily to subject on treatment arm 5 on Days 2 to 15.
Placebo Comparator: Chloroquine only On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered.	Drug: Chloroquine 600mg; 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial; Drug: Chloroquine 300mg; 300mg Chloroquine given to each subject on Day 3 of the trial
Experimental: Tafenoquine 300mg (Part 2) On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 300mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.	Drug: Chloroquine 600mg (Part 2 ); 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial.; Drug: Chloroquine 300mg (Part 2 ); 300mg Chloroquine given to each subject on Day 3 of the trial.; Drug: Tafenoquine 300mg (Part 2); single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2.
Active Comparator: Primaquine 15mg (Part 2) On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 15mg Primaquine once daily Days 2-15	Drug: Chloroquine 600mg (Part 2 ); 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial.; Drug: Chloroquine 300mg (Part 2 ); 300mg Chloroquine given to each subject on Day 3 of the trial.; Drug: Primaquine 15mg (Part2 ); 15mg Primaquine given once daily to subject on treatment arm 3 on Days 2 to 15.
Placebo Comparator: Chloroquine only (Part 2) On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered	Drug: Chloroquine 600mg (Part 2 ); 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial.; Drug: Chloroquine 300mg (Part 2 ); 300mg Chloroquine given to each subject on Day 3 of the trial.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Recurrence-free Efficacy at 6 Months Post Dose [6 months post dose]

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

Secondary Outcome Measures

1. Number of Participants With Recurrence-free Efficacy at 4 Months Post Dose [4 months post dose]

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

2. Time to Recurrence of P Vivax Malaria [Up to Day 180]

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

3. Time to Parasite Clearance [Up to Day 180]

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

4. Time to Fever Clearance [Up to Day 180]

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

5. Number of Participants With Hemoglobin Decline From Baseline Over First 29 Days [Baseline and up to Day 29]

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

6. Number of Participants With Treatment Emergent Adverse Events (TEAEs) Potentially Related to Hemoglobin Decrease [Up to Day 180]

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

7. Number of Participants Who Received Blood Transfusion [Up to Day 180]

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

8. Number of Participants With Acute Renal Failure [Up to Day 180]

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

9. Change From Baseline in Percent Methemoglobin [Baseline and up to Day 120]

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

10. Number of Participants With Gastrointestinal Disorders [Up to Day 180]

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

11. Number of Participants With Keratopathy [Up to Day 180]

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

12. Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores [Up to Day 180]

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

13. Number of Participants With Retinal Changes From Baseline [Baseline and up to Day 180]

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

14. Number of Participants With TEAEs and Serious TEAEs [Up to Day 180]

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

15. Number of Participants With TEAEs by Maximum Intensity [Up to Day 180]

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

16. Number of Participants With Hematology Laboratory Data Outside the Reference Range [Up to Day 120]

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

17. Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range [Up to Day 120]

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

18. Cost Associated With Recurrence Episode of P Vivax Malaria [Up to Day 180]

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

19. Cost Incurred With Purchase of Medications Associated With Recurrence Episode of Malaria [Up to Day 180]

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

20. Time Lost by Participants or Care Givers From Normal Occupation [Up to Day 180]

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

21. Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria [Up to Day 180]

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

22. Oral Clearance (CL/F) of TQ [Day 2, Day 8, Day 15, Day 29 and Day 60]

    Apparent population oral clearance of TQ

23. Volume of Distribution (Vc/F) of TQ [Day 2, Day 8, Day 15, Day 29 and Day 60]

    Apparent population central volume of distribution of TQ

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: - Positive Giemsa smear for P. vivax

• Parasite density >100 and <200,000/μL

• ≥16 years

• A female is eligible if she is non-pregnant, nonlactating and if she is of: - non-child bearing potential defined as: post-menopausal (12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone >40 mIU/mL), pre-menopausal and has had a hysterectomy or a bilateral oophorectomy (removal of the ovaries) or a bilateral tubal ligation with medical report verification, negative pregnancy test or,

• child-bearing potential, has a negative serum pregnancy test at screening, and agrees to comply with one of the following during the treatment stage of the study and for a period of 90 days after stopping study drug:

• Use of oral contraceptive, either combined or progestogen alone used in conjunction with double barrier method as defined below

• Use of an intrauterine device with a documented failure rate of <1% per year

• Use of depo provera injection (part 2)

• Double barrier method consisting of spermicide with either condom or diaphragm

• Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female.

• Complete abstinence from intercourse for 2 weeks prior to administration of study drug, throughout the study and for a period of 90 days after stopping study drug.

• A signed and dated informed consent is obtained from the subject or the subject's legal representative prior to screening.

NB Assent is obtained from subjects <18 years, where applicable and written or oral witnessed consent has been obtained from parent or guardian.

• The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned.

• Willing to be hospitalized for 3 days and return to clinic for all follow-up visits including Day 180

• QTc <450 msec at screening, based on a single QTcF value at screening (part 1 only) or as an average of triplicate Electrocardiogram obtained over a brief recording period by machine or manual over-read if first is >450 msec.- Exclusion Criteria: - Mixed malaria infections (e.g. identified by Giemsa-stained smear or rapid diagnostic test)

• Severe vivax malaria as defined by World Health Organisation criteria.

• Severe vomiting (no food or inability to take food during previous 8 hours)

• Screening haemoglobin concentration <7 g/dL.

• Glucose 6-phosphate dehydrogenase deficiency, assessed by a quantitative spectrophotometric phenotype assay:

Part 1 - Males: Any subject with an enzyme level <70% of the site median value for Glucose 6-phosphate dehydrogenase normals will be excluded. Females: Those females with a screening Hb ≥ 10 g/dL will only be excluded if their enzyme level is <70% of the site median value for Glucose 6-Phosphate dehydrogenase normals. hose females with Hb ≥7 but < 10 g/dL will be excluded if an enzyme level is not > 90% of the site median value for Glucose 6-Phosphate dehydrogenase normals.

Part 2 - Any subject with enzyme level <70% of the site median value for Glucose 6-phosphate dehydrogenase normals will be excluded

• Liver function test alanine transaminase >2x Upper Limit of Normal

• Any clinically significant concurrent illness (e.g. pneumonia, septicaemia), pre-existing conditions (e.g. renal disease, malignancy), conditions that may affect absorption of study medication (e.g. vomiting or severe diarrhea) or clinical signs and symptoms of severe cardiovascular disease (e.g. uncontrolled congestive heart failure or severe coronary artery disease). These abnormalities may be identified on the screening history and physical or laboratory examination.

• Subject has taken antimalarials (e.g. ACT, mefloquine, primaquine, chloroquine) or drugs with anti-malarial activity within the past 30 days by history.

• History of allergy to chloroquine, mefloquine, tafenoquine, primaquine or to any other 4- or 8-aminoquinolines.

• Any contraindications to chloroquine or primaquine administration including a history of porphyria, psoriasis or epilepsy (please refer to chloroquine and primaquine locally approved prescribing information).

• Subject who has previously received study medication for this protocol (all parts) or has received treatment with any other investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.

• History of illicit drug abuse or heavy alcohol intake within 6 months of the study.

• Subjects who have taken or will likely require the use of medications from the prohibited medication list which include the following classes: Histamine-2 blockers and antacids.

• Drugs with haemolytic potential.

• Drugs known to prolong the QTc interval

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Bandarban		Bangladesh
2	GSK Investigational Site	Manaus	Amazonas	Brazil	69040-000
3	GSK Investigational Site	Porto Velho	Rondônia	Brazil	76812-329
4	GSK Investigational Site	Oddar Meancheay Province		Cambodia
5	GSK Investigational Site	Gondar		Ethiopia
6	GSK Investigational Site	Jimma		Ethiopia
7	GSK Investigational Site	Bikaner		India
8	GSK Investigational Site	Chennai		India	600016
9	GSK Investigational Site	Lucknow		India	226003
10	GSK Investigational Site	Secunderabad		India	500 003
11	GSK Investigational Site	Iquitos	Loreto	Peru	Iqui 01
12	GSK Investigational Site	Rio Tuba, Bataraza		Philippines	5306
13	GSK Investigational Site	Bangkok		Thailand	10400
14	GSK Investigational Site	Tak		Thailand	63110

Sponsors and Collaborators

• GlaxoSmithKline
• Medicines for Malaria Venture

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01376167
• Other Study ID Numbers: 112582; TAF112582
• First Posted: Jun 20, 2011
• Last Update Posted: Apr 23, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Malaria; Malaria, Vivax; Chloroquine; Chloroquine diphosphate; Primaquine; Tafenoquine

Study Results

Participant Flow

Recruitment Details	This was a multi-centre, double-blind, randomized, parallel-group, active-controlled study to evaluate the efficacy, safety and tolerability of tafenoquine (TQ) in participants with Plasmodium vivax (P vivax) malaria. TAF112582 consisted of two parts-Part 1 (Phase 2 dose ranging) and Part 2 (Phase 3 pivotal). Results have been presented for Part 2.
Pre-assignment Detail	A total of 683 participants were screened of which 161 failed screening and 522 participants were randomized to receive chloroquine (CQ) + 300 milligrams (mg) TQ, CQ + 15 mg primaquine (PQ) and CQ alone regimen in a ratio of 2:1:1.

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

Baseline Characteristics

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ	Total
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.	Total of all reporting groups
Overall Participants	133	260	129	522
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	35.3 (14.23)	35.0 (14.39)	34.7 (14.26)	35.0 (14.29)
Sex: Female, Male (Count of Participants)
Female	36 27.1%	64 24.6%	30 23.3%	130 24.9%
Male	97 72.9%	196 75.4%	99 76.7%	392 75.1%
Race/Ethnicity, Customized (Count of Participants)
American(Amer) Indian(Ind) or Alaska(Al) Native(N)	43 32.3%	81 31.2%	41 31.8%	165 31.6%
Asian-South East Asian (A) Heritage (Her)	26 19.5%	50 19.2%	26 20.2%	102 19.5%
Black or African (Afr) Amer	14 10.5%	28 10.8%	13 10.1%	55 10.5%
White-White/Caucasian(Cau)/European(Eur) Her	3 2.3%	4 1.5%	2 1.6%	9 1.7%
Multiple-Afr Amer/Afr Her/Amer Ind or Al N	47 35.3%	95 36.5%	47 36.4%	189 36.2%
Multiple-Afr Amer/Afr Her/White-White/Cau/Eur Her	0 0%	1 0.4%	0 0%	1 0.2%
Multiple-Amer Ind or Al N/A-Central/South A Her	0 0%	1 0.4%	0 0%	1 0.2%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Number [Participants]	35 26.3%	155 59.6%	83 64.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CQ Only, TQ + CQ
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The Cox proportional hazards model was fitted with region and treatment as covariates.
	Method	Cox Proportional Hazards Model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.299
	Confidence Interval	(2-Sided) 95%; 0.222 to 0.404
	Parameter Dispersion	Type: Value:
	Estimation Comments	A hazard ratio<1 indicated a lower chance of relapse compared to CQ only.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CQ Only, PQ + CQ
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The Cox proportional hazards model was fitted with region and treatment as covariates.
	Method	Cox Proportional Hazards Model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.262
	Confidence Interval	(2-Sided) 95%; 0.178 to 0.387
	Parameter Dispersion	Type: Value:
	Estimation Comments	A hazard ratio<1 indicated a lower chance of relapse compared to CQ only.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	CQ Only, TQ + CQ
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Logistic regression model was fitted with region and treatment as covariates. Participants with a zero P vivax asexual parasite count at Baseline were excluded from the analysis.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.241
	Confidence Interval	(2-Sided) 95%; 0.152 to 0.382
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios < 1 suggested a smaller chance of recurrence compared to CQ Only.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	CQ Only, PQ + CQ
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Logistic regression model was fitted with region and treatment as covariates. Participants with a zero P vivax asexual parasite count at Baseline were excluded from the analysis.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.198
	Confidence Interval	(2-Sided) 95%; 0.117 to 0.335
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios < 1 suggested a smaller chance of recurrence compared to CQ Only.

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Number [Participants]	47 35.3%	177 68.1%	90 69.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CQ Only, TQ + CQ
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The Cox proportional hazards model was fitted with region and treatment as covariates.
	Method	Cox Proportional Hazards Model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.271
	Confidence Interval	(2-Sided) 95%; 0.195 to 0.376
	Parameter Dispersion	Type: Value:
	Estimation Comments	A hazard ratio<1 indicated a lower chance of relapse compared to CQ only.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CQ Only, PQ + CQ
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The Cox proportional hazards model was fitted with region and treatment as covariates.
	Method	Cox Proportional Hazards Model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.255
	Confidence Interval	(2-Sided) 95%; 0.167 to 0.390
	Parameter Dispersion	Type: Value:
	Estimation Comments	A hazard ratio<1 indicated a lower chance of relapse compared to CQ only.

3. Secondary Outcome

Title	Time to Recurrence of P Vivax Malaria
Description	Recurrence was defined as the first confirmed presence of P vivax asexual stage parasites after clearance of initial parasitemia following CQ treatment. Time to recurrence was defined as the time (in days) from initial parasite clearance to recurrence. The time to recurrence was analyzed by the Kaplan-Meier method. NA indicates data was not available due to insufficient number of participants with events during the follow up period in the study. The median number of days to recurrence along with 95% confidence interval has been presented for each treatment group.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Median (95% Confidence Interval) [Days]	86	NA	NA

4. Secondary Outcome

Title	Time to Parasite Clearance
Description	Parasite clearance time was defined as time needed to clear asexual parasite from the blood that is, parasite numbers falling below the limit of detection in the thick blood smear and remaining undetectable after 6 to 12 hours. The time taken to achieve parasite clearance was analyzed using Kaplan Meier Methodology. The median parasite clearance time along with 95% confidence interval has been presented for each treatment group.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Median (95% Confidence Interval) [Hours]	43	45	42

5. Secondary Outcome

Title	Time to Fever Clearance
Description	Fever clearance time was defined as time from first dose of treatment to the time when body temperature falls to normal within Study Days 1-4 and remains normal for at least 48 hours up to the Day 8 visit. Fever clearance was considered to have been achieved once an initial temperature of more than 37.40 degree Celsius is reduced to a value less than or equal to 37.40 degree Celsius and in the absence of value more than 37.40 degree Celsius in the following 48 hours up to the Day 8 visit. The time taken to achieve fever clearance was analyzed using Kaplan Meier Methodology. The median fever clearance time along with 95% confidence interval has been presented for each treatment group.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Median (95% Confidence Interval) [Hours]	7	7	8

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	259	129
<=20 grams/liter (g/L)	120 90.2%	214 82.3%	114 88.4%
>20g/L to <=30 g/L	11 8.3%	31 11.9%	12 9.3%
>30 g/L or >=30%	2 1.5%	14 5.4%	3 2.3%

7. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) Potentially Related to Hemoglobin Decrease
Description	TEAEs are defined as adverse events (AEs) with an onset date and time on or after that of the start of first dose of study medication (including CQ). The number of participants with TEAEs potentially related to hemoglobin decrease has been presented.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Haemoglobin decreased	2 1.5%	14 5.4%	2 1.6%
Fatigue	2 1.5%	1 0.4%	0 0%
Hyperbilirubinaemia	1 0.8%	0 0%	0 0%
Pallor	0 0%	1 0.4%	0 0%

8. Secondary Outcome

Title	Number of Participants Who Received Blood Transfusion
Description	The number of participants who received blood transfusion as a result of hemoglobin decline has been summarized.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Number [Participants]	0 0%	0 0%	0 0%

9. Secondary Outcome

Title	Number of Participants With Acute Renal Failure
Description	There were no participants with acute renal failure in the study.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Number [Participants]	0 0%	0 0%	0 0%

10. Secondary Outcome

Title	Change From Baseline in Percent Methemoglobin
Description	Methemoglobin assessment was made with the aid of a non-invasive signal extraction pulse CO-Oximeter handheld machine (Masimo). The change from Baseline in percent methemoglobin by treatment, time and sex has been summarized. The last assessment performed prior to the first dose of study medication (CQ or randomized treatment) was considered as Baseline. Change from Baseline was calculated as the post baseline assessment minus the Baseline assessment for percent methemoglobin. Only those participants with data available at the specified data points were analyzed.
Time Frame	Baseline and up to Day 120

Outcome Measure Data

Analysis Population Description

Safety Population

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

11. Secondary Outcome

Title	Number of Participants With Gastrointestinal Disorders
Description	Gastrointestinal tolerability was analyzed by the number of par experiencing gastrointestinal disorders such as abdominal pain, heartburn, diarrhea, constipation, nausea, and vomiting. The number of participants with gastrointestinal disorders for each treatment group has been summarized.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Nausea	12 9%	21 8.1%	9 7%
Vomiting	9 6.8%	22 8.5%	11 8.5%
Abdominal pain upper	13 9.8%	11 4.2%	7 5.4%
Diarrhoea	6 4.5%	15 5.8%	5 3.9%
Abdominal pain	5 3.8%	8 3.1%	6 4.7%
Dyspepsia	5 3.8%	6 2.3%	2 1.6%

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	29	65	31
Baseline; right eye	0 0%	0 0%	0 0%
Baseline; left eye	0 0%	0 0%	0 0%
Day 1; right eye	0 0%	0 0%	0 0%
Day 1; left eye	0 0%	0 0%	0 0%
Day 29; right eye	0 0%	0 0%	0 0%
Day 29; left eye	0 0%	0 0%	0 0%
Day 90; right eye	0 0%	1 0.4%	0 0%
Day 90; left eye	0 0%	0 0%	0 0%
Day 180; right eye	0 0%	0 0%
Day 180; left eye	0 0%	0 0%
Any time post Baseline; right eye	0 0%	1 0.4%	0 0%
Any time post Baseline; left eye	0 0%	0 0%	0 0%

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	29	65	31
Baseline; right eye	0.041 (0.0825)	0.046 (0.1045)	0.029 (0.0461)
Baseline; left eye	0.048 (0.0859)	0.039 (0.0652)	0.048 (0.1306)
Day 29; right eye	0.039 (0.0906)	0.049 (0.1159)	0.021 (0.0412)
Day 29; left eye	0.032 (0.0580)	0.032 (0.0565)	0.045 (0.1325)
Day 90; right eye	0.044 (0.0928)	0.038 (0.1083)	0.016 (0.0374)
Day 90; left eye	0.041 (0.0599)	0.028 (0.0971)	0.041 (0.1303)
Day 180; right eye	0.033 (0.0577)	0.000 (NA)
Day 180; left eye	0.033 (0.0577)	0.000 (NA)

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	29	65	31
Day 29, Definite change, right eye	1 0.8%	0 0%	0 0%
Day 29, Ques change, right eye	0 0%	0 0%	0 0%
Day 29, Definite change, left eye	1 0.8%	0 0%	0 0%
Day 29, Ques change, left eye	0 0%	0 0%	0 0%
Day 90, Definite change, right eye	1 0.8%	1 0.4%	1 0.8%
Day 90, Ques change, right eye	0 0%	0 0%	1 0.8%
Day 90, Definite change, left eye	1 0.8%	1 0.4%	0 0%
Day 90, Ques change, left eye	0 0%	1 0.4%	2 1.6%
Day 180, Definite change, right eye	0 0%	0 0%
Day 180, Ques change, right eye	0 0%	0 0%
Day 180, Definite change, left eye	0 0%	0 0%
Day 180, Ques change, left eye	0 0%	0 0%

15. Secondary Outcome

Title	Number of Participants With TEAEs and Serious TEAEs
Description	An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/ birth defect, other situations and is associated with possible drug induced liver injury with hyperbilirubinemia. TEAEs is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with TEAEs and serious TEAEs have been presented.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
TEAEs	86 64.7%	164 63.1%	76 58.9%
Serious TEAEs	6 4.5%	21 8.1%	4 3.1%

16. Secondary Outcome

Title	Number of Participants With TEAEs by Maximum Intensity
Description	An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with AEs based on severity has been presented.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	65	31
Mild or Grade 1	30 22.6%	70 26.9%	38 29.5%
Moderate or Grade 2	52 39.1%	89 34.2%	37 28.7%
Severe or Grade 3	3 2.3%	2 0.8%	1 0.8%
Grade 4	1 0.8%	0 0%	0 0%
Grade 5	0 0%	1 0.4%	0 0%

17. 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) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.
Time Frame	Up to Day 120

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	260	129
Blood eosinophils, High	18 13.5%	38 14.6%	28 21.7%
Blood leukocytes, Low	0 0%	3 1.2%	2 1.6%
Blood lymphocytes, Low	7 5.3%	4 1.5%	0 0%
Blood lymphocytes, High	23 17.3%	32 12.3%	13 10.1%
Blood neutrophils, Low	2 1.5%	5 1.9%	7 5.4%
Blood platelets, Low	14 10.5%	35 13.5%	15 11.6%
Blood reticulocytes, High	72 54.1%	141 54.2%	85 65.9%
Methemoglobin, High	4 3%	5 1.9%	11 8.5%

18. Secondary Outcome

Title	Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range
Description	Blood samples were collected for the evaluation of clinical chemistry parameters including Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk. Phos), Aspartate Aminotransferase (AST), bilirubin, creatine kinase, creatinine, glomerular filtration rate (GFR), indirect bilirubin and urea. The number of participants with clinical chemistry laboratory data outside the extended normal range (F3) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.
Time Frame	Up to Day 120

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	CQ Only	TQ + CQ	PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
Measure Participants	133	259	129
ALT, High	11 8.3%	10 3.8%	5 3.9%
Alk Phos, High	3 2.3%	1 0.4%	1 0.8%
AST, High	5 3.8%	7 2.7%	2 1.6%
Bilirubin, High	18 13.5%	23 8.8%	12 9.3%
Creatine kinase, High	8 6%	5 1.9%	8 6.2%
Creatinine, High	0 0%	1 0.4%	0 0%
GFR, Low	0 0%	1 0.4%	0 0%
Indirect bilirubin	11 8.3%	22 8.5%	8 6.2%
Urea, High	42 31.6%	85 32.7%	46 35.7%

19. Secondary Outcome

Title	Cost Associated With Recurrence 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 (inpatient/outpatient), traditional healer, other). The reported costs by type and by site has been summarized. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	First Malaria Recurrence	First Malaria Recurrence Follow-up
Arm/Group Description	Participants from all treatment arms (CQ only, CQ+TQ and PQ+TQ) with a recurrence episode of malaria were included.	Participants from all treatment arms (CQ only, CQ+TQ and PQ+TQ) who had a follow-up visit for recurrence episode of malaria were included.
Measure Participants	193	193
Brazil (Drug shop for care)	4.76 (3.24)
Brazil (Enrollment clinic for care)	6.17 (2.39)	6.15 (2.14)
Brazil (other location for care)	4.23 (0)
Peru (Drug shop for care)	1.47 (1.30)
Peru (Enrollment clinic for care)	8.78 (7.94)	8.54 (8.52)
Peru (Attended another clinic)	2.71 (4.69)	3.94 (1.42)
Peru (Other location for care)	0.72 (0.41)	1.30 (0)
Thailand (Drug shop for care)	4.60 (0)
Thailand (Enrollment clinic for care)	19.15 (10.60)
Thailand (In-hospital care)	6.13 (0)

20. Secondary Outcome

Title	Cost Incurred With Purchase of Medications Associated With Recurrence Episode of Malaria
Description	Health outcomes were evaluated based on the cost of medications purchased. The reported total medication cost for paracetamol associated with recurrence episode of P vivax malaria has been reported by site. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Medications recorded as "Other" and medications without costs are excluded from the analysis. Only those participants with data available at the specified data points were analyzed.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	First Malaria Recurrence	First Malaria Recurrence Follow-up
Arm/Group Description	Participants from all treatment arms (CQ only, CQ+TQ and PQ+TQ) with a recurrence episode of malaria were included.	Participants from all treatment arms (CQ only, CQ+TQ and PQ+TQ) who had a follow-up visit for recurrence episode of malaria were included.
Measure Participants	29	3
Peru, n=23, 3	0.49 (0.1941)	0.32 (1)
Brazil, n=6, 0	1.70 (0.144)

21. Secondary Outcome

Title	Time Lost by Participants or Care Givers From Normal Occupation
Description	Health outcomes were evaluated based on total time lost by participants or care givers due to an episode of malaria. The reported time lost due to recurrence episode of P vivax malaria has been summarized by category and by site. Where categories by site have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	First Malaria Recurrence	First Malaria Recurrence Follow-up
Arm/Group Description	Participants from all treatment arms (CQ only, CQ+TQ and PQ+TQ) with a recurrence episode of malaria were included.	Participants from all treatment arms (CQ only, CQ+TQ and PQ+TQ) who had a follow-up visit for recurrence episode of malaria were included.
Measure Participants	193	188
Brazil, Housework	1	0
Brazil, Farming	8	0
Brazil, paid employment	8	0
Brazil, Other	3	5
Cambodia, Farming	17	24
Ethiopia, Housework	4	3
Ethiopia, Farming	2.5	3
Ethiopia, Student	3	0
Ethiopia, Paid employment	2	4
Ethiopia, Other	1	7
Peru, Housework	24	29
Peru, Farming	19	28
Peru, Student	1	6
Peru, Paid employment	6	8.5
Peru, Other	26	32
Philippines, Farming	0
Thailand, paid employment	20	0
Thailand, Other	1	0

22. Secondary Outcome

Title	Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria
Description	Health outcomes were evaluated based on the actions taken by the participants to treat recurrence episode of P vivax malaria. The reported action taken by site is summarized. Where no action by site have been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	First Malaria Recurrence	First Malaria Recurrence Follow-up
Arm/Group Description	Participants from all treatment arms (CQ only, CQ+TQ and PQ+TQ) with a recurrence episode of malaria were included.	Participants from all treatment arms (CQ only, CQ+TQ and PQ+TQ) who had a follow-up visit for recurrence episode of malaria were included.
Measure Participants	193	188
Brazil, Nothing	21 15.8%	5 1.9%
Brazil, Drug shop	2 1.5%	0 0%
Brazil, Trial clinic	62 46.6%	76 29.2%
Brazil, Other	2 1.5%	0 0%
Cambodia, Nothing	13 9.8%	14 5.4%
Ethiopia, Nothing	12 9%	13 5%
Ethiopia, Another clinic	1 0.8%	0 0%
Ethiopia, Other	1 0.8%	0 0%
Ethiopia, Trial clinic	0 0%	1 0.4%
Peru, Nothing	1 0.8%	0 0%
Peru, Drug shop	8 6%	0 0%
Peru, Trial clinic	61 45.9%	63 24.2%
Peru, Another clinic	10 7.5%	54 20.8%
Peru, Other	15 11.3%	1 0.4%
Philippines, Nothing	1 0.8%
Thailand, Nothing	1 0.8%	16 6.2%
Thailand, Drug shop	1 0.8%	0 0%
Thailand, Trial clinic	13 9.8%	0 0%
Thailand, In hospital	1 0.8%	0 0%

23. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Participants in TQ Only Arms
Arm/Group Description	TQ only arms
Measure Participants	259
Median (90% Confidence Interval) [Liters per hour]	2.96

24. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Participants in TQ Only Arms
Arm/Group Description	TQ only arms
Measure Participants	259
Median (90% Confidence Interval) [Liters]	915

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	CQ Only		TQ + CQ		PQ + CQ
Arm/Group Description	Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. TQ placebo was administered on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.		Participants were administered a single oral dose of CQ 600 mg on Days 1 and Day 2 and CQ 300 mg on Day 3. Participants were dosed with TQ 300 mg either on Day 1 or Day 2. PQ placebo capsule was administered once daily for 14 days starting from either Day 1 or Day 2.		Participants were administered a single oral dose of CQ 600 mg on Days 1 and 2 and CQ 300 mg on Day 3. Participants were dosed with TQ placebo either on Day 1 or Day 2 and PQ 15 mg was administered once daily for 14 days starting from either Day 1 or Day 2.
All Cause Mortality
	CQ Only		TQ + CQ		PQ + CQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/133 (0%)		0/260 (0%)		0/129 (0%)
Serious Adverse Events
	CQ Only		TQ + CQ		PQ + CQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/133 (4.5%)		21/260 (8.1%)		4/129 (3.1%)
Gastrointestinal disorders
Diarrhoea	0/133 (0%)	0	1/260 (0.4%)	1	1/129 (0.8%)	1
Nausea	0/133 (0%)	0	0/260 (0%)	0	1/129 (0.8%)	1
Vomiting	0/133 (0%)	0	0/260 (0%)	0	1/129 (0.8%)	1
Hepatobiliary disorders
Drug-induced liver injury	0/133 (0%)	0	1/260 (0.4%)	1	0/129 (0%)	0
Infections and infestations
Abscess limb	0/133 (0%)	0	1/260 (0.4%)	1	0/129 (0%)	0
Gastroenteritis	1/133 (0.8%)	1	0/260 (0%)	0	0/129 (0%)	0
Hepatitis E	0/133 (0%)	0	1/260 (0.4%)	1	0/129 (0%)	0
Urinary tract infection	0/133 (0%)	0	1/260 (0.4%)	1	0/129 (0%)	0
Investigations
Haemoglobin decreased	2/133 (1.5%)	2	14/260 (5.4%)	14	2/129 (1.6%)	2
Electrocardiogram QT prolonged	3/133 (2.3%)	3	0/260 (0%)	0	0/129 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/133 (0%)	0	0/260 (0%)	0	1/129 (0.8%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/133 (0%)	0	1/260 (0.4%)	1	0/129 (0%)	0
Reproductive system and breast disorders
Menorrhagia	0/133 (0%)	0	1/260 (0.4%)	1	0/129 (0%)	0
Other (Not Including Serious) Adverse Events
	CQ Only		TQ + CQ		PQ + CQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/133 (54.1%)		119/260 (45.8%)		56/129 (43.4%)
Gastrointestinal disorders
Nausea	12/133 (9%)	13	21/260 (8.1%)	22	8/129 (6.2%)	8
Vomiting	9/133 (6.8%)	10	22/260 (8.5%)	22	10/129 (7.8%)	10
Abdominal pain upper	13/133 (9.8%)	13	11/260 (4.2%)	14	7/129 (5.4%)	9
Diarrhoea	6/133 (4.5%)	6	14/260 (5.4%)	14	4/129 (3.1%)	4
Infections and infestations
Nasopharyngitis	7/133 (5.3%)	7	19/260 (7.3%)	19	9/129 (7%)	11
Pharyngitis	4/133 (3%)	4	13/260 (5%)	14	8/129 (6.2%)	8
Investigations
Blood creatine phosphokinase increased	8/133 (6%)	9	10/260 (3.8%)	10	7/129 (5.4%)	7
Alanine aminotransferase increased	8/133 (6%)	8	6/260 (2.3%)	6	3/129 (2.3%)	3
Musculoskeletal and connective tissue disorders
Myalgia	19/133 (14.3%)	24	15/260 (5.8%)	15	10/129 (7.8%)	11
Nervous system disorders
Headache	19/133 (14.3%)	23	27/260 (10.4%)	34	10/129 (7.8%)	13
Dizziness	11/133 (8.3%)	13	25/260 (9.6%)	30	9/129 (7%)	9
Skin and subcutaneous tissue disorders
Pruritus	20/133 (15%)	23	34/260 (13.1%)	35	14/129 (10.9%)	14

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.