A Pharmacokinetics, Safety and Efficacy Study of Tafenoquine (TQ) in Pediatric Subjects With Plasmodium Vivax (P. Vivax) Malaria

Study Overview
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Brief Summary
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This is a prospective, open-label, multicenter, non-comparative, single arm study of pediatric subjects with Plasmodium vivax (P. vivax) malaria, aged 6 months to <16 years of age. A total of 60 subjects will be enrolled. Potential subjects who are slide-positive for P. vivax will be started by the site on chloroquine (CQ) per local/national guidelines. Sites will have up to 48 hours to obtain consent. Once full consent is provided, all subjects will be screened and, if eligible, receive Tafenoquine (TQ), given as a single dose on Day 1. All study medication should be taken with food. After the treatment period, subjects will attend up to 7 follow-up visits through Day 120 (Days 3, 8, 15, 29, 60, 90 and 120). The main cohort will consist of subjects aged >=2 years to <16 years with no restriction on gender. Subjects will be dosed according to four weight bands. Within the total of 60 enrolled pediatric subjects, a second cohort of up to 6 infants aged >=6 months to <2 years (weighing >=5 kilogram [kg]) will be recruited following completion of a planned first interim analysis. An interim analysis will be conducted once sufficient data from 16 subjects is available to assess pharmacokinetic (PK) and safety parameters. If needed, a second interim analysis will be conducted after a total of 32 subjects have enrolled. The primary objective of this PK bridging study is to adequately characterize the systemic TQ exposure in the pediatric population in order to identify appropriate doses that achieve a similar exposure to that of the TQ adult dose of 300 milligram (mg).

Official Title
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An Open Label, Non-comparative, Multicenter Study to Assess the Pharmacokinetics, Safety and Efficacy of Tafenoquine (SB-252263, WR238605) in the Treatment of Pediatric Subjects With Plasmodium Vivax Malaria

Conditions
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Malaria, Vivax

Intervention / Treatment
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* Drug: Tafenoquine
* Drug: Chloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is >=2 years to <16 years of age at the time of signing of the assent and/or informed consent. An additional cohort of subjects aged >=6 months to <2 years may be recruited following the first interim analysis. The subject has a positive malarial smear for P. vivax. The subject has a history of fever within 48 hours prior to enrollment. The subject has a glucose 6-phosphate dehydrogenase (G6PD) value (measured by a quantitative spectrophotometric phenotype assay) >=70% of the site median value for G6PD normal adult males. The subject has a screening Hb value >=8 gram per decilitre (g/dL). The subject has a body weight >=5 kg. Males and females are eligible to enter the study. A female is eligible to enter and participate in this study if she is non-pregnant, non-lactating and if she is of: Non-childbearing potential (i.e., premenstrual); or Child-bearing potential, has a negative pregnancy test at screening, and agrees to comply with one of the following during the treatment stage of the study and for a period of 90 days after stopping study medication: Complete abstinence from intercourse for 2 weeks prior to administration of study medication, throughout the study and for a period of 90 days after stopping study medication; Use of combined oral contraceptive consisting of spermicide with either condom or diaphragm; Use of intrauterine device with a documented failure rate of <1% per year; Use of depo provera injection; Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female. The subject and/or the subject's parent(s)/legal guardian(s) agree to G6PD genotyping in the context of a subsequent hemolytic anemia AE. The subject and parent(s)/legal guardian(s) are willing and able to comply with the study protocol. In accordance with regional/local laws and regulations, the parent(s)/legal guardian(s) has given written informed, dated consent; and the subject has given written assent, if applicable, to participate in the study. Exclusion Criteria: The subject has a mixed malaria infection (identified by a malarial smear or rapid diagnostic test). The subject has a condition that may affect absorption of study medication, such as severe vomiting (no food or inability to take food during the previous 8 hours). The subject has a liver alanine aminotransferase (ALT) >2 time the upper limit of normal (ULN). The subject has a clinically significant concurrent illness (for example; pneumonia, meningitis, septicaemia, coagulopathy, severe hemorrhage), pre-existing condition (e.g., renal disease, malignancy, malnutrition, known pre-existing human immunodeficiency virus [HIV]), febrile convulsions prior to consent, or clinical signs and symptoms of severe cardiovascular disease (for example; congenital heart disease). The subject has a history of porphyria, psoriasis, or epilepsy. The subject has taken anti-malarials (for example; artemisinin-based combination therapies, mefloquine, primaquine, or any other 4- or 8-aminoquinoline) or drugs with antimalarial activity within 30 days prior to study entry. The subject has received treatment with any investigational drug within 30 days of study entry, or within 5 half-lives, whichever is longer. The subject has taken or will likely require during the study the use of: histamine-2 blockers, antacids, anti-diabetic drugs of the biguanide class (i.e., phenformin, buformin), anti-arrhythmic agents dofetilide, procainamide, pilsicainide. The subject has a serum creatinine above the ULN and is currently taking metformin. The subject has a history of allergy or intolerance to chloroquine, mefloquine, tafenoquine, primaquine, or to any other 4- or 8-aminoquinoline. The subject has previously enrolled in this study. The subject has severe P. vivax malaria as defined by world health organization (WHO) criteria

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tafenoquine 50 mg<br>Subjects with weight band of >=5 to <=10 kilogram (kg) will receive 50 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines. | Drug: Tafenoquine<br>* Tafenoquine tablet is supplied as film-coated tablet (100 mg, 150 mg, 200 mg and 300 mg) and fast-dispersing film coated tablet (50 mg).<br>Drug: Chloroquine<br>* Subjects may receive chloroquine according to local/national treatment guidelines.<br>|
| Experimental: Tafenoquine 100 mg<br>Subjects with weight band of >10 to <=20 kg will receive 100 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines. | Drug: Tafenoquine<br>* Tafenoquine tablet is supplied as film-coated tablet (100 mg, 150 mg, 200 mg and 300 mg) and fast-dispersing film coated tablet (50 mg).<br>Drug: Chloroquine<br>* Subjects may receive chloroquine according to local/national treatment guidelines.<br>|
| Experimental: Tafenoquine 150 mg<br>Subjects with weight band of >10 to <=20 kg will receive 150 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines. | Drug: Tafenoquine<br>* Tafenoquine tablet is supplied as film-coated tablet (100 mg, 150 mg, 200 mg and 300 mg) and fast-dispersing film coated tablet (50 mg).<br>Drug: Chloroquine<br>* Subjects may receive chloroquine according to local/national treatment guidelines.<br>|
| Experimental: Tafenoquine 200 mg<br>Subjects with weight band of >20 to <=35 kg will receive 200 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines. | Drug: Tafenoquine<br>* Tafenoquine tablet is supplied as film-coated tablet (100 mg, 150 mg, 200 mg and 300 mg) and fast-dispersing film coated tablet (50 mg).<br>Drug: Chloroquine<br>* Subjects may receive chloroquine according to local/national treatment guidelines.<br>|
| Experimental: Tafenoquine 300 mg<br>Subjects with weight band of >35 kg will receive 300 mg tafenoquine on Day 1. Subject may receive CQ per local/national guidelines. | Drug: Tafenoquine<br>* Tafenoquine tablet is supplied as film-coated tablet (100 mg, 150 mg, 200 mg and 300 mg) and fast-dispersing film coated tablet (50 mg).<br>Drug: Chloroquine<br>* Subjects may receive chloroquine according to local/national treatment guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time 0 Extrapolated to Infinite Time (AUC[0-infinity]) of Tafenoquine by Weight Band in Participants Aged >=2 Years to <16 Years (Weighing >=5 kg) | Blood samples were collected at indicated time points for pharmacokinetic analysis of tafenoquine. Pharmacokinetic parameters were determined using standard non-compartmental methods. AUC(0-infinity) of tafenoquine was evaluated for participants aged >=2 years to <16 years (weighing >=5 kg). Pharmacokinetic (PK) population consisted of all participants with at least one PK sample taken at Days 3, 15, 29 and 60, with accurate dosing and sample time histories. | Days 3, 15, 29 and 60 post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Gastrointestinal Adverse Events | Number of participants experiencing gastrointestinal adverse events including vomiting, abdominal pain, diarrhea, gastrointestinal disorder, epigastric discomfort and nausea were assessed. Number of participants with gastrointestinal adverse events for each treatment group have been presented. Safety Population consisted of all participants who received at least one dose of study medication (tafenoquine). | Up to Day 120 | 
| Number of Participants With Hemoglobin Decline From Baseline Over First 10 Days | Glucose-6-phosphate dehydrogenase (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 decrease of >=30 percent (%) of >30 grams per liter (g/L) from Baseline; or, an overall drop in hemoglobin below 60.0 g/L in the first 15 days of the study were considered as protocol defined serious adverse events (SAEs). Number of participants with hemoglobin decline from Baseline over first 10 days have been presented. Baseline was defined as the latest pre-tafenoquine dose assessment on Day 1. | Baseline and up to Day 10 | 
| Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. An 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 liver injury. | Up to Day 120 | 
| Number of Participants With Worst Case Hematology Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline | Blood samples were collected for analysis of eosinophils, lymphocytes, platelets and reticulocytes. PCI ranges were >1.5*10^9 (high) cells per liter (cells/L) for eosinophils, <0.5*10^9 cells/L (low) or >4*10^9 cells/L (high) for lymphocytes, <50*10^9 cells/L (low) for platelet count and >1*upper limit of normal (ULN) 10^12 cells/L (high) for reticulocyte count. Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change category. Participants were counted twice if the participant has values that changed 'To Low' and 'To High', so the percentages may not add to 100%. Baseline value is the latest pre-tafenoquine dose assessment on Day 1. | Baseline (Day 1) and up to Day 8 | 
| Number of Participants With Worst Case Clinical Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline | Blood samples were collected for analysis of clinical chemistry parameters. PCI ranges were >3*ULN international units per liter (IU/L) (alanine aminotransferase [ALT]), >2.5*ULN IU/L (alkaline phosphatase), >3*ULN IU/L (aspartate aminotransferase [AST]), >1.5*ULN micromoles/L (mcmol/L) (bilirubin), >5*ULN IU/L (creatine kinase [CK]), 3*ULN mcmol/L (creatinine), >1.5*ULN mcmol/L (indirect bilirubin), and >11.067 millimoles/L (urea). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the To within Range or No Change category. Participants were counted twice if participant has values that changed To Low and To High, so the percentages may not add to 100%. Baseline value is the latest pre-Tafenoquine dose assessment on Day 1. | Baseline (Day 1) and up to Day 8 | 
| Number of Participants With Relapse-Free Efficacy at 4 Months | Relapse is defined as positive blood smear with or without vivax malaria symptoms. A participant was considered to have demonstrated relapse-free efficacy if: a) Participant is slide positive for Plasmodium vivax (P. vivax) at Baseline. b) Participant showed initial clearance of P. vivax parasitemia defined as a negative slide at or before the Day 29 visit. c) Participant is not slide-positive for P. vivax at any assessment. 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 4 months defined as a negative asexual P. vivax parasite slide at the first parasite assessment performed during study. Microbiologic-Intent-To-Treat (mITT) Population consisted of all participants who received a dose of study treatment (tafenoquine) and had microscopically-confirmed vivax parasitemia at Baseline. | 4 months | 
| AUC(0-infinity) of Tafenoquine by Weight Band in Participants Aged >=6 Months to <2 Years (Weighing >=5 kg) | Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of tafenoquine. | Days 3, 15, 29 and 60 post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetic, pediatric, Tafenoquine, Plasmodium vivax Malaria, G6PD deficiency