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

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ClinicalTrials.gov Identifier: NCT02216123
Recruitment Status : Completed
First Posted : August 13, 2014
Results First Posted : May 16, 2018
Last Update Posted : May 16, 2018
Sponsor:
Collaborator:
Medicines for Malaria Venture
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE June 19, 2014
First Posted Date  ICMJE August 13, 2014
Results First Submitted Date  ICMJE November 1, 2017
Results First Posted Date  ICMJE May 16, 2018
Last Update Posted Date May 16, 2018
Actual Study Start Date  ICMJE April 30, 2015
Actual Primary Completion Date November 4, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 17, 2018)
  • Percentage of Participants With Clinically Relevant Hemolysis. [ Time Frame: Up to Day 180 ]
    Clinically relevant hemolysis is defined as a decrease in hemoglobin of >=30% or >3 grams per deciliter (g/dL) from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL at any visit after the first dose of study medication. The percentage of participants with clinically relevant hemolysis has been summarized. Safety Population comprised of all randomized participants who received at least one dose of blinded study medication.
  • Percentage of Female Participants With Moderate Glucose-6 Phosphate Dehydrogenase (G6PD) Deficiency Experiencing Clinically Relevant Hemolysis. [ Time Frame: Up to Day 180 ]
    Clinically relevant hemolysis is defined as a decrease in hemoglobin of >=30% or >3 g/dL from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL at any visit after the first dose of study medication. Despite additional efforts, no females with moderate G6PD-deficiency were enrolled that experienced clinically-significant hemolysis during the study; hence, the end point could not be estimated.
Original Primary Outcome Measures  ICMJE
 (submitted: August 11, 2014)
  • Proportion of all subjects with Plasmodium vivax (P. vivax) experiencing clinically relevant hemolysis [ Time Frame: Up to Day 180 ]
    Clinically relevant hemolysis in all subjects is defined as, a decrease in haemoglobin (Hb) of >=30% or >3 gram per decilitre (g/dL) from baseline; or, an overall drop in Hb below 6.0 g/dL.
  • Proportion of female subjects with P. vivax who are moderately (40-70 percent) G6PD deficient experiencing clinically relevant hemolysis [ Time Frame: Up to Day 180 ]
    Clinically relevant hemolysis in all subjects is defined as, a decrease in haemoglobin (Hb) of >=30% or >3 g/dL from baseline; or, an overall drop in Hb below 6.0 g/dL.
Change History Complete list of historical versions of study NCT02216123 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 17, 2018)
  • Rate of Relapse-free Efficacy at Six Months Post Dose [ Time Frame: 6 months post dose ]
    A participant was considered to have demonstrated relapse-free efficacy at 6 months if: a) Participant had non-zero P. vivax asexual parasite count at Baseline. b) Participant showed initial clearance of P. vivax parasitemia defined as two negative asexual P. vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the interval. c) Participant had no positive asexual P. vivax parasite count at any assessment prior to or on Study Day 201 following initial parasite clearance. d) Participant did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment. e) Participant is parasite-free at 6 months. The rate of relapse-free efficacy was estimated by Kaplan-Meier methodology. The percentage of participants who were relapse-free at 6 months post dose has been presented along with 95% confidence interval.
  • Rate of Relapse-free Efficacy at Four Months Post Dose [ Time Frame: 4 months post dose ]
    A participant was considered to have demonstrated recurrence-free efficacy at 4 months if: a) Participant had non-zero P. vivax asexual parasite count at Baseline. b) Participant showed initial clearance of P. vivax parasitemia. c) Participant had no positive asexual P. vivax parasite count at any assessment prior to or on Study Day 130 following initial parasite clearance. d) Participant did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment after Study Day 109 (up to and including Study Day 130). e) Participant is parasite-free at 4 months. The rate of relapse-free efficacy was estimated by Kaplan-Meier methodology. The percentage of participants who were relapse-free at 4 months post dose has been presented along with 95% confidence interval.
  • Time to Relapse of P. Vivax Malaria [ Time Frame: Up to Day 180 ]
    Relapse is defined by a positive blood smear with or without vivax symptoms. Relapse is described as any recurrence of malaria that occurred after Day 32 of the study. The time to relapse was analyzed by the Kaplan-Meier method. The median number of days to relapse along with 95% confidence interval has been presented for each treatment group.
  • Time to Parasite Clearance [ Time Frame: Up to Day 180 ]
    Parasite clearance time is defined as time needed to clear asexual parasite from the blood that is, parasite numbers falling below the limit of detection in the thick blood smear and remaining undetectable after 6 to 12 hours later. The time to achieve parasite clearance was analyzed by Kaplan-Meier methodology. The median parasite clearance time along with 95% confidence interval has been presented for each treatment group.
  • Time to Fever Clearance [ Time Frame: Up to Day 9 ]
    Fever clearance time is defined as the time from first dose of treatment to the time when body temperature falls to normal within Study Days 1-4 and remains normal for at least 48 hours up to the Day 8 visit. Fever clearance was considered to have been achieved once an initial temperature of more than 37.4 degree Celsius is reduced to a value less than or equal to 37.4 degree Celsius, in the absence of value more than 37.4 degree Celsius in the following 48 hours up to the Day 8 visit. The time taken to achieve fever clearance was analyzed by Kaplan-Meier method.
  • Time to Gametocyte Clearance [ Time Frame: Up to Day 180 ]
    Gametocyte clearance time is defined as time from first dose until the first slide that was gametocyte negative and remained so at the next slide reading. The time taken to achieve gametocyte clearance was analyzed by Kaplan-Meier method.
  • Number of Participants With Recrudescence [ Time Frame: Up to Day 32 ]
    Recrudescence is defined as any P. vivax parasitemia occurring on or before Day 32 (that is, blood stage treatment failure). A participant was considered to have had a recrudescence if both of the following were true: a) Participant had a positive P. vivax asexual parasite count at Baseline and demonstrated clearance (that is, did not have two negative asexual P. vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the interval). b) Participant had a positive genetically homologous asexual P. vivax parasite count, after their zero count in Days 1 to 5, but on or before Study Day 32. The number of participants with recrudescence before Study Day 33 has been presented.
  • Number of Participants With Genetically Homologous and Genetically Heterologous P. Vivax Infections [ Time Frame: Up to Day 180 ]
    Two drops of peripheral blood were collected onto pre-printed filter paper for subsequent deoxyribonucleic acid (DNA) extraction and polymerase chain reaction (PCR) analysis of Plasmodium species on all participants at screening (Day 1; pre-dose) and; if necessary, at the time of the first recrudescence/relapse or re-infection. PCR of the P. vivax genes, was used to distinguish between genetically homologous and genetically heterologous infection. The number of participants with genetically homologous and genetically heterologous P. vivax infections has been summarized for each treatment group. Only those participants with an infection occuring on or after Study Day 33 were analyzed.
  • Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range [ Time Frame: Up to Day 120 ]
    Plasma or serum samples were anlalyzed to evaluate clinical chemistry parameters such as alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, creatine kinase, creatinine, glomerular filtration rate (GFR), indirect bilirubin and urea. The number of participants with clinical chemistry laboratory values outside the extended normal range (F3) has been presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Safety Population consisted of all randomized participants who received at least one dose of blinded study medication.
  • Number of Participants With Hematology Laboratory Data Outside the Reference Range [ Time Frame: 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) has been presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Participants having both High and Low values for Normal Ranges at any post-baseline visits for safety parameters were counted in both the High and Low categories.
  • Number of Participants With Abnormal Urinalysis Dipstick Results [ Time Frame: Up to Day 120 ]
    Mid-stream urine was collected and analyzed for bilirubin, glucose, ketones, leukocyte esterase (LE), nitrites, occult blood, proteins and urobilinogen by dipstick method. The number of participants with abnormal urinalysis results (Trace, +, ++, +++, ++++) has been presented. Only those participants with data available at the specified data points were analyzed.
  • Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: Up to Day 180 ]
    An adverse event (AE) is defined as any untoward medical occurrence in a participant under clinical investigation, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/ birth defect, other situations such as important medical events and events of possible drug induced liver injury with hyperbilirubinemia. TEAEs are defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with TEAEs and serious TEAEs have been presented.
  • Number of Participants With Electrocardiogram (ECG) Findings [ Time Frame: Up to Day 29 ]
    12 lead ECG was performed with the participant in a semi-supine position having rested in this position for at least 10 minutes. ECG assessments were performed in triplicate at screening followed by single ECGs 12 hours after the first dose of study medication and at Day 29. The number of participants with abnormal-clinically significant ECG findings have been presented. The 12 Hour Post Randomized Treatment (11.5-12.5 Hours) timepoint included all readings taken between 11.5 and 12.5 hours post randomized treatment. The 12 Hour Post Randomized Treatment (8-72 Hours) timepoint is a sensitivity analysis of the 12 Hour post randomized treatment timepoint, including all readings taken between 8 and 72 hours post randomized treatment. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) [ Time Frame: Baseline and up to Day 180 ]
    Vital signs were measured twice a day on Days 1 through 3, at least 4 hours apart, and immediately prior to pharmacokinetic (PK) measurements. MAP was calculated as the sum of SBP and two times DBP divided by 3. The mean and standard deviation of SBP, DBP and MAP has been presented. The values presented does not include Day 3 assessments for participant number 570. Baseline value is defined as the latest pre-treatment assessment where treatment is their first dose of study medication (CQ/PQ/TQ/Placebo). Change from Baseline is the value at post dose minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Change From Baseline in Pulse Rate [ Time Frame: Baseline and up to Day 180 ]
    Vital signs were measured twice a day on Days 1 through 3, at least 4 hours apart, and immediately prior to PK measurements. The mean and standard deviation of pulse rate has been presented. The values presented does not include Day 3 assessments for participant number 570. Baseline value is defined as the latest pre-treatment assessment where treatment is their first dose of study medication (CQ/PQ/TQ/Placebo). Change from Baseline is the value at post dose minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Change From Baseline in Temperature [ Time Frame: Baseline and up to Day 180 ]
    Vital signs were performed twice a day on Days 1 through 3, at least 4 hours apart, and immediately prior to PK measurements. The mean and standard deviation of pulse rate has been presented. The values presented does not include Day 3 assessments for participant number 570. Baseline value is defined as the latest pre-treatment assessment where treatment is their first dose of study medication (CQ/PQ/TQ/Placebo). Change from Baseline is the value at post dose minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Number of Participants With P. Falciparum [ Time Frame: Up to Day 180 ]
    Microscopic blood slides (two thick film and one thin film slide) were prepared and examined for asexual parasite count. The number of participants with positive P. falciparum asexual parasite count post Baseline has been summarized for each treatment arm.
  • Number of Participants With Keratopathy [ Time Frame: Up to Day 180 ]
    Ophthalmic assessments were carried out at pre-qualified sites prior to randomization and at Days 29 and 90 and at withdrawal follow-up visit. Assessments were carried out at Day 180 (and up to resolution) if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. The number of participants displaying keratopathy in each eye has been summarized for each visit. The number of participants with new keratopathy at any time post Baseline is also reported. Ophthalmic Safety Population comprised of all participants in the Safety Population who have results from any eye assessments. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Number of Participants With Change in Best Corrected Visual Acuity Test Scores [ Time Frame: Baseline and up to Day 180 ]
    Ophthalmic assessments were carried out at pre-qualified sites prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Change from Baseline is the value at post dose visit minus the Baseline value. Best corrected visual acuity was assessed individually for each eye. Scores were recorded as a ratio. The values were used to derive a logMAR score for statistical analysis where logMAR=-1x log10 (ratio score). The number of participants with change in Best Corrected Visual Acuity Test Scores from Baseline has been presented where possible change is defined as a change from Baseline >=0.12 to <0.3 and definite change is defined as a change from Baseline >=0.3 logMAR score. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Number of Participants With Retinal Changes From Baseline [ Time Frame: Baseline and up to Day 180 ]
    Ophthalmic assessments were carried out at pre-qualified sites prior to randomization and at Days 29 and 90 and at withdrawal follow-up. Assessments were carried out at Day 180 (and up to resolution) if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Change from Baseline was calculated as the value at post dose visit minus the Baseline value. The number of participants with definite retinal change and questionable (ques) retinal change from Baseline has been presented. The number of participants with maximum change post-Baseline (definite when absent or questionable at Baseline) has been presented for either eye. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Change From Baseline in Percent Methemoglobin [ Time Frame: Baseline and up to Day 120 ]
    Methemoglbin is an oxidized and inactive form of hemoglobin. Methemoglobin assessment was made with the aid of a non-invasive signal extraction pulse CO-Oximeter handheld machine. The change from Baseline in percent methemoglobin by treatment, time and sex has been summarized. The latest pre-treatment assessment where treatment is their first dose of study medication (CQ/PQ/TQ/Placebo) was considered as Baseline value. Change from Baseline is the value at post dose visit minus the Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Cost Associated With Relapse Episode of P Vivax Malaria [ Time Frame: 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 emergency center, other). The costs associated with a relapse episode of P. vivax malaria has been presented. Participants may be represented in more than one category, so the total number of participants may be less than the number quoted. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Cost Associated With a Hemolysis Event [ Time Frame: Up to Day 180 ]
    Health outcomes were evaluated based on cost incurred due to clinically relevant hemolysis. The total cost was evaluated based on the amount spent on treatment, transport, medication and test. The costs associated with hemolysis event has been presented. The aim of this outcome measure was to determine the cost to a participant due to an event of hemolysis, regardless of treatment received in the study. It was not expected there would be major cost differences with hemoglobin decrease between the treatment arms. This was pre-specified in the statistical analysis plan.
  • Cost Incurred With Purchase of Medications Associated With Relapse Episode of P. Vivax Malaria [ Time Frame: Up to Day 180 ]
    Health outcomes were evaluated based on the cost of medications purchased. The total medication cost for paracetamol associated with relapse episode of P vivax malaria has been presented. Medications recorded as "Other" and medications without costs are excluded from the analysis. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Cost Incurred With Purchase of Medications Associated With Hemolysis Event [ Time Frame: Up to Day 180 ]
    Health outcomes were evaluated based on the cost of medications purchased. The total medication cost associated with hemolysis event has been presented. Medications recorded as "Other" and medications without costs are excluded from the analysis. The aim of this outcome measure was to determine the cost to a participant due to an event of hemolysis, regardless of treatment received in the study. It was not expected there would be major cost differences with hemoglobin decrease between the treatment arms. This was pre-specified in the statistical analysis plan.
  • Number of Participants or Care Givers Who Had Taken Time Off From Normal Occupation Due to Relapse Episode of Malaria [ Time Frame: 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 number of participants or care givers who had taken off from their normal occupation due to relapse episode of P vivax malaria has been presented by country. Participants may be represented in more than one category, so the total number of participants may be less than the number quoted. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Number of Participants or Care Givers Who Had Taken Time Off From Normal Occupation Due to a Hemolysis Event [ Time Frame: Up to Day 180 ]
    Health outcomes were evaluated based on total time lost by participants or care givers due to a hemolysis event. The number of participants or care givers who took days off from work due to a hemolysis event has been presented based on the normal occupation. The aim of this outcome measure was to determine the time taken off by participants due to an event of hemolysis, regardless of treatment received in the study. It was not expected there would be major differences in time taken off by participants with hemoglobin decrease between the treatment arms. This was pre-specified in the statistical analysis plan.
  • Number of Participants With Action Taken to Treat Relapse Episode of P. Vivax Malaria [ Time Frame: Up to Day 180 ]
    Health outcomes were evaluated based on the actions taken by the participants to treat relapse episode of P vivax malaria. The number of participants with the type of action taken to treat relapse episode of P vivax malaria has been presented by country. Participants may be represented in more than one category, so the total number of participants may be less than the number quoted. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
  • Number of Participants With Action Taken to Treat a Hemolysis Event [ Time Frame: Up to Day 180 ]
    Health outcomes were evaluated based on the actions taken by the participants to treat hemolysis events. The number of participants in Brazil who attended the trial clinic to treat a hemolysis event has been presented. The aim of this outcome measure was to determine the action taken by a participant due to an event of hemolysis, regardless of treatment received in the study. It was not expected there would be major differences in action taken by the participants with hemoglobin decrease between the treatment arms. This was pre-specified in the statistical analysis plan.
  • Oral Clearance (CL/F) of TQ [ Time Frame: Day 2, Day 3, Day 8, Day 15, Day 29, Day 60 and Day 180 ]
    Apparent population oral clearance of TQ
  • Volume of Distribution (Vc/F) of TQ [ Time Frame: Day 2, Day 3, Day 8, Day 15, Day 29, Day 60 and Day 180 ]
    Apparent population central volume of distribution of TQ
Original Secondary Outcome Measures  ICMJE
 (submitted: August 11, 2014)
  • Proportion of subjects with relapse-free efficacy six months post-dosing [ Time Frame: After Day 32 of the study Up to day 180 ]
    Relapse is defined by a positive blood smear with or without P. vivax symptoms. The term "relapse" will be used to describe any recurrence of malaria that occurs after Day 32 of the study.
  • Proportion of subjects with relapse-free efficacy four months post-dosing [ Time Frame: After Day 32 of the study Up to day 120 ]
    Relapse is defined by a positive blood smear with or without vivax symptoms. The term "relapse" will be used to describe any recurrence of malaria that occurs after Day 32 of the study.
  • Time to relapse [ Time Frame: After Day 32 of the study Up to day 180 ]
  • Parasite clearance time [ Time Frame: Up to Day 180 ]
    Time needed to clear asexual parasite from the blood defined as parasite numbers falling below the limit of detection in the thick blood smear and remaining undetectable 6-12 hours later.
  • Fever clearance time [ Time Frame: Up to day 180 ]
    Time from first dose of treatment to the time when body temperature falls to normal and remains normal for at least 48 hours.
  • Gametocyte clearance time [ Time Frame: Up to day 180 ]
    Time from first dose until the first slide that was gametocyte negative and remained so at the next slide reading. Subjects with no gametocytes at baseline will be censored, with a time to clearance of zero.
  • Proportion of subjects with recrudescence [ Time Frame: Up to Day 29 ]
    Recrudescence is defined as any P. vivax parasitemia occurring on or before Day 29 (i.e., blood stage treatment failure).
  • Incidence of genetically homologous and genetically heterologous P. vivax infections [ Time Frame: Up to Day 180 ]
    Polymerase Chain Reaction (PCR) analysis of Plasmodium species such as PvMSP-1, PvCSP and PvAMA-1 will be used to distinguish between genetically homologous and genetically heterologous infection on all subjects at screening (Day 1; pre-dose), and at all times of potential recrudescence/relapse or re-infection.
  • Healthcare resource use for P. vivax relapses [ Time Frame: Up to day 180 ]
    Healthcare resource use (excluding clinic visits scheduled as part of the study) data will be collected to characterize P. vivax relapse at study enrolment (for the primary P. vivax infection), the Day 15 visit, and at study visits from Day 22 onwards for subjects with confirmed P. vivax parasitemia.
  • Population pharmacokinetic profile profile for tafenoquine [ Time Frame: Days 2, 3, 8, 15, 29 and 60 ]
    Blood samples will be collected on Days 2, 3, 8, 15, 29 and 60 of the study for pharmacokinetic analyses, including but not limited to oral clearance (CL/F) and volume of distribution (V/F).
  • Proportion of P. falciparum malaria [ Time Frame: Up to Day 180 ]
  • Safety as assessed by adverse events [ Time Frame: Up to Day 180 ]
  • Safety as assessed by Electrocardiogram (ECG) [ Time Frame: 12 hours after first dose of blinded study medication, Day 29, at relapse or premature withdrawal visit, assessed Up to Day 180 ]
    12-lead ECG will be performed in triplicate at screening but single ECGs will be performed subsequently as indicated unless prolonged QTc is seen.
  • Adverse events caused by treatment to prevent P. vivax relapses, especially hemolytic anemia [ Time Frame: Up to Day 180 ]
  • Safety as assessed by clinical chemistry parameters [ Time Frame: Up to Day 180 ]
    Clinical chemistry includes creatine phosphokinase, blood urea nitrogen, serum creatinine, total and indirect bilirubin and liver clinical chemistry.
  • Safety as assessed by clinical hematology parameters [ Time Frame: Up to Day 180 ]
    Hematology includes hemoglobin, hematocrit, red blood cell/white blood cell/platelet counts, mean cell volume, white blood cell differential and reticulocyte count.
  • Safety as assessed by clinical urinalysis [ Time Frame: Up to Day 180 ]
    Urinalysis includes protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen and leukocyte esterase by dipstick method.
  • Over-the-counter medications purchased during the study for P. vivax relapses [ Time Frame: Up to day 180 ]
    The data will be collected for over-the-counter medications purchase to assess socio-economic impact of P. vivax relapses.
  • Any travel or other costs incurred in seeking or receiving healthcare during the study for P. vivax relapses [ Time Frame: Up to day 180 ]
    The data will be collected for any travel or other costs incurred in seeking or receiving healthcare during the study for P. vivax relapses, excluding travel for clinic visits scheduled as part of the study .
  • Time lost from normal occupation during the study due to P. vivax relapses [ Time Frame: Up to day 180 ]
    The data will be collected for to assess time lost from normal occupation during the study for P. vivax relapses, excluding time lost to attend clinic visits scheduled as part of study.
  • Correlation between tafenoquine plasma concentration and P. vivax relapses at 4 and 6 month, if data permit [ Time Frame: Up to Day 180 ]
  • Correlation between tafenoquine plasma concentration and change in methemoglobin, if data permit [ Time Frame: Up to Day 180 ]
  • Correlation between tafenoquine plasma concentration and change in hemoglobin, if data permit [ Time Frame: Up to Day 180 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB-252263, WR238605) Versus Primaquine in Subjects With Plasmodium Vivax Malaria
Official Title  ICMJE A Randomized, Double-Blind, Double Dummy, Comparative, Multicenter Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB-252263, WR238605) Versus Primaquine in the Treatment of Subjects With Plasmodium Vivax Malaria
Brief Summary

This is a prospective, double-blind, double-dummy, multicenter, comparative study. A total of 300 subjects will be randomized to treatment on Day 1, of which a minimum of 50 female subjects must be enrolled that display moderate glucose-6-phosphate dehydrogenase (G6PD) deficiency (>=40% - <70% of the site median G6PD value). Subjects must have a blood smear that is positive for P. vivax at entry. Subjects will be randomized 2:1 to receive tafenoquine (TQ)/chloroquine(CQ) or the active comparator primaquine (PQ)/CQ. All subjects will receive CQ on Days 1 to 3, followed by TQ or PQ and matching placebo beginning on Day 1 or 2. Tafenoquine, or matching placebo, will be given as a single, 300mg dose. Subjects will receive PQ (15mg once daily) or matching placebo for 14 days. The duration of the study is 180 days, including screening and randomization to treatment (Day 1), three in-hospital days (Days 1-3), four out-patient visits while on treatment with study medication (Days 5, 8, 11 and 15) and seven follow-up visits (Days 22, 29, 60, 90, 120, 150 and 180).

The primary safety data collected in this study will help to understand the hemolysis risk to both G6PD-normal and G6PD-deficient subjects. The efficacy data produced from this study will support the results for sister study TAF112582, the pivotal phase III efficacy and safety study of the TQ program.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Malaria, Vivax
Intervention  ICMJE
  • Drug: Tafenoquine
    Tafenoquine will be supplied as a dark pink, capsule-shaped, film-coated tablet that is plain on both sides. Each tablet will contain 150mg TQ.
  • Drug: Tafenoquine Placebo
    Placebo TQ tablets will be supplied as a dark pink, capsule-shaped, film-coated tablet that is plain on both sides, with common excipients of appropriate quality.
  • Drug: Chloroquine

    One of two formulations of commercially available generic chloroquine may be utilized in this study:

    1. tablets containing 500 mg chloroquine phosphate (equivalent to 300 mg chloroquine free base); or,
    2. tablets containing 250 mg chloroquine phosphate (equivalent to 155 mg chloroquine free base).
  • Drug: Primaquine
    Commercially available primaquine containing primaquine phosphate united states pharmacopeia (USP), 26.3 mg (equivalent to primaquine base 15 mg) will be utilized in this study. Primaquine, a pink film-coated tablet imprinted W on one side and P97 on the other side. The PQ tablets for this study have been over-encapsulated in a Swedish orange size B supro capsule.
  • Drug: Primaquine Placebo
    Placebo to match PQ will be supplied as Swedish orange size B supro capsules with common excipients of appropriate quality.
Study Arms  ICMJE
  • Experimental: Tafenoquine+ Chloroquine
    All subjects will receive one of two formulations of CQ from Days 1 to 3 (600 mg [2×CQ 300 mg] on Day 1, 600 mg on Day 2 and 300 mg on Day 3, each once daily [OD] orally; OR, 620 mg [4×CQ 155 mg] on Day 1, 620 mg on Day 2 and 310 mg on Day 3, each once daily [OD] orally). Tafenoquine 300mg (2×TQ 150 mg) will be given as a single oral dose on Day 1 or Day 2. Primaquine matching placebo will be given OD orally beginning on Day 1 or Day 2 and continue for 14 days total dosing. All subjects will be followed-up till 180 days.
    Interventions:
    • Drug: Tafenoquine
    • Drug: Chloroquine
    • Drug: Primaquine Placebo
  • Experimental: Primaquine+ Chloroquine
    All subjects will receive one of two formulations of CQ from Days 1 to 3 (600 mg [2×CQ 300 mg] on Day 1, 600 mg on Day 2 and 300 mg on Day 3, each once daily [OD] orally; OR, 620 mg [4×CQ 155 mg] on Day 1, 620 mg on Day 2 and 310 mg on Day 3, each once daily [OD] orally). Primaquine 15mg will be given OD orally beginning on Day 1 or Day 2 and continue for 14 total dosing. Tafenoquine matching placebo will be given as a single oral dose on Day 1 or Day 2. All subjects will be followed-up till 180 days.
    Interventions:
    • Drug: Tafenoquine Placebo
    • Drug: Chloroquine
    • Drug: Primaquine
Publications * Llanos-Cuentas A, Lacerda MVG, Hien TT, Vélez ID, Namaik-Larp C, Chu CS, Villegas MF, Val F, Monteiro WM, Brito MAM, Costa MRF, Chuquiyauri R, Casapía M, Nguyen CH, Aruachan S, Papwijitsil R, Nosten FH, Bancone G, Angus B, Duparc S, Craig G, Rousell VM, Jones SW, Hardaker E, Clover DD, Kendall L, Mohamed K, Koh GCKW, Wilches VM, Breton JJ, Green JA. Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria. N Engl J Med. 2019 Jan 17;380(3):229-241. doi: 10.1056/NEJMoa1802537.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 20, 2017)
251
Original Estimated Enrollment  ICMJE
 (submitted: August 11, 2014)
300
Actual Study Completion Date  ICMJE November 4, 2016
Actual Primary Completion Date November 4, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • A female is eligible to enter and participate in the study if she is non-pregnant, nonlactating and if she is of: a. Non-childbearing potential defined as: post-menopausal (12 months of spontaneous amenorrhea or <6 months of spontaneous amenorrhea with serum follicle-stimulating hormone >40 milli-International units per milliliter [mIU/mL]), or pre-menopausal and has had a hysterectomy or a bilateral oophorectomy (removal of the ovaries) or a bilateral tubal ligation, negative pregnancy test or, b. Child-bearing potential, has a negative pregnancy test at screening, and agrees to comply with one of the following during the treatment stage of the study and for a period of 90 days after stopping study medication: 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; 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 medication, throughout the study and for a period of 90 days after stopping study medication.
  • The subject has a glucose 6-phosphate dehydrogenase (G6PD) value (measured by a quantitative spectrophotometric phenotype assay) as follows: Female subjects must have an enzyme level >= 40 percent of the site median value for G6PD normal males. Male subjects must have an enzyme level >= 70 percent of the site median value for G6PD normal males.
  • The subject has a screening hemoglobin (Hb) value as follows: Any subject with a G6PD value >=70 percent of the site median value must have a screening Hb value >=7 g/dL; Female subjects with a G6PD value is >=40 - <70 percent of the site median value must have a screening Hb value >=8 g/dL.
  • The subject has a QT duration corrected for heart rate by Fridericia's Formula (QTcF) <450 milisecond (msec). Reading based on an average of triplicate Electrocardiograms (ECGs) obtained over a brief recording period by machine or manual over-read.
  • The subject has a positive malarial smear for P. vivax .
  • The subject has a parasite density of >100 and <100,000 per microliter (μL).
  • Male or female subject aged 16 years or older (18 years or older in Ethiopia) at the time of signing the informed consent.
  • The subject agrees to G6PD genotyping.
  • The subject is willing and able to comply with the study protocol.
  • The subject or parent/legal guardian, as applicable, 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 severe P. vivax malaria as defined by World Health Organization (WHO) criteria.
  • The subject has a history of allergy to chloroquine, mefloquine, tafenoquine, primaquine, or to any other 4- or 8-aminoquinoline.
  • The subject has a liver alanine aminotransferase (ALT) >2 x upper limit of normal (ULN).
  • The subject has severe vomiting (no food or inability to take food during the previous 8 hours).
  • The subject has a clinically significant concurrent illness (e.g., pneumonia, septicemia), pre-existing condition (e.g., renal disease, malignancy), condition that may affect absorption of study medication (e.g., vomiting, severe diarrhea), or clinical signs and symptoms of severe cardiovascular disease (e.g., uncontrolled congestive heart failure, severe coronary artery disease).
  • The subject has a history of porphyria, psoriasis, or epilepsy.
  • The subject has a history of significant ocular disease (e.g. surgery to the globe, glaucoma, diabetic retinopathy) or has evidence of corneal or retinal abnormalities identified in the clinical screening ophthalmologic examination.
  • The subject has taken anti-malarials (e.g., artemisinin-based combination therapies, mefloquine, primaquine, or any other 4- or 8-aminoquinoline) within 30 days prior to study entry.
  • The subject has taken or will likely require during the study the use of medications from the following classes: Histamine-2 blockers and antacids; Drugs with hemolytic potential; Drugs known to prolong the QTcF interval; The biguanides phenformin and buformin (but excluding metformin); Drugs that are substrates of the renal transporters OCT2, MATE1 AND MATE-2K and have a narrow therapeutic index (for example, the anti-arrhythmic agents dofetilide, procainamide and pilsicainide)
  • 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 a recent history of illicit drug abuse or heavy alcohol intake, such that full participation in the study could be compromised.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil,   Colombia,   Ethiopia,   Peru,   Thailand,   Vietnam
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02216123
Other Study ID Numbers  ICMJE 116564
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Medicines for Malaria Venture
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP