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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: 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 Treatm

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 Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome:

  • 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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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 32 ]
    Recrudescence is defined as any P. vivax parasitemia occurring on or before Day 32 (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: Assessed up to Day 120, and at relapse or premature withdrawal visit ]
    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: Assessed up to Day 120, and at relapse or premature withdrawal visit ]
    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: Assessed up to Day 120, and at relapse or premature withdrawal visit ]
    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-cou

    Original Secondary Outcome:

    • 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

      Information By: GlaxoSmithKline

      Dates:
      Date Received: June 19, 2014
      Date Started: April 30, 2015
      Date Completion:
      Last Updated: April 10, 2017
      Last Verified: April 2017