Clinical Trial: Efficacy and Safety Study of Tafenoquine (TQ) Co-administered With Dihydroartemisinin-piperaquine (DHA-PQP) for the Radical Cure of Plasmodium Vivax (P. Vivax) Malaria

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: Study 200894: A Double-blind, Double-dummy, Randomized, Parallel Group, Placebo-controlled Superiority Study to Evaluate the Efficacy and Safety of Tafenoquine (SB-252263, WR238605) Co-administered Wi

Brief Summary: Tafenoquine (TQ) is an 8-aminoquinoline anti-malarial drug which is in development as a single-dose treatment for the radical cure of P.vivax malaria when given with standard doses of chloroquine. Currently, the only available drug for radical cure is primaquine (PQ) which requires administration over 14 days, resulting in poor compliance. In Indonesia, chloroquine has been replaced by artemisinin-based combination therapy (i.e. ACTs) due to widespread chloroquine resistance. This study will evaluate the efficacy and safety of a single dose of tafenoquine when co-administered with an ACT (i.e. DHA-PQP). This single-center, double-blind, double-dummy, randomized study will test the superiority of DHA-PQP plus TQ against DHA-PQP alone in the prevention of P. vivax malaria relapse at 6 months. The study will be conducted in male Indonesian soldiers diagnosed with P.vivax malaria on return from deployment to a malarious region of Indonesia. A PQ plus DHA-PQP comparator arm is included to provide an informal comparison against the standard 14 day treatment for P.vivax malaria in Indonesia. Subjects who are glucose-6-phosphate dehydrogenase deficient (G6PD deficient) will be excluded due to the risk of acute hemolysis following dosing with 8-aminoquinolines drugs. Subjects who have a recurrence of P.vivax malaria during the study will be treated with an ACT plus PQ (0.5mg/kg for 14 days), in line with local treatment guidelines. At the end of the 6 month follow up period, any subject who has not relapsed will be given open label PQ (0.5mg/kg daily for 14 days) to minimize the likelihood of relapse after the study. Approximately 200 subjects will be screened to achieve 150 randomized subjects. The total duration of study for each subject will be 180-195 days. This study is being carried out to support registration of TQ in Indonesia and other countries where ACTs are first line therapy.

Detailed Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome: Subjects with relapse-free efficacy six months post-dosing (that is clearance of initial infection without subsequent microscopically confirmed recurrence during the 6 month follow up) [ Time Frame: Up to Day 180 ]

Subjects for whom initial clearance of parasitemia is confirmed, who do not present with Plasmodium vivax asexual stage parasites within six months, who did not take concomitant medication with anti-malarial activity (excluding study treatment) during the study will be considered as treatment success.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Subjects with relapse-free efficacy four months post-dosing. [ Time Frame: Up to Day 120 ]
  • Time to relapse [ Time Frame: Up to Day 180 ]
    Time from initial parasite clearance to time of relapse.
  • Time to fever clearance (in subjects with fever at baseline) [ Time Frame: Up to Day 180 ]
    Time from first dose of treatment to time when body temperature falls to normal and remains normal for at least 48 hours.
  • Time to parasite clearance [ Time Frame: Up to Day 180 ]
    Time needed to clear asexual parasites from blood and remain undetectable for at least 48 hours.
  • Percentage of subjects with recrudescence (blood stage treatment failure) on or before Day 14 [ Time Frame: Up to Day 14 ]
    Percentage of subjects with a recurrence of P. vivax parasites which is genetically homologous to the baseline P. vivax infection on or before Day 14.
  • Safety as assessed by adverse events (AE) and serious adverse events (SAE) [ Time Frame: Up to Day 195 ]
  • Safety as assessed by number of subjects with abnormal hematology parameters [ Time Frame: Up to Day 120 ]
    Hematology includes hemoglobin, hematocrit, platelet count, mean corpuscular volume (MCV), white blood cells (WBC) count, red blood cells (RBC) levels, WBC differential (neutrophils and lymphocytes as a minimum).
  • Safety assessed by clinical chemistry [ Time Frame: Up to Day 120 ]
    Clinical chemistry includes creatinine, blood urea nitrogen (BUN), total bilirubin, indirect bilirubin, aspartate amino-transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine phosphokinase (CPK).
  • Safety as assessed by Electrocardiogram (ECG) [ Time Frame: Up to Day 28 ]
    12 lead ECGs will be done in triplicate on Day 1. Subsequent ECGs will be done as single ECGs unless prolonged QT corrected by Friderica's formula (QTcF) is seen.
  • Safety as assessed by body temperature [ Time Frame: Up to Day 180 ]
    Body temperature will be measured in semi-supine position after 5 minutes rest.
  • Safety as assessed by systolic and diastolic blood pressure [ Time Frame: Up to Day 180 ]
    Blood pressure will be measured in semi-supine position after 5 minutes rest.
  • Safety as assessed by pulse rate assessment [ Time Frame: Up to Day 180 ]
    Pulse rate will be measured in semi-supine position after 5 minutes rest.
  • Safety as assessed by respiratory rate [ Time Frame: Up to Day 180 ]
    Respiratory rate will be measured in semi-supine position after 5 minutes rest.
  • Safety as assessed by Gastrointestinal (GI) tolerability [ Time Frame: Up to Day 180 ]
    Number of subjects with abdominal pain, heartburn, diarrhoea, constipation, nausea and vomiting
  • Safety as assessed by change from baseline in methemoglobin [ Time Frame: Baseline and up to Day 60 ]
    Methemoglobinemia is an indicator of hematological toxicity
  • Safety as assessed by change from baseline in QTc [ Time Frame: Baseline and Day 28 ]
    QTc will be corrected by Friderica's formula.
  • Safety as assessed by incidence of protocol-defined SAEs (that is a decrease in hemoglobin of >=30% or >3 g/dL from baseline; or, a drop in absolute hemoglobin to <7.0 g/dL, in the first 15 days) [ Time Frame: Baseline and up to 15 Days ]
  • Assessment of oral clearance (CL/F) of tafenoquine when co-administered with DHA-PQP [ Time Frame: Up to Day 60 ]
  • Assessment of volume of distribution (V/F) of tafenoquine when co-administered with DHA-PQP [ Time Frame: Up to Day 60 ]


Original Secondary Outcome: Same as current

Information By: GlaxoSmithKline

Dates:
Date Received: May 26, 2016
Date Started: January 15, 2018
Date Completion: February 1, 2019
Last Updated: April 27, 2017
Last Verified: April 2017