Eight Week Primaquine Regimen for the Treatment of Vivax Malaria
Condition: Malaria; Vivax Malaria
MeSH terms: Malaria; Malaria, Vivax
Study type: Interventional
Phase: Phase 3

Summary: 
      Plasmodium vivax represents a major health problem throughout the tropics. Outside Africa it
      accounts for over 50% of cases, affecting an estimated 70-80 million people per year. A
      substantial proportion of clinical cases are not caused by infective bites of Anopheles spp,
      but by activation of latent hypnozoites in the liver. These relapses may significantly impede
      development since each illness may result in 5-15 days of absence from work or school.

      Primaquine(PQ) is the only drug available that eliminates hypnozoites, though its use is
      beset by clinical problems; it may precipitate haemolytic anaemia in individuals deficient in
      the blood enzyme glucose 6 phosphate dehydrogenase (G6PD). Without affordable G6PD testing,
      primaquine use is precluded. Evidence suggests, however, that a course of 8 weekly doses may
      be a safe and effective alternative to the traditional 14 day course of the drug. The aim of
      the proposed study, therefore, is to test whether 8 weekly doses of primaquine is as
      effective as the 14 day course at preventing relapse malaria, without the risk of hemolysis
      in G6PD deficient individuals.
    

Detailed description: 
      Old evidence suggests that successful PQ therapy is not a function of the length of the
      course of treatment, nor the circulating concentration of the drug, but of the total dosage
      administered. The same dose administered over 7 days, 14 days, and 8 weeks equally prevented
      relapse in vivax malaria. The hemolysis seen in shorter courses is often self-limiting,
      suggesting that feedback mechanisms up-regulate production of red cells in response to
      haemolytic challenge. The proposed extended course is likely to be well tolerated in G6PD
      deficient individuals as a result of these safeguards, especially in this population which
      has been exposed to the 5 day PQ regimen for a number of years without reported adverse
      effects.

      The aim of the study, therefore, is to test whether an 8 week regimen proves effective,
      without the associated risk of haemolysis in G6PD deficient individuals. However, operational
      concerns remain about adherence to this protracted treatment regimen. Therefore we will
      compare the 8 week course in 2 different groups; the first to be directly observed dosing,
      the second to be unsupervised dosing using pre-packaged, foil wrapped PQ in appropriately
      labelled individual boxes, supplied with strong health education messages. This would be
      appropriate for deployment in a resource-poor setting if it proved effective and safe.

      Objectives:

      To evaluate whether an eight week primaquine regimen, using single weekly doses, can provide
      adequate radical cure of vivax malaria under experimental and operational conditions and is
      safe in and acceptable to a population with glucose 6 phosphate dehydrogenase deficiency. The
      specific objectives of the study are set out below.

        1. Determine the efficacy of an eight-week primaquine regime, using single weekly doses, in
           preventing relapses of P. vivax infections following supervised versus unsupervised
           administration of the drug.

        2. Compare the efficacy and operational aspects (e.g. adherence) between the two week,
           eight week supervised and eight week blister package regimes.

        3. Monitoring of the effect of 8 week PQ on G6PD deficient individuals.

        4. Examine the user acceptability and economic advantages of this course of treatment.

      Study population:

      Vivax positive individuals from Adizai and Baghicha refugee camps, Pakistan, and Jalalabad,
      Afghanistan.

      Laboratory Examination:

      All suspected malaria cases attending basic health units will have thick and thin blood films
      taken and examined by conventional light microscopy. Cases diagnosed with P. vivax infection
      will be asked to participate in the study unless the exclusion criteria are met. All patients
      will then be tested for G6PD deficiency by near patient testing. The test is a colorimetric
      qualitative test for G6PD in red cells requiring 0.05 ml of blood. In addition, a filter
      paper blood spot will be collected to allow molecular typing of the parasite. This will
      differentiate between a new and a relapse infection.

      Design

      Randomised placebo controlled study comparing the following four study groups:

        1. Initial 3 day chloroquine with supervised weekly placebo for 8 weeks.

        2. Initial 3 day chloroquine followed by supervised 14 day primaquine treatment.

        3. Initial 3 day chloroquine followed by supervised 8 week primaquine treatment (45 mg /
           week).

      All patients will be given health education messages and strongly advised to complete the
      course. In addition a safety arm will be used for G6PD deficient patients; this will be used
      to compare PCV with group 3 (above). This will be an 8 week regimen, administered by direct
      observation, and will receive close monitoring for haemolysis.

      Treatment:

      All patients will be given a full therapeutic course of chloroquine. Primaquine will be
      administered to the study groups according to the respective protocol schedule. All relapses
      and new cases will be re-treated using the same regime and procedure as at the time of
      admission.

      Monitoring:

      Patients in treatment groups 1, 2, and 3 will be monitored for the initial 8 weeks of
      treatment for adverse events; G6PD deficient patients will be monitored for signs of
      hemolysis every other day for the first 2 weeks of treatment and then once per week (prior to
      dosing) until completion of the course. Following the treatment period, patients will be
      monitored for 1 year for the following outcomes:

      Primary Efficacy Variable: Proportion with relapse(s) of P. vivax in 12 months of follow-up.

      Secondary Efficacy Variables: Time to subsequent relapse episode, number of relapse episodes
      in 12 months, side effects / adverse events

      Patients will be advised to return to the BHU in the event of recurrent symptoms within 12
      months following enrolment to the study. A patient will be deemed to have completed the study
      after 12 months of follow-up. In any event each patient will be contacted once every 2 weeks
      during the follow-up period in order to collect relevant information. At each episode, a
      sample of blood will allow molecular typing of the parasite and define whether the patient
      has a new infection or a relapse.
    

Intervention name(s): primaquine
Intervention type(s): Drug
Intervention MeSH terms: Primaquine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Vivax; Treatment; Primaquine; Asia