Phase II Artesunate Study in Severe Malaria
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 2

Summary: 
      The primary objective of the study is to evaluate the effectiveness of 2 intravenous
      artesunate dosing regimens (2.4 mg/kg initially and at 12, 24, 48, and 72 hours or 4.0 mg/kg
      initially and at 24 and 48 hours) in clearing P. falciparum parasites in children with severe
      malaria.

      Secondary objectives include:

        -  To compare the tolerability and safety of the 2 intravenous artesunate dosing regimens.

        -  To evaluate differences in the pharmacokinetic profile of intravenous artesunate by
           patient age and clinical presentation.
    

Detailed description: 
      This is a Phase II, double-blind, multicenter, randomized, parallel-group study of the
      antimalarial activity and safety of 2 intravenous artesunate regimens in children with severe
      P. falciparum malaria (Appendix B). It will compare the efficacy, safety and tolerability of
      the SEAQUAMAT regimen, the recommended dosing regimen for adults,8 which requires twice daily
      artesunate dosing on the first day, to a simpler once daily regimen. The study will also
      evaluate the pharmacokinetic profile of artesunate in pediatric patients.

      Prior to study initiation, the protocol will be approved by the Independent Ethics
      Committee/Institutional Review Board(s) (IEC/IRB) of each site and the national regulatory
      authority of each study site.

      Approximately 200 patients will be randomized at 3 study sites in Africa, which are part of
      the Severe Malaria in African Children (SMAC) network. Patients will be randomized to 1 of 2
      treatment cohorts:

        -  Cohort 1: artesunate 2.4 mg/kg initially, and at 12, 24, 48, and 72 hours (12 mg/kg
           total dose); or

        -  Cohort 2: artesunate 4 mg/kg initially, and at 24 and 48 hours (12 mg/kg total dose),
           normal saline will be administered as a placebo at 12 and 72 hours in order to maintain
           the study blind.

      The study is divided into 3 main periods including the Pre-Treatment Period (Screening/Day
      0), the Treatment Period (Days 0 through 3; Day 0 is the first day of study drug dosing), and
      the Post-Treatment Period (including evaluations on Days 7, 14, and 28). Children presenting
      to the study hospitals with signs/symptoms of severe malaria will be screened for study
      enrollment. Those with presumed severe malaria will be identified and informed consent for
      participation from parents/guardians will be obtained while confirmation of malaria is
      determined by microscopic analysis of a Giemsa-stained thick smear. Patients who meet study
      inclusion criteria and none of the exclusion criteria will be randomized and promptly treated
      with 1 of the artesunate regimens, while hospitalized for at least 4 days (Days 0, 1, 2, and
      3). Adjunctive therapy, including fluids, glucose, and blood, will follow SMAC standards,
      based on WHO guidelines for the treatment of severe malaria (Appendix C). As soon as the
      patient is able to receive oral medication and no signs and symptoms of severe malaria are
      present, but not before the last pharmacokinetic sample is taken (approximately 50 hours
      after the start of therapy), a single dose of sulfadoxine/pyrimethamine will be administered
      to ensure parasitological cure. Patients who received sulfadoxine/pyrimethamine within 14
      days prior Study Day 0 will receive mefloquine instead of SP,, to ensure effective
      parasitological cure.

      If the parasitemia is controlled and the safety laboratory tests from Day 3 indicate no
      clinical concern warranting prolonged hospitalization, the patient may be discharged at the
      discretion of the investigator. If a patient is discharged from the hospital on Day 3, he/she
      will return to the study site on Day 7 for evaluation. If the patient is unable to tolerate
      oral liquids or food within 6-24 hours after the last dose of artesunate, the patient will
      continue to be hospitalized and treated with parenteral antimalarial therapy until he/she is
      able to resume oral intake or a total of 7 days of therapy have been completed. All patients
      will return to the study site for evaluation on Days 14 and 28 to assess resolution of
      clinical complications and monitor for safety of therapy.

      Efficacy will be assessed by various parasite clearance parameters. Safety evaluations
      including physical examinations, vital signs, hematology and chemistry laboratory parameters
      and monitoring of adverse events will be performed throughout the study. Pharmacokinetic
      assessments will be performed at 3 different timepoints during the study.

      If adverse events reported during the study are unresolved by Day 28, patients will be
      followed for an additional 30 days or until resolution of the event or determination that no
      further medical management is deemed necessary. Similarly, the investigator will instruct the
      parents/guardians to return the patient to the study site if any untoward event occurs within
      30 days of completing study drug.
    

Intervention name(s): Artesunate
Intervention type(s): Drug
Intervention description(s): intravenous application
Intervention MeSH terms: Artesunate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: intravenous artesunate; severe malaria; Plasmodium falciparum; Africa; Severe Plasmodium falciparum Malaria