This study evaluates the efficacy and safety of 3 months of malaria chemoprevention post-discharge using dihydroartemisinin piperaquine (DHA-P) in children under 5 years of age admitted with severe anemia. One half will receive monthly DHA-P and the other half placebo.

Children hospitalized with severe anemia in Africa are at high risk of readmission or death within 6 months after discharge. No strategy specifically addresses this post-discharge period. In Malawi, 3 months of post-discharge malaria chemoprevention with monthly 3-day treatment courses of artemether-lumefantrine (AL) in children with severe malarial anemia prevented 31% of deaths and readmissions. This study is a confirmatory efficacy trial in Kenya and Uganda to determine the efficacy and safety of malaria chemoprevention post-discharge. We hypothesize that an additional three months of malaria chemoprevention with monthly 3-day treatment courses with DHA-piperaquine (each providing about 4 weeks of post-treatment prophylaxis) provided during the post-discharge period to children recently admitted with severe anemia is superior to reduce all-cause readmission and mortality rates by 6 months compared with 2 weeks of post-treatment prophylaxis provided by the single course of oral AL when given as part of the standard in-hospital care around the time of discharge.

Inclusion Criteria:

• Pre-study screening

  1. Haemoglobin <5.0 g/dl or PCV < 15%, or requirement for blood transfusion for other clinical reasons on or during admission to the hospital
  2. Aged less than 59.5 months
  3. Body weight >5 kg
  4. Resident in catchment area Enrolment in study(t=0)
  1. Fulfilled the pre-study screening eligibility criteria
  2. Aged < 59.5 months
  3. Clinically stable, able to take oral medication
  4. Subject completed blood transfusion(s) or became clinically stable without transfusion
  5. Able to feed (for breastfeeding children) or eat (for older children)
  6. Absence of know cardiac problems
  7. Provision of informed consent by parent or guardian Randomisation (t=2 weeks)
  1. Fulfilled enrolment eligibility criteria and was enrolled during recent admission
  2. Aged <60 months
  3. Still clinically stable, able to take to oral medication, able to feed (for breastfeeding children) or eat (for older children) and able to sit unaided (for older children who were already able to do so prior to hospitalisation)

Exclusion Criteria:

• Pre-study screening

  1. Recognised specific other cause of severe anaemia (e.g. trauma, haematological malignancy, known bleeding disorder)
  2. Known sickle cell disease
  3. Anticipated to reach the 5th birthday (60 months of age) within 2 weeks from enrolment (i.e. prior to randomization)
  4. Child will reside for more than 25%of the 6 months study period (i.e. 6 weeks or more) outside of catchment area Enrolment in study (t=0)
  1. Previous enrolment in the present study
  2. Known hypersensitivity to study drug
  3. Sickle cell disease
  4. Use or known need at the time of enrolment for concomitant prohibited medication during the 14 weeks PMC treatment period.
  5. Ongoing or planned participation in another clinical trial involving ongoing or scheduled treatment with prohibited medicinal products or active follow-up during the course of the study (6 months from enrolment)
  6. A known need at the time of enrolment for scheduled surgery during the subsequent course of the study (6 months from enrolment)
  7. Suspected non-compliance with the follow-up schedule
  8. Know heart conditions, or family history of congenital prolongation of the QTc interval.
  9. Taking medicinal products that are known to prolong the QTc interval Randomisation (t=2 weeks)
  1. Used dihydroartemisinin since enrolment
  2. Use or known need at the time of randomisation for concomitant prohibited medication during the 14 weeks PMC treatment period.
  3. Enrolled, or known agreement to enrol into another clinical trial involving ongoing or scheduled treatment with medicinal products during the course of the study (6 months from enrolment)
  4. A known need at the time of randomisation for scheduled surgery during the subsequent course of the study (6 months from enrolment)
  5. Suspected non-compliance with the follow-up schedule
  6. Withdrawal of consent since enrolment

All individual-participant data collected during this trial will be stored in a public data repository after de-identification. Data and documents, including the study protocol, and the statistical analysis plan, will be made available and access to data provided when a proposal has been approved by the investigators, after consideration of overlap between the proposal and any ongoing efforts. Data will be available beginning at three months after publication of this Article.

3 months after publication of this Article

Proposals should be directed to feiko.terkuile@lstmed.ac.uk and Bjarne.Robberstad@uib.no; to gain access, data requesters will need to sign a data access agreement, and the de-identified database will be transferred electronically