Dihydroartemisinin-Piperaquine or Sulphadoxine-Pyrimethamine for the Chemoprevention of Malaria in Sickle Cell Anaemia
Condition: Sickle Cell Anemia in Children; Malaria
MeSH terms: Malaria; Anemia; Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 3

Summary: 
      Sickle Cell Anaemia (SCA) is an inherited disease that makes the body produce red blood cells
      with abnormal sickle-shaped cells. The sickle-shaped cells are rigid, not flexible and break
      up easily resulting in anaemia. The abnormal cells also stick to the vessel walls, causing a
      blockage that slows or stops the flow of blood. When this happens, oxygen cannot reach nearby
      tissues. The lack of oxygen can cause attacks of sudden, severe pain, called pain crises,
      stroke or damage to important organs such as the spleen. All of these can lead to death.
      These attacks can occur without warning and are often started and made worse by infections
      such as malaria. Therefore, in many countries in Africa where malaria is common, children
      with SCA are given malaria medicines to prevent the infection. However, many of the medicines
      do not work effectively, are too difficult to take or they have side effects, resulting in
      poor adherence.

      The aim of this study is to find safe, acceptable and effective medicines for malaria
      prevention in children with SCA in eastern and southern Africa. The investigators propose to
      conduct a study to find out whether giving weekly doses of dihydroartemisinin-piperaquine,
      also called DP, is safe, more effective, acceptable and cost-effective than the current
      strategy of monthly sulphadoxine-pyrimethamine (SP) to prevent malaria in children with
      sickle cell anaemia. Overall, 548 children aged 6 months to 15 years will be chosen randomly
      to receive either weekly DP or monthly SP for about 18 months. To test if the study medicine
      is effective, the study will compare the case burden of malaria. The investigators will also
      monitor every child for any type of illness, blood transfusions and other complications of
      sickle cell anaemia and admissions to the hospital. In addition, the study will evaluate the
      impact of DP on the development of resistance by malaria parasites. The study will also
      include nested safety studies on the effect of DP on the heart. All study participants will
      receive all the other usual care and treatments, including patient education on home care,
      and daily penicillin if younger than 5 years. If proven safe and efficacious,
      chemoprophylaxis with DP may decrease the incidence of malaria in children with SCA, prevent
      ill-health and deaths, and improve wellbeing.
    

Detailed description: 
      Background and rationale:

      An estimated 300,000 babies are born with Sickle Cell Anaemia (SCA) annually. Affected
      children have chronic ill health and many suffer a premature death. Ill health is commonly
      precipitated by febrile illnesses including malaria. Antimalarial chemoprophylaxis is an
      important strategy, but current regimes are either sub-optimally effective (e.g., monthly
      sulphadoxine-pyrimethamine, SP) or difficult to adhere to (e.g., daily proguanil). The
      investigators propose dihydroartemisinin-piperaquine (DP) as the agent with the most
      potential to be used across Africa.

      Objectives:

      Our objective is to determine the efficacy, safety, uptake, and cost-effectiveness of malaria
      chemoprevention with weekly single day courses of DP vs monthly single day courses of SP in
      children with SCA in eastern and southern Africa.

      Hypothesis:

      The hypothesis is that weekly single day courses of DP, is safe and more efficacious,
      compared to monthly single day courses of SP, for the malaria chemoprevention in children
      with SCA in eastern and southern Africa.

      Design:

      This will a randomised, double-blind controlled parallel-group superiority trial of weekly
      single day courses of DP for an average of 18 months compared to monthly single-day courses
      of SP in SCA patients. The study will be conducted in Uganda and Malawi. Participants will be
      randomised to DP or SP (1:1), stratified by bodyweight and study centre. The study will also
      assess the acceptability and uptake of the two interventions, the safety and pharmacokinetics
      of weekly DP, the development of resistance to DP and cost-effectiveness. At the end of the
      study, this information will be used to inform regional health policy.

      Sites:

      Participants will be recruited from Jinja Regional Referral hospital and Kitgum General
      hospital in Uganda and Queen Elizabeth (Blantyre) hospital in Malawi.

      Interventions:

      The intervention will be oral DP administered weekly for an average of 18 months based on
      weight categories. DP will be provided as tablets of D-ARTEPP® (Guilin Pharmaceutical Co.
      Ltd) and administered as dihydroartemisinin (20mg) and piperaquine (160 mg) at approximate
      doses of dihydroartemisinin 2.5mg/kg/day and piperaquine 20mg/kg/day. The active control will
      be the current standard of care for chemoprevention in Uganda and Malawi - monthly
      single-dose SP (S=25mg/kg). The same manufacturer will provide SP as the generic SP (in
      500/25mg scored tablets).

      Other care:

      In addition to the above-mentioned malaria regimens, the participants will receive the
      standard of care for Sickle Cell Anaemia (including parental education on care, treatment for
      both the acute and chronic complications of Sickle Cell Anaemia, and daily penicillin
      prophylaxis if <5 years).

      Sample size:

      With the minimum incidence rate of clinical malaria in SCA patients receiving monthly SP
      estimated at 0.2 events per year, and an effect size of 50% if DP is used, at a power of 0.9
      and 0.05 level of significance, followed up for 18 months and allowing for 20% losses to
      follow up, and one interim analysis, the investigators will need 548 participants (274 in
      either arm) followed up for an average 18 months or until 824 person-years.

      Follow up:

      Participants will be followed for up for an average of 18 months or until 412 person-years of
      observation is achieved in each group (a combined total of 824 person-years of observation).
      This will be achieved by following between 548 and 824 participants for an average of 12 to
      18 months each.

      Outcome measures:

      The primary efficacy outcome measures will be the incidence of clinical malaria. Secondary
      efficacy outcomes will include the incidence of malaria parasitaemia, all-cause sick-child
      clinic visits, SCA-related vaso-occlusive events (including severe pain events and
      dactylitis), acute chest syndrome, stroke, hospitalisations, blood-transfusions, and death.

      Secondary safety outcome measures: QTc-prolongation on ECG recordings and incidence of
      serious cardiac adverse events (e.g., convulsions or syncope within 48 hours after drug
      intake). Tolerance: % vomiting drug within 30 minutes of administration. Others are
      cost-effectiveness, development of resistance to piperaquine, feasibility, acceptability, and
      uptake.

      Data Analysis: Primary analysis will be by intention to treat. Incidence rates will be
      calculated, and rate ratios estimated using Poisson regression, with treatment (as
      randomised) as the predictor variable and the stratification factors site and weight-band as
      covariates.
    

Intervention name(s): Dihydroartemisinin Piperaquine
Intervention type(s): Drug
Intervention description(s): Administered as dihydroartemisinin (20mg) and piperaquine (160 mg)
Other intervention name(s): D-ARTEPP® (Guilin Pharmaceutical Co. Ltd)
Intervention MeSH terms: Piperaquine; Artenimol
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This will be a randomized, double-blind, parallel-group superiority trial of weekly single-day courses of DP for an average of 18 months compared to monthly single-day courses of SP in SCA patients. The study will be conducted in Uganda and Malawi, using randomisation stratified by bodyweight and study centre. Participants will be randomized using an allocation of 1:1 to DP or SP. Patients on DP will also receive an SP placebo, and those on SP will in addition, receive a DP placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: dihydroartemisinin-piperaquine; sulphadoxine pyrimethamine; sickle cell; malaria; chemoprevention; prophylaxis