CHEMCHA

An estimated 300,000 babies are born with Sickle Cell Anaemia (SCA) annually. Affected children have chronic ill health and many suffer 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). We propose Dihydroartemisinin-Piperaquine (DP) as the agent with most potential to be used across Africa. 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.
This is a randomised, double-blind placebo controlled parallel group superiority trial of weekly single day courses of DP for an average 18 months compared to monthly single-day courses of SP in SCA patients. The study is conducted in Uganda and Malawi. Participants are randomised in an allocation of 1:1 to DP or SP. We will also assess the toxicity from cumulative DP dosing, development of resistance to DP, acceptability, uptake and cost-effectiveness of the two interventions.

All participants are provided long lasting insecticide impregnated mosquito nets and receive outpatient care for SCA (including parental education on care, treatment for both the acute and chronic complications of SCA, daily folic acid (0.4 mg /day daily but if this is unavailable, they are provided with folic acid 2.5mg once daily if <1 year or 5mg daily if 1 year and older for 3 weeks every month except for the week after administration of SP when none will be taken), immunisation (as is appropriate), daily penicillin prophylaxis if <5 years) and hydroxyurea according to national guidelines.

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 and allowing for 20% losses we need 552 participants (276 in either arm) followed up for an average 18 months or until 828 person years of observation is achieved.

The primary outcome measure is the incidence of clinical malaria. Secondary efficacy outcomes include 1) incidence of malaria parasitaemia 2) all-cause sick-child clinic visits 3) SCA-related vaso-occlusive events (including severe pain events and dactylitis) 4)acute chest syndrome, stroke 5)hospitalisations 6) blood-transfusions and 6) death.
Secondary safety outcome measures include: QTc-prolongation on ECG recordings and incidence of serious cardiac adverse events (convulsions or syncope within 48 hours after drug intake). Tolerance: % vomiting drug within 30 minutes of administration. Other outcomes include cost effectiveness, development of resistance to piperaquine, feasibility, acceptability and uptake.