Effectiveness and safety of intermittent preventive treatment for malaria using either dihydroartemisinin-piperaquine or artesunate-amodiaquine in reducing malaria related morbidities and improving cognitive ability in school-aged children in Tanzania: a study protocol for a controlled randomised trial

Abstract Background In high transmission settings, up to 70% of school-aged children harbour malaria parasites without showing any clinical symptoms. Thus, epidemiologically, school aged children contribute substantial reservoir for malaria transmission. Asymptomatic Plasmodium infections induce inflammation leading to iron deficiency anaemia. Consequently, anaemia retards child growth, predisposes children to other disease and reduces cognitive potential that could lead to poor academic performance. School aged children become increasingly more vulnerable as compared to those aged less than five years due to delayed acquisition of protective immunity. None of the existing Intermittent preventive treatment (IPT) strategies is targeting school-aged children. Here we describe the study protocol of a clinical trial conducted in north eastern Tanzania to expand the IPT by testing effectiveness and safety of two antimalarial drugs, namely Dihydroartemisinin-piperaquine (DP) and Artesunate-amodiaquine (ASAQ) in preventing malaria related morbidity in school aged children (IPTsc) living in a high endemic area. Methods/Design The trial is a phase IIIb, individual randomized, open label, controlled trial enrolling school children aged 5-15 years, who receive either DP or ASAQ or control (no drug), using a “balanced block design” with the “standard of care” arm as reference. The interventional treatments are given three times a year for the first year. A second non-interventional year will assess possible rebound effects. Sample size was estimated to 1602 school children (534 per group) from selected primary schools in an area with high malaria endemicity. A thick and thin blood smear (to measure malaria parasitaemia using microscope) were obtained prior to treatment at baseline, and will be obtained again at month 12 and 20 from all participants. Haemoglobin concentration using a haemoglobinometer (HemoCue AB, Sweden) will be measured four monthly. Finger-prick blood (dried bloodspot-DBS) prepared on Whatman 3 M filter paper, will be used for sub microscopic parasite detection (by PCR), detect markers of drug resistance (using next generation sequencing(NGS) technology), and malaria serological assays (using ELISA). To determine the benefit of IPTsc on cognitive and psychomotor ability test of everyday attention for children (TEA-Ch) and a ‘20 metre Shuttle run’ respectively will be conducted at baseline, month 12 and 20. The primary endpoints are change in mean haemoglobin from baseline concentration and reduction in clinical malaria incidence at month 12 and 20 of follow up. Mixed design methods are used to assess the acceptability, cost-effectiveness and feasibility of IPTsc as part of a more comprehensive school children health package. Statistical analysis will be in the form of multilevel modelling, owing to repeated measurements and clustering effect of participants. Discussion Malaria intervention using IPTsc strategy may be integrated in the existing national school health programme, however, there is limited systematic evidence to assess the operational feasibility of this approach. School-aged children are easily accessible in any endemic malaria setting. The suggested strategy may provide effective protection against malaria morbidity, anaemia and could contribute to the burden reduction in endemic countries. Trial registration Clinicaltrials.gov: NCT03640403, registered on 21 Aug 2018, prospectively registered. URL https://www.clinicaltrials.gov/ct2/show/NCT03640403?term=NCT03640403&rank=1 .