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 Schoolchildren in Tanzania: A Controlled Randomised Trial

Background: In high transmission settings, the majority of school-aged children harbour malaria parasites without showing symptoms (asymptomatic), consequently leading to anaemia that may impair their psychomotor and cognitive abilities. We determined the effectiveness and safety of intermittent preventive treatment for malaria in school-aged children (IPTsc) living in highly endemic areas.Methods: An open-label, individual randomised, clinical trial was conducted in seven primary schools in north-eastern, Tanzania. Schoolchildren (aged 5-15 years) were randomly assigned to receive either Dihydroartemisinin-piperaquine (DP) (n=526) or Artesunate-amodiaquine (ASAQ) (n=527) or no antimalarial treatment (control, n=513), using a balanced block design. The primary endpoints were a change from baseline in haemoglobin (Hb) and a reduction in malaria incidence and prevalence after one year of intervention. Schoolteachers administered the interventional treatments at 4-month intervals during the first year. A second non-interventional year was set to assess possible rebound effects. Data were analysed by both the intention to treat (ITT) and per-protocol (PP). Findings: During the one year of intervention, compared to the control arm, on ITT analysis, the increase in mean Hb was 0.50g/dL (95%CI 0.20-0.80, p<0.001) and 0.44g/dL (95%CI 0.10-0.70, p<0.001) for the DP and ASAQ arms, respectively. On PP analysis, the respective mean Hb increase was 0.61g/dL (95%CI 0.30-1.00, p<0.001) and 0.44g/dL (95% CI 0.10-0.80, p<0.001). On ITT analysis, the protective effect (PE) of IPTsc on malaria parasitaemia was 65% (95%CI 39-80, p<0.001) and 51% (95% CI 21-70, p=<0.012) for DP and ASAQ arms, respectively, and was 78% (95%CI 52-90, p<0.001) in both interventional arms on PP analysis. The overall PE on clinical malaria was 21% (95% CI 2-36, p=0.014) and 22% (95% CI 4-37, p=<0.018) for DP and ASAQ arms respectively. In the non-interventional year, there was no significant difference in malaria prevalence or Hb change in all study arms. The impact of IPTsc on both psychomotor and cognitive functions was not significant. DP and ASAQ were safe and effective when used for IPTsc.Interpretation: IPTsc restores malaria-related anaemia, reduces malaria parasitaemia, and is feasibly implementable through schoolteachers.Trial Registration Details: This study is registered with ClinicalTrials.gov, number NCT03640403.Funding Information: The study was funded by the Flemish Interuniversity Council (VLIRUOS), Belgium, TEAM initiative, grant number TZ2017TEA451A102. Additional funding was provided by the MaReCa project as part of the EDCTP2 programme supported by the European Union (grant number TMA2015SF–998-MaReCa, awarded to Prof. Dr. John P. A. Lusingu), and the sandwich PhD scholarship Global Minds 2019 in support for a PhD student. Declaration of Interests: Authors declare no competing interest.Ethical Approval Statement: The study obtained ethical clearance from the Medical Research Coordinating Committee (MRCC, Tanzania) with approval number NIMR/HQ/R.8a/Vol.IX/2818 and NIMR/HQ/R.8c/Vol.I/668 (for amendment) also NIMR/HQ/R.8c/Vol.I/1276 for ethical clearance extension. We obtained regulatory approval from the Tanzania Medicines and Medical Devices Authority (TMDA) with approval number TFDA0017/CTR/0018/07. Each participant signed an informed consent to join the study. The study also obtained permissions from different levels of local government including local school committees.