The Effectiveness of Reactive Focal Mass Drug Administration (rfMDA) and Reactive Focal Vector Control (RAVC) to Reduce Malaria Transmission: A Cluster-Randomised Controlled Open Label Two-by-Two Factorial Design Trial from the Low-Endemic Setting of Namibia

Background: In low-endemic malaria settings, screening and treatment near index cases (reactive case detection, RACD) is practiced for surveillance and response; however, other approaches may be more effective. Methods: We conducted a cluster-randomised controlled two-by-two factorial design trial to evaluate the impact of reactive focal mass drug administration, rfMDA, and reactive focal vector control, RAVC, in the low-endemic setting of Zambezi, Namibia. Fifty-six clusters were randomised to: RACD or rfMDA, and RAVC or no RAVC (RACD: rapid diagnostic testing and treatment with artemether-lumefantrine (AL); rfMDA: presumptive treatment with AL; RAVC: indoor residual spraying using pirimiphos-methyl), with interventions administered within 500 meters of index cases. To evaluate the effectiveness of interventions targeting the parasite reservoir in humans (rfMDA vs RACD), in mosquitos (RAVC vs no RAVC), and in both humans and mosquitoes (rfMDA+RAVC vs RACD only), a modified intention-to-treat analysis was used to compare cumulative incidence of locally acquired malaria cases and cross-sectional prevalence of infection with parasites. Trial registration: ClinicalTrials.gov NCT02610400. Findings: From Jan-Nov 2017, 55 clusters had index cases triggering 342 interventions that covered 8 948 individuals. Incidence per 1 000 person-years for rfMDA, RAVC, and rfMDA+RAVC clusters vs control was: 30·8 vs 38·3 (adjusted incidence rate ratio (aIRR) 0·54 [95% CI 0·14-0·94, p=0·03]), 30·2 vs 38·9 (aIRR 0·51 [0·12-0·90, p=0·01]), and 25·0 vs 41·4 (aIRR 0·28 [0·10-0·84, p=0·02]), respectively. Compared to control, prevalence of infection (%) for rfMDA, RAVC, and rfMDA+RAVC vs control was 3·2 vs 3·8 (adjusted prevalence ratio (aPR) 0·58 [95% CI 0·18-0·98, p=0·04]), 2·9 vs 4·1 (aPR 0·34 [0·11-0·57, p<0·001]), and 1·8 vs 3·7 (aPR 0·15 [0·04-0·55, p=0·01]), respectively. Interpretation: In a low-endemic setting, rfMDA and RAVC implemented alone, but particularly in combination, reduced malaria transmission and should be considered as alternatives to RACD for malaria elimination. Funding: Novartis Foundation, Bill and Melinda Gates Foundation, Horchow Family Fund. Declaration of Interest: All authors declare no competing interests. Ethical Approval: Ethics approval was obtained from Namibia Ministry of Health and Social Services (MoHSS) (17/3/3), Institutional Review Boards of the University of Namibia (MRC/259/2017), University of California San Francisco (15-17422) and London School of Hygiene and Tropical Medicine (10411).