This community-based cluster randomized controlled trial aims to evaluate the effectiveness of time-limited, community-wide mass drug administration (MDA) with dihydroartemisinin-piperaquine (DHA-PPQ) and single low-dose primaquine (SLD-PQ) on Plasmodium falciparum transmission compared to standard-of-care seasonal malaria chemoprevention (SMC). The study will be conducted in a moderate-to-low malaria transmission setting of Senegal with optimized malaria control measures (e.g., proactive community case management and piperonyl butoxide pyrethroid long-lasting insecticidal nets (PBO LLINS)).

Over the past two decades in Senegal, the scale-up of malaria control measures [e.g., access to prompt testing and case management, LLINs, and SMC] has led to a 78% reduction in malaria incidence. However, gains have not been uniform, with lower transmission areas in the north implementing pre-elimination activities and higher transmission areas in the south implementing control interventions (including SMC). The purpose of this study is determine whether MDA will be able to rapidly reduce malaria incidence in areas of moderate-to-low malaria transmission of southern Senegal (where control activities are ongoing) so that the program can reorient their malaria strategy to implement elimination interventions in these settings.

The study aims to deliver three rounds of community-wide MDA with DHA-PPQ + SLD-PQ. MDA drugs will be administered over the course of three days. All three doses of DHA-PPQ will be given via supervised DOT (as per administration of SMC by national malaria guidelines) through a door-to-door approach.

The research objectives are:

1. To evaluate the impact of three rounds of MDA with DHA-PPQ and SLD-PQ on village-level confirmed malaria case incidence, malaria prevalence, and on reaching a target malaria incidence of <5 cases per 1000 person-years compared to standard-of-care SMC when provided in the context of optimized control (proactive community case management + PBO LLINs).
2. To determine the cost, coverage, operational feasibility, and acceptability of three rounds of MDA with DHA-PPQ and SLD-PQ compared to standard-of-care SMC.
3. To determine the impact of three rounds of MDA with DHA-PPQ and SLD-PQ compared to standard-of-care SMC on parasite population dynamics and drug resistance.

Inclusion Criteria:

• Age ≥3 months
• Willingness to comply with trial procedures and written informed consent to be obtained at the beginning of the study

Exclusion Criteria:

• Severe illness or self-reported chronic illness (e.g., HIV, tuberculosis, heart/liver/kidney disease, and severe malnutrition)
• Known hypersensitivity to study drug

Additional exclusion criteria for DHA-PPQ:

• First trimester pregnancy assessed by history and/or urine pregnancy testing
• Concurrent artemisinin-based combination therapy (ACT) use
• Taking drugs that influence cardiac function or prolong QTc interval

Additional exclusion criteria for PQ:

• Pregnancy (any trimester) or currently breastfeeding an infant <6 months of age assessed by history and/or urine pregnancy testing
• <2 years of age