This is a cluster randomised controlled trial with factorial study design comparing the impact of reactive community-based malaria interventions: 1) presumptive treatment (or rfMDA, reactive focal mass drug administration) versus reactive case detection (RACD), and 2) reactive IRS (indoor residual spraying) versus control on the incidence of malaria in Namibia.

In recent years, many countries, including Namibia, have experienced reductions in malaria transmission in association with the scale-up of effective interventions and are now moving towards malaria elimination. In malaria control, the goal is to reduce the clinical burden of malaria. In malaria elimination, the aim is to interrupt transmission, and it becomes necessary to address not only symptomatic malaria, but also asymptomatic infections that contribute to transmission. Since malaria transmission is highly geographically heterogeneous, elimination activities should target hot spots, or areas where the risk of future infection is highest. Hence, in the transition from control to elimination, enhanced surveillance and response is necessary to target hot spots with interventions to interrupt transmission.

Reactive case detection (RACD), active surveillance in communities around passively detected cases, is a recommended elimination strategy to identify secondary cases and hot spots. However, RACD can be labour-, time-, and cost- intensive, and misses people who are absent during screening or refuse to have their blood drawn. Furthermore, both microscopy and rapid diagnostic tests (RDTs) utilized in RACD have shortcomings, for instance, the suboptimal sensitivity of RDTs for low parasite density and non-falciparum infections. Polymerase chain reaction (PCR) offers markedly improved sensitivity over RDTs but requires hours of processing time, sophisticated technical skills, and expensive equipment. Given these limitations, presumptive treatment may be a more feasible and effective strategy to reduce and interrupt transmission.

Reactive focal mass drug administration (rfMDA), a form of presumptive treatment, has been used successfully in China to overcome some of the weaknesses of RACD. rfMDA targets remaining reservoirs of infection in low endemic settings by treating everyone at high risk (subjects residing around an index case), rather than rely on RDT results, which have been shown to miss infections. In a low transmission setting such as Namibia, only a small proportion of the populations is at high risk of infection, therefore, only a small number of people need to be targeted (perhaps 20-50 people). Additional indoor residual spraying (IRS) targeted to homes in high risk locations can also be implemented.

rfMDA is a promising strategy, but evidence does not yet exist to prove its efficacy in Africa. Questions remain about where to target rfMDA, what drugs to use, and whether drugs should be used alone or in combination with additional vector control. For rfMDA to be most successful, it is necessary to kill parasites in the human as well as the vector population of the target area. However, one challenge of pre-transmission season IRS is that it is difficult to predict where future infections will occur. A reactive approach, in conjunction with the pre-transmission approach, will ensure coverage of effective vector control in the highest risk areas. Further, if there is unknown resistance to the insecticide used during pre-transmission season, the subsequent reactive use of a different, and presumably effective insecticide, will provide better protection.

In this study the investigators will utilise a cluster randomized controlled study design to evaluate rfMDA in response to a passively identified index case and compare it to RACD. The investigators will study each intervention (rfMDA, RACD) both with and without additional focal insecticide spraying.

56 enumeration areas (EAs) within catchment areas of 11 study health facilities will be randomized to one of four intervention arms:

1. RACD only
2. RACD with RAVC
3. rfMDA only
4. rfMDA with RAVC

A rapid reporting surveillance system will capture confirmed, passively identified cases at all study health facilities, and those cases will trigger an intervention by the study team if located in one of the study EAs.

Inclusion Criteria:

1. Index Case Investigation Inclusion Criteria:

   • Malaria infection (either locally transmitted or imported) detected at a health facility via passive surveillance, and
   • Resides in a study Enumeration Area (EA), and
   • Provides informed consent

2. RACD Intervention Inclusion Criteria:

   • Provides informed consent, and
   • Index case resides in study EA, and
   • All non-index cases that reside or spent at least one night in the Target Area in the past 4 weeks, and
   • Residents of the six houses closest to the index case, and
   • If 25 people are not enrolled in the study at the first six houses, plus the index case household, after the second visit then additional houses can be approached on the third visit.

3. rfMDA Intervention Inclusion Criteria:

   • Provides informed consent, and
   • Index case resides in study EA, and
   • All non-index cases that reside or spent at least one night in the Target Area in the past 4 weeks, and
   • Residents of the six houses closest to the index case, and
   • If 25 people are not enrolled in the study at the first six houses, plus the index case household, after the second visit then additional houses can be approached on the third visit.

4. Artemether/Lumefantrine (A-L) (combination medication) Inclusion Criteria:

   • Consent to take A-L medication
   • Does not meet A-L Exclusion Criteria under item #4 below

5. Pill count Inclusion Criteria:

   • Provides consent, and
   • People who receive any number of RACD or rfMDA drug dose(s)

6. Reactive Vector Control Inclusion Criteria:

   • Informed consent provided by head of household or person in otherwise in charge of household, and
   • Index case resides in study EA, and
   • Index household and 6 non-index households closest to index household

7. Endline Survey, Individual, Inclusion Criteria:

   • Provides informed consent, and
   • Resides or spent at least 1 night in the EA in the preceding 4 weeks

8. Acceptability Assessment: Individual Interviews with study participants, Inclusion Criteria:

   • Provides informed consent, and
   • Resident of index household or of neighbouring households

9. Acceptability Assessment: Individual Interviews with key stakeholders, Inclusion Criteria:

   • In leadership position within Zambezi region, and
   • Provides informed consent

10. Acceptability Assessment: Individual Interview with refusers, Inclusion Criteria:

    • Refused to participate in rfMDA, RACD, and/or RAVC, and
    • Provides informed consent to take part in the anonymous survey

11. Acceptability Assessment: Focus group discussions with study participants, Inclusion Criteria:

    • Provides informed consent, and
    • Was eligible to be enrolled in the study in participant's Target Area, and
    • Either took part in RACD or rfMDA intervention (+/- RAVC), OR refused these interventions

Exclusion Criteria:

1. Index Case Investigation Exclusion Criteria:

   • Malaria infection identified through active case detection
   • Refusal to participate

2. RACD Intervention Exclusion Criteria:

   • Index case does not reside in study EA, or
   • Refusal to participate in RACD, or
   • Household received the intervention in the previous 5 weeks, or
   • Household > 500 m from the index case, or
   • Severe or complicated malaria as assessed by study nurse (this will lead to referral for further evaluation at health facility but not enrolment in study)

3. rfMDA Intervention Exclusion Criteria:

   • Index case does not reside in study EA, or
   • Refusal to participate in rfMDA, or
   • Household received the intervention in the previous 5 weeks, or
   • Household > 500 m from the index case, or
   • Severe or complicated malaria as assessed by study nurse (this will lead to referral for further evaluation at health facility but not enrolment in study)

4. Artemether/Lumefantrine (combination medication) Exclusion Criteria:

   • Pregnancy in first trimester, or

   • Previous regular menstruation, with no menstruation for most recent 4 weeks, or

   • Weight < 5 kg*, or

   • Severe malaria, or

   • Known allergy to A-L, or

   • Refusal of the offered A-L

     • Note regarding A-L weight exclusion: Because of the pre-set required field at the top of the Eligibility section of this Application, the investigators have indicated a 6 month minimum age limit, primarily to note to the reader that there will be a lower age limit to infants enrolled. Yet during the actual conduct of this trial the investigators will utilize 5 kg weight as the cutoff, rather than using age. A lower weight cutoff of 5 kg is in accordance with A-L's manufacturer (Novartis)'s guidance on supporting pediatric data.

5. Pill count Exclusion Criteria:

   • Refusal to participate in pill count, or
   • Individuals who did not receive any drug doses through RACD or rfMDA

6. Reactive Vector Control Exclusion Criteria:

   • Refusal by head of household to participate in RAVC, or
   • Already received RAVC during current transmission season, or
   • Household is > 500 m from index case household (note: refusal to participate in RACD or rfMDA is not an exclusion criterion for RAVC)

7. Endline Survey, Individual, Exclusion Criteria:

   • Refusal to participate in Endline Survey (note: lack of participation in rfMDA or RACD is not an exclusion criterion)

8. Acceptability Assessment: Individual Interviews with study participants, Exclusion Criteria:

   • Refusal to participate in Acceptability Assessment, or
   • Speaks language not understood or able to be translated, or
   • Key stakeholder [see below]
   • Age < 15 years

9. Acceptability Assessment: Individual Interviews with key stakeholders, Exclusion Criteria:

   • Refusal to participate in Acceptability Assessment, or
   • Speaks language not understood or able to be translated, or
   • Not in leadership position

10. Acceptability Assessment: Individual Interview with refusers, Exclusion Criteria:

    • Refusal to participate in Acceptability Assessment, or
    • Speaks language not understood or able to be translated, or
    • Age < 15 years

11. Acceptability Assessment: Focus group discussions with study participants, Exclusion Criteria:

    • Refusal to participate in Acceptability Assessment, or
    • Speaks language not understood or able to be translated, or
    • Key stakeholder or in another leadership position, or
    • Age < 15 years