Understanding and Maximizing the Community Impact of Antimalarial Treatment (INDIE-SMC)

Study Overview
=================
Brief Summary
-----------------
Seasonal Malaria Chemoprophylaxis (SMC) is a fundamental component of malaria control. The SMC program involves that sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) is given to children below the age of 5 years during the peak transmission season in areas of seasonal malaria transmission. Yet, its efficacy is increasingly below expectations. This study involves an Operational evaluation of a modified existing intervention and its implementation are prepared in direct interaction with the Ministry of Health (MoH) to tailor data collection to local needs. The main questions it aims to answer are: what are the reasons for the continued high infection rates in the SMC-targeted population; what are the implications for transmission of sub-optimal SMC in children less than 5 years old; can the impact of SMC be improved by including older age groups that would both expand the population that experiences direct chemoprophylactic benefits and concurrently reduce transmission to the wider community Researchers will: i) Compare SMC effectiveness as implemented by the national malaria control program and SMC implemented in a research context where all doses are directly observed. ii) Quantify the infectious reservoir and the contribution of different age groups to transmission with conventional SMC (<5 years) and extended SMC (<10 years) iii) Determine the impact of drug resistance and drug absorption on SMC efficacy iv) Understand social barriers and enablers interfering with SMC efficacy and how SMC uptake is related to health equity with special attention to gender inequalities. v) Quantify SMC efficacy decay under programmatic conditions and key drivers of this decay.

Detailed Description
-----------------
Seasonal Malaria Chemoprophylaxis is a well established method of malaria control. Sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) is given to children below the age of 5 years during the peak transmission season in areas of seasonal malaria transmission. Whilst highly effective in controlled research studies, the impact of SMC in terms of reducing infection prevalence is less following operational delivery. It is currently unclear why and what drivers of SMC coverage and uptake play a role. In addition, the relative importance of parasite drug resistance, limited adherence, poor drug absorption and frequent re-infections remain largely unexplored. Lastly, the World Health Organization has recently widened the scope for SMC to target all vulnerable populations. The Ministry of Health (MoH) in Burkina Faso is considering extending SMC to all children below 10 years of age; the impact of SMC on clinical incidence and parasite prevalence in this population with markedly different immunity is unknown. Moreover, this older age group is known to be highly relevant for onward malaria transmission, making it important to quantify the impact of SMC on the human infectious reservoir for malaria and broader benefits to the community. The investigators propose a cluster-randomized trial in Saponé Health District, Burkina Faso, with three study arms: i. SMC in children under the age of 5 years, implemented by the MoH without directly observed treatment for the full course of SMC ii. SMC in children under the age of 5 years, with directly observed treatment for the full course of SMC iii. SMC in children under the age of 10 years, with directly observed treatment for the full course of SMC The investigators will deliver the different arms of the intervention to 40 clusters of 3 households/compounds (i.e. 120 compounds per arm). The primary endpoint is parasite prevalence at the end of the malaria transmission season, secondary endpoints include the impact of SMC on clinical incidence, gametocyte carriage and potential for onward parasite transmission to mosquitoes. As relevant factors in determining these efficacies, drivers of SMC uptake and treatment adherence will be determined, as well as drug concentrations, parasite resistance markers and transmission of parasites to mosquitoes.

Official Title
-----------------
Understanding and Maximizing the Community Impact of Antimalarial Treatment (INDIE-SMC)

Conditions
-----------------
Malaria, Malaria,Falciparum

Intervention / Treatment
-----------------
* Other: Seasonal Malaria Chemoprophylaxis (under 5 year old) implemented by the MoH without DOT
* Other: Seasonal Malaria Chemoprophylaxis (under 5 years old) with DOT
* Other: Seasonal Malaria Chemoprophylaxis (under 10 years old) with DOT


Participation Criteria
=================
Eligibility Criteria
-----------------
The study population will be derived from individuals aged 3 months to up to 10 years old eligible for SMC. Inclusion criteria: Eligible for chemoprevention for SMC as per the current recommendations Age 3- 59 months for arms i. and ii. Age 60 months up to 10 years old for arm iii. Absence of symptomatic falciparum malaria, defined by fever on enrolment Absence of other non-P. falciparum species on blood film No evidence of acute severe or chronic disease Able and willing to comply with the study protocol and follow-up schedule Parent or guardian provides written, informed consent on behalf of child Exclusion criteria: Symptoms of malaria (axillary fever ≥ 37.5 °C and/or history of fever in the past 48 hours) Previous reaction to study drugs / known allergy to study drugs Signs of severe malaria, including hyperparasitemia (defined as asexual parasitemia > 100,000 parasites / µL) Signs of acute or chronic illness, including hepatitis The use of other medication (except for paracetamol and/or aspirin) Presence of severe malnutrition according to WHO's child growth standards

Ages Eligible for Study
-----------------
Minimum Age: 3 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study involves and Operational evaluation of a modified existing intervention delivered in independent clusters. The project and its implementation are prepared in direct interaction with the Ministry of Health (MoH) to tailor data collection to local needs.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>SMC in children under the age of 5 years, implemented by the MoH without directly observed treatment for the full course of SMC | Other: Seasonal Malaria Chemoprophylaxis (under 5 year old) implemented by the MoH without DOT<br>* Standard approach for SMC strategy used by the Ministry of Health (without directly-observed therapy) and without any interference of the study team. Implemented over 4 rounds, carried out in June-October 2023 with  30 days between rounds.<br>|
| Experimental: Arm 2<br>SMC in children under the age of 5 years, with directly observed treatment for the full course of SMC | Other: Seasonal Malaria Chemoprophylaxis (under 5 years old) with DOT<br>* SMC will be implemented with the same number of rounds and the same timing as in active comparator arm but village health workers will visit the participants at home to administer each dose of study treatment (with DOT-directly-observed therapy)<br>|
| Experimental: Arm 3<br>SMC in children under the age of 10 years, with directly observed treatment for the full course of SMC | Other: Seasonal Malaria Chemoprophylaxis (under 10 years old) with DOT<br>* SMC will be implemented as in arm 2 but age of participants is extended up to 10 years: each dose of study treatment (with DOT-directly-observed therapy) distributed at home by village health workers.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasite prevalence by quantitative PCR (qPCR) at the end of the transmission season in age groups targeted by seasonal malaria chemoprevention. | This endpoint will be compared between arms 1 and 2 (in children aged 3-59 months) and arms 2 and arm 3 (in children aged 3 months-9 years). | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasite prevalence by qPCR at the end of the transmission season in all age groups | This endpoint will compare the parasite prevalence in all age groups between intervention arms. | 4 weeks | 
| Parasite prevalence by microscopy prior to SMC rounds 2, 3 and 4 in SMC-targeted age groups | This endpoint will compare the prevalence by microscopy before SMC rounds (2, 3 and 4) between intervention arms. | 8 weeks | 
| Rate of re-infection with P. falciparum at weeks 3, 4 and 5 after the last round of SMC, assessed in SMC-targeted age groups | This endpoint will assess the rate of malaria reinfection at different time points after the alst round of SMC between intervention arms | 10 weeks | 
| Gametocyte prevalence by qRT-PCR at weeks 3, 4 and 5 after the last round of SMC, assessed in SMC-targeted age groups | This endpoint will compare the gametocyte prevalence between intervention arms at different time points after the last round of SMC. | 10 weeks | 
| Gametocyte prevalence by qRT-PCR at the end of the transmission season in all age groups | This endpoint will compare the gametocyte prevalence between intervention arms in all age groups | 8 weeks | 
| Plasma levels of AQ and DESAQ after the 4th round of SMC in children aged 3 months-9 years | This endpoint will compare the plasma levels of AQ and DESAQ between intervention arms. | 6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Plasmodium falciparum, Seasonal Malaria Chemoprevention, Antimalarial treatment, Burkina Faso, SP+AQ