Adjunctive Ivermectin Mass Drug Administration for Malaria Control

Phase 3

• Conditions: Malaria,Falciparum; Strongyloidiasis; Lymphatic Filariasis; Hook Worm; Scabies; Neglected Tropical Diseases; Soil Transmitted Helminths
• Interventions: Drug: Ivermectin; Drug: Placebo; Drug: Dihydroartemisinin-piperaquine

• Registration Number: NCT04844905
• Lead Sponsor: London School of Hygiene and Tropical Medicine

Brief Summary

This is a cluster-randomized placebo-controlled clinical trial to evaluate the additive benefit of Ivermectin (IVM) (or Placebo) mass drug administration (MDA) to dihydroartemisinin-piperaquine (DP) MDA for malaria control in a moderate to low malaria-endemic setting as an adjunctive strategy to existing programmatic malaria control measures. The regime of DP and IVM will target both human reservoirs of Plasmodium falciparum and the Anopheles gambiae vector respectively, with the aim of interrupting transmission. The trial will be conducted on the Bijagos Archipelago, where islands (clusters) will be randomised to receive seasonal DP and IVM or DP and Placebo MDA. The primary outcome will be the prevalence of infection with Plasmodium falciparum in all age groups detected by nucleic acid amplification testing during the peak malaria transmission season after two years of intervention.

Detailed Description

The objectives of this trial are

1. To evaluate the impact of adjunctive IVM to DP MDA on malaria transmission in communities with high ITN coverage.

2. To evaluate the impact of IVM MDA on An. gambiae population density and age-structure.

3. To evaluate the impact of IVM MDA on the prevalence of co-endemic IVM-susceptible Neglected Tropical Diseases (lymphatic filariasis, soil transmitted helminths and scabies)

4. To evaluate acceptability, feasibility and access to MDA as a strategy for malaria control and to identify the most acceptable way of achieving and sustaining high coverage MDA with IVM and DP.

This cluster-randomized placebo-controlled trial has two arms. A total of 24 clusters will be randomly assigned to receive DP + IVM MDA or DP+ Placebo MDA using computer-generated random numbers. To mitigate against contamination effects, the majority of clusters will be separate islands and will be separated by distances greater than 2km. On the two islands that are divided (each into two clusters), a buffer zone of 2km between each cluster will be ensured. The total population of the archipelago is 24,000. The investigators will ensure balance between trial arms with respect to population size, baseline Plasmodium falciparum prevalence and access to health care. All clusters will receive the standard programmatic malaria control interventions implemented by the National Malaria Control Programme which includes insecticide-treated nets (ITN), intermittent preventative treatment in pregnancy (IPTp), seasonal malarial chemoprophylaxis (SMC) for children aged 3-59 months and case diagnosis and treatment (CDT) with Artemether-lumefantrine.

Study Timeline

• Study First Submitted: 2021-03-17
• Study First Submitted QC: 2021-04-12
• Study First Posted: 2021-04-14
• Study Start: 2021-05-03
• Status Verified: 2022-02
• Last Update Submitted: 2022-02-22
• Last Update Posted: 2022-02-24
• Primary Completion: 2023-03
• Study Completion: 2023-08

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 24000

Inclusion Criteria

1. Age over six months to receive dihydroartemisinin-piperaquine
2. Height over 90cm or weight over 15kg to receive ivermectin or placebo
3. Willingness to adhere to trial procedures
4. Individual written, informed consent from the participant or parent/guardian in the case of participants below the age of 18 years (and assent in young people between the ages of 12 and 17 years of age)

Exclusion Criteria

1. Known severe chronic illness (AIDS, Tuberculosis, chronic malnutrition)
2. Known hypersensitivity to either dihydroartemisinin-piperaquine or ivermectin
3. Pregnancy (any trimester) and breastfeeding (for ivermectin (or placebo)) and pregnancy (first trimester only) (for dihydroartemisinin-piperaquine)
4. Travel to a Loa loa endemic country (eg Central African Republic) (for ivermectin (or placebo))
5. Concomitant drugs that influence cardiac function or affect the corrected QT interval (for dihydroartemisinin-piperaquine)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ivermectin Mass Drug Administration	Ivermectin	Ivermectin and Dihydroartemisinin-piperaquine MDA will be given to all eligible participants in each cluster (island) in addition to the standard national malaria control programme interventions.
Ivermectin Mass Drug Administration	Dihydroartemisinin-piperaquine	Ivermectin and Dihydroartemisinin-piperaquine MDA will be given to all eligible participants in each cluster (island) in addition to the standard national malaria control programme interventions.
Placebo Mass Drug Administration	Placebo	Placebo and Dihydroartemisinin-piperaquine MDA will be given to all eligible participants in each cluster (island) in addition to the standard national malaria control programme interventions.
Placebo Mass Drug Administration	Dihydroartemisinin-piperaquine	Placebo and Dihydroartemisinin-piperaquine MDA will be given to all eligible participants in each cluster (island) in addition to the standard national malaria control programme interventions.

Primary Outcome Measures

Name	Time	Method
Prevalence of infection with Plasmodium falciparum	2 years	Prevalence of infection with Plasmodium falciparum in all age groups estimated using a cross-sectional survey sample conducted during peak transmission season after 2 years of intervention

Secondary Outcome Measures

Name	Time	Method
Vector parous rate	7-14 days post-MDA	Vector parous rate will be determined by assessment of mosquitoes trapped 7-14 days following MDA. Vector parity will be used to determine Anopheles gambiae age structure to estimate vector survival between arms.
Incidence of clinical malaria (Active Case Detection)	For six months during the malaria transmission season	Incidence of clinical malaria confirmed by malaria Rapid Diagnostic Test in a cohort of 50 children per cluster aged 5-14 years
Prevalence of infection with Plasmodium falciparum	1 year	Prevalence of infection with Plasmodium falciparum in all age groups estimated using a cross-sectional survey sample conducted after the first year of intervention
Vector density	For six months during the malaria transmission season	Total number of trapped mosquitoes per cluster
Incidence of clinical malaria (Passive Case Detection)	For six months during the malaria transmission season	Incidence of clinical malaria diagnosed at health facilities confirmed by malaria Rapid Diagnostic Test
Vector species composition	For six months during the malaria transmission season	Species characterisation using nucleic acid amplification tests as a proportion of total mosquitoes caught in traps
MDA coverage estimates	During MDA in year 1 and year 2	Cluster level coverage estimates calculated from MDA distribution and denominator census
Age-adjusted prevalence of recent exposure to Plasmodium falciparum	Peak transmission season at 1 year and 2 years	Mean Median Fluorescence Intensity of serological markers associated with recent exposure to Plasmodium falciparum in all age groups estimated using a cross-sectional survey sample during peak transmission season after each year of intervention
Prevalence of exposure to Anopheles exposure	Peak transmission season at 1 year and 2 years	Mean Median Fluorescence Intensity of serological markers associated with exposure to Anopheles salivary antigen in all age groups estimated using a cross-sectional survey sample
Vector sporozoite rates	For six months during the malaria transmission season	Proportion of Plasmodium falciparum circumsporozoite antibody (CSP) positive mosquitoes caught in traps
Prevalence of Ivermectin-susceptible Neglected Tropical Diseases (NTDs)	2 years	Prevalence of IVM-susceptible NTDs (scabies, strongyloides, other soil-transmitted helminths and lymphatic filariasis) and head lice using clinical and serological parameters estimated using a cross-sectional survey sample during the dry season after two years of intervention.
Prevalence of resistance to artemisinin and partner drugs in humans	Peak transmission season at 1 year and at 2 years	Prevalence of resistance to artemisinin and partner drugs in humans using molecular markers of resistance in all age groups estimated using a cross-sectional survey sample

Trial Locations

Locations (1)

Bijagos Archipelago (islands); 🇬🇼 Bissau, Guinea-Bissau