Adjunctive Ivermectin Mass Drug Administration for Malaria Control

London School of Hygiene and Tropical Medicine24,000 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Interventions

IvermectinDRUG

Ivermectin will be given as tablets of 3 or 6mg. It will be given at 300-400μg/kg/day for 3 days (to the nearest whole tablet) each month for 3 months. It will be taken on an empty stomach with water.

PlaceboDRUG

Placebo will be given as tablets of 3 or 6mg (identical to Ivermectin in colour, size, shape and packaging). It will be given at 300-400μg/kg/day for 3 days (to the nearest whole tablet) each month for 3 months. It will be taken by mouth with water and without food.

Dihydroartemisinin-piperaquineDRUG

Dihydroartemisinin-piperaquine will be given as tablets of 320/40mg (adult) and 160/20mg (child) piperaquine/dihydroartemisinin per tablet. Administration of a full course of dihydroartemisinin-piperaquine will be given in accordance with the manufacturer's guidelines once daily for 3 days each month for 3 months according to body weight. Dihydroartemisinin-piperaquine will be taken by mouth with water and without food.

Eligibility

Sex: ALLMin age: 6 MonthsHealthy volunteers:

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

Prevalence of infection with Plasmodium falciparum

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

Time frame: 2 years

Secondary Outcomes

Vector parous rate

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.

Time frame: 7-14 days post-MDA

Prevalence of infection with Plasmodium falciparum

Prevalence of infection with Plasmodium falciparum in all age groups estimated using a cross-sectional survey sample conducted after the first year of intervention

Time frame: 1 year

Incidence of clinical malaria (Passive Case Detection)

Incidence of clinical malaria diagnosed at health facilities confirmed by malaria Rapid Diagnostic Test