Low Dose Primaquine for Clearance of Gametocytes

Study Overview
=================
Brief Summary
-----------------
Primaquine (PQ) is currently the only available drug that can clear mature transmission stages of P. falciparum parasites. PQ was previously shown to clear gametocytes that persist after artemisinin-combination therapy. However, there are safety concerns about the use of PQ at the currently recommended dose of 0.75mg/kg in individuals who are glucose-6-phosphate dehydrogenase (G6PD) deficient. PQ causes transient but significant haemolysis in G6PD deficient individuals; this side-effect is dose dependent. There are indications that a lower dosing of PQ may effectively reduce gametocyte carriage but the lowest efficacious dose for gametocyte clearance is currently unknown. Recently, the World Health Organization changed their recommendation to a low dose of primaquine, 0.25mg/kg. However, there is no direct evidence on the extent to which (low dose) PQ prevents malaria transmission to mosquitoes and what the lowest efficacious dose is. In the current study we aim to identify the lowest efficacious dose of PQ in individuals with normal G6PD function. Children with asymptomatic malaria and normal G6PD enzyme function will be randomized to treatment with artemether-lumefantrine alone or in combination with low doses of PQ. All enrolled individuals will receive a full three-day course of AL, and will be randomized to receive a dose of primaquine or placebo with their fifth dose of AL. Efficacy will be determined based on gametocyte carriage during follow-up, measured by molecular methods. For a subset of participants with patent gametocytes, primaquine effect on infectivity to mosquitoes will be assessed by membrane feeding assays

Official Title
-----------------
A Double Blind Randomized Controlled Trial to Assess the Efficacy and Safety of Low Dose Primaquine for Clearance of Gametocytes in Asymptomatic Individuals Infected With P. Falciparum in Burkina Faso

Conditions
-----------------
Malaria, Asymptomatic Malaria, Plasmodium Falciparum

Intervention / Treatment
-----------------
* Drug: Artemether-lumefantrine combination
* Drug: Artemether-Lumefantrine with a single dose of 0.25mg/kg primaquine
* Drug: Artemether-Lumefantrine with a single dose of 0.4mg/kg primaquine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age > 2 years and <15 years Weight over 10kg P. falciparum parasitaemia >1,000 parasites and <200,000 parasites/µl P. falciparum gametocytes detected by microscopy Normal G6PD enzyme function Informed consent by legally acceptable representative Exclusion Criteria: Enrolled in another study Fever or history of fever in the last 24 hours Evidence of severe illness/ danger signs Known allergy to study medications Hb < 8g/dL Started menstruation Pregnancy or breastfeeding Antimalarials taken within the last 2 days Primaquine taken within the last 4 weeks Blood transfusion within the last 90 days Non-falciparum malaria co-infection

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 15 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Artemether-Lumefantrine<br>Artemether-Lumefantrine combination | Drug: Artemether-lumefantrine combination<br> <br> |
| Experimental: Artemether-Lumefantrine-Primaquine 0.25<br>Artemether-Lumefantrine with a single dose of 0.25mg/kg primaquine | Drug: Artemether-Lumefantrine with a single dose of 0.25mg/kg primaquine<br> <br> |
| Experimental: Artemether-Lumefantrine-Primaquine 0.4<br>Artemether-Lumefantrine with a single dose of 0.4mg/kg primaquine | Drug: Artemether-Lumefantrine with a single dose of 0.4mg/kg primaquine<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gametocyte carriage | Gametocyte prevalence at enrolment and on days 2, 3, 7, 10, 14 during follow-up. The duration of gametocyte carriage in days will be estimated. | 14 days during follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transmission to Anopheles gambiae mosquitoes | Mosquito membrane feeding assays will be used to determine the proportion of infected mosquitoes and the oocyst burden in infected mosquitoes. | day -1, day 3, day 7 | 
| Haematological recovery | Haemoglobin concentration will be determined at enrolment and on days 2, 3, 7, 10 and 14 during follow-up. Haemoglobin concentration will be presented as grams per decilitre and as concentration relative to enrolment value. | 14 days during follow-up | 
| Primaquine and lumefantrine pharmacokinetics | The pharmacokinetic sampling will measure primaquine, lumefantrine and metabolites. Sampling involves 7 venous blood samples during the first 72 hours after treatment and a single later time point at day 7 post initiation of treatment. Drug plasma levels will be related to treatment arm and to the participant's Cytochrome P450 2D6 metabolizer status. CYP2D6 is an enzyme involved in primaquine metabolism. | 7 days during follow-up |