Low Dose Primaquine for Clearance of Gametocytes

Phase 2

Completed

• Conditions: Malaria; Asymptomatic Malaria; Plasmodium Falciparum
• Interventions: 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

• Registration Number: NCT01935882
• Lead Sponsor: London School of Hygiene and Tropical Medicine

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

Detailed Description

Not available

Study Timeline

• Study Start: 2013-09
• Study First Submitted: 2013-09-02
• Study First Submitted QC: 2013-09-04
• Study First Posted: 2013-09-05
• Primary Completion: 2015-07
• Study Completion: 2015-07
• Status Verified: 2015-09
• Last Update Submitted: 2015-09-01
• Last Update Posted: 2015-09-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 360

Inclusion Criteria

1. Age > 2 years and <15 years
2. Weight over 10kg
3. P. falciparum parasitaemia >1,000 parasites and <200,000 parasites/µl
4. P. falciparum gametocytes detected by microscopy
5. Normal G6PD enzyme function
6. Informed consent by legally acceptable representative

Exclusion Criteria

1. Enrolled in another study
2. Fever or history of fever in the last 24 hours
3. Evidence of severe illness/ danger signs
4. Known allergy to study medications
5. Hb < 8g/dL
6. Started menstruation
7. Pregnancy or breastfeeding
8. Antimalarials taken within the last 2 days
9. Primaquine taken within the last 4 weeks
10. Blood transfusion within the last 90 days
11. Non-falciparum malaria co-infection

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Artemether-Lumefantrine	Artemether-lumefantrine combination	Artemether-Lumefantrine combination
Artemether-Lumefantrine-Primaquine 0.25	Artemether-Lumefantrine with a single dose of 0.25mg/kg primaquine	Artemether-Lumefantrine with a single dose of 0.25mg/kg primaquine
Artemether-Lumefantrine-Primaquine 0.4	Artemether-Lumefantrine with a single dose of 0.4mg/kg primaquine	Artemether-Lumefantrine with a single dose of 0.4mg/kg primaquine

Primary Outcome Measures

Name	Time	Method
Gametocyte carriage	14 days during follow-up	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.

Secondary Outcome Measures

Name	Time	Method
Transmission to Anopheles gambiae mosquitoes	day -1, day 3, day 7	Mosquito membrane feeding assays will be used to determine the proportion of infected mosquitoes and the oocyst burden in infected mosquitoes.
Haematological recovery	14 days during follow-up	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.
Primaquine and lumefantrine pharmacokinetics	7 days during follow-up	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.

Trial Locations

Locations (1)

Centre National de Recherche et de Formation sur le Paludisme; 🇧🇫 Ouagadougou, Burkina Faso