Malaria, Asymptomatic Malaria, Plasmodium Falciparum
Conditions
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
Interventions
DRUGArtemether-Lumefantrine with a single dose of 0.25mg/kg primaquine
DRUGArtemether-Lumefantrine with a single dose of 0.4mg/kg primaquine
Sponsors
Radboud University Medical Center
Centre national de recherche et de formation sur le paludisme
London School of Hygiene and Tropical Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 15 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Burkina Faso
Outcome results
None listed