Low Dose Primaquine for Clearance of Gametocytes (LOPRIM)

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

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

Study Overview

• Status: Completed
• Conditions: Malaria; Plasmodium Falciparum; Asymptomatic Malaria
• 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

• Study Type: Interventional
• Enrollment (Actual): 360
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Burkina Faso
  • Ouagadougou, Burkina Faso
    • Centre National de Recherche et de Formation sur le Paludisme

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: Radboud University Medical Center; Centre national de recherche et de formation sur le paludisme
• Investigators: Principal Investigator: Alfred Tiono, PhD, MD, Centre National de Recherche et de Formation sur le Paludisme

Publications and helpful links

General Publications

• Goncalves BP, Pett H, Tiono AB, Murry D, Sirima SB, Niemi M, Bousema T, Drakeley C, Ter Heine R. Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children. Antimicrob Agents Chemother. 2017 Apr 24;61(5):e02590-16. doi: 10.1128/AAC.02590-16. Print 2017 May.
• Goncalves BP, Tiono AB, Ouedraogo A, Guelbeogo WM, Bradley J, Nebie I, Siaka D, Lanke K, Eziefula AC, Diarra A, Pett H, Bougouma EC, Sirima SB, Drakeley C, Bousema T. Single low dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission after artemether-lumefantrine in children with asymptomatic infection: a randomised, double-blind, placebo-controlled trial. BMC Med. 2016 Mar 8;14:40. doi: 10.1186/s12916-016-0581-y.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: September 2, 2013
• First Submitted That Met QC Criteria: September 4, 2013
• First Posted (Estimate): September 5, 2013

Study Record Updates

• Last Update Posted (Estimate): September 2, 2015
• Last Update Submitted That Met QC Criteria: September 1, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Lumefantrine; Artemether; Primaquine; Artemether, Lumefantrine Drug Combination
• Other Study ID Numbers: LOPRIM-1