Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial

Summary Background Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin–piperaquin...

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Published in:The Lancet infectious diseases 2016-06, Vol.16 (6), p.674-684
Main Authors: Dicko, Alassane, Prof, Brown, Joelle M, PhD, Diawara, Halimatou, MD, Baber, Ibrahima, PhD, Mahamar, Almahamoudou, PharmD, Soumare, Harouna M, PharmD, Sanogo, Koualy, MD, Koita, Fanta, PharmD, Keita, Sekouba, MS, Traore, Sekou F, PhD, Chen, Ingrid, PhD, Poirot, Eugenie, MPH, Hwang, Jimee, MD, McCulloch, Charles, Prof, Lanke, Kjerstin, BSc, Pett, Helmi, MSc, Niemi, Mikko, MD, Nosten, François, Prof, Bousema, Teun, PhD, Gosling, Roly, Dr
Format: Article
Language:English
Subjects:
Animals
Anopheles - parasitology
Antimalarials - therapeutic use
Artemisinins - administration & dosage
Dehydrogenases
Drug Administration Schedule
Drug Therapy, Combination
Enzymes
Humans
Infectious Disease
Infectious diseases
Malaria
Malaria, Falciparum - drug therapy
Malaria, Falciparum - transmission
Mali
Methods
Mosquitoes
Pain
Plasmodium falciparum
Primaquine - administration & dosage
Quinolines - therapeutic use
Single-Blind Method
Studies
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Summary:Summary Background Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin–piperaquine in male patients in Mali. Methods In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification. In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0·125 mg/kg, and 0·5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0·25 mg/kg primaquine or 0·0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin–piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane-feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov , number NCT01743820. Findings Between Jan 2, 2013, and Nov 27, 2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0·25 mg/kg primaquine dose group (n=15) and 0·5 mg/kg primaquine dose group (n=14) had significantly lower me
ISSN:1473-3099
1474-4457
DOI:10.1016/S1473-3099(15)00479-X