title: Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial.
abstract: 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.
  
  
  RESULTS
  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 mean within-person reductions in infectivity at day 2-92·6% (95% CI 78·3-100; p=0·0014) for the 0·25 mg/kg group; and 75·0% (45·7-100; p=0·014) for the 0·5 mg/kg primaquine group-compared with those in the control group (n=14; 11·3% [-27·4 to 50·0]). Reductions were not significantly different from control for participants assigned to the 0·0625 mg/kg dose group (n=16; 41·9% [1·4-82·5]; p=0·16) and the 0·125 mg/kg dose group (n=12; 54·9% [13·4-96·3]; p=0·096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups.
  
  
  CONCLUSIONS
  A single dose of 0·25 mg/kg primaquine, given alongside dihydroartemisinin-piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine.
  
  
  BACKGROUND
  Bill & Melinda Gates Foundation.
authors.affiliation: Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Alassane
authors.initials: A
authors.lastname: Dicko
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Joelle M
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Halimatou
authors.initials: H
authors.lastname: Diawara
authors.affiliation: Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Ibrahima
authors.initials: I
authors.lastname: Baber
authors.affiliation: Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Almahamoudou
authors.initials: A
authors.lastname: Mahamar
authors.affiliation: Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Harouna M
authors.initials: HM
authors.lastname: Soumare
authors.affiliation: Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Koualy
authors.initials: K
authors.lastname: Sanogo
authors.affiliation: Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Fanta
authors.initials: F
authors.lastname: Koita
authors.affiliation: Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Sekouba
authors.initials: S
authors.lastname: Keita
authors.affiliation: Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Sekou F
authors.initials: SF
authors.lastname: Traore
authors.affiliation: Global Health Group, Malaria Elimination Initiative, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Chen
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA; Global Health Group, Malaria Elimination Initiative, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Poirot
authors.affiliation: Global Health Group, Malaria Elimination Initiative, University of California San Francisco, San Francisco, CA, USA; Malaria Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA; President's Malaria Initiative, Washington, DC, USA.
authors.forename: Jimee
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: McCulloch
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Kjerstin
authors.initials: K
authors.lastname: Lanke
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Helmi
authors.initials: H
authors.lastname: Pett
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Immunology & Infection, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Teun
authors.initials: T
authors.lastname: Bousema
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA; Global Health Group, Malaria Elimination Initiative, University of California San Francisco, San Francisco, CA, USA. Electronic address: roly.gosling@ucsf.edu.
authors.forename: Roly
authors.initials: R
authors.lastname: Gosling
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000635:transmission; D008302:Mali; D011319:Primaquine / Q000008:administration & dosage*; D011804:Quinolines / Q000627:therapeutic use; D016037:Single-Blind Method; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011319:Primaquine; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines