Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial

Walter R J Taylor ,Adugna Woyessa,Mohammad Anwar Hasanzai,Lorenz Von Seidlein,Ashenafi Assefa,Phaik Yeong Cheah,Mehul Dhorda,Krisin Chand,Awab Ghulam Rahim,Sarah Auburn,Hiwot Solomon,Jutta Marfurt,Pasathron Sirithiranont,Syahril Pasaribu,Thanawat Assawariyathipat,Prayoon Yuentrakul,Fahmi Fahmi,Ayodhia Pitaloka Pasaribu,Htee Khu,Benedikt Ley,Yoel Lubell,Angela Devine,Kamala Thriemer,Tran Tinh Hien,Mohammad Nader Naddim,Ngo Viet Thanh,Herawati Sudoyo,Inge Sutanto,Tamiru Shibru Degaga,Nguyen Hoang Chau,Asrat Hailu,Naomi Waithira,Cholrawee Promnarate,Nguyen Thi Tuyet-Trinh,Hussein Mohammad,Le Thanh Dong,Fazal Yamin ,Nicholas J White ,Kerryn A Moore ,Lenny L Ekawati ,Arjen M Dondorp ,Nicholas P J Day ,J Kevin Baird ,Julie A Simpson ,Ric N Price

doi:10.1016/s0140-6736(19)31285-1

Abstract

SummaryBackgroundPrimaquine is the only widely used drug that prevents Plasmodium vivax malaria relapses, but adherence to the standard 14-day regimen is poor. We aimed to assess the efficacy of a shorter course (7 days) of primaquine for radical cure of vivax malaria.MethodsWe did a randomised, double-blind, placebo-controlled, non-inferiority trial in eight health-care clinics (two each in Afghanistan, Ethiopia, Indonesia, and Vietnam). Patients (aged ≥6 months) with normal glucose-6-phosphate dehydrogenase (G6PD) and presenting with uncomplicated vivax malaria were enrolled. Patients were given standard blood schizontocidal treatment and randomly assigned (2:2:1) to receive 7 days of supervised primaquine (1·0 mg/kg per day), 14 days of supervised primaquine (0·5 mg/kg per day), or placebo. The primary endpoint was the incidence rate of symptomatic P vivax parasitaemia during the 12-month follow-up period, assessed in the intention-to-treat population. A margin of 0·07 recurrences per person-year was used to establish non-inferiority of the 7-day regimen compared with the 14-day regimen. This trial is registered at ClinicalTrials.gov (NCT01814683).FindingsBetween July 20, 2014, and Nov 25, 2017, 2336 patients were enrolled. The incidence rate of symptomatic recurrent P vivax malaria was 0·18 (95% CI 0·15 to 0·21) recurrences per person-year for 935 patients in the 7-day primaquine group and 0·16 (0·13 to 0·18) for 937 patients in the 14-day primaquine group, a difference of 0·02 (−0·02 to 0·05, p=0·3405). The incidence rate for 464 patients in the placebo group was 0·96 (95% CI 0·83 to 1·08) recurrences per person-year. Potentially drug-related serious adverse events within 42 days of starting treatment were reported in nine (1·0%) of 935 patients in the 7-day group, one (0·1%) of 937 in the 14-day group and none of 464 in the control arm. Four of the serious adverse events were significant haemolysis (three in the 7-day group and one in the 14-day group).InterpretationIn patients with normal G6PD, 7-day primaquine was well tolerated and non-inferior to 14-day primaquine. The short-course regimen might improve adherence and therefore the effectiveness of primaquine for radical cure of P vivax malaria.FundingUK Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (MR/K007424/1) and the Bill & Melinda Gates Foundation (OPP1054404).

Highlights

Plasmodium vivax malaria is a major cause of morbidity and a contributor to mortality in Asia, Oceania, the Horn of Africa, and the Americas.[1,2] The infection is characterised by an acute febrile illness followed by recurrent febrile illnesses in the weeks to months after the initial infection.[3]
Primaquine, an 8-aminoquinoline, is the only widely available drug that kills hypnozoites and prevents relapses,[8] but its use is limited by the risk of acute haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency
Added value of this study Our large multicentre clinical trial in patients with P vivax was done at eight sites in four countries with differing P vivax endemicity, to assess the safety and radical curative efficacy of a 7-day high-dose (1 mg/kg per day) primaquine regimen compared with a 14-day regimen (0·5 mg/kg per day)

Summary

Introduction

Plasmodium vivax malaria is a major cause of morbidity and a contributor to mortality in Asia, Oceania, the Horn of Africa, and the Americas.[1,2] The infection is characterised by an acute febrile illness followed by recurrent febrile illnesses in the weeks to months after the initial infection.[3]. A 14-day regimen of primaquine effect ively prevents P vivax relapses.[9,10,11] in most malaria-endemic settings, daily supervision of a prolonged treatment regimen is not practical; an unsupervised

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