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

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

Abstract

Background: Primaquine 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.

Methods: We 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).

Findings: Between 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).

Interpretation: In 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.

Funding: UK 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).

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile G6PD=glucose-6-phosphate dehydrogenase. ITT=intention-to-treat. PP=per-protocol.
Figure 2
Figure 2
Forest plot of IRRs and HRs IRR=incidence rate ratio. HR=hazard ratio.
Figure 3
Figure 3
Cumulative incidence of the first symptomatic recurrence of Plasmodium vivax parasitaemia

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