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Randomized Controlled Trial
. 2019 Sep 14;394(10202):929-938.
doi: 10.1016/S0140-6736(19)31285-1. Epub 2019 Jul 18.

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

Walter R J Taylor  1 , Kamala Thriemer  2 , Lorenz von Seidlein  3 , Prayoon Yuentrakul  1 , Thanawat Assawariyathipat  1 , Ashenafi Assefa  4 , Sarah Auburn  2 , Krisin Chand  5 , Nguyen Hoang Chau  6 , Phaik Yeong Cheah  1 , Le Thanh Dong  7 , Mehul Dhorda  8 , Tamiru Shibru Degaga  9 , Angela Devine  10 , Lenny L Ekawati  5 , Fahmi Fahmi  11 , Asrat Hailu  12 , Mohammad Anwar Hasanzai  13 , Tran Tinh Hien  14 , Htee Khu  1 , Benedikt Ley  2 , Yoel Lubell  1 , Jutta Marfurt  2 , Hussein Mohammad  4 , Kerryn A Moore  15 , Mohammad Nader Naddim  13 , Ayodhia Pitaloka Pasaribu  11 , Syahril Pasaribu  11 , Cholrawee Promnarate  8 , Awab Ghulam Rahim  16 , Pasathron Sirithiranont  1 , Hiwot Solomon  17 , Herawati Sudoyo  18 , Inge Sutanto  19 , Ngo Viet Thanh  6 , Nguyen Thi Tuyet-Trinh  20 , Naomi Waithira  1 , Adugna Woyessa  4 , Fazal Yamin Yamin  21 , Arjen Dondorp  1 , Julie A Simpson  22 , J Kevin Baird  23 , Nicholas J White  3 , Nicholas P Day  3 , Ric N Price  24
Affiliations
Randomized Controlled Trial

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

Walter R J Taylor et al. Lancet. .

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).

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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
See this image and copyright information in PMC

Comment in

References

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