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 & 25 others 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

    Research output: Contribution to journalArticleResearchpeer-review

    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).

    Original languageEnglish
    Pages (from-to)929-938
    Number of pages10
    JournalThe Lancet
    Volume394
    Issue number10202
    DOIs
    Publication statusPublished - 14 Sep 2019

    Fingerprint

    Primaquine
    Vivax Malaria
    Placebos
    Recurrence
    Glucosephosphate Dehydrogenase
    Incidence
    Afghanistan
    Ethiopia
    Indonesia
    Parasitemia
    Vietnam
    National Institutes of Health (U.S.)
    Hemolysis
    Pharmaceutical Preparations
    Biomedical Research
    Delivery of Health Care

    Cite this

    Taylor, Walter R.J. ; Thriemer, Kamala ; von Seidlein, Lorenz ; Yuentrakul, Prayoon ; Assawariyathipat, Thanawat ; Assefa, Ashenafi ; Auburn, Sarah ; Chand, Krisin ; Chau, Nguyen Hoang ; Cheah, Phaik Yeong ; Dong, Le Thanh ; Dhorda, Mehul ; Degaga, Tamiru Shibru ; Devine, Angela ; Ekawati, Lenny L. ; Fahmi, Fahmi ; Hailu, Asrat ; Hasanzai, Mohammad Anwar ; Hien, Tran Tinh ; Khu, Htee ; Ley, Benedikt ; Lubell, Yoel ; Marfurt, Jutta ; Mohammad, Hussein ; Moore, Kerryn A. ; Naddim, Mohammad Nader ; Pasaribu, Ayodhia Pitaloka ; Pasaribu, Syahril ; Promnarate, Cholrawee ; Rahim, Awab Ghulam ; Sirithiranont, Pasathron ; Solomon, Hiwot ; Sudoyo, Herawati ; Sutanto, Inge ; Thanh, Ngo Viet ; Tuyet-Trinh, Nguyen Thi ; Waithira, Naomi ; Woyessa, Adugna ; Yamin, Fazal Yamin ; Dondorp, Arjen ; Simpson, Julie A. ; Baird, J. Kevin ; White, Nicholas J. ; Day, Nicholas P. ; Price, Ric N. / Short-course primaquine for the radical cure of Plasmodium vivax malaria : a multicentre, randomised, placebo-controlled non-inferiority trial. In: The Lancet. 2019 ; Vol. 394, No. 10202. pp. 929-938.
    @article{f9c7735ce1e74ea793c726e63c3394b5,
    title = "Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial",
    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).",
    author = "Taylor, {Walter R.J.} and Kamala Thriemer and {von Seidlein}, Lorenz and Prayoon Yuentrakul and Thanawat Assawariyathipat and Ashenafi Assefa and Sarah Auburn and Krisin Chand and Chau, {Nguyen Hoang} and Cheah, {Phaik Yeong} and Dong, {Le Thanh} and Mehul Dhorda and Degaga, {Tamiru Shibru} and Angela Devine and Ekawati, {Lenny L.} and Fahmi Fahmi and Asrat Hailu and Hasanzai, {Mohammad Anwar} and Hien, {Tran Tinh} and Htee Khu and Benedikt Ley and Yoel Lubell and Jutta Marfurt and Hussein Mohammad and Moore, {Kerryn A.} and Naddim, {Mohammad Nader} and Pasaribu, {Ayodhia Pitaloka} and Syahril Pasaribu and Cholrawee Promnarate and Rahim, {Awab Ghulam} and Pasathron Sirithiranont and Hiwot Solomon and Herawati Sudoyo and Inge Sutanto and Thanh, {Ngo Viet} and Tuyet-Trinh, {Nguyen Thi} and Naomi Waithira and Adugna Woyessa and Yamin, {Fazal Yamin} and Arjen Dondorp and Simpson, {Julie A.} and Baird, {J. Kevin} and White, {Nicholas J.} and Day, {Nicholas P.} and Price, {Ric N.}",
    year = "2019",
    month = "9",
    day = "14",
    doi = "10.1016/S0140-6736(19)31285-1",
    language = "English",
    volume = "394",
    pages = "929--938",
    journal = "Lancet",
    issn = "0140-6736",
    publisher = "The Lancet Publishing Group",
    number = "10202",

    }

    Taylor, WRJ, Thriemer, K, von Seidlein, L, Yuentrakul, P, Assawariyathipat, T, Assefa, A, Auburn, S, Chand, K, Chau, NH, Cheah, PY, Dong, LT, Dhorda, M, Degaga, TS, Devine, A, Ekawati, LL, Fahmi, F, Hailu, A, Hasanzai, MA, Hien, TT, Khu, H, Ley, B, Lubell, Y, Marfurt, J, Mohammad, H, Moore, KA, Naddim, MN, Pasaribu, AP, Pasaribu, S, Promnarate, C, Rahim, AG, Sirithiranont, P, Solomon, H, Sudoyo, H, Sutanto, I, Thanh, NV, Tuyet-Trinh, NT, Waithira, N, Woyessa, A, Yamin, FY, Dondorp, A, Simpson, JA, Baird, JK, White, NJ, Day, NP & Price, RN 2019, 'Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial', The Lancet, vol. 394, no. 10202, pp. 929-938. https://doi.org/10.1016/S0140-6736(19)31285-1

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

    In: The Lancet, Vol. 394, No. 10202, 14.09.2019, p. 929-938.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Short-course primaquine for the radical cure of Plasmodium vivax malaria

    T2 - a multicentre, randomised, placebo-controlled non-inferiority trial

    AU - Taylor, Walter R.J.

    AU - Thriemer, Kamala

    AU - von Seidlein, Lorenz

    AU - Yuentrakul, Prayoon

    AU - Assawariyathipat, Thanawat

    AU - Assefa, Ashenafi

    AU - Auburn, Sarah

    AU - Chand, Krisin

    AU - Chau, Nguyen Hoang

    AU - Cheah, Phaik Yeong

    AU - Dong, Le Thanh

    AU - Dhorda, Mehul

    AU - Degaga, Tamiru Shibru

    AU - Devine, Angela

    AU - Ekawati, Lenny L.

    AU - Fahmi, Fahmi

    AU - Hailu, Asrat

    AU - Hasanzai, Mohammad Anwar

    AU - Hien, Tran Tinh

    AU - Khu, Htee

    AU - Ley, Benedikt

    AU - Lubell, Yoel

    AU - Marfurt, Jutta

    AU - Mohammad, Hussein

    AU - Moore, Kerryn A.

    AU - Naddim, Mohammad Nader

    AU - Pasaribu, Ayodhia Pitaloka

    AU - Pasaribu, Syahril

    AU - Promnarate, Cholrawee

    AU - Rahim, Awab Ghulam

    AU - Sirithiranont, Pasathron

    AU - Solomon, Hiwot

    AU - Sudoyo, Herawati

    AU - Sutanto, Inge

    AU - Thanh, Ngo Viet

    AU - Tuyet-Trinh, Nguyen Thi

    AU - Waithira, Naomi

    AU - Woyessa, Adugna

    AU - Yamin, Fazal Yamin

    AU - Dondorp, Arjen

    AU - Simpson, Julie A.

    AU - Baird, J. Kevin

    AU - White, Nicholas J.

    AU - Day, Nicholas P.

    AU - Price, Ric N.

    PY - 2019/9/14

    Y1 - 2019/9/14

    N2 - 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).

    AB - 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).

    UR - http://www.scopus.com/inward/record.url?scp=85071980923&partnerID=8YFLogxK

    U2 - 10.1016/S0140-6736(19)31285-1

    DO - 10.1016/S0140-6736(19)31285-1

    M3 - Article

    VL - 394

    SP - 929

    EP - 938

    JO - Lancet

    JF - Lancet

    SN - 0140-6736

    IS - 10202

    ER -