Improving the radical cure of vivax malaria (IMPROV): A study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens

Benedikt Ley, Ric Price, Kamala Ley-Thriemer, Tesfay Abreha, B H Alemayehu, Ashenafi Assefa, Ghulam Awab, J Kevin Baird, Beay Bezabih, Phaik Cheah, Nicholas Day, Angela Devine, Mehul Dorda, Arjen Dondorp, Samuel Girma, Tran Tinh Hien, D Jima, Bilcha Kassahun, Amha Kebende, [...and others]

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    Abstract

    Background: Plasmodium vivax malaria is a major cause of morbidity and recognised as an important contributor to mortality in some endemic areas. The current recommended treatment regimen for the radical cure of P. vivax includes a schizontocidal antimalarial, usually chloroquine, combined with a 14 day regimen of primaquine. The long treatment course frequently results in poor adherence and effectiveness. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising safety. The proposed multicentre randomised clinical trial aims to provide evidence across a variety of endemic settings on the safety and efficacy of high dose short course primaquine in glucose-6-phosphate-dehydrogenase (G6PD) normal patients.

    Design: This study is designed as a placebo controlled, double blinded, randomized trial in four countries: Indonesia, Vietnam, Afghanistan and Ethiopia. G6PD normal patients diagnosed with vivax malaria are randomized to receive either 7 or 14 days high dose primaquine or placebo. G6PD deficient (G6PDd) patients are allocated to weekly primaquine doses for 8 weeks. All treatment is directly observed and recurrent episodes are treated with the same treatment than allocated at the enrolment episode. Patients are followed daily until completion of treatment, weekly until 8 weeks and then monthly until 1 year after initiation of the treatment. The primary endpoint is the incidence rate (per person year) of symptomatic recurrent P. vivax parasitaemia over 12 months of follow-up, for all individuals, controlling for site, comparing the 7 versus 14-day primaquine treatment arms. Secondary endpoints are other efficacy measures such as incidence risk at different time points. Further endpoints are risks of haemolysis and severe adverse events.

    Discussion:
    This study has been approved by relevant institutional ethics committees in the UK and Australia, and all participating countries. Results will be disseminated to inform P. vivax malaria treatment policy through peer-reviewed publications and academic presentations. Findings will contribute to a better understanding of the risks and benefits of primaquine which is crucial in persuading policy makers as well as clinicians of the importance of radical cure of vivax malaria, contributing to decreased transmission and a reduce parasite reservoir.
    Original languageEnglish
    Article number558
    Pages (from-to)1-15
    Number of pages15
    JournalBMC Infectious Diseases
    Volume15
    DOIs
    Publication statusPublished - 7 Dec 2015

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    Ley, B., Price, R., Ley-Thriemer, K., Abreha, T., Alemayehu, B. H., Assefa, A., Awab, G., Baird, J. K., Bezabih, B., Cheah, P., Day, N., Devine, A., Dorda, M., Dondorp, A., Girma, S., Hien, T. T., Jima, D., Kassahun, B., Kebende, A., & [...and others] (2015). Improving the radical cure of vivax malaria (IMPROV): A study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens. BMC Infectious Diseases, 15, 1-15. [558]. https://doi.org/10.1186/s12879-015-1276-2