IMPROV (Improving the Radical Cure of Vivax Malaria)

Summary

The main determinant of primaquine efficacy is the total dose of primaquine administered, rather than the dosing schedule. Previous trials have demonstrated that the standard low dose regimen of primaquine (3.5 mg/kg total) fails to prevent relapses in many different endemic locations. For this reason the 2010 WHO antimalarial guidelines now recommend a high dose regimen of 7 mg/kg (equivalent to an adult dose of 30mg per day), although many countries still recommend lower doses for fear of causing more serious harm to unscreened G6PDd patients. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising efficacy. Primaquine also has relatively weak but clinically relevant asexual stage activity against P. vivax so larger daily doses may substantially augment chloroquine's blood stage activity at low levels of resistance. In Thailand directly observed primaquine (1mg/kg/day) administered over 7 days was well tolerated and reduced relapses by day 28 to 4%. This is encouraging but not definitive since many relapses present after one month. Longer follow-up is needed to distinguish whether relapse was prevented or deferred. If the efficacy, tolerability and safety of short-course, high-dose primaquine regimens can be assured across the range of endemic settings, along with reliable point-of-care G6PDd diagnostics, then this new primaquine regimen would be a major advance in malaria treatment improving adherence to and thus the effectiveness of anti-relapse therapy. Due to the long duration of standard primaquine treatment regimens, courses are difficult to supervise, are poorly adhered to and lack effectiveness. This proposed multicentre randomised clinical trial will provide evidence across a variety of endemic settings on the safety and efficacy of high dose-short course primaquine in G6PD normal patients. In a parallel single arm study the investigators will also gather safety data on the use of weekly primaquine in patients with G6PDd. This study aims to generate evidence that will directly inform global public health policy for the radical cure of P. vivax. A better understanding of the risks and benefits of primaquine is crucial in persuading policy makers and clinicians of the importance of the radical cure of vivax malaria that will reduce the parasite reservoir and decrease transmission. The funder is Medical Research Council, UK. Grant number: MRC Reference: MR/K007424/1

Timeline

Start

2014-07

Primary completion

2018-02-28

Completion

2018-02-28

Publications

• Background 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. Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial. Lancet. 2019 Sep 14;394(10202):929-938. doi: 10.1016/S0140-6736(19)31285-1. Epub 2019 Jul 18.
• Taylor WRJ, Meagher N, Ley B, Thriemer K, Bancone G, Satyagraha A, Assefa A, Chand K, Chau NH, Dhorda M, Degaga TS, Ekawati LL, Hailu A, Hasanzai MA, Naddim MN, Pasaribu AP, Rahim AG, Sutanto I, Thanh NV, Tuyet-Trinh NT, Waithira N, Woyessa A, Dondorp A, von Seidlein L, Simpson JA, White NJ, Baird JK, Day NP, Price RN. Weekly primaquine for radical cure of patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase deficiency. PLoS Negl Trop Dis. 2023 Sep 6;17(9):e0011522. doi: 10.1371/journal.pntd.0011522. eCollection 2023 Sep.
• Thriemer K, Commons RJ, Rajasekhar M, Degaga TS, Chand K, Chau NH, Assefa A, Naddim MN, Pasaribu AP, Rahim AG, Sutanto I, Hien TT, Hailu A, Hasanzai MA, Ekawati LL, Woyessa A, Teferi T, Waithira N, Taylor WRJ, Ley B, Dondorp A, Baird JK, White NJ, Day NP, Price RN, Simpson JA, von Seidlein L. The heterogeneity of symptom reporting across study sites: a secondary analysis of a randomised placebo-controlled multicentre antimalarial trial. BMC Med Res Methodol. 2023 Sep 4;23(1):198. doi: 10.1186/s12874-023-02022-3.
• IMPROV Study Group. 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 Infect Dis. 2015 Dec 7;15:558. doi: 10.1186/s12879-015-1276-2.

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