Abstract
BackgroundThere are very few drugs that prevent the relapse of Plasmodium vivax malaria in man. Tinidazole is a 5-nitroimidazole approved in the USA for the treatment of indications including amoebiasis and giardiasis. In the non-human primate relapsing Plasmodium cynomolgi/macaque malaria model, tinidazole cured one of six macaques studied with an apparent mild delay to relapse in the other five of 14–28 days compared to 11–12 days in controls. One study has demonstrated activity against P. vivax in man. Presented here are the results of a pilot phase II, randomized, open-label study conducted along the Thai-Myanmar border designed to evaluate the efficacy of tinidazole to prevent relapse of P. vivax when administered with chloroquine.MethodsThis study utilized a modified triangular test sequential analysis which allows repeated statistical evaluation during the course of enrolment while maintaining a specified power and type 1 error and minimizing recruitment of subjects. Enrolment was to be halted when a pre-specified success/failure ratio was surpassed. The study was designed to have a 5% type 1 error and 90% power to show whether tinidazole would produce a relapse rate of less than 20% or greater than 45% through Day 63 of weekly follow-up after initiation of treatment and initial parasite clearance with 3 days of an oral weight based dosing of chloroquine and five days of 2 grams/day of tinidazole.ResultsAll subjects cleared their parasitaemia by Day 3. Six of the first seven subjects treated with tinidazole relapsed prior to Day 63 (average Day 48.3 (range 42–56)). This exceeded the upper boundary of the triangular test and enrolment to receive tinidazole was halted. A concurrent cohort of five subjects definitively treated with standard doses of primaquine and chloroquine (historically 100% effective) showed no episodes of recurrent P. vivax parasitaemia during the 63-day protocol specified follow-up period.ConclusionsTinidazole is ineffective in preventing relapse of P. vivax at the dose used. The macaque relapsing model appeared to correctly predict outcome in humans. Use of the modified triangular test allowed minimal enrolment and limited unnecessary exposure to the study drug and reduced costs. This adds weight to the ethical and economic advantages of this study design to evaluate similarly situated drugs.Trial registrationClinicalTrials.gov NCT00811096
Highlights
There are very few drugs that prevent the relapse of Plasmodium vivax malaria in man
Plasmodium vivax accounts for 40% of malaria and is one of the forms of relapsing malaria due to a persistent liver stage of the disease in the form of hypnozoites
Primaquine and other members of its 8-aminoquinoline class cause dose-dependent oxidative haemolysis, in G6PD deficient individuals and requires 14 day dosing leading to problems with compliance [1,2,3,4]
Summary
There are very few drugs that prevent the relapse of Plasmodium vivax malaria in man. There is presently only one approved treatment (primaquine 15-30 mg base/d for 14 days) that adequately eliminates the persistent liver stage of P. vivax, achieving what is referred to as “radical cure” when used in combination with a blood-stage anti-malarial agent. It is important to discover new drugs with an acceptable safety and tolerability profile, with a shorter course of treatment that can eliminate the persistent liver stage of P. vivax, improving compliance, and which can be given without medical supervision, and do not require any pre-treatment screening test. While it is possible to study drug efficacy against primate relapsing forms of malaria, there is no equivalent animal model available for P. vivax. While the P. cynomolgi primate model has a well demonstrated predictive value against P. vivax in humans [5], results from any P. cynomolgi trial and its applicability to human P. vivax infection can only be definitively assessed with a human trial
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