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

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. Trial registration ClinicalTrials.gov Identifier: NCT01814683. Registered March 18, 2013 Electronic supplementary material The online version of this article (doi:10.1186/s12879-015-1276-2) contains supplementary material, which is available to authorized users.

Participants with any clinical complaints suggestive of malaria will have their blood films read immediately and those detected to have peripheral parasitaemia will be treated immediately.
Asymptomatic carriage is common (~5-10%) in malaria coendemic settings, particularly in partially immune adults, and normally goes undetected and untreated. To reflect the usual clinical scenario asymptomatic parasitaemia will not be actively detected in the study participants; instead the blood film of these individuals will be stored and read in batches at a later date. The close follow up and prompt provision of healthcare of our study population will ensure that if these patients become symptomatic, they will be detected and treated promptly.
Another important ethical consideration in this trial is the proposed withholding of primaquine therapy in the control group. At some study sites (Pakistan, Ethiopia) this is standard of care governments do not recommend primaquine therapy fearing more harm than benefit in doing so in unscreened patients. However, at all other sites primaquine therapy is recommended with expressed warnings on toxicity in G6PDd patients. G6PD testing is advised prior to commencing primaquine therapy, but in practice it is almost invariably omitted. Each governing IRB must carefully consider the withholding of primaquine and be assured of both the necessity and safety of doing so.
Primaquine has been the only drug available for the radical cure of vivax malaria since 1952 and yet its efficacy has yet to be addressed in a standardized and systematic manner [1].
The reasons for this knowledge gap are related to the technical difficulty of the clinical assessment of anti-relapse efficacy in patients remaining in malaria endemic zones.
Experimental challenge trials in volunteers in non-endemic zones (e.g. North America) can't replace trials in endemic settings and come with their own ethical and other challenges [2,3]. Secondly, there has been an inappropriate perception that vivax malaria is a relatively benign public health problem [3,4]. Lastly the administration of primaquine in G6PD deficient individuals can potentially trigger episodes of haemolysis. Consequently current World Health Organization guidelines continue to recommend the administration of primaquine spread out over 14 days. This is an impractical regimen that neither national malaria control programs prioritize, nor is it adhered to by physicians or the patients. It is becoming increasingly apparent that a safe and effective therapy against relapse is required to eliminate vivax malaria in a large population (between 100-400 million clinical attacks annually) [5,6].There is a broad consensus that the efficacy of primaquine, a 60-year-old drug should be urgently and rigorously assessed in randomized controlled trials (RCTs).
The Problem: A major challenge in estimating the efficacy of primaquine comes from our inability to distinguish relapsing from new P. vivax infections. Secondly the timing and rate of relapse vary across regions [7]. In temperate regions (e.g. Korea) there may be as few as a single relapse in 10% of vivax patients after 8 months or more. In contrast there is a very high risk (>80%) in equatorial regions (e.g. Indonesia) beginning as early as 21 days following the primary infection [8]. Without understanding the timing and risk of local relapse, it is impossible to estimate antirelapse efficacy. An example of this is exemplified by the Indian treatment guidelines for vivax malaria which recommended until recently the administration of a 5 day course of primaquine (15mg per day) [9]. The relapse rate with such a 5 day course was found to be around 10% and was considered acceptable by international standards. It only became obvious through RCTs comparing the 5-day regimen to patients not receiving primaquine that relapse rates between the groups were indistinguishable, and thus the 5 day regimen in effect had zero efficacy [9]. A control group is equally important for the assessment of the tolerability and safety. Primaquine can cause gastrointestinal upset and in some people with G6PD deficiency it can trigger haemolysis [10]. It is not possible to estimate how much of these adverse events is attributable to the administration of primaquine and how much to the malaria itself causing red cell rupture and loss of red cell mass [5].
The Solution: A recent comprehensive review of the use of primaquine has documented all published primaquine clinical trials since 1954 [11]. The review came to the conclusion that a prerequisite for the interpretation of primaquine efficacy trials is a control arm in which patients do not receive primaquine treatment. The natural rate of recurrence and reinfection in the no-primaquine group effectively serves as the only credible denominator from which one can estimate primaquine efficacy. Such studies are referred to as randomized, relapsecontrolled clinical trials (RRCTs).
The Ethical Dilemma: In many vivax endemic countries, national malaria treatment guidelines advocate the use primaquine. Hence patients in the control arm will not receive the potential benefit of primaquine therapy. This situation requires a careful review with special consideration of the following factors: 1) Globally vivax malaria causes a considerable disease burden. Millions of people live in vivax malaria endemic regions and are at risk for malaria [12]. Treatment for recurrent vivax episodes in the form of primaquine is available, but the optimal use of the drug is unknown and treatment is underutilized resulting in the continued transmission of vivax malaria.
2) National and WHO treatment guidelines focus on the need for prompt and effective . There was agreement that the large majority of vivax patients never receive primaquine, that more evidence from clinical trials is needed and that a control group is critical for scientific integrity of such trials. 7) Patient safety cannot be compromised. All patients in the IMPROV studies will be treated immediately with highly effective blood schizontocidal therapy for their primary presentation and each subsequent episode. This therapy assures the cure of the acute disease. Inactive sleeper stages of P. vivax in liver are completely silent and are not associated with any ongoing pathology or symptoms. 8) Subjects in the IMPROV study will be actively and closely monitored for early indications of recurrent of parasitaemia and onset of illness initially at weekly and then at monthly intervals. This will ensure immediate and effective therapy against blood stage infections. Conclusion: Randomized, controlled clinical trials come with a compelling scientific methodological rational, along with clinical and public health implications. Subjects randomized to the control arms (no-primaquine) will have their acute disease promptly and effectively treated, and are therefore at no risk of serious or threatening illness. The use of a control group, whether placebo-controlled or not, should be considered fundamentally ethical provided the trial ensures that participants are fully informed before consenting to participate and the trial provides virtually complete freedom from risk of serious illness or permanent disability resulting from participation.