Improving the radical cure of vivax malaria: A multicentre randomised comparison of short and long course primaquine regimens

Plasmodium vivax malaria is a major cause of morbidity and an important contributor to mortality in poorly resourced endemic areas in Asia, South America and Africa. The greatest burden of vivax malaria is in South and Southeast Asia, where 2.85 billion people are at risk and experience 100 to 300 million cases of vivax malaria each year. Plasmodium vivax causes repetitive febrile illness associated with worsening anaemia particularly in young children and in pregnant women. Severe anaemia and low birth weight resulting in direct and indirect mortality. Despite the very large population affected by vivax malaria and its socioeconomic burden, it has been and continues to be a neglected disease; global malaria R&D spending on combating P. vivax amounted to just 3% of total spending on malaria between 2007-2009. Since the 1950s chloroquine has been the mainstay of treatment for acute vivax malaria. However resistance to chloroquine was first reported in Papua, Indonesia and there is now good evidence that it is prevalent across the Indonesian archipelago and has spread throughout much of the vivax endemic world.
Unlike Plasmodium falciparum, P. vivax has in addition to the blood stage a liver stage of the parasite (known as hypnozoite) capable of reawakening weeks or even months after the primary infection. The complete treatment of vivax malaria requires administration of antimalarials to eradicate both the blood and liver stages of the parasite. Primaquine remains the only drug on the market for its liver stage activity. However the efficacy of primaquine resistance is difficult to determine due to variable relapsing patterns of P. vivax and the need for prolonged follow up to capture the late relapses. The widespread use of primaquine has been severely limited because of concerns regarding both its efficacy and safety. Primaquine causes haemolysis in patients with G6PD deficiency, an inherited disorder occurring in 5-35% of patients in endemic zones. There a few readily available, affordable and reliable diagnostic tools for the rapid testing of GPD deficiency, and thus clinicians often reluctant to prescribe a therapy that is potentially harmful with limited perceived benefit. When it is prescribed adherence to the currently recommended 14 day treatment regimen is poor.
This proposal aims to provide critical evidence on the use of primaquine, a drug which is being increasingly recognised as a crucial tool in the global fight against malaria. We hypothesise that a shorter course high dose primaquine regimens will provide a practical approach to antirelapse therapy that is safe and effective. Our randomized placebo controlled multicentred trial will compare two different regimens of primaquine against schizontocidal treatment alone in 5 Asian countries. Trial centres will be established in South Asia (India, Pakistan and Afghanistan) where 70% of all cases occur and the interval between vivax relapses is relatively long, as well as two sites from South East Asia (Vietnam and Indonesia) where the interval between relapses is shorter and the risk of relapse greater.
The primary objective will be to compare two primaquine regimens giving the same total dose primaquine over either 7 or 14 days. Patients presenting with pure vivax malaria, meeting the inclusion criteria will be randomly assigned to receive one of the following three treatments:
Option 1 - Standard blood schizontocidal therapy + 14 days of supervised primaquine (7mg/kg total dose).
Option 2 - Standard blood schizontocidal therapy + 7 days of supervised primaquine (7mg/kg total dose).
Option 3 - Standard schizontocidal therapy. Treatment with primaquine will be deferred until the end of the follow up period. This is the control regimen.
Following treatment, patients will be followed for 12 months to monitor the number of vivax recurrences and the level of anaemia. Each recurrence of vivax malaria will be treated with the same allocated regimens.

This is a multi-centre, open label, three-arm randomised non-inferiority trial to compare two primaquine anti-relapse regimens. The same total dose 7mg primaquine/kg will be given either over 14 or over 7 days. A control arm which receives only schizontocidal therapy without anti-relapse therapy will provide the comparison for safety, tolerability and relapse data.

Once randomised into one treatment arm the subject will receive the same prescribed regimen for subsequent recurrent vivax episodes throughout the 12 months follow-up period.

All potential study participants will be tested for G6PD deficiency. Patients identified as having G6PD deficiency will receive standard blood schizontocidal therapy plus 8 weeks of weekly primaquine dosing (7mg/kg total dose).

The primary beneficiaries of the proposed trial are the 2.8 billion people at risk of infection by P. vivax and the 100 to 400 million patients who may be prescribed primaquine therapy against relapse. These patients would receive a regimen of therapy supported by clinical evidence of safety and efficacy, including, possibly, G6PDd patients, pregnant women, and small children now typically excluded from therapy for want of evidence of safety. The economic and societal impacts of these benefits will be diminished burdens of morbidity and mortality caused by this infection that would very likely follow with more aggressive advocacy for the application of primaquine therapy with the confidence of doing so without causing serious harm and with the greater certainty of deriving public health benefit that comes with proven efficacy. In many endemic areas, the successful application of primaquine in a single patient may avert secondary attacks, each attack coming with greater probability of severe illness and a potential for transmission. In short, this trial develops the necessary clinical evidence to support broad attack on the most significant reservoir of P. vivax.

The National Malaria Control Programmes (NMCP) of the countries where this study will take place will be major beneficiaries of the study. Our study seeks both to inform and involve policymakers and stakeholders in the early phase of the study so as to ensure local ownership. We will invite policymakers and stakeholders to planning meetings as early as possible and keep them updated about the progress of the study. On completion of the study, the implications and policy relevance of the results will be discussed with project partners, national policy makers, and representatives of local communities at a stakeholders' meeting. The efficacy and safety of high dose primaquine compared with the control arm will inform countries partners, on the risks and benefits of such a policy. Based on emerging consensus, policy-ready documents will be prepared and disseminated by the partners. It is anticipated that policy impact will occur within 6-12 months of study completion and will result in improved treatment guidelines for the delivery of antirelapse treatment regimens.

At a regional level, the importance of safe and effective radical cure of P. vivax has already been recognized by regional experts as a critical step in the control and elimination of malaria in the Asia-Pacific. Policy recommendations coming from the proposed trial will help develop better malaria control strategies for other Asian countries.

WHO reports and opinions influence regional policymakers. Several of the investigators of the proposed project participate in and on occasion chair WHO technical advisory groups on malaria chemotherapy. In their capacity as technical consultants they will feed back the results of this study not only to rationalise the risk benefits of primaquine therapy, as well as the experience gathered on the optimal study design of subsequent antirelapse studies. The data gathered on the safety of primaquine will inform the use of primaquine for both P. vivax radical cure and also P. falciparum transmission blocking regimens. Thus the evidence developed in this trial will improve the capacity of national malaria control programs to achieve elimination goals.

Research capacity in country research partner institutes will be enhanced by providing both short term and long term training and mentorship for research staff and students. The proposed project will build on existing trials capacity. Collaborative staff in the Mahidol Oxford University research Unit will provide support to write new proposals for research funding for studies beyond the end of the trial. Health worker capacity will be strengthened through training on the administration of antirelapse treatment, improving skills in malaria diagnosis and drug administration.