Short Course Primaquine for the Radical Cure of P. Vivax Malaria - Indonesia (SCOPE)

Feasibility of High Daily Dose Short Course Primaquine After G6PD Testing for the Radical Cure of Plasmodium Vivax Malaria

Gadjah Mada University, Universitas Sumatera Utara, Indonesia University, Yayasan Pengembangan Kesehatan dan Masyarakat, Indonesian National Malaria Control Program, Ministry of Health, National Research and Innovation Agency of Indonesia, Burnet Institute, University of Melbourne, Medicines for Malaria Venture, PATH, UNITAID, Institute of Tropical Medicine, Belgium

The proportion of malaria that is the Plasmodium vivax species is increasing in Indonesia. Reducing vivax malaria will require innovative solutions to cure both the blood and liver stages of the disease. This study will evaluate of the feasibility of implementing point-of-care glucose-6-phosphate dehydrogenase deficiency (G6PD) testing. This will be followed by high dose, short course primaquine treatment regimens for patients with vivax malaria, and combined with patient education, surveillance, and pharmacovigilance. We plan to implement the study at 6 health facilities across Indonesia using a staged before-and-after study, with a mixed method evaluation.

Significant gains have been made in reducing the overall burden of malaria worldwide, however these have been far greater for Plasmodium falciparum than P. vivax. P. vivax remains a major obstacle to malaria control and elimination efforts, largely due to its ability to form dormant liver stages (hypnozoites) that allow it to escape detection and treatment. Importantly, they are susceptible only to 8 aminoquinolines such as primaquine however, primaquine is associated with risk of haemolysis in individuals with a genetic condition, called glucose-6-phosphate dehydrogenase (G6PD) deficiency. Additionally, the recommended 14-day prolonged treatment regimen is associated with poor treatment adherence hence ineffective primaquine treatment. Innovative solutions to the radical cure of both the blood and liver stages of P. vivax are urgently required. The Indonesian Ministry of Health has requested a pragmatic study of the feasibility and cost-effectiveness of implementing point-of-care G6PD testing followed by high-dose, short-course primaquine treatment regimens for patients with vivax malaria. These interventions are to be combined with practicable enhancements to patient education, supervision, malariometric surveillance and pharmacovigilance. This will be a before-after longitudinal health facility-based study implemented at six sites in Indonesia; four in Papua, one in North Sumatra and one in Lampung. We will use a staged approach for the implementation of the revised case management strategy, including patient education and counselling,community-based clinical review, with mixed methods evaluation.

Point-of-care quantitative G6PD testing using G6PDSTANDARD (SD Biosensor) prior to use of primaquine (Day 0) Prescription of short course primaquine (7 mg/kg total)(Day 0): PQ7 (1 mg/kg/day for 7 days) if G6PD activity greater than 70 percent PQ14 (0.5 mg/kg/day for 14 days) if G6PDactivity is 30-70 percent PQ8w (0.75 mg/kg/week for 8 weeks) if G6DPactivity less than 30 percent Participant counselling at the health facility (Day 0): Supervision of first dose of primaquine Education regarding the importance and risks of primaquine therapy and necessity to take primaquine with food Community based clinical review on Day 3 (and Day 7 for the first 300 participants) to detect and manage gastrointestinal or haemolytic adverse effects of treatment and encourage adherence to full treatment regime Improved malariometric surveillance and pharmacovigilance to support wider scale use of the revised case management

Proportion of patients experiencing at least one Adverse Event of Special Interest(AESI) during treatment

AESIs (haemolysis, methaemoglobinaemia and gastrointestinal discomfort) are collected during clinical review using a study-specific questionnaire

Proportion of patients with P. vivax malaria who correctly receive all components of the revised case management package

Measured by completion of G6PD testing and the correct prescription of primaquine based on G6PD activity, completion of patients counselling and community based follow up on Day 3

This will be assessed by linking patients G6PD activity results measured during study enrolment with primaquine dose prescribed on the same day

Perception of and experience with new radical cure tools among health care providers and community members

Proportion of eligible P. vivax malaria patients receiving the correct dose of primaquine based on the result of the G6PD test

Proportion of P. vivax malaria patients who are ineligible for daily primaquine and are incorrectly given primaquine (including infants, pregnant females and G6PD deficient patients

Factors influencing acceptability and feasibility of the new radical cure tools among health care providers are identified

Factors influencing compliance with G6PD testing and perceptions of new drug regimens and serious adverse events among health care providers are identified

Required knowledge, skills, and training to administer the revised case management and patient-counselling identified

Factors influencing the barriers and facilitators to patient adherence to primaquine after the rollout of the revised case management identified

Factors influencing the acceptability and feasibility of community-based clinical review at Day 3 of primaquine treatment identified

Perceptions of the new radical cure tools and serious adverse events at the community level identified

Local acceptability of the revised case management algorithms among patients, their families, and healthcare workers established

The monthly incidence of confirmed symptomatic P. vivax malaria episodes (mono-infection or mixed) before implementation versus after implementation

This will be assessed by comparing facility surveillance data before implementation with facility surveillance data after implementation

The prevalence of P. vivax parasitaemia in patients presenting with fever before implementation versus after implementation

This will be assessed by comparing cross-sectional data on n=200 patients (per facility) collected before implementation to the prevalence collected in n=200patients (per facility) after implementation

Cumulative risk of representation to the same clinic with symptomatic P. vivax malaria within 6 months

Costs of implementing policy from a healthcare provider perspective, including health systems strengthening processes

If revised case management package is effective (significantly reduces the incidence of malaria), then the cost-effectiveness of implementing the revised case management as compared with usual care

Proportion of CHWs who correctly act on early signs of haemolytic anaemia and GI events (i.e. refer patients for further medical review, instruct patient to discontinue treatment)

Number of patients with an SAE who are identified by community or clinic staff follow-up and referred to hospital for further management

This will be assessed by linking enrolment data, clinical review, study specific questionnaire and SAE form

This will be assessed by comparing the facility surveillance data before implementation with facility surveillance data after implementation

Inclusion Criteria: Patients with vivax malaria Exclusion Criteria: Patients who are pregnant Patients who are breastfeeding Patients with a Hb <8g/dL Patients with a previous adverse reaction to primaquine Patient with severe malaria

Study Protocol and Statistical Analysis Plan will be made available to others. The results will be published in peer-reviewed open access journals and disseminated to stakeholders. De-identified quantitative data for the purposes of confirming risk of adverse events will be available to researchers who provide a methodological sound proposal that is in line with the aims of the approved protocol.

Access is subject to approval by the SCOPE Data Access Committee to ensure that the use of data protects the interests of the participants and researchers according to the terms of ethics approval and principles of equitable data sharing. Requests can be submitted to the Requests can be submitted to Professor Ric Price, Menzies School of Health Research, Email:ric.price@menzies.edu.au and Dr Jeanne Rini Poespoprodjo, Universitas Gadjah Mada, Email:didot2266@yahoo.com