High daily dose Short COurse PrimaquinE after G6PD testing for the radical cure of Plasmodium vivax malaria in Indonesia and Papua New Guinea: The SCOPE implementation study protocol

IntroductionPlasmodium vivax malaria remains an important threat to the public in the Asia Pacific region. Preventing P. vivax relapses is crucial for reducing morbidity from malaria and ultimately controlling and eliminating this species. Primaquine is the only widely available drug with antirelapse activity against dormant stages of P. vivax. Its widespread use in clinical practice is limited by its potential to cause severe haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methods and analysisThe primary aims of this staged, binational, multicentre, before-and-after implementation study are to determine the safety, feasibility, and cost-effectiveness of a revised package of case management interventions for improved P. vivax radical cure. The interventions include: i) pre-treatment testing of patients for G6PD deficiency using a semi-quantitative point-of-care device from SDBiosensor (ROK); ii) prescription of high dose primaquine (7mg/kg total dose) either over 7 days for G6PD normal patients ([&ge;]70% activity) or 14 days for intermediate patients (30-<70% activity), or lower dose weekly primaquine over 8 weeks for deficient patients (<30% activity); iii) improved patient education processes; iv) routine community-based review on day 3 (and day 7 for Stage 1) and v) enhanced malariometric surveillance and community pharmacovigilance. Stage 1 of the study (800 patients) will be implemented at 4 community clinics across Indonesia and Papua New Guinea (PNG) and will focus on analysis of treatment safety. If safety of the intervention is confirmed during Stage 1, the study will proceed to Stage 2, in which patient recruitment will be expanded to 10 clinics across Indonesia and PNG, and the feasibility of the similar intervention package will be assessed, but with a single community-based review on day 3. Stage 2 will run for 12 months and recruit approximately 11,410 patients. Mixed methods analyses of Stage 2 data will focus on the operational feasibility and cost-effectiveness of the revised case management package, with effectiveness determined through analysis of individual-level risk of P. vivax recurrence and population-level changes in incidence (with comparison to the pre-implementation period). Feasibility will be assessed via qualitative observations, in-depth interviews and focus groups of health care workers and participants. DiscussionThe intervention package will provide critical information on the safety, feasibility and cost-effectiveness of achieving radical cure with G6PD testing prior to high dose primaquine treatment and community-based follow-up. The study results will inform national malaria programs aiming to eliminate P. vivax in Indonesia and PNG by 2030. Ethics and disseminationThis study has been approved by the World Health Organization Ethics Committee (Indonesia: ERC 0003810, PNG: ERC 0003892); Menzies School of Health Research (HREC: 2023-4524), Alfred Health (Burnet Institute) (Project No: 18/23), University of Gadjah Mada (KE/FK/0079/EC/2023), University of Indonesia (KET-347/UN2.F1/ETIK/PPM.00.02/2023), University of Sumatra Utara (80/KEPK/USU/2023), Institute of Tropical Medicine (1655/23), PNG Institute of Medical Research (PNGIMR) (IRB: 22.02), and the PNG National Department of Health Medical Research Advisory Committee (MRAC: 22.66). The study was registered on clinicaltrials.gov for Indonesia: NCT05879224 and PNG: NCT05874271. All participants will provide written, informed consent to join the study. For qualitative observations of health workers, a waiver of consent was granted by all ethics committees, and health centres will be made aware that observations on staff will be carried out. Dissemination plans include presentations at scientific conferences, peer-reviewed publications, and reporting at the national and community level. Strengths and limitations of this StudyO_LIThe staged design of this study will enable confirmation of the safety of high daily dose primaquine and provide operational insights on G6PD testing and community-based reviews, thereby facilitating the adoption of optimal practices in preparation for wide scale roll-out. C_LIO_LIStage 2 will follow real-world conditions with treatment and follow-up embedded within local clinic procedures and implemented by clinic healthcare staff and community-based health workers. These efforts will enable a realistic assessment of the interventions feasibility, cost-effectiveness, and scalability. C_LIO_LIStudy sites in Indonesia and PNG are publicly funded facilities servicing populations from areas with markedly different malaria endemicity and workloads, supporting the generalisability of our results to regions across both countries with varying malaria epidemiology. C_LIO_LIImplementation of the intervention may be limited by the informed consent process, potentially restricting enrolment and coverage of the intervention across the study clinics. C_LIO_LIMultiple time-varying confounders, such as government-initiated malaria control activities, may influence malaria incidence and, therefore, impair the ability to determine the true population-level impact of the study interventions. C_LI