Short Course Primaquine for the Radical Cure of P. Vivax - Papua New Guinea

Study Overview
=================
Brief Summary
-----------------
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 allows 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 PNG National Department 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 P. vivax malaria. This revised case management is 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 Napapar and Mugil health centres and Baro and Wirui clinics. A staged approach for the implementation of the revised case management strategy will be used, including patient education and counselling, community-based clinical review, with mixed methods evaluation.

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

Conditions
-----------------
Vivax Malaria, G6PD Deficiency

Intervention / Treatment
-----------------
* Combination Product: Revised case management package


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 12 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Revised case management package<br> | Combination Product: Revised case management package<br>* Point-of-care quantitative G6PD testing using G6PD STANDARD (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 G6PD activity is 30-70 percent PQ8w (0.75 mg/kg/week for 8 weeks) if G6DP activity less than 30 percent Participant counselling at the health facility (Day 0): Supervision of first dose of primaquine Education regarding 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients experiencing at least one Serious Adverse Event (SAE) during treatment. | SAEs are collected during clinical review using a study-specific questionnaire | During treatment (up to 8 weeks) | 
| 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 | During treatment (up to 8 weeks) | 
| 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 | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with any AESI during treatment | AESIs are collected during clinical review using a study-specific questionnaire | During treatment (up to 8 weeks) | 
| The proportion of patients with a gastrointestinal (GI) AESI during treatment | AESIs are collected during clinical review using a study-specific questionnaire | During treatment (up to 8 weeks) | 
| The proportion of patients with an AESI related to haemolysis during treatment | AESIs are collected during clinical review using a study-specific questionnaire | During treatment (up to 8 weeks) | 
| The proportion of patients an AESI related to methaemoglobinaemia | AESIs are collected during clinical review using a study-specific questionnaire | During treatment (up to 8 weeks) | 
| Proportion of patients permanently stopping PQ before end of treatment | Discontinuation of PQ will be assessed using a study-specific questionnaire | During treatment (up to 8 weeks) | 
| The proportion of patients receiving correct treatment based on G6PD activity | This will be assessed by linking patients G6PD activity results measured during study enrolment with primaquine dose prescribed on the same day | 1 day | 
| Proportion of patients who were reviewed on Day 3 and Day 7 | This will be assessed by linking patients enrolment data with Day 3 and Day 7 clinical review data | 1 week | 
| Perception of and experience with new radical cure tools among health care providers and community members | This will be assessed using stakeholder interviews | 6 months | 
| Proportion of health care practitioners who comply with the revised radical cure treatment algorithm | The outcome will be assessed from patients' enrolment data | 1 day | 
| Proportion of patients receiving a SD Biosensor G6PD test | The outcome will be assessed from patients' enrolment data | 1 day | 
| Proportion of eligible P. vivax malaria patients receiving the correct dose of primaquine based on the result of the G6PD test | The outcome will be assessed from patients' enrolment data | 1 day | 
| 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) | The outcome will be assessed from patients' enrolment data | 1 day | 
| Proportion of P. vivax malaria patients that are reviewed on Day 3 | This will be assessed by linking patients' enrolment data with clinical review data | 3 days | 
| Proportion of P. vivax malaria patients that adhere to their prescribed primaquine regimen | This will be assessed by linking patients' enrolment data with clinical review data | 3 days | 
| Factors influencing acceptability and feasibility of the new radical cure tools among health care providers are identified | This will be assessed using stakeholder interviews, observations and focus groups | 3 days | 
| Barriers and enablers of uptake and implementation at the sub-national levels are identified | This will be assessed using stakeholder interviews and focus groups | 18 months | 
| Factors influencing compliance with G6PD testing and perceptions of new drug regimens and serious adverse events among health care providers are identified | This will be assessed using stakeholder interviews and focus groups | 18 months | 
| Required knowledge, skills, and training to administer the revised case management and patient-counselling identified | This will be assessed using stakeholder interviews and focus groups | 18 months | 
| Factors influencing the barriers and facilitators to patient adherence to primaquine after the rollout of the revised case management identified | This will be assessed using stakeholder interviews and focus groups | 18 months | 
| Factors influencing the acceptability and feasibility of community-based clinical review at Day 3 of primaquine treatment identified. | This will be assessed using stakeholder interviews and focus groups | 18 months | 
| Perceptions of the new radical cure tools and serious adverse events at the community level identified | This will be assessed using stakeholder interviews and focus groups | 18 months | 
| Local acceptability of the revised case management algorithms among patients, their families, and healthcare workers established | This will be assessed using stakeholder interviews and focus groups | 18 months | 
| 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 | 18 months | 
| 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=200 patients (per facility) after implementation | 18 months | 
| Cumulative risk of representation to the same clinic with symptomatic P. vivax malaria within 6 months | This will be assessed by linking patients' enrolment data | 18 months | 
| Costs of implementing policy from a healthcare provider perspective, including health systems strengthening processes | This will be assessed from health system data collected throughout the study | 18 months | 
| Household costs per P. vivax episode | This will be assessed from a household cost survey on a subset of patients | 3 days | 
| Overall cost-effectiveness of changing policy if revised case management is effective | This will be assessed from health system data collected throughout the study | 18 months | 
| Cost per episode of P. vivax malaria from the healthcare provider and societal perspectives | This will be assessed from health system data collected throughout the study | 18 months | 
| Cost per component of the revised case management package | This will be assessed from health system data collected throughout the study | 18 months | 
| 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 | This will be assessed from health system data collected throughout the study | 18 months | 
| 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) | This will be assessed from clinical review data and study-specific questionnaire | 3 days | 
| 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 clinical review data, study specific questionnaire and SAE form | During treatment (up to 8 weeks) | 
| The proportion of patients eligible to receive PQ who had a SAE during treatment | This will be assessed by linking enrolment data, clinical review, study specific questionnaire and SAE form | During treatment (up to 8 weeks) | 
| Prevalence of severe anaemia in patients presenting with fever before and after implementation | This will be assessed by comparing the facility surveillance data before implementation with facility surveillance data after implementation | 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
primaquine