Reducing the Risk of P. Vivax After Falciparum Infections in Co-endemic Areas

Study Overview
=================
Brief Summary
-----------------
This study is designed as a multi-centre randomized, open label trial to compare the safety and efficacy of a high dose primaquine (PQ) treatment in G6PD normal patients with P. falciparum to reduce the risk of subsequent P. vivax episodes to current standard practice of providing only schizontocidal treatment.

Detailed Description
-----------------
Plasmodium vivax forms dormant liver stages that reactivate weeks or months following an acute infection. Recurrent infections can be associated with a febrile illness, a cumulative risk of severe anaemia, direct and indirect mortality, and are the most important source of onward transmission of the parasite. In co-endemic areas, there is a very high risk (up to 50%) of patients representing with P. vivax malaria following treatment of P. falciparum. Hence, in co-endemic regions there is a strong rationale for eradicating P. vivax hypnozoites from the liver in patients presenting with uncomplicated P. falciparum infections. The recently completed multicentre IMPROV study compared the efficacy of a 7 day primaquine regimen (1.0 mg/kg/day for 7 days) with a 14 day regimen (0.5 mg/kg/day for 14 days). The 7 day PQ regimen was non-inferior to the 14 day regimen and 5-fold more efficacious at reducing P. vivax recurrence than the control. This study is designed as a multicentre randomized, open label trial to compare the safety and efficacy of a high dose PQ treatment in G6PD normal patients with P. falciparum to reduce the risk of subsequent P. vivax episodes to current standard practice of providing only schizontocidal treatment.

Official Title
-----------------
Reducing the Risk of P. Vivax After Falciparum Infections in Co-endemic Areas - a Randomized Controlled Trial

Conditions
-----------------
Malaria, Vivax Malaria, Falciparum Malaria

Intervention / Treatment
-----------------
* Drug: primaquine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: P. falciparum mono-infection Fever (axillary temperature ≥37.5⁰C) or history of fever in preceding 48 hours Age >1 years (≥ 18 years at the Ethiopia site) G6PD normal as defined by the Biosensor (SD Biosensor, ROK) at ≥70% of the adjusted male median (AMM) for each site Written informed consent Able to comply with all study procedures and timelines Exclusion Criteria: General danger signs or symptoms of severe malaria Anaemia, defined as Hb <8g/dl Pregnant women as determined by Urine β-HCG pregnancy test Breast feeding women Known hypersensitivity to any of the drugs given Regular use of drugs with haemolytic potential Blood transfusion within the last 4 months

Ages Eligible for Study
-----------------
Minimum Age: 1 Year

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PQ7<br>high dose primaquine regimen over 7 days (1.0 mg/kg/day for 7 days) | Drug: primaquine<br>* Primaquine regimen over 7 days (1.0 mg/kg/day for 7 days)<br>|
| No Intervention: standard care<br>As per national guidelines for P. falciparum treatment | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence risk of any P. vivax parasitaemia at day 63 | The incidence risk of any P. vivax parasitaemia at day 63 | 63 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence risk of symptomatic P. vivax parasitaemia at day 63 | incidence risk of symptomatic P. vivax parasitaemia at day 63 | 63 days | 
| Incidence risk of all any P. vivax parasitaemia at day 28 and 42 | Incidence risk of all any P. vivax parasitaemia at day 28 and 42 | 28 and 42 days | 
| Incidence risk of any P. falciparum malaria at day 28, 42 and 63 | incidence risk of any P. falciparum malaria at day 28, 42 and 63 | 28/42/63 days | 
| proportion of patients vomiting their medication within 1 hour of administration | proportion of patients vomiting their medication on the day of enrollment within 1 hour of administration | 1 hour | 
| proportion of patients vomiting any of their PQ doses within 1 hour of administration | proportion of patients vomiting any of their PQ doses within 1 hour of administration | 7 days | 
| proportion of adverse events and serious adverse events | proportion of adverse events and serious adverse events | 63 days | 
| incidence risk of severe anaemia (Hb<5g/dl) and moderately severe anaemia (<7g/dl) and/or the risk for blood transfusion between day 3 and 7 | incidence risk of severe anaemia (Hb<5g/dl) and moderately severe anaemia (<7g/dl) and/or the risk for blood transfusion between day 3 and 7 | 7 days | 
| • The incidence risk of ≥25% fall in haemoglobin since baseline with and without hemoglobinuria at day 3 and day 7 | • The incidence risk of ≥25% fall in haemoglobin since baseline with and without hemoglobinuria at day 3 and day 7 | 7 days | 
| The incidence risk of ≥25% fall in haemoglobin to under 7g/dl with and without hemoglobinuria at day 3 and day 7 | The incidence risk of ≥25% fall in haemoglobin to under 7g/dl with and without hemoglobinuria at day 3 and day 7 | day 7 | 
| Incidence risk of P. falciparum gametocytaemia between day 7 and 63 | Incidence risk of P. falciparum gametocytaemia between day 7 and 63 | 63 days | 
| Parasite clearance on day 1, 2 and 3 | Parasite clearance on day 1, 2 and 3 | 3 days | 
| Fever clearance on day 1, 2 and 3 | Fever clearance on day 1, 2 and 3 | 3 days |