Investigation of Short Course, High Dose Primaquine Treatment for Liver Stages of Plasmodium Vivax Infection

Study Overview
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Brief Summary
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This study specifically seeks to provide data on the safety, tolerability and pilot efficacy of short course, high dose primaquine treatment in Papua New Guinean children aged 5-10 years, in a cross-sectional study design. Community screened asymptomatic cases and/or cases of clinically diagnosed malaria admitted to the out-patient units of the health center, will be screened for Glucose-6-phosphate dehydrogenase deficiency (G6PD) and malaria illness by rapid diagnostic test and P. vivax infection confirmed by light microscopy. Following treatment with artemether-lumefantrine (Coartem), G6PD normal children will be enrolled into the study and followed for 2 months. Primaquine treatment will be allocated to study participants in a step-wise design; firstly receiving the current 14 day treatment regimen of 0.5 mg/kg total dose (n=40); secondly, a 7 day treatment regimen receiving a total dose of 1.0 mg/kg/day; then thirdly, receive 1.0 mg/kg twice daily dose (bd) for a total of 3.5 days, should the 7 day treatment prove to be safe and well tolerated. In addition to this dose-escalation study, the pharmacokinetic profiles of single doses of 0.5 mg/kg and 1.0 mg/kg will be determined using an intensive sampling protocol, in children aged 5-10 years. The pharmacokinetic profiles obtained by this sub-study will be essential for modeling the population pharmacokinetic data obtained from the dose-escalation study. As there is currently no data on the safety, tolerability and efficacy of primaquine in children, the present study will validate previous observation and contribute to the knowledge of primaquine as a treatment for liver stages of Plasmodium vivax infection.

Official Title
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Safety, Tolerability and Pilot Efficacy of Short Course, High Dose Primaquine Treatment for Liver Stages of Plasmodium Vivax Infection

Conditions
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Plasmodium Vivax

Intervention / Treatment
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* Drug: Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Permanent resident in study area Absence of history of hypersensitivity reactions to pre-treatment drugs Positive for P. vivax infections on blood smear or PCR Normal G6PD enzyme activity Exclusion Criteria: Features of severe malaria Clinical evidence of nonmalarial illness Severe malnutrition (weight for age nutritional Z score <60th percentile) Moderate to severe anemia (Hb <8g/dL) Permanent disability which prevents or impedes study participation

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 14 day dose regimen<br>0.5 mg/kg oral Primaquine administered daily for 14 days | Drug: Primaquine<br>* Primaquine treatment given in a step-wise manner; (a) 0.5 mg/kg total dose daily for 14 days (n=40), (b) 1.0 mg/kg total dose daily for 7 days (n=40), (c) 1.0 mg/kg twice daily for 3.5 days (n=40)<br>* Other names: Primaquine phosphate;|
| Active Comparator: 7 day dose regimen<br>1.0 mg/kg oral Primaquine administered daily for 7 days | Drug: Primaquine<br>* Primaquine treatment given in a step-wise manner; (a) 0.5 mg/kg total dose daily for 14 days (n=40), (b) 1.0 mg/kg total dose daily for 7 days (n=40), (c) 1.0 mg/kg twice daily for 3.5 days (n=40)<br>* Other names: Primaquine phosphate;|
| Active Comparator: 3.5 day dose regimen<br>1.0 mg/kg oral Primaquine administered twice daily (bd) for 3.5 days | Drug: Primaquine<br>* Primaquine treatment given in a step-wise manner; (a) 0.5 mg/kg total dose daily for 14 days (n=40), (b) 1.0 mg/kg total dose daily for 7 days (n=40), (c) 1.0 mg/kg twice daily for 3.5 days (n=40)<br>* Other names: Primaquine phosphate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability as measured by hemoglobin |  | 2 months post baseline | 
| Safety and tolerability as measured by methemoglobin |  | 2 months post baseline | 
| Safety and tolerability as measured by liver biochemistry |  | 2 months post baseline | 
| Safety and tolerability as measured by symptom questionnaire |  | 2 months post baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first or only Plasmodium vivax infection by light microscopy and polymerase chain reaction (PCR) | Thick and thin blood films, along with PCR samples, will be collected at time of recruitment and then at any time the participant develops fever within the study period. | 2 months from baseline | 
| Time to first or only clinical Plasmodium vivax episode |  | 2 months from baseline | 
| Comparison of the rate of incidence of P. vivax relapses in 3.5 or 7 day treatment arm compared to standard 14 day regimen |  | 2 months from baseline | 
| Pharmacokinetics - elimination half-life (t1/2) |  | 42 days | 
| Pharmacokinetics - clearance (CL) |  | 42 days | 
| Pharmacokinetics - volume of distribution (Vd) |  | 42 days | 
| Pharmacokinetics - maximal concentration (Cmax) |  | 42 days | 
| Pharmacokinetics - area under the curve (AUC) |  | 42 days |