Study to Evaluate Primaquine for Radical Cure of Uncomplicated Plasmodium Vivax Malaria in Children

Study Overview
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Brief Summary
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The main determinant of primaquine efficacy is the total dose of primaquine administered, rather than the dosing schedule. Infants and children younger than 4 years of age are at a higher risk of frequent relapses than older age groups, which may lead to severe anaemia. In view of this issue, after Glucose-6-phosphate dehydrogenase (G6PD) testing, WHO recommends the use of a low dose (0·25 mg/kg of bodyweight) of primaquine for 14 days in infants aged 6 months and older, as a follow-up treatment for malaria caused by P. vivax and P. ovale. Nevertheless, previous trials have demonstrated that the standard low dose regimen of primaquine (3.5 mg/kg total) fails to prevent relapses in many different endemic locations. For this reason, the 2010 WHO antimalarial guidelines now recommend a high dose regimen of 7 mg/kg (equivalent to an adult dose of 30mg per day), although many countries still recommend lower doses for fear of causing more serious harm to unscreened G6PD deficiency patients. The pharmacokinetics of several antimalarial drugs are different in children younger than 10 years of age or who are underweight for their age compared with children of 10 years and older and adults.The doses of several antimalarials in children are suboptimal. This oversight is a consequence of designing dosing regimens in a different population (i.e., adults) for the one most affected by the disease and this has led to revisions of some dosing recommendations. The different pharmacokinetic performance of drugs in children might also relate to maturation (e.g., of metabolic processes, particularly in the first 2 years of life). Pharmacogenomic factors affecting drug metabolism are increasingly being studied. Polymorphisms in cytochrome P4502D6 are associated with different primaquine metabolizer phenotypes with resulting differing efficacies for radical cure. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and, thus, effectiveness without compromising efficacy. If the efficacy, tolerability and safety of short-course, high-dose primaquine regimens can be assured across the range of endemic settings, along with reliable point-of-care G6PD deficiency diagnostics, then this would be a major advance in malaria treatment by improving adherence and thus the effectiveness of anti-relapse therapy.

Official Title
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Phase IIB Study to Evaluate Primaquine Safety and Tolerability for Radical Cure of Uncomplicated Plasmodium Vivax Malaria in Children < 15 Years-old (CHILDPRIM)

Conditions
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Malaria, Vivax

Intervention / Treatment
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* Drug: Primaquine
* Drug: Primaquine
* Drug: Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infection with P.vivax parasitaemia; ≥ 6 months and ˂ 15 years of age; Body weight ≥ 5 Kg; Hb > 7 g/dL presence of axillary temperature >37.5 Celsius or history of fever during the past 48 hours; ability to swallow oral medication; Abscence of severe malnutrition (defined as a child whose growth standard is below -3-Z-score, has symmetrical oedema involving at least the feet or has a mid-upper arm circumference < 110 mm) Abscence of febrile conditions due to disease other than malaria (e.g., measles, acute lower respiratory tract infection, severe diarrhea with dehydration) or the known underlying chronic or severe diseases (e.g., cardiac, renal, hepatic diseases, HIV/AIDS); History of hypersensitivity reactions to or contraindicated for any of the medicine(s) being teste d or used as alternative treatment(s); A negative pregnancy test or non-lactating Ability and willingness to comply with the study protocol for the duration of the study, including 6 months of follow up; Informed consent from the patient/parent/guardian. Informed assent in addition to parental consent of any participant between 7 and 14 years of age; Pregnancy test consent from girls of childbearing age (defined as having had menarche) and their parents or guardians; Exclusion Criteria: G6PD- Deficiency (< 4.0 U/g Hb) The subject has severe P. vivax malaria as defined by the World Health Organization (WHO) criteria intolerance of or allergy to one of the medications in the study Pregnant or breastfeeding women Inability to tolerate oral medication Blood tranfusion in the last 3 months (as this may mask the G6PD deficiency) Serious or chronic medical condition (cardiac, renal, hepatic diseases, sickle cell disease, HIV/AIDS) History of malaria in the last 30 days

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 14 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Primaquine (3.5mg x 7d)<br>Primaquine 7 days Standard blood schizontocidal therapy plus 7 days of unsupervised primaquine (3.5 mg/kg total dose) administered once per day (0.5 mg/kg OD). | Drug: Primaquine<br>* 7 days of unsupervised primaquine (3.5 mg/kg total dose) administered once per day (0.5 mg/kg OD).<br>* Other names: Low-standard dose;|
| Active Comparator: Primaquine (7.0mg x 7d)<br>Primaquine 7 days Standard blood schizontocidal therapy plus 7 days of unsupervised primaquine (7.0 mg/kg total dose) administered once per day (1.0 mg/kg OD). | Drug: Primaquine<br>* 7 days of unsupervised primaquine (7.0 mg/kg total dose) administered once per day (1.0 mg/kg OD).<br>* Other names: High-dose short course;|
| Active Comparator: Primaquine (7.0mg x 14d)<br>Primaquine 14 days Standard blood schizontocidal therapy plus 14 days of unsupervised primaquine (7.0 mg/kg total dose) administered once per day (0.5 mg/kg). | Drug: Primaquine<br>* 14 days of unsupervised primaquine (7mg/kg total dose) administered once per day (0.5 mg/kg).<br>* Other names: High-dose long course;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Adverse Event | To diagnose, resolve and catalog adverse events of any intensity, whether clinical or laboratory | 6 months after randomization | 
| Efficacy - Radical cure | The incidence rate (i.e., per person-year) of symptomatic recurrent P. vivax parasitaemia (detected by microscopy) over 6 months of follow-up in the 3.5 mg/Kg total dose versus 7.0 mg/Kg total dose primaquine groups | 6 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate (per person-year) of recurrent P. vivax | The overall incidence rate (per person-year) of any recurrent P. vivax parasitaemia detected by microscopy over 6 months of follow-up in the 3.5 mg/Kg total dose group versus the 7.0 mg/Kg total dose groups | 6 months after randomization | 
| Incidence risk of any recurrent symptomatic P. vivax malaria | The incidence rate (per person-year) of any recurrent symptomatic P. vivax parasitaemia over 6 months of follow-up in either the 7-day or the 14-day primaquine arms of 7.0 mg/kg total dose compared with 7-day primaquine arm of 3.5 mg/Kg total dose. | 6 months after randomization | 
| The hematological recovery in patients with vivax malaria | Hematological recovery will be assessed as the incidence risk of severe anaemia (Hb<7g/dl) and/or blood transfusion within the 6 month follow up period, and the mean fall in baseline Hb on day 7 and day 14. These outcomes will be compared between the treatment arms | 6 months after randomization | 
| Proportion of patients with any adverse drug reactions | The proportion of patients with one or more adverse drug reactions within 42 days of their primary treatment and also at 6 months | 6 months after randomization | 
| Primaquine tolerability 1 hour | Tolerability of primaquine will be assessed by comparing the proportion of patients with nausea, vomiting, abdominal pain and vomiting of a dose within 1 hour of administration between the treatment arms | 7 to 14 days after randomization | 
| Primaquine tolerability | Drug tolerability between the treatment arms will also be assessed by comparing the proportion of patients completing a full course of primaquine therapy | 7 to 14 days after randomization | 
| Pharmacogenetics CYP2D6 | Characterize hepatic cytochrome CYP2D6 enzyme phenotypes using Activity Score A (AS-A) | 1 day after randomization | 
| Genotype CYP2D6 | Genotype CYP2D6 alleles in this study population | 1 day after randomization | 
| Metabolomics | Describe the metabolic signatures present in patients with adverse events (AEs) and severe AEs (SAEs) | 28 days after randomization |