Clinical trial NCT05044637: Study to Evaluate Primaquine for Radical Cure of Uncomplicated Plasmodium Vivax Malaria in Children
Official title: Phase IIB Study to Evaluate Primaquine Safety and Tolerability for Radical Cure of Uncomplicated Plasmodium Vivax Malaria in Children < 15 Years-old (CHILDPRIM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malaria, Vivax
Lead sponsor: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
name: Conselho Nacional de Desenvolvimento Científico e Tecnológico
First posted: 2021-09-16
Enrollment: 100
Sex: ALL
Minimum age (years): 6
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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;
* Absence 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)
* Absence 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 (with additional informed assent for 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
* Belonging to the indigenous community

Primary outcomes:
measure: Safety - Adverse Event
timeFrame: 6 months after randomization
measure: Efficacy - Radical cure
timeFrame: 6 months after randomization
Secondary outcomes:
measure: Incidence rate (per person-year) of recurrent P. vivax
timeFrame: 6 months after randomization
measure: Incidence risk of any recurrent symptomatic P. vivax malaria
timeFrame: 6 months after randomization
measure: The hematological recovery in patients with vivax malaria
timeFrame: 6 months after randomization
measure: Proportion of patients with any adverse drug reactions
timeFrame: 6 months after randomization
measure: Primaquine tolerability 1 hour
timeFrame: 7 to 14 days after randomization
measure: Primaquine tolerability
timeFrame: 7 to 14 days after randomization
measure: Pharmacogenetics CYP2D6
timeFrame: 1 day after randomization
measure: Genotype CYP2D6
timeFrame: 1 day after randomization
measure: Metabolomics
timeFrame: 28 days after randomization
Other outcomes:
measure: Exploratory - Pharmacokinetics of primaquine Area Under the Curve (AUC)
timeFrame: 24 hours
measure: Exploratory - Pharmacokinetics of primaquine Conc
timeFrame: 24 hours
measure: Exploratory - Pharmacokinetics of primaquine Elimination rate
timeFrame: 24 hours
measure: Exploratory - Pharmacokinetics of primaquine Elimination half-life
timeFrame: 24 hours
Locations:
city: Cruzeiro Do Sul
country: Brazil
facility: Universidade Federal do Acre
state: Acre
city: Manaus
country: Brazil
facility: Fundação de Medicina Tropical Doutor Heitor Vieira Dourado
state: Amazonas
Study officials:
affiliation: Fundação de Medicina Tropical - HVD
name: Maria das Graças C Alecrim, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References: