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Completed

NCT Number: NCT05044637

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

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.

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Key information

Conditions

Malaria, Vivax Infections Malaria Mosquito-Borne Diseases Parasitic Diseases Protozoan Infections Vector Borne Diseases

Age range

6 month–14 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Universidade Federal do Acre, Cruzeiro do Sul, Acre, Brazil

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Primaquine

Drug

7 days of unsupervised primaquine (3.5 mg/kg total dose) administered once per day (0.5 mg/kg OD).

Other names: Low-standard dose

Primary outcomes

  1. Safety - Adverse Event

    Time frame: 6 months after randomization

    To diagnose, resolve and catalog adverse events of any intensity, whether clinical or laboratory

  2. Efficacy - Radical cure

    Time frame: 6 months after randomization

    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

Secondary outcomes

  1. Incidence rate (per person-year) of recurrent P. vivax

    Time frame: 6 months after randomization

    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

  2. Incidence risk of any recurrent symptomatic P. vivax malaria

    Time frame: 6 months after randomization

    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.

  3. The hematological recovery in patients with vivax malaria

    Time frame: 6 months after randomization

    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

  4. Proportion of patients with any adverse drug reactions

    Time frame: 6 months after randomization

    The proportion of patients with one or more adverse drug reactions within 42 days of their primary treatment and also at 6 months

  5. Primaquine tolerability 1 hour

    Time frame: 7 to 14 days after randomization

    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

  6. Primaquine tolerability

    Time frame: 7 to 14 days after randomization

    Drug tolerability between the treatment arms will also be assessed by comparing the proportion of patients completing a full course of primaquine therapy

  7. Pharmacogenetics CYP2D6

    Time frame: 1 day after randomization

    Characterize hepatic cytochrome CYP2D6 enzyme phenotypes using Activity Score A (AS-A)

  8. Genotype CYP2D6

    Time frame: 1 day after randomization

    Genotype CYP2D6 alleles in this study population

  9. Metabolomics

    Time frame: 28 days after randomization

    Describe the metabolic signatures present in patients with adverse events (AEs) and severe AEs (SAEs)

Other outcomes

  1. Exploratory - Pharmacokinetics of primaquine Area Under the Curve (AUC)

    Time frame: 24 hours

    Area under the plasma concentration time AUC 0-∞curve for primaquine and metabolites (mPQ)

  2. Exploratory - Pharmacokinetics of primaquine Conc

    Time frame: 24 hours

    Primaquine and metabolites maximum concentrations

  3. Exploratory - Pharmacokinetics of primaquine Elimination rate

    Time frame: 24 hours

    Primaquine and metabolites (mPQ) elimination rate constants (mPQ-λz)

  4. Exploratory - Pharmacokinetics of primaquine Elimination half-life

    Time frame: 24 hours

    Primaquine and metabolites (mPQ) elimination half- life (mPQ-t1/2)

Sponsors and collaborators

Lead sponsor

Fundação de Medicina Tropical Dr. Heitor Vieira Dourado

Other

Collaborators

  • Bill and Melinda Gates Foundation
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico

Registry information

Official study title

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

Acronym: CHILDPRIM

Important dates

Study start
2021
Primary completion
2024
Study completion
2025
First posted
Sep 16, 2021
Registry last updated
Feb 20, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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