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

Malaria, Vivax Clinical Trial

— CHILDPRIM  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05044637
• Other study ID #: CAAE: 50193921.6.1001.0005
• Status: Recruiting
• Phase: Phase 2
• Start date: August 26, 2021
• Est. completion date: December 1, 2023

Study information

• Verified date: February 2023
• Source: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
• Contact: Marcus Vinicius G Lacerda, PhD, MD
• Phone: +559221273498
• Email: marcuslacerda.br[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: December 1, 2023
• Est. primary completion date: May 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 14 Years

Eligibility

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

Related Conditions & MeSH terms

• Malaria
• Malaria, Vivax

Intervention

Drug:
• Primaquine
7 days of unsupervised primaquine (3.5 mg/kg total dose) administered once per day (0.5 mg/kg OD).
• Primaquine
7 days of unsupervised primaquine (7.0 mg/kg total dose) administered once per day (1.0 mg/kg OD).
• Primaquine
14 days of unsupervised primaquine (7mg/kg total dose) administered once per day (0.5 mg/kg).

Locations

Country	Name	City	State
Brazil	Universidade Federal do Acre	Cruzeiro Do Sul	Acre
Brazil	Fundação de Medicina Tropical Doutor Heitor Vieira Dourado	Manaus	Amazonas

Sponsors (3)

Lead Sponsor	Collaborator
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado	Bill and Melinda Gates Foundation, Conselho Nacional de Desenvolvimento Científico e Tecnológico

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory - Pharmacokinetics of primaquine Area Under the Curve (AUC)	Area under the plasma concentration time AUC 0-8curve for primaquine and metabolites (mPQ)	24 hours
Other	Exploratory - Pharmacokinetics of primaquine Conc	Primaquine and metabolites maximum concentrations	24 hours
Other	Exploratory - Pharmacokinetics of primaquine Elimination rate	Primaquine and metabolites (mPQ) elimination rate constants (mPQ-?z)	24 hours
Other	Exploratory - Pharmacokinetics of primaquine Elimination half-life	Primaquine and metabolites (mPQ) elimination half- life (mPQ-t1/2)	24 hours
Primary	Safety - Adverse Event	To diagnose, resolve and catalog adverse events of any intensity, whether clinical or laboratory	6 months after randomization
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Pharmacogenetics CYP2D6	Characterize hepatic cytochrome CYP2D6 enzyme phenotypes using Activity Score A (AS-A)	1 day after randomization
Secondary	Genotype CYP2D6	Genotype CYP2D6 alleles in this study population	1 day after randomization
Secondary	Metabolomics	Describe the metabolic signatures present in patients with adverse events (AEs) and severe AEs (SAEs)	28 days after randomization