Pyronaridine and Artesunate (3:1) in Children With Acute Uncomplicated Plasmodium Falciparum Malaria

Uncomplicated Plasmodium Falciparum Malaria Clinical Trial

Official title:

An Open-label, Phase II, Dose-Escalation Clinical Study to Assess the Pharmacokinetics, Safety, Tolerability and Pharmacodynamics of Fixed Dose Combination of Pyronaridine and Artesunate (3:1) in Children With Acute Falciparum Malaria

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00331136
• Other study ID #: SP-C-003-05
• Status: Completed
• Phase: Phase 2
• Start date: June 2006
• Est. completion date: December 2006

Study information

• Verified date: May 2022
• Source: Medicines for Malaria Venture
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate three dose levels of a combination tablet and a fixed dose granule formulation of pyronaridine and artesunate (PA) for the treatment of acute uncomplicated falciparum malaria in children.

Description:

This is a Phase II, open-label, sequential-group, dose-escalation, single-centre study to study pharmacokinetics, bioavailability comparison of tablets vs. granules, and safety/tolerability of PA in paediatric patients with acute symptomatic uncomplicated P. falciparum malaria. The study population will include 60 patients, comprising male and female children recruited from a single study site located in the endemic region of Gabon.

Patients will be assigned sequentially to 1 of 4 treatment groups (15 per group): Group A (Tablets) PA (48 mg + 16 mg), Group B (Tablets) PA (72 mg + 24 mg), Group C (Tablets) PA (96 mg + 32 mg), Group D (Granules) PA (60 mg + 20 mg). Oral tablets will be taken once daily for 3 consecutive days (Days 0, 1 and 2). The dose given to each patient depends on the dosing cohort group and the patient's body weight.

Each patient will attend the study site for screening and baseline procedures, as well as receipt of the first dose of study drug on Day 0 (Visit 1, baseline). Patients will be hospitalised for the first 72 hours and remain near the study site for the entire duration of the study. The patients will return to the study site for all scheduled follow-up visits until discharge on Day 42.

The primary efficacy end point for the study is the incidence of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. In the case of adverse events reported and unresolved at Day 42, patients will be followed up for a further 30 days, or until resolution of the event.

Other known NCT identifiers

• NCT00329875

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: December 2006
• Est. primary completion date: December 2006
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 14 Years

Eligibility

Inclusion Criteria:

Patients presenting with symptoms of acute uncomplicated falciparum malaria with the following inclusion criteria:

• Male or female children, being between 2 and 14 years of age inclusive

• Weight between 10 and 40 kg inclusive

• Written informed consent, in accordance to local practice, provided by parent/guardian. If the parent/guardian is unable to write, witnessed consent is permitted according to local ethical considerations. Where possible, parent assent will be sought

• Absence of severe malnutrition (defined as mid upper arm circumference <110mm)

• Presence of acute symptomatic uncomplicated P. falciparum malaria with a diagnosis confirmed by a positive blood smear with asexual forms of P. falciparum only (i.e. no mixed infection) plus measured temperature of =37.5°C (depending on method of measurement as below) or history of fever within the past 24 hours :

• the acceptable range is between 1,000 and 200,000 asexual parasite count/µl of blood and

• axillary/tympanic temperature of =37.5°C or oral/rectal temperature of =38.0°C

• Females of childbearing potential are not allowed to be pregnant or lactating and must be willing to use adequate measures of contraception during the study period

• Ability to comply with the study visit schedule and the study protocol for the duration of the study

Exclusion Criteria:

• Patients with signs and symptoms of severe/complicated malaria requiring parenteral antimalarial treatment according to the WHO Criteria 2000

• Mixed Plasmodium infection

• Severe vomiting, defined as >3 times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or severe diarrhoea defined as >3 watery stools per day

• Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, acute QTc interval greater or equal to 450 msec), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other abnormality (including head trauma)

• Presence of febrile conditions caused by diseases other than malaria

• Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins

• Use of any other antimalarial treatment within 2 weeks prior to start of the study as confirmed by Lignin test and Saker Solomon urine test

• For females of childbearing potential, positive urine pregnancy test or lactating

• Use of an investigational drug within the past 8 weeks

• Known active Hep A immunoglobulin, Hep B surface antigen, or Hep C antibody

• Known seropositive HIV antibody

• Liver function tests (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] levels) >3 times the upper limit of normal

• Known significant renal impairment as indicated by a serum creatinine =2 mg/dL

• Previous participation in this clinical study

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum
• Uncomplicated Plasmodium Falciparum Malaria

Intervention

Drug:
• Pyronaridine-Artesunate
Once a day for 3 days

Locations

Country	Name	City	State
Gabon	Medical Research Unit, Albert Schweitzer Hospital	Lambaréné

Sponsors (3)

Lead Sponsor	Collaborator
Medicines for Malaria Venture	Institute of Tropical Medicine, University of Tuebingen, Shin Poong Pharmaceuticals

Country where clinical trial is conducted

Gabon, 

References & Publications (1)

Ringwald P, Bickii J, Basco L. Randomised trial of pyronaridine versus chloroquine for acute uncomplicated falciparum malaria in Africa. Lancet. 1996 Jan 6;347(8993):24-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Patients With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 28	Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 28 days, without previously meeting any of the criteria for early treatment failure, late clinical failure, or late parasitological failure.	Day 28
Secondary	Parasite Clearance Time	The time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of parasites for 2 consecutive negative readings taken between 8 and 24 hours apart.	Day 3
Secondary	Treatment Success or Failure	Treatment success for the ACPR analysis is defined as the clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 28 days, without previously meeting any of the criteria for early treatment failure, late clinical failure, or late parasitological failure. Early and late failures are classified according to the WHO Protocol 2005.	Day 28
Secondary	Fever Clearance Time	The time from first dosing to the first normal reading with fever clearance, defined as 2 consecutive assessments without fever (<37.5°C) taken between 8 and 24 hours apart.; NB: Time to fever clearance was only summarised for subjects who had fever at baseline or within the first 24 hours after the start of study treatment. Since only 12 subjects in total had fever during this time, the time to fever clearance estimates are not very meaningful.	Day 3
Secondary	Number of Patients With PCR-corrected ACPR on Day 14	Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 14 days.	Day 14
Secondary	Number of Patients With Parasite Clearance at Day 1, 2 and 3	Zero presence of parasites for 2 consecutive negative readings taken between 8 and 24 hours apart.	Days 1, 2, 3
Secondary	Number of Subjects With P. Falciparum Gametocytes During the Trial	The number of gametocytes per µl at Days 0, 3, 7, 14, 21, 28, 35, and 42 summarised from blood slides taken on the respective days.; P. falciparum gametocytes are responsible for transmission from host to vector.	Day 42
Secondary	Percentage of Patients With Fever Clearance at Day 1, 2 and 3	Patient without fever for 2 consecutive readings taken between 8 and 24 hours apart.; NB: Percentage of fever clearance was only summarised for subjects who had fever at baseline or within the first 24 hours after the start of study treatment. Since only 12 subjects in total had fever during this time, the time to fever clearance estimates are not very meaningful.	Days 1, 2, 3
Secondary	Crude ACPR on Day 14, 28 and 42	The proportion of patients with crude (non-PCR corrected) ACPR.	Days 14, 28, 42
Secondary	Number of Patients With PCR-corrected ACPR on Day 42	Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 42 days.	Day 42

External Links

•   Medicines for Malaria Venture
•   Shin Poong Pharmaceuticals