Pyronaridine and Artesunate (3:1) in Children With Acute Uncomplicated Plasmodium Falciparum Malaria
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
Study Overview
Status
Conditions
Intervention / Treatment
Detailed 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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
-
Lambaréné, Gabon
- Medical Research Unit, Albert Schweitzer Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Factorial Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Group A (Tablets)
Pyronaridine artesunate 6:2 mg/kg.
The tablet strength is 48:16 mg oral PA, with the number of tablets depending on body weight.
|
Once a day for 3 days
Other Names:
|
|
Experimental: Group B (Tablets)
Pyronaridine artesunate 9:3 mg/kg.
The tablet strength is 72:24 mg oral PA, with the number of tablets depending on body weight.
|
Once a day for 3 days
Other Names:
|
|
Experimental: Group C (Tablets)
Pyronaridine artesunate 12:4 mg/kg.
The tablet strength is 96:32 mg oral PA, with the number of tablets depending on body weight.
|
Once a day for 3 days
Other Names:
|
|
Experimental: Group D (Granules)
Pyronaridine artesunate 9:3 mg/kg.
The sachet of granules strength is 60:20 mg PA, with the number of sachets depending on body weight, and is administered as a suspension with water.
|
Once a day for 3 days
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Percentage of Patients With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 28
Time Frame: 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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Parasite Clearance Time
Time Frame: Day 3
|
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
|
|
Treatment Success or Failure
Time Frame: Day 28
|
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
|
|
Fever Clearance Time
Time Frame: Day 3
|
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
|
|
Number of Patients With PCR-corrected ACPR on Day 14
Time Frame: Day 14
|
Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 14 days.
|
Day 14
|
|
Number of Patients With Parasite Clearance at Day 1, 2 and 3
Time Frame: Days 1, 2, 3
|
Zero presence of parasites for 2 consecutive negative readings taken between 8 and 24 hours apart.
|
Days 1, 2, 3
|
|
Number of Subjects With P. Falciparum Gametocytes During the Trial
Time Frame: Day 42
|
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
|
|
Percentage of Patients With Fever Clearance at Day 1, 2 and 3
Time Frame: Days 1, 2, 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
|
|
Crude ACPR on Day 14, 28 and 42
Time Frame: Days 14, 28, 42
|
The proportion of patients with crude (non-PCR corrected) ACPR.
|
Days 14, 28, 42
|
|
Number of Patients With PCR-corrected ACPR on Day 42
Time Frame: Day 42
|
Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 42 days.
|
Day 42
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Michael Ramharter, MD, Albert Schweitzer Hospital, Lambaréné, Gabon
Publications and helpful links
General Publications
- Ayyoub A, Methaneethorn J, Ramharter M, Djimde AA, Tekete M, Duparc S, Borghini-Fuhrer I, Shin JS, Fleckenstein L. Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients. Antimicrob Agents Chemother. 2015 Dec 14;60(3):1450-8. doi: 10.1128/AAC.02004-15.
- Duparc S, Borghini-Fuhrer I, Craft CJ, Arbe-Barnes S, Miller RM, Shin CS, Fleckenstein L. Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials. Malar J. 2013 Feb 21;12:70. doi: 10.1186/1475-2875-12-70.
- 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. doi: 10.1016/s0140-6736(96)91558-5.
- Ramharter M, Kurth F, Schreier AC, Nemeth J, Glasenapp Iv, Belard S, Schlie M, Kammer J, Koumba PK, Cisse B, Mordmuller B, Lell B, Issifou S, Oeuvray C, Fleckenstein L, Kremsner PG. Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon. J Infect Dis. 2008 Sep 15;198(6):911-9. doi: 10.1086/591096.
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- SP-C-003-05
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.