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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Uncomplicated Plasmodium Falciparum Malaria

Intervention / Treatment
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* Drug: Pyronaridine-Artesunate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (Tablets)<br>Pyronaridine artesunate 6:2 mg/kg. The tablet strength is 48:16 mg oral PA, with the number of tablets depending on body weight. | Drug: Pyronaridine-Artesunate<br>* Once a day for 3 days<br>* Other names: Pyramax;|
| Experimental: Group B (Tablets)<br>Pyronaridine artesunate 9:3 mg/kg. The tablet strength is 72:24 mg oral PA, with the number of tablets depending on body weight. | Drug: Pyronaridine-Artesunate<br>* Once a day for 3 days<br>* Other names: Pyramax;|
| Experimental: Group C (Tablets)<br>Pyronaridine artesunate 12:4 mg/kg. The tablet strength is 96:32 mg oral PA, with the number of tablets depending on body weight. | Drug: Pyronaridine-Artesunate<br>* Once a day for 3 days<br>* Other names: Pyramax;|
| Experimental: Group D (Granules)<br>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. | Drug: Pyronaridine-Artesunate<br>* Once a day for 3 days<br>* Other names: Pyramax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Crude ACPR on Day 14, 28 and 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 | Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 42 days. | Day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, P. falciparum, artemisinin based combination therapy (ACT), antimalarial, pyronaridine artesunate (Pyramax)