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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Percentage of Patients With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 28
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 14 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Pyronaridine-Artesunate (Drug)
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.
干预措施: Pyronaridine-Artesunate (Drug)
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.
干预措施: Pyronaridine-Artesunate (Drug)
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.
干预措施: Pyronaridine-Artesunate (Drug)
结局指标
主要结局
Percentage of Patients With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 28
时间窗: 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.
次要结局
- Parasite Clearance Time(Day 3)
- Treatment Success or Failure(Day 28)
- Number of Patients With PCR-corrected ACPR on Day 14(Day 14)
- Number of Patients With Parasite Clearance at Day 1, 2 and 3(Days 1, 2, 3)
- Number of Subjects With P. Falciparum Gametocytes During the Trial(Day 42)
- Percentage of Patients With Fever Clearance at Day 1, 2 and 3(Days 1, 2, 3)
- Crude ACPR on Day 14, 28 and 42(Days 14, 28, 42)
- Number of Patients With PCR-corrected ACPR on Day 42(Day 42)
- Fever Clearance Time(Day 3)