Phase III Comparative, Open-labelled, Randomised, Clinical Study to Assess a Fixed Dose of Oral Pyronaridine Artesunate Granule Formulation vs. Coartem® Crushed Tablets in Infants With Acute Uncomplicated Plasmodium Falciparum Malaria
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 535
- 试验地点
- 8
- 主要终点
- Percentage of Participants With PCR-Corrected ACPR on Day 28
研究概览
简要总结
The primary objective of this Phase III clinical study is to demonstrate the efficacy of the fixed combination of pyronaridine artesunate (PA) granule formulation (60:20 mg; pediatric PYRAMAX®) by showing a PCR-corrected adequate clinical and parasitological cure rate (ACPR) of more than 90%.
Secondary objectives of this clinical study are to compare the efficacy (non-inferiority) and safety of the PA granule formulation compared to Coartem® (ie, the combination of artemether/lumefantrine [AL]) crushed tablets in a paediatric population and to assess the safety of the PA granule formulation.
详细描述
This is a multi-centre, comparative, randomised, open-label, parallel-group study of the efficacy and safety of a 3-day regimen of a fixed combination of PA (3:1) versus AL in the treatment of acute uncomplicated Plasmodium falciparum mono-infection. The study population will include 534 patients, comprising male and female infants and children (body weight ≥5 and <25 kg) recruited from study sites in East, Central, and West Africa and South East Asia (max. 150 patients/site).
Patients will be randomised in a 2:1 ratio to receive either oral PA (60:20 mg granules) once a day for 3 consecutive days (Days 0, 1, and 2) or AL (20:120 mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). The study drug will be administered by a Third Party Investigator unblinded to the study treatment, while the Investigator will remain blinded. For PA, the dose range covered by this regimen is 7.0:2.3 mg to 13.3:4.4 mg, which has been shown to be effective and safe in Phase I and II studies. Posology will be based on body weight ranges for both the PA and AL regimens.
Patients will be confined to the study facility ≥4 days (Days 0, 1, 2, and 3) and remain near the study site for ≥7 days, or once fever and parasite clearance has been confirmed for ≥24 hours - whichever occurs earlier.
The primary efficacy end point for this study is the proportion of subjects with PCR-corrected ACPR on Day 28. Scheduled follow-up visits will continue until completion of the study at Day 42. 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
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients ≤12 years of age.
- •Body weight ≥ 5 kg and < 25 kg with no clinical evidence of severe malnutrition (defined as a child whose weight-for-height is below -3 standard deviations or <70% of the median of the NCHS/WHO normalised reference values).
- •Presence of acute uncomplicated P. falciparum mono-infection confirmed by:
- •Fever, as defined by axillary temperature ≥37.5°C or oral/tympanic/rectal temperature ≥38°C, or documented history of fever in the previous 24 hours and,
- •Positive microscopy of P. falciparum with parasite density between 1,000 and 200,000 asexual parasite count/µl of blood.
- •Written informed consent, in accordance with 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, patient assent will be sought.
- •Ability to swallow whole volume of liquid in which medication is suspended.
- •Female patients of child-bearing potential must be neither pregnant (as demonstrated by a negative pregnancy test) nor lactating, and must be willing to take measures to not become pregnant during the study period.
- •Ability and willingness to participate based on information given to parent or guardian and access to health facility. The patient is to comply with all scheduled follow up visits until D42.
排除标准
- •Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000 [Attachment 3].
- •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, QTc interval ≥450 milliseconds), respiratory (including active tuberculosis), history of jaundice, hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or other abnormality (including recent head trauma).
- •Presence of significant anaemia, as defined by Hb <8 g/dL.
- •Presence of febrile conditions caused by diseases other than malaria.
- •Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, lumefantrine or artesunate or other artemisinins.
- •Patients with known disturbances of electrolytes balance, e.g. hypokalaemia or hypomagnesaemia.
- •Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by reported patient history.
- •Pregnant or breastfeeding.
- •Patients taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (flecainide, metoprol, imipramine, amitriptyline, clomipramine).
- •Received an investigational drug within the past 4 weeks.
- •Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab).
- •Known positive for HIV antibody.
- •Liver function tests [ASAT/ALAT levels] >2.5 times upper limit of normal range.
- •Known significant renal impairment as indicated by serum creatinine of >1.4 mg/dL.
- •Previous participation in any clinical study with pyronaridine artesunate.
研究组 & 干预措施
PA group
Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2).
Posology based on body weight ranges.
干预措施: pyronaridine artesunate (Drug)
AL group
Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2).
Posology based on body weight ranges.
干预措施: arthemeter lumefantrine (Drug)
结局指标
主要结局
Percentage of Participants With PCR-Corrected ACPR on Day 28
时间窗: Day 28
Percentage of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. The PCR-corrected ACPR on Day 28 is defined as the absence of parasitaemia on Day 28 without the patient's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure
次要结局
- Fever Clearance Time(Day 0 and every 8 hours over ≥72 hours following first study drug administration or temperature normalization for ≥2 readings between 7 and 25 hours apart, then at each visit and as clinically indicated (within the 42-day study period))
- Percentage of Participants With PCR-Corrected ACPR on Day 14(Day 14)
- Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28(Days 14 and 28)
- Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3(Days 1, 2, and 3)
- Number of Subjects With ≥1 Adverse Event(Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier)
- Parasite Clearance Time(Days 0, 3, 7, 14, 21, 28, 35, and 42 or on any other day if the subject spontaneously returned within the 42-day study period)
- Proportion of Subjects With Fever Cleared on Days 1, 2, and 3(Days 1, 2, and 3)