A Multi-centre, Open-label Randomised Trial to Assess the Efficacy, Safety and Tolerability of the Triple ACT Artemether-lumefantrine+Amodiaquine (AL+AQ) Compared to the ACT Artemether-lumefantrine (AL) in Uncomplicated Falciparum Malaria in Cambodia and Vietnam
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 310
- 试验地点
- 4
- 主要终点
- Polymerase Chain Reaction Corrected Efficacy Defined as Adequate Clinical and Parasitological Response (ACPR) by Study Arm
研究概览
简要总结
This study is a multi-centre, open-label randomised trial to assess the efficacy, safety and tolerability of the Triple ACT artemether-lumefantrine+amodiaquine (AL+AQ) compared to the ACT artemether-lumefantrine (AL) in uncomplicated falciparum malaria in Cambodia and Vietnam. The estimated total sample size is 600 patients from 2 sites in Cambodia and 2 sites in Vietnam. There are 2 treatment arms Arm 1: Artemether-lumefantrine for 3 days Arm 2: Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days. According to the World Health Organization guideline, all patients except children under 10 kilograms will also be treated with a single dose of primaquine as a gametocytocidal treatment.
Funder :Bill & Melinda Gates Foundation (BMGF) Grant reference number: OPP1132628
详细描述
"The study of artemether-lumefantrine or artemether-lumefantrine combined with amodiaquine will be a two-arm randomized open label comparative study.
The main activity proposed is a series of detailed in vivo clinical, parasitological and pharmacological assessments in 600 subjects across 2 sites in Cambodian (400 subjects) and 2 sites in Vietnam (200 subjects). The subjects will be randomized between the ACT artemether-lumefantrine and the TACT artemether-lumefantrine+amodiaquine.
Parasite clearance rates will be assessed by repeated assessments of the parasite counts after the start of the antimalarial treatments. Efficacy, safety and tolerability of ACTs and TACTs will be assessed through weekly follow up visits where vital signs, symptom questionnaires, physical examinations, blood smears, biochemistry assays and full blood counts will be performed.
Ex vivo assessments of parasite susceptibility to artemisinins and partner drugs will be measured and compared to historical data, clinical phenotype and other sites in an effort to identify artemisinin and partner drug resistance.
This study will obtain data on the effect of antimalarials on the corrected QT intervals. In addition, the effects of antimalarials on factors such as post-treatment haematocrit and haemoglobin levels will be assessed. Extensive pharmacokinetic analysis will allow for an assessment of drug-drug interactions.
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
- 2 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, aged from 2 years to 65 years old
- •Acute uncomplicated P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. falciparum (or mixed with non-falciparum species)
- •Asexual P. falciparum parasitaemia: 16 to 200,000/microlitre, determined on a thin or thick blood film
- •Fever defined as > 37.5°C tympanic temperature or a history of fever within the last 24 hours
- •Written informed consent (by parent/guardian in case of children)
- •Willingness and ability of the patients or parents/guardians to comply with the study protocol for the duration of the study
排除标准
- •Signs of severe/complicated malaria
- •Haematocrit < 25% or Hb < 8 g/dL at screening
- •Acute illness other than malaria requiring treatment
- •For females: pregnancy, breast feeding
- •Patients who have received artemisinin or a derivative or an artemisinin-containing combination therapy (ACT) within the previous 7 days
- •History of allergy or known contraindication to artemisinins, lumefantrine or amodiaquine
- •Previous splenectomy
- •corrected QT interval > 450 milliseconds at moment of presentation
- •Documented or claimed history of cardiac conduction problems
- •Previous participation in the current study or another study in the previous 3 months
研究组 & 干预措施
ACT
Artemether-lumefantrine for 3 days plus primaquine at hour 24
干预措施: ACT (Drug)
TACT
Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days plus primaquine at hour 24
干预措施: TACT (Drug)
结局指标
主要结局
Polymerase Chain Reaction Corrected Efficacy Defined as Adequate Clinical and Parasitological Response (ACPR) by Study Arm
时间窗: 42 days
Efficacy is defined as participants, following initial parasite and fever clearance, not having a recrudescence of the original plasmodium infection and fever, up to 42 days of follow up.
次要结局
- 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region(42 day)
- Parasite Clearance Half-life(42 day)
- Fever Clearance Time(42 day)
- Number of Severe Adverse Events by Study Arm(42 days)
- Incidence of Adverse Events Concerning Markers of Hepatic or Renal Toxicity(42 day)
- Incidence of Prolongation of the Corrected QT Interval(28 day)
- Prolongation of the Corrected QT Interval(Hour 4, Hour 24, Hour 28, Hour 48, Hour 52, Hour 60, Hour 64, Day 7 and Day 28 and between these time points)
- Parasite Reduction Rates(24 and 48 hours)
- Parasite Count to Fall 50%(42 days)
- Parasite Count to Fall 90%(42 days)
- Parasite Count to Fall 99%(42 days)
- Change in Haematocrit(Day 1 to 7, 14, 21, 28, 35, 42)
- Correlation Between the Host Genotype and the Pharmacokinetics and Pharmacodynamics of Antimalarials(42 day)
- Proportion of Patients That Reports Completing a Full Course of Observed TACT or ACT(42 day)
- Prevalence of Kelch13 Mutations of Known Significance(42 day)
- Prevalence/Incidence of Other Genetic Markers of Antimalarial Drug Resistance Such as Multidrug Resistance Gene 1 Copy Number and Multidrug Resistance Gene 1 Mutations(48 hours)
- Genome Wide Association With in Vivo/in Vitro Sensitivity Parasite Phenotype(42 day)
- Correlation Between Single Nucleotide Polymorphisms and Whole Genome Sequencing(42 day)
- A Comparison of Transcriptomic Patterns Between Sensitive and Resistant Parasites(baseline and t = 6 hours)
- Correlation Between Quantitative Polymerase Chain Reaction Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics(14 days)
- Proportion of Patients With Gametocytaemia Before, During and After Treatment With TACT or ACT(At admission and up to day 14)
- Levels of RNA Transcription Coding for Male or Female Specific Gametocytes(14 days)
- Pharmacokinetic Profiles and Interactions (AUC) of Artemisinin-derivatives and Partner Drugs(42 days)
- Day 7 Drug Levels of Partner Drugs in Association With Treatment Efficacy and Treatment Arm(7 days)
- Correlation Between Histidine-rich Protein 2 (HRP2) Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics(42 days)
- In Vitro Sensitivity of P. Falciparum to Artemisinins and Partner Drugs(At admission & subjects with recurrent parasitaemia, up to 42 days)
- Pharmacokinetic Profiles and Interactions (Cmax) of Artemisinin-derivatives and Partner Drugs(42 days)