A Multi-centre, Open-label Randomised Trial to Assess the Efficacy, Safety and Tolerability of Triple Artemisinin-based Combination Therapies (TACTs) Com-pared to Artemisinin-based Combination Therapies (ACTs) in Uncomplicated Falciparum Malaria and to Map the Geographical Spread of Artemisinin and Partner Drug Resistance
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 1,110
- 试验地点
- 20
- 主要终点
- PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR)
研究概览
简要总结
This study is an open-label randomised trial comparing standard ACT treatment with matching triple artemisinin-based combination therapies (TACTs), evaluating efficacy in safety and tolerability. The estimated total sample size is 2040 patients from 16 sites in Asia and 1 site in Africa. There are 2 arm study groups that have 2 treatment arms each.
Study group A:
A.1: Artemether-lumefantrine for 3 days. versus: A.2: Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days.
Study group B:
B.1: Dihydroartemisinin-piperaquine for 3 days. versus: B.2: Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.
Study group C:
C.1: Artesunate-mefloquine for 3 days versus: C.2: Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.
According to the WHO guideline, all patients except for children under the age of 1 year or a weight below 10 kilograms will also be treated with a single dose of low dose primaquine.
详细描述
In Laos, Myanmar, Bangladesh, India and DRC, the following two combinations will be used:
- Artemether-lumefantrine combined with amodiaquine (TACT arm) or
- Artemether-lumefantrine (ACT arm)
In Myanmar and Vietnam the following two combinations will be used:
- Dihydroartemisinin-piperaquine combined with mefloquine (TACT arm) or
- Dihydroartemisinin-piperaquine (ACT arm)
In Cambodia and Thailand the following two combinations will be used:
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
- 6 Months 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 6 months 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: 5,000 to 200,000/uL, de-termined on a thin or thick blood film (In Cambodia patients with a parasitaemia of 16 to 200,000/uL are eligible. In DRC patients with a parasitaemia of 10,000 to 250,000/ul are eligi-ble)
- •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 < 5 g/dL at screening (DRC: Hct<15% and Hb <5 g/dL due to high prevalence of anemia).
- •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
- •Treatment with mefloquine in the 2 months prior to presentation will be an exclusion criteria in the DHA-P+MQ sites
- •History of allergy or known contraindication to artemisinins, or to the ACT or TACT to be used at the site e.g. neuropsychiatric disorders will be a contraindication for the use of mefloquine.
- •Previous splenectomy
- •QTc-interval > 450 milliseconds at moment of presentation
- •Documented or claimed history of cardiac conduction problems
- •Earlier participation within the TRACII trial or another trial in the previous 3 months.
研究组 & 干预措施
ACT-arms
1.1 Artemether-lumefantrine for 3 days.
1.2 Dihydroartemisinin-piperaquine for 3 days
1.3 Artesunate-Mefloquine for 3 days
干预措施: ACT (Drug)
TACT-arms
2.1: Artemether-lumefantrine for 3 days.plus: Amodiaquine for 3 days.
2.2: Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days.
2.3 Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days.
干预措施: TACT (Drug)
结局指标
主要结局
PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR)
时间窗: 42 days
次要结局
- Parasite clearance half-life(42 days)
- Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy(at 24 and 48 hours)
- Time for parasite count to fall to 50% of initial parasite density(42 days)
- Time for parasite count to fall to 90% of initial parasite density(42 days)
- Time for parasite count to fall to 99% of initial parasite density(42 days)
- Fever clearance time(42 days)
- Incidence of adverse events and serious adverse events(42 days)
- Incidence of adverse events concerning markers of hepatic toxicity(42 days)
- Incidence of adverse events concerning markersof renal toxicity(42 days)
- Incidence of prolongation of the QTc-interval(3 days)
- Change in hemoglobin/hematocrit(42 days)
- Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study(42 days)
- Prevalence of Kelch13 mutations of known functional significance(42 days)
- Prevalence/incidence of other genetic markers of antimalarial drug resistance(42 days)
- Genome wide association with in vivo/in vitro sensitivity parasite phenotype(42 days)
- Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples(42 days)
- Transcriptomic patterns at t=0 and t=6h comparing sensitive and resistant parasites(6hrs after start of treatment)
- Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics(14 days)
- Proportion of patients with gametocytemia before,after treatment with Primaquine(assessed at admission, up to day 14)
- Levels of RNA transcription coding for male or female specific gametocytes(at admission up to day 14)
- In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs(42 days)
- • Pharmacokinetic profiles and interactions of artemisinin-derivatives and partner drugs (half-life, Cmax, AUC, Tmax) in 20 ACT treated and 20 TACT treated patients of both study arms(42 days)
- Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm(Day 7)