A Multicentre, Randomised Trial to Detect in Vivo Resistance of Plasmodium Falciparum to Artesunate in Patients With Uncomplicated Malaria.
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 1,700
- 试验地点
- 18
- 主要终点
- Parasite clearance rate
研究概览
简要总结
Because the artemisinins are the most potent antimalarial drugs, the reduction in parasite numbers is rapid. Therefore, early measures of reducing parasite counts are needed. This study will look at conventional markers of parasite reduction e.g. parasite clearance time, parasite reduction ratio, and the time to achieve a fall of 50%, 90% and 99% of the pre-treatment parasitaemia.
Defining artemisinin resistance requires the use of artesunate (AS) alone because it is now appreciated that the partner drug in a combination treatment has a significant impact on the rate of parasite clearance. This study will dose patients for 3 days with AS alone (or longer until parasites clear) and measure the parasite count frequently in order to be able to define an accurate regression line of a graph of the natural logarithm of the parasite count (Y axis) versus time (X axis). This will be followed by a full course of an artemisinin combination therapy (ACT). Two different dose regimens of artesunate will be compared at all sites except those in western Cambodia, as unpublished observations from the Thai-Myanmar border suggest the standard lower daily dose of 2mg/kg may enable the earlier detection of low level resistance than a 4mg/kg daily dose.
详细描述
Background:
Artemisinins are the cornerstone of current antimalarial treatment. Evidence of reduced susceptibility to artemisinins in Western Cambodia was first presented in January 2007 and confirmed in a subsequent detailed pharmacokinetic-pharmacodynamic study conducted by our group. Artemisinin resistance was manifest by a marked slowing of parasite clearance. The spread of highly artemisinin resistant falciparum malaria would have devastating consequences for malaria control and elimination. The response to artemisinin resistance in P. falciparum depends critically upon answering one pivotal question: how far has it spread? This research proposal focuses on filling critical gaps in knowledge that are essential to planning an effective response.
Objectives/Hypothesis/Questions:
This is a multi-centre study with the primary objective of comparing the P. falciparum parasite clearance compared to a reference parasite clearance rate obtained from historical data in artemisinin sensitive falciparum malaria.
The aim of this large scale study is to determine if artemisinin resistance has spread and if so, how far it has spread.
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, inclusive
- •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: 10,000 to 200,000/uL, 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 legally acceptable representative in case of children)
- •Willingness and ability of the patients/guardians to comply with the study protocol for the duration of the study
排除标准
- •Signs of severe/complicated malaria (WHO, 2000)
- •Haematocrit < 25% or haemoglobin (Hb) < 8 g/dL at enrollment
- •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, or to the ACT to be used at the site
- •Previous splenectomy
研究组 & 干预措施
Artesunate 2
Artesunate 2 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine
干预措施: Artesunate 2 (Drug)
Artesunate 4
Artesunate 4 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine
干预措施: Artesunate 4 (Drug)
结局指标
主要结局
Parasite clearance rate
时间窗: Day 42
Defined by the slope of the linear portion of the natural logarithm parasite clearance curve.
次要结局
- Parasite clearance time(Day 42)
- Fever clearance time(> 24 hours)
- Gametocytemia in patients(days 0, 3, 7 and 14)
- Parasite reduction rates and ratios(Day 42)
- Time for parasite count to fall(50%, 90%, and 99%)
- Parasite molecular markers of drug resistance(Day 42)
- Gametocyte carriage rates(14 days)
- In vitro susceptibility of P.falciparum to artemisinins(Day 42)
- Pharmacokinetics relationships for artesunate and Dihydroartemisinin (DHA)(Day 42)
- Identification of host factors that correlate with slow parasite clearance(Day 42)
- Efficacy at D42(Day 42)
- Pharmacodynamics relationships for artesunate and Dihydroartemisinin (DHA)(Day 42)