A Multi-centre Randomised Controlled Non-inferiority Trial to Compare the Efficacy, Safety and Tolerability of Triple Artemisinin-based Combination Therapies Versus First-line ACTs + Placebo for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Asia
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 103
- 试验地点
- 3
- 主要终点
- Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).
研究概览
简要总结
A partially blinded randomised controlled non-inferiority trial comparing the efficacy, tolerability and safety of Triple ACTs artemether-lumefantrine + amodiaquine (AL+AQ) and artesunate- mefloquine+piperaquine (AS-MQ+PPQ) with the ACTs artemether-lumefantrine + placebo (AL+PBO) and artesunate- mefloquine + placebo (AS-MQ+PBO) (with single-low dose primaquine in some sites) for the treatment of uncomplicated Plasmodium falciparum malaria to assess and compare their efficacy, safety, tolerability.
详细描述
Subjects will be randomized to up to four arms: artemether-lumefantrine + amodiaquine, artemether-lumefantrine + placebo, artesunate-mefloquine + piperaquine and artesunate-mefloquine + placebo. As a contingency measure in case of significant differences in the efficacy or safety of one of the combinations being tested and/or study drug expiry or unavailability, subjects may be randomised to 2 arms with a matching ACT-TACT pair, i.e., with artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine OR artesunate-mefloquine + placebo or artesunate-mefloquine + piperaquine.
Some sites may randomize between 2 arms only with matching ACT-TACT pairs, i.e., artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine OR artesunate-mefloquine + placebo or artesunate-mefloquine + piperaquine.
In the control arms, the ACT will be co-packed with a matched (appearance) placebo.
In lower transmission settings (Annual Parasite Incidence <50 per 1000 population per year) the treatment will include a single 0.25 mg/kg gametocytocidal dose of primaquine as recommended by the WHO for children ≥10 kg. All drug administrations will be observed.
Subjects will be treated in an in-patient unit for 3 days and followed up weekly up to D63. Microscopy to detect and quantify malaria parasitaemia will be performed daily (more frequently in patients with parasite density of >5000/µL at inclusion) during hospitalization, at all weekly and unscheduled visits. A physical examination and measurements of vital signs along with a symptom questionnaire for tolerability will be performed and recorded through a standardized method at baseline, daily during admission and weekly during follow up through D42 and at all unscheduled visits. Physical exam, vital sign measurements and assessments of symptoms will be performed on D49, D56, and D63 only for patients who are parasitaemic or those who report fever or other symptoms. Electrocardiographs will be performed during admission (H0, H4, H52, or H64) and day 42 of follow up to assess and compare the effect of ACTs and TACTs antimalarials on QT or QTc-intervals.
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
- Single (Participant)
入排标准
- 年龄范围
- 6 Months 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, >/= 6 months
- •Ability to take oral medication
- •Acute uncomplicated P. falciparum monoinfection
- •Asexual P. falciparum parasitaemia: 96 to 200,000/µL, determined on a peripheral blood film
- •Fever defined as >/= 37.5°C tympanic temperature or a history of fever within the last 24 hours
- •Written informed consent by the subject or parent/guardian in case of children lower than the age of consent and assent if required (per local regulations)
- •Willingness and ability of the subjects or parents/guardians to comply with the study protocol for the duration of the study
排除标准
- •Signs of severe malaria (adapted from WHO criteria)
- •Patients not fulfilling criteria for severe malaria but with another indication for parenteral antimalarial treatment at the discretion of the treating physician
- •Haematocrit < 20% at screening
- •Subjects who have received artemisinin or a derivative within the previous 7 days OR lumefantrine or amodiaquine within the previous 14 days OR mefloquine or piperaquine within the previous 30 days
- •Acute illness other than malaria requiring systemic treatment
- •Severe acute malnutrition
- •Known HIV infection
- •Known tuberculosis infection
- •For females: pregnant, trying to get pregnant or are lactating
- •History of allergy or known contraindication to any of the study drugs, including neuropsychiatric disorders and epilepsy
- •Previous splenectomy
- •Enrolment in DeTACT in the previous 3 months
- •Participation in another interventional study in the previous 3 months
- •Criteria for severe malaria
- •Impaired consciousness (Glasgow Coma Scale, Blantyre Coma Scale)
- •Prostration
- •Respiratory distress (defined as maximal respiratory rate, by age)
- •≥2 convulsions in the past 24 hours
- •Circulatory collapse
- •Pulmonary edema
- •Abnormal bleeding
- •Visible jaundice
- •Haemoglobinuria (blackwater)
- •Hyperparasitaemia (>10%)
研究组 & 干预措施
Artemether-lumefantrine+amodiaquine (AL+AQ)
Triple ACTs
干预措施: Artemether-lumefantrine+amodiaquine (Drug)
Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)
Triple ACTs
干预措施: Artesunate-mefloquine+piperaquine (Drug)
artemether-lumefantrine+placebo (AL+PBO)
ACTs
干预措施: Artemether-lumefantrine+placebo (Drug)
Artesunate-mefloquine+placebo (AS-MQ+PBO)
ACTs.
干预措施: Artesunate-mefloquine+placebo (Drug)
结局指标
主要结局
Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).
时间窗: 42 days
次要结局
- Plasma levels of partner drugs in correlation with treatment efficacy and treatment arm(7 days)
- Number of cardiotoxicity events(52 or 64 hours depends on treatment arm)
- Parasite clearance half-life(7 days)
- Change in haemoglobin stratified for G6PD status/genotype(28 days)
- Proportion of subjects that reports completing a full course of observed ACT(3 days)
- Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR)(63-day)
- Efficacy defined as adequate clinical and parasitological response (ACPR)(42-day)
- proportion of subjects with microscopically detectable P. falciparum parasitaemia(3 days)
- Number of serious adverse events(42 days)
- Pharmacokinetic profiles and interactions (including Cmax) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy(42 days)
- Pharmacokinetic profiles and interactions (AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy(42 days)
- Efficacy defined as adequate clinical and parasitological response (PCR)(63-day)
- Fever clearance time(7 days)
- Proportion of subjects with gametocytemia during and after treatment stratified by presence of gametocytes at enrolment(63 days)
- Number of adverse events(42 days)
- Proportion of subjects that reports completing a full course of observed TACT(3 days)
- Proportion of subjects requiring retreatment due to vomiting within 1 hour after administration of the study drugs(1 hour)