An Open-label, Randomised, Controlled, Non-inferiority Trial to Compare the Efficacy, Safety and Tolerability of a Fixed Dose Triple Artemisinin-based Combination Therapy (TACT) Artemether-lumefantrine-amodiaquine Versus First-line Artemisinin-based Combination Therapies (ACTs) for the Treatment of Uncomplicated Plasmodium Falciparum Malaria
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 1,680
- 试验地点
- 1
- 主要终点
- 28-day efficacy
研究概览
简要总结
The goal of this open-label randomised, controlled, non-inferiority trial is to assess and compare the efficacy, tolerability and safety of a fixed dose TACT artemether-lumefantrine-amodiaquine (ALAQ) to the ACTs artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) (with single low-dose primaquine in some sites) for the treatment of uncomplicated Plasmodium falciparum malaria in patient. The main question it aims to answer is whether ALAQ, a fixed dose TACT, is as efficacious, safe and tolerable in comparison with AL and ASAQ.
Participants will be enrolled, admitted and randomised to receive the study drug (ALAQ, AL or ASAQ). Patients will receive directly observed treatments and will be followed up at least once daily for the first 3 days after enrolment followed by weekly visits from D7 up to D42. Patients will be asked to report to the clinics between scheduled visits in case of any illness or other symptoms or complaints.
详细描述
Study participants with an uncomplicated P. falciparum monoinfection complying with all the inclusion criteria and without any of the exclusion criteria will be enrolled and randomised to three arms TACT (ALAQ), ACT1 (AL), ACT2 (ASAQ) at the sites in Africa and two arms TACT (ALAQ) and ACT (AL) at the site in Asia. Competitive recruitment with overall trial sample size 1,680 subjects (840 ALAQ, 420 AL, 420 ASAQ, i.e. a 2:1:1 ratio overall). 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 World Health Organization (WHO) for patients ≥10 kg. Primaquine may be given if local treatment policy includes it.
Participants will be admitted for three days to an in-patient unit for directly observed treatment and to perform all the required study procedures from D0H0 (time of first dose intake) to D3 (H72). They will be followed up weekly starting D7 up to D42.
Microscopy to detect and quantify malaria parasitaemia will be performed daily (more frequently in participants with parasite density of >5000/µL at screening) during hospitalization and at all weekly and unscheduled visits. In participants with parasite densities >5000/µL at screening, parasite clearance rates will be assessed by repeated assessments of the parasite counts after the start of the antimalarial treatments. A capillary blood sample will be taken at each of the time-points for these parasite counts.
A physical examination and measurements of vital signs along with a symptom questionnaire 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.
Safety assessments will be performed by measuring markers of renal and hepatic toxicity, haemoglobin, platelet counts, absolute and differential white blood cell counts and electrocardiographs (ECGs). ECGs will be performed during hospitalization (H0, H4, and 4 hours after the last dose) and day 42 of follow up to assess and compare the effect of the TACT and ACTs on QT or corrected QT (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
- None
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, aged ≥6 months (no upper limit unless one is required by local regulations) and bodyweight ≥5 kg
- •Ability to take oral medication
- •Fever defined as ≥38°C tympanic temperature or a history of fever within the last 24 hours
- •Acute uncomplicated P. falciparum monoinfection
- •Asexual P. falciparum parasitaemia: 1,000/µL to 250,000/µL determined on a peripheral blood film
- •Written informed consent by the participant, or by the parent/guardian in case of children lower than the age of consent, and assent if required (per local regulations)
- •Willingness and ability of the participants 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 other indication(s) for parenteral antimalarial treatment at the discretion of the treating physician
- •Haemoglobin <7 g/dL at screening
- •Participants who have received artemisinin or a derivative within the previous 7 days OR lumefantrine or amodiaquine within the previous 14 days
- •In applicable countries: use of seasonal malaria chemoprophylaxis (SMC) within the last 30 days
- •Acute illness other than malaria requiring systemic treatment
- •Severe acute malnutrition
- •Known HIV, tuberculosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other severe infection
- •For women of child-bearing age: pregnant, trying to get pregnant or lactating
- •History of allergy or known contraindication to any of the study drugs, including neuropsychiatric disorders and epilepsy
- •Previous splenectomy
- •Participation in the previous 3 months and/or ongoing follow-up for an interventional study (including FD-TACT)
研究组 & 干预措施
Artemether-Lumefantrine-Amodiaquine (ALAQ)
TACT group
干预措施: Artemether-Lumefantrine-Amodiaquine (ALAQ) (Drug)
Artemether-Lumefantrine (AL)
ACT 1 group
干预措施: Artemether-Lumefantrine (AL) (Drug)
Artesunate-Amodiaquine (ASAQ)
ACT 2 group
干预措施: Artesunate-Amodiaquine (ASAQ) (Drug)
结局指标
主要结局
28-day efficacy
时间窗: 28 days
28-day efficacy defined as the proportion of patients with Polymerase Chain Reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) at Day 28, i.e., absence up to Day 28 of P. falciparum parasitaemia (detected by microscopy) with parasites genetically identical to those detected at baseline (as determined by PCR product length polymorphisms)
次要结局
- 42-day PCR-uncorrected efficacy(42 days)
- Proportion of participants with microscopically detectable P. falciparum parasitaemia at Day 3(3 days)
- 28-day PCR uncorrected efficacy(28 days)
- 42-day efficacy(42 days)
- Incidence of adverse events (AEs)(42 days)
- Parasite clearance half-life(3 days)
- Proportion of participants requiring retreatment due to vomiting(1 hour after administration of each dose of the treatment)
- Proportion of participants who report completing a full course of observed TACT(3 days)
- Proportion of participants who report completing a full course of observed ACT(2 or 3 days depending on the treatment)
- Peak plasma concentration(42 days)
- Area under curve(42 days)
- Pharmacokinetic interactions - peak plasma concentration(42 days)
- Pharmacokinetic interactions - area under curve(42 days)
- Plasma levels of partner drugs(7 days)
- Fever clearance time(42 days)
- Proportion of participants with gametocytaemia(42 days)
- Incidence of serious adverse events (SAEs)(42 days)
- Number of cardiotoxicity events(42 days)