A Randomized, Open-label, Multicenter Study to Compare Efficacy, Safety and Tolerability of KLU156 With Coartem® in the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Adults and Children Followed by an Extension Phase With Repeated KLU156 Treatment
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,720
- 试验地点
- 33
- 主要终点
- PCR-corrected adequate clinical and parasitological response (ACPR)
研究概览
简要总结
This study aims to confirm the efficacy, safety and tolerability of KLU156, a fixed dose combination of ganaplacide (KAF156) and a solid dispersion formulation of lumefantrine (lumefantrine-SDF), when administered once daily for three days in adults and children ≥ 10 kg of body weight suffering from uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection).
In the Extension phase, the safety, tolerability and efficacy of repeated treatment with KLU156 will be assessed for a maximum of two years in patients who did not experience early treatment failure (ETF), who did not experience any study treatment-related SAE (Serious Adverse Event) previously and who gave informed consent to participate in the Extension phase.
详细描述
The purpose of this study is to confirm the efficacy, safety and tolerability of KLU156 in patients with uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection) by demonstrating that KLU156 is non-inferior to Coartem.
- The study duration will be 43 days (Core phase) plus up to 24 months (Extension phase).
- The treatment duration will be 3 days for each malaria episode.
- The visit frequency will be Days 1-3 (hospitalized) and 5 follow-up visits (Days 4, 8, 22, 29 and 43) in the Core phase and Days 1-3 (hospitalized) and 3 follow-up visits (Days 4, 8 and 29) in the Extension phase.
This study has two different primary outcomes depending on the submission (US New Drug Application (NDA) or non-US submissions).
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 (Outcomes Assessor)
盲法说明
The Novartis clinical trial team (CTT) will be blinded to the identity of the treatment from the time of randomization until the database lock for the analysis of the Core phase. Prior to unblinding the data of the Core phase (for the Novartis CTT), at least three DMC reviews are planned to minimize risks in this vulnerable patient population:
- Once the first 200 patients (across both treatment arms) in the Core phase have been dosed and followed up to at least Day 22.
- Once the first 750 patients (across both treatment arms) in the Core phase have been dosed and followed up to at least Day 22.
- Additional DMC reviews may be conducted ad-hoc during the study, as deemed necessary.
All safety data from the Core phase as well as from the Extension phase that are available at these 2 scheduled timepoints will be included in the DMC reviews. After the database lock of the Core phase, the CTT will be unblinded.
入排标准
- 年龄范围
- 2 Months 至 100 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(Core phase)
- •Male or female patients ≥ 10 kg of body weight.
- •Microscopically confirmed diagnosis of uncomplicated P. falciparum malaria with an asexual P. falciparum parasitemia ≥ 1,000 and ≤ 200,000 parasites/µL at the time of pre-screening with or without other Plasmodium spp. co-infection.
- •Axillary temperature ≥ 37.5 ºC or oral temperature ≥ 38.0 ºC or tympanic/rectal temperature ≥ 38.5 ºC; or history of fever during the previous 24 hours (at least documented verbally)
- •Negative pregnancy test for patients of childbearing potential
- •Signed informed consent must be obtained before any assessment is performed; for minors, signed informed consent must be obtained from parent/legal guardian. If the parent/legal guardian is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients who are capable of providing assent, must provide it along with parent/legal guardian consent or as per local ethical standards
- •The patient and/or their parent/legal guardian is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned.
排除标准
- •(Core phase)
- •Signs and symptoms of severe malaria according to WHO 2015 (World Health Organization)
- •Concurrent febrile illnesses (e.g., typhoid fever, known or suspected dengue fever, known COVID19)
- •Severe malnutrition. For patients ≥ 12 years: body mass index (BMI) < 16.
- •For children < 12 years: less than 70% of median normalized WHO reference weight or very low mid-upper arm circumference (MUAC < 115 mm)
- •Repeated vomiting (defined as > 3 times in the 24 hours prior to start of screening) or severe diarrhea (defined as > 3 watery stools in the 24 hours prior to start of screening)
- •Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia
- •Anemia (hemoglobin level <7 g/dL)
- •Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (e.g., Human immunodeficiency virus (HIV) patients on antiretroviral therapy (ART) or tuberculosis (TB) patients on treatment), or which may jeopardize the patient in case of participation in the study.
- •Any of the following:
- •Aspartate Aminotransferase/ Alanine Aminotransferase (AST/ALT) > 3 x the upper limit of normal (ULN), regardless of the level of total bilirubin
- •Total bilirubin > 3 x ULN
- •Resting QT interval corrected by Fridericia's formula (QTcF) > 450 ms at screening
- •Prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five plasma half-lives (or within 4 weeks of screening if half-life is unknown)
- •History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease
- •Pregnant or nursing (lactating) patients.
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
KLU156
KLU156 once daily (QD) for 3 days under fed conditions (light meal).
干预措施: KLU156 (Drug)
Coartem
Coartem twice a day (BID) for 3 days under fed conditions.
干预措施: Coartem (Drug)
结局指标
主要结局
PCR-corrected adequate clinical and parasitological response (ACPR)
时间窗: Day 29 (i.e., 28 days post-first dose administration)
To confirm the efficacy of KLU156 in adults and children ≥ 10 kg of body weight suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) by demonstrating that KLU156 is non-inferior to Coartem (non-inferiority margin = 5%) based on the PCR-corrected ACPR at Day 29. This primary outcome is applicable to non-US submission.
Uncorrected ACPR (US NDA submission)
时间窗: Day 29
To further confirm the efficacy of KLU156 by demonstrating non-inferiority of KLU156 to Coartem (NI margin 7.5%) based on the uncorrected ACPR at Day 29. This primary outcome is applicable to US New Drug Application (NDA) submission.
次要结局
- Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)(Day 43)
- Uncorrected ACPR(Day 29)
- PCR-corrected and uncorrected ACPR(Days 22 and 43 (i.e., 21 and 42 days post-first dose administration))
- Incidence rate of recrudescence and new infection(Days 22, 29 and 43)
- Fever Clearance Time(Up to Day 3)
- Parasite Clearance Time(Up to Day 3)
- Gametocyte Clearance Time(Up to Day 3)
- Proportion of patients with parasitemia(12, 24, 48 and 72 hours after treatment)
- Gametocytemia(From baseline up to Day 43)
- Extension phase: PCR-corrected and uncorrected ACPR(Day 29 of malaria episode)
- Extension phase: KLU156-related AE/SAE incidence and severity by malaria episode(Up to 2 years)
- Extension phase: Gametocyte carriage over time(Up to 2 years)