A Phase 2 Interventional, Multicenter, Randomized Open Label Study to Determine the Effective and Tolerable Dose of KAF156 and Lumefantrine Solid Dispersion Formulation in Combination, Given Once Daily for 1, 2 and 3-days to Adults and Children With Uncomplicated Plasmodium Falciparum Malaria
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 524
- 试验地点
- 1
- 主要终点
- Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29
研究概览
简要总结
This study was designed to determine the most effective and tolerable dose at the shortest dosing regimen of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in adult/adolescent and pediatric patients with uncomplicated Plasmodium falciparum malaria.
There is unmet medical need for anti-malarial treatment with new mechanism of action to reduce probability of developing resistance, and for duration shorter than 3 days of treatment and/or reduced pill burden.
详细描述
This was a Phase 2 multi-center and open-label study with a single cohort pharmacokinetic (PK) Run-in Part followed by 2 randomized parallel-group parts, Part A and Part B, in adults and children with confirmed and uncomplicated Plasmodium falciparum malaria. Each part (PK Run-in, Part A and Part B) had the same design structure: A screening phase of up to 24 hours where participants were evaluated for eligibility and randomized (Part A and B) into different cohorts. A treatment phase of up to 3 days where participants were treated for 1, 2 or 3 consecutive days. Finally, participants were followed up until Day 43, where the rescue medication was the local standard at the discretion of the Investigator and participants
PK Run-in part: Adult/adolescent participants (≥ 12 years old) were dosed with a single dose of 200 mg KAF156 and 960 mg LUM-SDF at Day 1. The purpose of this part was to assess potential PK interactions between the compounds when dosed together.
Part A: Adult/adolescent participants (≥ 12 years old) were randomized into one of seven cohorts in a 2:2:2:2:2:2:1 ratio: six KAF156 and LUM-SDF cohorts at starting doses of 400 mg and 480 mg once daily (QD) for 1 day respectively and a control arm (Coartem twice a day (BID) for 3 days). Upon completion of Part A, all the dosing groups were evaluated in an interim assessment to determine the effective and tolerated KAF156 and LUM-SDF dosing regimen and dosages to be used in Part B.
Part B: Children participants (2 to < 12 years old) were randomized to three KAF156 and LUM-SDF cohorts at dosages and dosing regimens selected from Part A and the control arm (Coartem) in a 2:2:2:1 ratio.
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)
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Part A: male and female patients ≥ 12 years and with a body weight ≥ 35.0 kg. Part B: after determining the effective/tolerated doses and regimens in adolescent and adult patients, male and female patients ≥ 2 and < 12 years and with a body weight ≥ 10.0 kg will be included.
- •Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films.
- •P. falciparum parasitaemia of more than 1000 and less than 150 000 parasites/µL at the time of pre-screening (i.e., Study Visit 1).
- •Axillary temperature ≥ 37.5 ºC or oral/tympanic/rectal temperature ≥ 38.3 ºC; or similar history of fever during the previous 24 hours (history of fever must be documented).
- •Written informed consent must be obtained before any assessment is performed. If the patient is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients < 18 years old, who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines.
排除标准
- •Mixed Plasmodium infections.
- •Signs and symptoms of severe malaria according to WHO (World Health Organization) 2015 criteria unless characterized by high parasitaemia only.
- •Patients with concurrent febrile illnesses (e.g., typhoid fever).
- •Severe vomiting, defined as more than 3 times in the 24 hours prior to inclusion in the study or severe diarrhea defined as more than 3 watery stools per day.
- •Pregnant or nursing (lactating) women.
- •Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia.
- •Anemia (Hemoglobin level < 8 g/dL).
- •Patients with prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five (5) 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 (heart rate-corrected QT) interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease.
- •Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the patient in case of participation in the study. The investigator should make this determination in consideration of the patient's medical history and/or clinical or laboratory evidence of any of the following:
- •AST/ALT > 2 x the upper limit of normal range (ULN), regardless of the level of total bilirubin
- •AST/ALT > 1.5 and ≤ 2 x ULN and total bilirubin is > ULN
- •Total bilirubin > 2 x ULN, regardless of the level of AST/ALT
研究组 & 干预措施
Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day
Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
干预措施: KAF156 (Drug)
Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day
Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 day
Participants received a single oral dose of KAF156 800 mg and LUM-SDF 960 mg
干预措施: KAF156 (Drug)
Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 day
Participants received a single oral dose of KAF156 800 mg and LUM-SDF 960 mg
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 days
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
干预措施: KAF156 (Drug)
Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 days
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 days
Participants received KAF156 200 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
干预措施: KAF156 (Drug)
Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 days
Participants received KAF156 200 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 days
Participants received KAF156 400 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
干预措施: KAF156 (Drug)
Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 days
Participants received KAF156 400 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 days
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
干预措施: KAF156 (Drug)
Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 days
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part A - Cohort 7: Coartem
Participants received Coartem twice daily via oral administration for 3 days
干预措施: Coartem (Drug)
PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 day
Participants received a single oral dose of KAF156 200 mg and LUM-SDF 960 mg
干预措施: KAF156 (Drug)
PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 day
Participants received a single oral dose of KAF156 200 mg and LUM-SDF 960 mg
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day
Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
干预措施: KAF156 (Drug)
Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day
Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 days
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
干预措施: KAF156 (Drug)
Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 days
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 days
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
干预措施: KAF156 (Drug)
Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 days
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
干预措施: Lumefantrine Solid Dispersion Formulation (Drug)
Part B - Cohort 4: Coartem
Participants received Coartem twice daily via oral administration for 3 days
干预措施: Coartem (Drug)
结局指标
主要结局
Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29
时间窗: 28 days post first dose
PCR-corrected ACPR defined as the absence of parasitaemia was evaluated at Day 29 (i.e., 28 days post first dose) based on the short half-life of the study drugs. Microscopic species identification was confirmed and determined by PCR genotyping methods to establish malaria recrudescence/reinfection. A participant was considered as PCR-corrected ACPR at Day 29 if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and was absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days was due to reinfection based on PCR. A presence of parasitaemia after 7 days of treatment initiation was considered as a reinfection only if the parasitaemia was clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later matched with the parasite strain at baseline based on PCR.
PK Run-in: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Treatment Dose (AUC0-24h) of KAF156
时间窗: 0, 1, 3, 6, 12, 18 and 24 hours post-dose
Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. AUC0-24h was determined using non-compartmental methods.
次要结局
- PK Run-in, Part A and Part B: Number of Participants With Parasitaemia(12, 24 and 48 hours post last dose)
- Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR)(14, 28 and 42 days post first dose)
- Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR)(14 and 42 days post first dose)
- Part A and Part B: Number of Participants With Recrudescence Events(42 days post first dose)
- Part A and Part B: Number of Participants With Reinfection Events(42 days post first dose)
- Part A and Part B: Fever Clearance Time (FCT)(42 days post first dose)
- PK Run-in, Part A and Part B: Parasite Clearance Time (PCT)(42 days post first dose)
- Part A and Part B: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Last Treatment Dose (AUC0-24h) of KAF156(3, 6, 18 and 24 hours post last dose)
- Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156(3, 6, 18, 24, 27, 30, 48, 51, 54, 68, 72 and 168 hours post last dose)
- PK Run-in and Part A: Elimination Half-life (T½) of KAF156(0, 1, 3, 6, 12, 18, 24, 27, 30, 36, 48, 72, 96 and 168 hours post last dose)
- PK Run-in and Part A (Cohorts 1 and 2): Time to Reach Maximum Blood Concentrations (Tmax) of KAF156(0, 1, 3, 6, 12, 18, 24, 30, 48, 96 and 168 hours post last dose)