A Phase 2 Interventional, Multicenter, Randomized, Open-label Study in Three Age-descending Cohorts to Evaluate Efficacy, Safety and Tolerability of KAF156 and Lumefantrine-SDF Combination in the Treatment of Acute Uncomplicated Plasmodium Falciparum Malaria in a Pediatric Population
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 295
- 试验地点
- 10
- 主要终点
- PCR-corrected adequate clinical and parasitological response (ACPR) at Day 29 (i.e., 28 days post-dose) (Cohorts 1 and 2 pooled).
研究概览
简要总结
This study aimed to determine the efficacy, safety and tolerability of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in pediatric patients (6 months to < 18 years of age) with uncomplicated P. falciparum malaria. There is an unmet medical need for anti-malarial treatment with a new mechanism of action to reduce the probability of developing resistance.
详细描述
This Phase 2 study aimed to evaluate the efficacy, safety and tolerability of the investigational drug KAF156 and a Solid Dispersion Formulation of lumefantrine (LUM-SDF) when administered in combination in pediatric patients 6 months to < 18 years of age with uncomplicated Plasmodium falciparum malaria. In addition, pharmacokinetics (PK) of the drug combination was also evaluated.
There were three age-descending cohorts in the study: Run-in Cohort (12 years to < 18 years), Cohort 1 (2 years to < 12 years) and Cohort 2 (6 months to < 2 years). The rationale for separated cohorts 1 and 2 was to allow enrolment of the youngest patients (cohort 2) after safety and exposure review of older patients in cohort 1. Given the age-independent symptoms of acute malaria, and to increase statistical power, for all outcomes measures the cohorts 1 and 2 were pooled (cohort 1/2). This new study first explored the effect of food on lumefantrine and KAF156 pharmacokinetics (PK) in patients 12 to < 18 years old with malaria caused by P. falciparum. Based on the data from the Run-in Cohort, recommendation on dose, dosing regimen, dosage administration (with food) and duration were provided before younger patients in Cohorts 1 and 2 were dosed with KAF156/LUM-SDF. Then, efficacy, safety, tolerability and PK of the combination of KAF156/LUM-SDF in comparison with Coartem®(Artemether/Lumefantrine) were evaluated in younger patients, in pooled Cohort 1/2.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Treatment and food condition during the Run-in cohort will be open to patients/patients' parents/legal guardian, investigators staff and study monitors, as well as to the Clinical Trial Team (CTT) to allow continuous review of safety, drug exposure and efficacy data in pediatric population. For Cohorts 1 and 2, treatment/food condition will be open to patients/patients' parents/legal guardian, investigators staff and study monitors but will be blinded to the Clinical Trial Team (CTT).
入排标准
- 年龄范围
- 6 Months 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •In run-in cohort: Male and female patients 12 to < 18 years of age, with a body weight
- •35.0 kg In Cohort 1: Male and female patients 2 to < 12 years of age, with a body weight ≥ 10.0 kg In Cohort 2: Male and female patients 6 months to < 2 years of age, with a body weight
- •Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films
- •P. falciparum parasitemia of ≥ 1,000 and ≤ 150,000 parasites/μL at the time of prescreening for the Run-in Cohort; and P. falciparum parasitemia of ≥ 1,500 and ≤ 150,000 parasites/μL at the time of pre-screening for Cohorts 1 and 2
- •Axillary temperature ≥ 37.5 ºC or oral/tympanic/rectal temperature ≥ 38.0 ºC; or history of fever during the previous 24 hours (at least documented verbally)
- •Written informed consent has been obtained from parent / legal guardian before any assessment is performed. 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 assent with parental/legal guardian consent or as per local ethical guidelines
- •The patient and his/her 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
- •Mixed Plasmodium infections as per light microscopy results
- •Signs and symptoms of severe malaria according to WHO 2015 (see Section 16.4)
- •Significant, non-plasmodial co-infections including tuberculosis
- •Patients with concurrent febrile illnesses (e.g., typhoid fever, known or suspected COVID19)
- •Known relevant liver disease e.g. chronic hepatitis, cirrhosis, compensated or decompensated, history of hepatitis B or C, hepatitis B or A vaccination in last 3 months, known gallbladder or bile duct disease, acute or chronic pancreatitis
- •Major congenital defects
- •Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection or family history of congenital or hereditary immunodeficiency
- •Immunosuppressive therapy (steroids, immune modulators or immune suppressors) within 3 months prior to recruitment. (For corticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topical steroids are allowed)
- •Repeated 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 in the 24 hours prior to inclusion in the study)
- •Active duodenal ulcer, ulcerative colitis, Crohn's disease, chronic (i.e., > 2 weeks) use of non-steroidal anti-inflammatory drugs (NSAIDs)
- •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., HIV patients on ART therapy or TB patients on treatment), 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 > 3 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
- •Resting QT interval corrected by Fridericia's formula (QTcF) > 450 ms at screening
- •Creatinine > 2 x ULN in the absence of dehydration. In case of dehydration, creatinine should be < 2 x ULN after oral/parenteral rehydration
- •Any severe disease condition which might prohibit participation in this study
- •Known chronic underlying disease such as sickle cell disease, and severe cardiac, renal, or hepatic impairment
- •Known active or uncontrolled thyroid disease
- •Inability to swallow oral medication (in tablet and/or liquid form)
- •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)
- •Use of other investigational drugs within 30 days of dosing or until the expected pharmacodynamic effect has returned to baseline, whichever is longer
- •Patients taking medications prohibited by the protocol
- •Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance within 3 months of dosing
- •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
- •Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study
- •History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes
- •For the Run-in Cohort only:
- •Pregnant or nursing (lactating) patients
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of investigational drug. Basic contraception methods include:
- •Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- •Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- •Male sterilization (at least 6 m prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient
- •Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps).
- •Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug. Women are considered not of child bearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
- •For Cohorts 1 and 2 only:
- •Patients of child bearing potential, defined as all girls post first menarche (except for Run-in Cohort)
研究组 & 干预措施
Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition
KAF156 and LUM-SDF QD (once daily) for 2 days in fasted condition
干预措施: LUM-SDF (Drug)
Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition
KAF156 and LUM-SDF QD (once daily) for 2 days in fed condition
干预措施: LUM-SDF (Drug)
Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition
KAF156 and LUM-SDF QD (once daily) for 2 days in fasted condition
干预措施: KAF156 (Drug)
Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition
KAF156 and LUM-SDF QD (once daily) for 2 days in fed condition
干预措施: KAF156 (Drug)
Cohort 1/2 - Coartem® BID (twice a day) for 3 days
Coartem® BID twice a day for 3 days (It was administered with a light meal and doses were based on patient's body weight as per product label).
干预措施: Coartem (Drug)
结局指标
主要结局
PCR-corrected adequate clinical and parasitological response (ACPR) at Day 29 (i.e., 28 days post-dose) (Cohorts 1 and 2 pooled).
时间窗: Day 29
The primary efficacy variable is the PCR corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 (Cohorts 1 and 2 pooled). In case that Cohort 2 stops early, such as after the first 24 patients, the study objectives will be assessed based on Cohort 1 data alone. A patient is considered as PCR corrected ACPR at Day 29 if the patient does not meet any of the criteria of early treatment failure (ETF) (up to Day 4), late clinical failure (LCF) (Day 5 to Day 29) or late parasitological failure (LPF) (Day 8 to Day 29), and is absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days (Day 8 or later) is due to reinfection based on PCR genotyping. A presence of parasitaemia after 7 days of treatment initiation is considered as a reinfection only if the parasitaemia is clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later match with the parasite strain at baseline based on PCR genotyping.
次要结局
- Pharmacokinetic of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Maximum Observed Plasma Concentration (Cmax)(From Day 1 to Day 8)
- Percentage of Participants with Polymerase Chain Reaction (PCR)-corrected and uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and 43(Day 15, Day 43)
- Percentage of Participants with Polymerase Chain Reaction (PCR)-corrected and uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 (Run-in Cohort)(Day 29)
- Time to parasite clearance (PCT)(up to 43 days)
- Time to fever clearance (FCT)(up to 43 days)
- Proportion of patients with Late Clinical Failure (LCF)(Day 5 to Day 43)
- Proportion of patients with Late Parasitological Failure (LPF)(Day 8 to Day 43)
- Incidence rate of recrudescence and reinfection(Day 15, Day 29 and Day 43)
- Number of Participants with On-Treatments Adverse Events, Serious Adverse Events, and Deaths(Day 1 to Day 43)
- Proportion of patients with Early Treatment Failure (ETF)(Day 1 to Day 4)
- Pharmacokinetics of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Area Under the Plasma Concentration-time Curve (AUC)(From Day 1 to Day 8)
- Pharmacokinetic of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Time to reach the maximum concentration after drug administration (Tmax)(From Day 1 to Day 8)
- Pharmacokinetics of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Plasma drug concentration 168 hours post first dose administration (C168h)(Day 8)
- Pharmacokinetics of LUM from Coartem arm (Cohorts 1 and 2): Maximum Observed Plasma Concentration (Cmax)(From Day 1 to Day 8)
- Pharmacokinetics of LUM from Coartem arm (Cohorts 1 and 2): Plasma drug concentration 168 hours post first dose administration (C168h)(Day 8)