An Adaptive, Randomized, Active-controlled, Open-label, Sequential Cohort, Multicenter Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of Intravenous Cipargamin (KAE609) in Adult and Pediatric Participants With Severe Plasmodium Falciparum Malaria (KARISMA - KAE609's Role In Severe Malaria)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 254
- 试验地点
- 10
- 主要终点
- Percentage of participants achieving at least 90% reduction in Plasmodium falciparum (P. falciparum) at 12 hours
研究概览
简要总结
The purpose of this study was to identify the safe and effective dose of intravenous cipargamin in participants with moderately severe and severe malaria.
The study also intended to evaluate clinical treatment success using a novel clinical endpoint for drug development in severe malaria.
Severe malaria is a medical emergency and is affecting primarily young children in Africa. Injectable artesunate is the standard of care for the treatment of severe malaria and is highly efficacious. However, the spread of artemisinin-resistance in Plasmodium falciparum in Asian countries poses a threat for future treatment of patients with this life-threatening disease. To mitigate this risk, there is a need for another drug in malaria-endemic countries. Cipargamin treatment results in rapid clearance of parasites, including artemisinin-resistant parasites.
详细描述
This study was an adaptive, multicenter, randomized, open label, sequential cohort study in participants aged ≥12 years old in Cohorts 1-2 and <12 years old to ≥6 months in Cohorts 3-5 with a diagnosis of moderately severe (Cohort 1) and severe P. falciparum malaria (Cohorts 2-5). This study investigated the efficacy (parasite reduction and clinical outcome), safety, tolerability, and pharmacokinetics (PK) of different intravenous (IV) dose regimens of cipargamin in comparison to IV artesunate.
Cohorts 1 and 2:
Participants were randomized to one of three treatment arms in a 1:1:1 ratio: two cipargamin-based treatment arms with dose levels of 20 mg and 40 mg, and the control arm with IV artesunate, a standard of care. The analysis of results from Cohorts 1 and 2 was planned to be used to determine the safe and efficacious exposure range and the corresponding dose (in a weight-adjusted manner) for the participants in Cohorts 3 to 5.
Cohorts 3 to 5:
Participants were randomized to 40 mg of cipargamin administered in a dose-adjusted manner and standard dose of IV artesunate in 1:1 ratio.
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
Although the study was open label, in order to minimize the potential impact of treatment knowledge, treatment allocation, dose information, PK/AAG assessment schedule and concentration data, as well as other data that could result in systematic unblinding, were not available to the Clinical Trial Team (CTT) (particularly clinicians, trial statisticians, trial programmers) until the database was locked after IA of Cohorts 1-2. After interim database lock, the CTT would be unblinded with the results, however, the blinding would then be continued for Cohorts 3-5 until the final database was locked.
入排标准
- 年龄范围
- 6 Months 至 100 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cohort 1: Participants aged ≥ 12 years with moderately severe malaria as defined in (prostration and/or repeated vomiting) without presence of other signs of severe malaria (and with high P. falciparum parasitemia (60,000-250,000 parasites per µl)
- •Subsequent Cohorts 2 to 5: Participants diagnosed with severe malaria as defined in modified version of WHO criteria and P. falciparum parasite count of ≥ 5000 per µl
- •Cohort 2: Participants aged ≥ 12 years
- •Cohort 3: Participants aged 6 - < 12 years
- •Cohort 4: Participants aged 2 - < 6 years
- •Cohort 5: Participants aged ≥ 6 months - < 2 years
排除标准
- •Exclusion criteria applying to all Cohorts 1 to 5:
- •Mixed Plasmodium infections
- •Treatment with quinine or artemisinin derivative or any other antimalarial drug or any antibiotic with known antimalarial activity within 12 hours of screening.
- •Signs/symptoms of severe malnutrition in general accordance with WHO guidelines:
- •Under 18 years: <-3 Z-scores of WHO growth standard for weight-for-height/length (in children < 5 years) or BMI for age (5-18 years), or very low mid-upper arm circumference (MUAC < 115 mm in children < 12 years, < 160mm 12-18 years), or bilateral pitting edema
- •Over 18 years: BMI < 16 kg/m2 or MUAC < 160mm or bilateral pitting edema
- •Known underlying illness, surgical or medical condition, which is not related to ongoing event of severe malaria and which might jeopardize the participant's health in case of participation in the study or which might alter the distribution, metabolism or excretion of study treatment. For example:
- •neurological or neurodegenerative disorders,
- •cardiac, renal, or hepatic disease, diabetes,
- •epilepsy, cerebral palsy,
- •known or suspected to be HIV-1 positive and/or receiving antiretroviral treatment
- •malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
- •known or suspected cases of active infections or concurrent febrile illness such as TB, Typhoid, COVID-19 etc.
- •Additional exclusion criteria are as follows:
- •Exclusion criteria for Cohort 1:
- •ALT > 5 x the upper limit of normal range (ULN), regardless the level of total bilirubin
- •Total bilirubin is > 3 mg/dL
- •Body weight of < 35 kg or >75 kg
- •Exclusion criteria for Cohort 2:
- •Body weight of < 35 kg or >75 kg
- •Participants diagnosed as moderately severe malaria due to repeated vomiting without presence of any of the symptoms of severe malaria
- •Exclusion criteria for Cohorts 3 to 5:
- •Body weight of < 5 kg
- •Participants diagnosed as moderately severe malaria due to repeated vomiting without presence of any of the symptoms of severe malaria
研究组 & 干预措施
IV Cipargamin 20 mg
Participants received intravenous cipargamin 20 mg, as a minimum of two doses every 24 hours, not exceeding 3 doses followed by oral medication (Coartem®, twice daily [b.i.d.] for 3 days).
干预措施: Coartem (Drug)
IV Cipargamin 40 mg
Participants received intravenous cipargamin 40 mg, as a minimum of two doses every 24 hours, not exceeding 3 doses followed by oral medication (Coartem®, twice daily [b.i.d.] for 3 days).
干预措施: Coartem (Drug)
IV Artesunate
Participants received IV artesunate according to label and followed by oral medication (Coartem® b.i.d. for 3 days).
干预措施: Coartem (Drug)
IV Artesunate
Participants received IV artesunate according to label and followed by oral medication (Coartem® b.i.d. for 3 days).
干预措施: IV Artesunate (Drug)
IV Cipargamin 40 mg
Participants received intravenous cipargamin 40 mg, as a minimum of two doses every 24 hours, not exceeding 3 doses followed by oral medication (Coartem®, twice daily [b.i.d.] for 3 days).
干预措施: Cipargamin (Drug)
IV Cipargamin 20 mg
Participants received intravenous cipargamin 20 mg, as a minimum of two doses every 24 hours, not exceeding 3 doses followed by oral medication (Coartem®, twice daily [b.i.d.] for 3 days).
干预措施: Cipargamin (Drug)
结局指标
主要结局
Percentage of participants achieving at least 90% reduction in Plasmodium falciparum (P. falciparum) at 12 hours
时间窗: Day 1 (12 Hours)
A blood draw will be performed at each collection time point for parasitemia assessment.
Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum) at 12 Hours
时间窗: 12 Hours
A blood draw was performed at each collection time point for parasitemia assessment.
次要结局
- Percentage of participants developing hemolysis (early and delayed) after treatment(Day 8 and Day 29)
- Percentage of participants achieving clinical success over time(Day 3 (48 Hours), Day 4 to Day 29)
- Percentage of participants with individual signs of severe malaria over time(Day 1 to Day 29)
- Percentage of participants achieving at least 90% reduction in Plasmodium falciparum (P. falciparum)(Day 2 (24 hours), Day 3 (48 hours))
- Number of Participants impacted on safety and tolerability assessments(Day 1 to Day 29)
- Observed maximum plasma concentration (Cmax) of IV Cipargamin(Day 1 - Day 8)
- Area Under the plasma concentration-time Curve from the time 0 to the last observed quantifiable concentration (AUC(0-t)) of IV Cipargamin(Day 1 - Day 8)
- Percentage of participants with neurological sequelae at Day 29(Day 29)
- Percentage of participants with recrudescence and reinfection(Day 29)
- Time to switch to oral therapy(Day 3 to Day 29)
- AUC(0-t) divided by the dose administered (AUC(0- t)/D) of IV Cipargamin(Day 1 - Day 8)
- Terminal elimination half life (T^1/2) of IV Cipargamin(Day 1 - Day 8)
- Time to parasite clearance (PCT)(Day 1 (12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours))
- Time to fever clearance (FCT)(Day 1 (12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours))
- Percentage of participants achieving P. falciparum parasite reduction ratios (PRR) at 12, 24 and 48 hours(Day 1 (12 hours), Day 2 (24 hours) and Day 3 (48 hours))
- Time to recover from prostration(Day 1 to Day 29)
- Time to discharge from hospital(Day 3 to Day 29)
- Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of IV Cipargamin(Day 1 - Day 8)
- Time of maximum observed drug concentration occurrence (Tmax) of IV Cipargamin(Day 1 - Day 8)
- Area under the concentration time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of IV Cipargamin(Day 1 - Day 8)
- Total systemic clearance for intravenous administration (CL) of IV Cipargamin(Day 1 - Day 8)
- volume of distribution during the terminal phase following intravenous elimination (Vz) of IV Cipargamin(Day 1 - Day 8)
- Percentage of Participants Achieving Clinical Success at 48 Hours(48 Hours)
- Percentage of Participants With Individual Signs of Severe Malaria Over Time(Baseline to Day 29)
- Percentage of Participants Developing Hemolysis (Early and Delayed) After Treatment(Day 8 and Day 29)
- Percentage of Participants With Neurological Sequelae at Day 29(Day 29)
- Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum)(24 hours and 48 hours)
- Time to Parasite Clearance (PCT)(Up to 72 hours)
- Parasite Clearance Estimator (PCE) Slope Half-life(Up to 72 hours)
- Time to Fever Clearance (FCT)(Up to 72 hours)
- P. Falciparum Parasite Reduction Ratios (PRR) at 12, 24 and 48 Hours(12 hours, 24 hours, and 48 hours)
- Percentage of Participants With Recrudescence and Reinfection(Day 29)
- Time to Switch to Oral Therapy(Day 3 to Day 29)
- Time to Discharge From Hospital(Day 3 to Day 29)
- Time to Recover From Prostration(Day 1 to Day 29)
- Number of Participants With Adverse Events or Serious Adverse Events, or Who Died(Day 1 to Day 29)
- Observed Maximum Plasma Concentration (Cmax) of IV Cipargamin(Day 1 - Day 8)
- Time of Maximum Observed Drug Concentration Occurrence (Tmax) of IV Cipargamin(Day 1 - Day 8)
- Area Under the Serum Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of IV Cipargamin(Day 1 - Day 8)
- Area Under the Concentration Time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUCinf) of IV Cipargamin(Day 1 - Day 8)
- Area Under the Plasma Concentration-time Curve From the Time 0 to 24 Hours (AUC0-24hours) of IV Cipargamin(Day 1 - Day 8)
- Terminal Elimination Half Life (T1/2) of IV Cipargamin(Day 1 - Day 8)
- Total Systemic Clearance for Intravenous Administration (CL) of IV Cipargamin(Day 1 - Day 8)
- Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) of IV Cipargamin(Day 1 - Day 8)