Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 3 Doses of MOTREM in Patients With Septic Shock. A Randomised, Double-blind, Two-Stage, Placebo Controlled Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Inotrem
- 入组人数
- 50
- 试验地点
- 4
- 主要终点
- Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion
研究概览
简要总结
This is a randomised, double-blind, two-stage, placebo controlled study. It is designed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of 3 doses of nangibotide versus placebo in adult patients with septic shock.
详细描述
This was a randomised, double-blind, two-stage, placebo-controlled study. It was composed of 2 stages with a similar treatment regimen in which 0.3, 1.0 or 3.0 mg/kg/h of nangibotide was tested versus placebo.
Stage 1 was performed to investigate ascending doses of nangibotide or placebo in a sequential design in cohorts of 4 patients (3:1 randomisation). After completion of a cohort (for up to 5 days of infusion), safety and available PK data were blindly reviewed by an independent data safety monitoring board (DSMB) before progressing to the next cohort. After completion of stage 1 DSMB evaluation, the study progressed to stage 2.
Stage 2 investigated 3 doses of nangibotide in a randomised, balanced, parallel-group design involving up to 3 doses of nangibotide and a placebo arm. Only dose arms of nangibotide considered to be safe and well tolerated during Stage 1 were to be administered in Stage 2.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provide written informed consent (proxy/legal representative) according to local regulations
- •Age 18 to 80 years
- •Documented or suspected infection: lung, abdominal or elderly UTI (≥65 years)
- •Organ dysfunction defined as acute change in SOFA score ≥ 2 points
- •Refractory hypotension requiring vasopressors to maintain MAP ≥65mm Hg despite adequate volume resuscitation of at least 20 ml/kg within 6 hours
- •Hyperlactatemia (blood lactate >2 mmol/L or 18 mg/dL). This criterion must be met at least once for the purpose of diagnosis within the 24 hours before study drug administration
排除标准
- •Previous episode of septic shock (vasopressor administration) within current hospital stay
- •Underlying concurrent immunodepression (specified in appendix 2)
- •Solid organ transplant requiring immunosuppressive therapy
- •Known pregnancy (positive serum pregnancy test)
- •Prolonged QT syndrome (QTc ≥ 440 ms)
- •Shock of any other cause, e.g. hypotension related to gastrointestinal bleeding
- •Ongoing documented or suspected endocarditis, history of prosthetic heart valves
- •End-stage neurological disease
- •End-stage cirrhosis (Child Pugh Class C)
- •Acute Physiology And Chronic Health Evaluation (APACHE) II score ≥ 34
- •End stage chronic renal disease requiring chronic dialysis
- •Home oxygen therapy on a regular basis for > 6 h/day
- •Severe obesity (BMI ≥ 40)
- •Recent CPR (within current hospital stay)
- •Moribund patients
- •Decision to limit full care taken before obtaining informed consent
- •Participation in another interventional study in the 3 months prior to randomisation
研究组 & 干预措施
nangibotide 0.3 mg/kg/h
干预措施: Nangibotide 0.3 mg/kg (Drug)
nangibotide 1.0 mg/kg/h
干预措施: Nangibotide 1 mg/kg (Drug)
nangibotide 3.0 mg/kg/h
干预措施: Nangibotide 3 mg/kg (Drug)
Placebo to nangibotide
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion
时间窗: Adverse events experienced until D28 (End of study visit)
Analyses were performed in the Safety Set composed of all randomized patients who received at least any dose of the study drug (nangibotide or placebo). Adverse events: Summary statistics of treatment emergent adverse events (TEAEs). Clinical events, including death, related to severe sepsis and sepsis complications were exempt from SAE reporting, unless the investigator deemed the event to be related to the administration of the study drug.
Systolic Blood Pressure (SBP)
时间窗: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5) and on final study day at day 28 (D28).
Systolic blood pressure measured by sphygmomanometer at study site. Median SBP at each visit is summarized by treatment group.
Diastolic Blood Pressure (DBP)
时间窗: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5) and on final study day at day 28 (D28).
Median DBP at each visit is summarized by treatment group.
Median Arterial Pressure (MAP)
时间窗: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5) and on final study day at day 28 (D28).
MAP at each visit is summarized by treatment group.
Heart Rate
时间窗: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5).
Median heart rate at each visit is summarized by treatment group.
Temperature
时间窗: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5).
Median temperature at each visit is summarized by treatment group.
Electrocardiogram
时间窗: Electrocardiogram was performed each day from D0 (before IMP initiation) to D5 (EOI) and on D28 (EOS).
Abnormal and emergent clinically significant electrocardiogram were summarized for each group.
Anti-Drug Antibodies (ADA Dimer)
时间窗: Anti-Drug Antibodies test were done at D0, D10 and D28 in all patients.
Anti-Drug Antibodies test was performed for all patients.
Anti-Drug Antibodies (ADA Monomer)
时间窗: Anti-Drug Antibodies test were measured at D0, D10 and D28.
Anti-Drug Antibodies test was performed for all patients.
次要结局
- Pharmacokinetic Parameters From the Non-compartmental Analysis: Cmax(Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI)
- Pharmacokinetic Parameters From the Non-compartmental Analysis: Tmax(Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI)
- Pharmacokinetic Parameters From the Non-compartmental Analysis: AUC0-last(Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI)
- Pharmacokinetic Parameters From the Non-compartmental Analysis: Cavg(Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI)
- Pharmacokinetic Parameters From the Non-compartmental Analysis: CL(Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI)