Multicenter, Randomized, Open-Label Phase 3 Study to Investigate Efficacy and Safety of Liposomal Transcrocetin(LEAF-4L6715) Plus Standard of Care Vs Standard of Care Alone for Treatment of Patients with Acute Respiratory Distress Syndrome
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 310
- 试验地点
- 1
- 主要终点
- Days free from invasive mechanical ventilation
研究概览
简要总结
Acute Respiratory Distress Syndrome (ARDS) is a serious condition where people in hospital care suddenly have trouble breathing because of infection, pneumonia, COVID-19 or other disease. People with ARDS may have to be put in an intensive care unit (ICU) and on a ventilator to help them breathe. This trial is to try to find out if injecting a product called LEAF-4L6715 makes the treatment better or worse than what is normally given. LEAF-4L6715 is a product that contains tiny bubbles to slowly release a substance named transcrocetin which scientific studies show may increase oxygen flow and reduce inflamed cells and protect tissues of the body.
详细描述
Study Design: Prospective, international, multicenter, open label, randomized, controlled, two-arm study.
Study Objective(s): The primary objective of the study is to determine if the addition of LEAF-4L6715 to Standard of Care (SOC) treatment may improve clinical outcomes at 30-days, including survival and duration of mechanical ventilation (MV), in patients with Acute Respiratory Distress Syndrome (ARDS) compared to SOC treatment alone.
The secondary objectives are to compare other relevant respiratory and clinical outcomes and safety between the two groups during Intensive Care Unit (ICU) stay, hospitalization, and follow-up, including percentage of patients alive at 60 days and 90 days from randomization.
Rationale: The scientific and clinical observations to date strongly suggest that transcrocetin (TC) may be a good candidate for the treatment of hypoxic conditions such as moderate to severe ARDS. Indeed, TC plays a major role in enhancing oxygen diffusion, but also in reducing inflammation and protecting tissues. However, TC's poor stability and solubility and its short in vivo half-life of ~30mins resulted in transient oxygenation effect. LEAF-4L6715 was designed to be a stable TC formulation with a 6-fold increase in half-life and a 12-fold increase in drug exposure compared to free TC, resulting in a more sustained oxygenation compared with free TC.
Developed as a liposomal formulation of TC, LEAF-4L6715 allows for a gradual release of the free drug and was evaluated at multiple levels (1) in vitro in Human Umbilical Vein Endothelial Cells (HUVECs); (2) in vivo in healthy mice (n=40) as well as in a mouse model of sepsis (n=10) and (3) in a clinical trial evaluating Pharmacokinetics (PK) and safety. A phase 1/2 trial which included 37 patients defined the optimal dose regimen and intravenous infusion timing and confirmed the safety of LEAF-4L6715. It also showed promising trends in therapeutic efficacy.
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
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients will be included if all of the following criteria are met:
- •Patients ≥18 years old
- •Signed and dated informed consent from patient's trusted person before any study related procedures, pursuing patient signature as soon as patient health condition allows
- •ARDS with a documented Positive End-Expiratory Pressure (PEEP) ≥5 and PaO2/FiO2 ratio of ≤200 mm Hg for a minimum of 24 hours prior to randomization
- •Patient with an endotracheal tube or tracheostomy tube and receiving MV support
- •Life expectancy of at least 24 hours from randomization
- •Alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) < 3 x upper limit of normal at the time of randomization
- •Male or non-pregnant female patient
- •Affiliated to a social security system (for France)
排除标准
- •Enrolled in any other therapeutic clinical trial or receiving an experimental drug (only observational studies allowed)
- •Hypersensitivity to crocetins, LEAF 4L6715 or any of its excipients.
- •Receiving extracorporeal membrane oxygenation (ECMO) treatment
- •On MV for more than 7 days
- •Chronic Obstructive Pulmonary Disease (COPD) or other respiratory insufficiency with home ventilation or oxygen therapy
- •Severe underlying pre-existing condition with expected 6 months mortality >50% or survival <50%
- •Patient moribund, decision to limit therapeutic interventions
- •Unwilling or unable to comply with study procedures
- •Under guardianship, curatorship or safeguard of justice (for France)
研究组 & 干预措施
LEAF-4L6715 (Liposomal Transcrocetin) + Supportive Care
LEAF-4L6715 administered Intravenously 200 mg every 12h for 2 days, then 200 mg Intravenously every 24 hours for 8 days (total 10 days dosing)
Supportive care, as considered necessary by the treating physician/Principal Investigator (PI), including mechanical ventilation, in line with therapeutic guidelines for ARDS and Multiorgan Failure
干预措施: LEAF-4L6715 (Drug)
LEAF-4L6715 (Liposomal Transcrocetin) + Supportive Care
LEAF-4L6715 administered Intravenously 200 mg every 12h for 2 days, then 200 mg Intravenously every 24 hours for 8 days (total 10 days dosing)
Supportive care, as considered necessary by the treating physician/Principal Investigator (PI), including mechanical ventilation, in line with therapeutic guidelines for ARDS and Multiorgan Failure
干预措施: Supportive Care (Drug)
Supportive Care
Description: Supportive care, as considered necessary by the treating physician/Principal Investigator (PI), including mechanical ventilation, in line with therapeutic guidelines for ARDS and Multiorgan Failure
干预措施: Supportive Care (Drug)
结局指标
主要结局
Days free from invasive mechanical ventilation
时间窗: 30 Days
From Randomization to Day 30
30 Day All-Cause Mortality
时间窗: 30 days
Survival at Day 30
次要结局
- PaO2/FiO2 ratio(30 days)
- Time to successful extubation(30 days)
- Total duration of mechanical ventilation(30 days)
- Pharmacokinetics (PK) assessments(Day 1, Day 3, Day 14 and Day 30)
- Mean total of Sequential Organ Failure Assessment (SOFA) score(30 days)
- Need for rescue procedures(30 days)
- Ventilator-associated pneumonia treated with antibiotics between randomization and 30 days.(30 days)
- Number of days alive without organ failure at 30 days and 60 days(60 days)
- Mean reduction in the WHO 9-point Ordinal Scale score(30 days)
- Length of ICU stay(60 days)
- Length of hospital stay(60 Days)
- Incidence of serious adverse events (SAEs), AEs, and treatment-emergent adverse events(90 Days or event resolution/stabilization)
- Change in Quality of Life (QOL) by Health economics and outcomes research assessments(90 days)
- Survival at 30, 60 and 90 days(90 days)
- Pharmacokinetic (PK) Assessments(Day 1, Day 3, Day 14 and Day 30)