Clinical trial NCT06640777: Efficacy and Safety of LEAF-4L6715 for Acute Respiratory Distress Syndrome
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Acute Respiratory Distress Syndrome
Keywords: ARDS
Lead sponsor: LEAF4Life, Inc.
Sponsor class: INDUSTRY
Collaborators: name: European Cardiovascular Research Center
First posted: 2024-10-15
Enrollment: 310
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, international, multicenter, open label, randomized, controlled, two-arm study.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Patients will be included if all of the following criteria are met:

  1. Patients ≥18 years old
  2. 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
  3. 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
  4. Patient with an endotracheal tube or tracheostomy tube and receiving MV support
  5. Life expectancy of at least 24 hours from randomization
  6. Alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) \< 3 x upper limit of normal at the time of randomization
  7. Male or non-pregnant female patient
  8. Affiliated to a social security system (for France)

Exclusion Criteria:

1. Enrolled in any other therapeutic clinical trial or receiving an experimental drug (only observational studies allowed)
2. Hypersensitivity to crocetins, LEAF 4L6715 or any of its excipients.
3. Receiving extracorporeal membrane oxygenation (ECMO) treatment
4. On MV for more than 7 days
5. Chronic Obstructive Pulmonary Disease (COPD) or other respiratory insufficiency with home ventilation or oxygen therapy
6. Severe underlying pre-existing condition with expected 6 months mortality \>50% or survival \<50%
7. Patient moribund, decision to limit therapeutic interventions
8. Unwilling or unable to comply with study procedures
9. Under guardianship, curatorship or safeguard of justice (for France)

Primary outcomes:
measure: Days free from invasive mechanical ventilation
timeFrame: 30 Days
measure: 30 Day All-Cause Mortality
timeFrame: 30 days
Secondary outcomes:
measure: Mean total of Sequential Organ Failure Assessment (SOFA) score
timeFrame: 30 days
measure: Need for rescue procedures
timeFrame: 30 days
measure: Ventilator-associated pneumonia treated with antibiotics between randomization and 30 days.
timeFrame: 30 days
measure: Number of days alive without organ failure at 30 days and 60 days
timeFrame: 60 days
measure: Mean reduction in the WHO 9-point Ordinal Scale score
timeFrame: 30 days
measure: Length of ICU stay
timeFrame: 60 days
measure: Length of hospital stay
timeFrame: 60 Days
measure: Incidence of serious adverse events (SAEs), AEs, and treatment-emergent adverse events
timeFrame: 90 Days or event resolution/stabilization
measure: Change in Quality of Life (QOL) by Health economics and outcomes research assessments
timeFrame: 90 days
measure: Survival at 30, 60 and 90 days
timeFrame: 90 days
measure: PaO2/FiO2 ratio
timeFrame: 30 days
measure: Time to successful extubation
timeFrame: 30 days
measure: Total duration of mechanical ventilation
timeFrame: 30 days
measure: Pharmacokinetics (PK) assessments
timeFrame: Day 1, Day 3, Day 14 and Day 30
measure: Pharmacokinetic (PK) Assessments
timeFrame: Day 1, Day 3, Day 14 and Day 30
Other outcomes:
Locations:
city: Paris
country: France
facility: Sorbonne University
Study officials:
affiliation: Hôpital de la Pitié Salpêtrière
name: Alain Combes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CERC - CARDIOVASCULAR EUROPEAN RESEARCH CENTER
name: Marie Claude Morice, Ph.D.
role: STUDY_DIRECTOR
affiliation: LEAF4Life, Inc.
name: Clet Niyikiza, Ph.D.
role: STUDY_CHAIR
References: