Efficacy and Safety of LEAF-4L6715 for Acute Respiratory Distress Syndrome

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: LEAF-4L6715; Drug: Supportive Care

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.

• Study Type: Interventional
• Enrollment (Estimated): 310
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ute Windhovel, Ph.D.; Phone Number: (609) 2168944; Email: uwindhovel@cerc-europe.org
• Study Contact Backup: Name: Solenne Paiva, Ph.D.; Email: spaiva@cerc-europe.org

Study Locations

• France
  • Paris, France
    • Sorbonne University
    • Contact: Alain Combes, MD
    • Contact: Alain Combes; Phone Number: +33 (0)1 42 16 38 18; Email: alain.combes@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: LEAF-4L6715; LEAF-4L6715: Administration at a dose of 200mg , for up to 10 days every 12 hours for the first 2 days, followed by once-a-day dosing for the next 8 days (days 3 through 10).; Other Names: Liposomal transcrocetin; Drug: Supportive Care; 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
Active Comparator: 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	Drug: Supportive Care; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days free from invasive mechanical ventilation	From Randomization to Day 30	30 Days
30 Day All-Cause Mortality	Survival at Day 30	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean total of Sequential Organ Failure Assessment (SOFA) score	Mean total of Sequential Organ Failure Assessment (SOFA) score and sub-scores during the treatment period.	30 days
Need for rescue procedures	Need for rescue procedures such as prone positioning, inhaled nitric oxide (NO), recruitment maneuvers, extracorporeal membrane oxygenation (ECMO).	30 days
Ventilator-associated pneumonia treated with antibiotics between randomization and 30 days.	Proportion of patients with 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	Number of days alive without organ failure at 30 days and 60 days, using the SOFA score and its components	60 days
Mean reduction in the WHO 9-point Ordinal Scale score	Mean reduction in the WHO 9-point Ordinal Scale score from start of treatment to 30 days	30 days
Length of ICU stay	Number of days patient was in Intensive Care Unit	60 days
Length of hospital stay	Number of days patient stayed in hospital	60 Days
Incidence of serious adverse events (SAEs), AEs, and treatment-emergent adverse events	Incidence of serious adverse events (SAEs), AEs, and treatment-emergent adverse events by maximum Common Terminology Criteria for Adverse Events (CTCAE) grade and/or change in baseline laboratory values	90 Days or event resolution/stabilization
Change in Quality of Life (QOL) by Health economics and outcomes research assessments	Change in Quality of Life (QOL) by Health economics and outcomes research assessments: to compare patient QOL using European QOL Five Dimension (EQ-5D-5L)	90 days
Survival at 30, 60 and 90 days	Number of patients alive at 30, 60 and 90 days from randomization.	90 days
PaO2/FiO2 ratio	Number of patients with an improvement of 25% in PaO2/FiO2 ratio at 72 hours post-treatment initiation and over time until acute treatment discontinuation.	30 days
Time to successful extubation	Time in hours to successful extubation without re-intubation or death within the next 48 Hours	30 days
Total duration of mechanical ventilation	Total duration of MV in days and the number of days, between randomization and 30 days, alive without MV.	30 days
Pharmacokinetics (PK) assessments	12. Maximum plasma concentration (Cmax) , units μg/ml	Day 1, Day 3, Day 14 and Day 30
Pharmacokinetic (PK) Assessments	Area under the curve (AUC) units h*μg/ml	Day 1, Day 3, Day 14 and Day 30

Collaborators and Investigators

• Sponsor: LEAF4Life, Inc.
• Collaborators: Cardiovascular European Research Center (CERC)
• Investigators: Principal Investigator: Alain Combes, MD, Hopital de La Pitie Salpetriere; Study Director: Marie Claude Morice, Ph.D., CERC - CARDIOVASCULAR EUROPEAN RESEARCH CENTER; Study Chair: Clet Niyikiza, Ph.D., LEAF4Life, Inc.

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2024
• Primary Completion (Estimated): November 9, 2026
• Study Completion (Estimated): November 9, 2027

Study Registration Dates

• First Submitted: August 9, 2024
• First Submitted That Met QC Criteria: October 11, 2024
• First Posted (Actual): October 15, 2024

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 11, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: ARDS
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protective Agents; Antioxidants; Anticarcinogenic Agents; Trans-sodium crocetinate
• Other Study ID Numbers: LEAF-4L6715-03-01-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes