FX06 to Rescue Acute Respiratory Distress Syndrome During Covid-19 Pneumonia (FX-COVID)

Vascular leakage following endothelial injury, responsible for interstitial and alveolar edema, is a major feature of pathogen induced acute lung injury. As acute respiratory distress syndrome (ARDS) due to pandemic Covid-19 is associated with more than 60% mortality, controlling vascular leakage may be a major target to decrease the mortality associated with the spreading of the disease in France.

FX06, a drug under clinical development containing fibrin-derived peptide beta15-42, is able to stabilize cell-cell interactions, thereby reducing vascular leak and mortality in several animal models, particularly during lipopolysaccharide-induced and dengue hemorrhagic shock . A phase I study was conducted in humans, with no specific adverse event detected with a dose up to 17.5 mg/kg. In a phase II randomized multicentre double-blinded trial in 234 patients suffering from ST+ acute coronary syndrome, FX06 treated patients exhibited a 58% decrease in the early necrotic core zone. Importantly, adverse events were highly comparable between groups, indicating a high safety profile for the drug . Lastly, the drug was used as a salvage therapy in a patient exhibiting a severe ARDS following EBOLA virus infection . Altogether, those data indicate that FX06 is well tolerated in humans and is a potent regulator of vascular leakage.

Our hypothesis here is that FX06 may decrease pulmonary vascular hyperpermeability during ARDS following SARS-CoV-2 infection, thereby improving gas exchanges and the outcome of infected patients.

Study Overview

• Status: Completed
• Conditions: Pneumonia; Covid19; Ards
• Intervention / Treatment: Drug: FX06; Drug: Placebo of FX06

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France, 49933
    • Service de Médecine Intensive Réanimation - CHU Angers
  • Chambourcy, France, 78240
    • Service de Médecine Intensive Réanimation - CHI de Poissy
  • Paris, France, 75013
    • Hopital Pitie Salpetriere

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. SARS-CoV-2 induced pneumonia confirmed by a positive PCR test in nasopharyngeal swab or respiratory tract secretions and ≤ 85 years
3. Acute respiratory distress syndrome (ARDS) according to Berlin criteria (bilateral pulmonary infiltrates on frontal chest x-ray, PaO2/FiO2 ratio ≤300 mmHg, objective assessment excluding hydrostatic pulmonary edema)
4. Need for endotracheal intubation and mechanical ventilation
5. Informed consent by patient or legal representative. According to the specifications of emergency consent, randomization without the close relative or surrogate consent could be performed.
6. Affiliated to a social security system
7. Highly effective method of contraception and negative highly sensitive pregnancy test, for women of childbearing potential

Exclusion Criteria:

1. Mechanically ventilation for more than 4 days
2. Patient receiving drugs interfering with inflammation: Non-steroidal anti-inflammatory drugs, immunoglobulins.
3. Patients receiving chemotherapy, radiotherapy or immunotherapy for malignancy
4. Participation in another interventional clinical trial
5. Pregnant or lactating women
6. Patient moribund on the day of randomization, defined by a SAPS-II score>90
7. Contra-indication for vascular access implantation for transpulmonary thermodilution monitoring
8. Severe or terminal renal insufficiency (creatinine clearance <30 ml/min)
9. Severe hepatic insufficiency (hepatic SOFA score>2)
10. Severe cardiac insufficiency, with left ventricular ejection fraction<30%
11. Any history of severe allergic drug reaction (anaphylactic shock or allergic angioedema)
12. Persons deprived of their liberty by a judicial or administrative decision (guardianship or tutelage measure)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo of FX06; Placebo i.v.: 400 mg per day (divided in two injections) during 5 days
EXPERIMENTAL: FX06	Drug: FX06; FX06 i.v.: 400 mg per day (divided in two injections) during 5 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in extravascular lung water index (EVLWi)	Assessed by transpulmonary thermodilution Transpulmonary thermodilution systems, part of the standard management in ICU, allow a direct evaluation of vascular hyperpermeability in the lungs using thermodilution technique. EVLWi is a reliable parameter, independently associated with mortality during ARDS	Between Day 1 and Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolution of daily extravascular lung water index (EVLWi)	measured by transpulmonary thermodilution during 7 days	Between Day 1 and Day 7
Evolution of daily cardiac index	measured by transpulmonary thermodilution during 7 days	Between Day 1 and Day 7
Evolution of global end-diastolic volume index	measured by transpulmonary thermodilution during 7 days	Between Day 1 and Day 7
Evolution of pulmonary vascular permeability index	measured by transpulmonary thermodilution during 7 days	Between Day 1 and Day 7
Overall survival		Day 30
Mortality rate in ICU and in hospital		Through study completion an average of 2 months
Rate of withdraw or withhold life-sustaining treatments decision		Day 30
Daily weight		Between Day 1 and Day 7
Daily fluid balance		Between Day 1 and Day 7
Evolution of albuminemia	Evolution of blood biological criteria (g/L)	Between Day 1 and Day 7
Duration of mechanical ventilation		Day 30
Proportion of participants alive and off invasive mechanical ventilation		Day 30
Evolution of Murray ARDS severity score		Day 1 to day 15
Evolution of radiological Weinberg score	Scale from 0 to 12 better with higher score indicating more severe radiological pulmonary severity	Day 1 to Day 30
Evolution of pulmonary Sequential Organ Failure Assessment) score.	Scale from 0 to 4 betterwith higher score indicating more severe pulmonary disease	Day 1 to day 15
Rate of rescue therapy with Veino-veinous V-ECMO		Through study completion an average of 2 months
Evolution of SOFA (Sequential Organ Failure Assessment) score	Scale from 0 to 24, lower is better.	Day 15
Organ failure free days	one or more SOFA sub-score >=3	Day 15
Renal replacement therapy free days		Day 30
Duration of renal replacement therapy free days		Day 30
Nature and frequency of adverse events		Through study completion an average of 2 months
Evolution of FX06 concentration	measured at day 1 at time 0 (before FX06 application) and after 5, 15, 30, 60 min	Day 1
Immunogenicity (antibody against FX06) induced by the drug, performed by ELISA according to manufacturer's procedure	A test for immunogenicity will be performed on a serum sample at day 7 (2 days after the end of treatment administration) to detect any antibody against FX06. The assay will consist in a three-fold procedure, as recommended by the manufacturer. An initial screening assay will qualitatively measure antibodies to FX06. Samples deemed positive will be subject to a confirmatory assay, which will determine the specificity of the detected antibody against FX06. The third tier of the assay will consist in titre analysis to semi-quantitatively assess the antibody response.	Day 7

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 13, 2020
• Primary Completion (ACTUAL): May 14, 2021
• Study Completion (ACTUAL): June 13, 2021

Study Registration Dates

• First Submitted: October 23, 2020
• First Submitted That Met QC Criteria: November 4, 2020
• First Posted (ACTUAL): November 5, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 22, 2021
• Last Update Submitted That Met QC Criteria: June 21, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: FX06; Pulmonary vascular hyperpermeability
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; COVID-19; Pneumonia; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: APHP200495; 2020-002056-20 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No