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

• ClinicalTrials.gov Identifier: NCT04618042
• Recruitment Status: Recruiting
• First Posted: November 5, 2020
• Last Update Posted: January 11, 2021
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Ards; Covid19; Pneumonia	Drug: FX06; Drug: Placebo of FX06	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: FX06 to Rescue Acute Respiratory Distress Syndrome During Covid-19 Pneumonia
• Actual Study Start Date: November 13, 2020
• Estimated Primary Completion Date: July 2021
• Estimated Study Completion Date: July 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: FX06	Drug: FX06; FX06 i.v.: 400 mg per day (divided in two injections) during 5 days
Placebo Comparator: Placebo	Drug: Placebo of FX06; Placebo i.v.: 400 mg per day (divided in two injections) during 5 days

Outcome Measures

Primary Outcome Measures :

1. Change in extravascular lung water index (EVLWi) [ Time Frame: Between Day 1 and Day 7 ]
   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

Secondary Outcome Measures :

1. Evolution of daily extravascular lung water index (EVLWi) [ Time Frame: Between Day 1 and Day 7 ]
   measured by transpulmonary thermodilution during 7 days
2. Evolution of daily cardiac index [ Time Frame: Between Day 1 and Day 7 ]
   measured by transpulmonary thermodilution during 7 days
3. Evolution of global end-diastolic volume index [ Time Frame: Between Day 1 and Day 7 ]
   measured by transpulmonary thermodilution during 7 days
4. Evolution of pulmonary vascular permeability index [ Time Frame: Between Day 1 and Day 7 ]
   measured by transpulmonary thermodilution during 7 days
5. Overall survival [ Time Frame: Day 30 ]
6. Mortality rate in ICU and in hospital [ Time Frame: Through study completion an average of 2 months ]
7. Rate of withdraw or withhold life-sustaining treatments decision [ Time Frame: Day 30 ]
8. Daily weight [ Time Frame: Between Day 1 and Day 7 ]
9. Daily fluid balance [ Time Frame: Between Day 1 and Day 7 ]
10. Evolution of albuminemia [ Time Frame: Between Day 1 and Day 7 ]
    Evolution of blood biological criteria (g/L)
11. Duration of mechanical ventilation [ Time Frame: Day 30 ]
12. Proportion of participants alive and off invasive mechanical ventilation [ Time Frame: Day 30 ]
13. Evolution of Murray ARDS severity score [ Time Frame: Day 1 to day 15 ]
14. Evolution of radiological Weinberg score [ Time Frame: Day 1 to Day 30 ]
    Scale from 0 to 12 better with higher score indicating more severe radiological pulmonary severity
15. Evolution of pulmonary Sequential Organ Failure Assessment) score. [ Time Frame: Day 1 to day 15 ]
    Scale from 0 to 4 betterwith higher score indicating more severe pulmonary disease
16. Rate of rescue therapy with Veino-veinous V-ECMO [ Time Frame: Through study completion an average of 2 months ]
17. Evolution of SOFA (Sequential Organ Failure Assessment) score [ Time Frame: Day 15 ]
    Scale from 0 to 24, lower is better.
18. Organ failure free days [ Time Frame: Day 15 ]
    one or more SOFA sub-score >=3
19. Renal replacement therapy free days [ Time Frame: Day 30 ]
20. Duration of renal replacement therapy free days [ Time Frame: Day 30 ]
21. Nature and frequency of adverse events [ Time Frame: Through study completion an average of 2 months ]
22. Evolution of FX06 concentration [ Time Frame: Day 1 ]
    measured at day 1 at time 0 (before FX06 application) and after 5, 15, 30, 60 min
23. Immunogenicity (antibody against FX06) induced by the drug, performed by ELISA according to manufacturer's procedure [ Time Frame: Day 7 ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Contacts

Contact: Nicolas BRECHOT, MD; +33142163835; nicolas.brechot@aphp.fr

Contact: David HAJAGE, MD; +33142160553; david.hajage@aphp.fr

Locations

France

Service de Médecine Intensive Réanimation - CHU Angers; Recruiting

Angers, France, 49933

Contact: Pierre ASFAR, MD piAsfar@chu-angers.fr

Service de Médecine Intensive Réanimation - CHI de Poissy; Recruiting

Chambourcy, France, 78240

Contact: Yan HAYON, MD jan.hayon@ght-yvelinesnord.fr

Hôpital Pitié Salpêtrière; Recruiting

Paris, France, 75013

Contact: BRECHOT Nicolas, MD nicolas.brechot@aphp.fr

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

More Information

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT04618042
• Other Study ID Numbers: APHP200495; 2020-002056-20 ( EudraCT Number )
• First Posted: November 5, 2020
• Last Update Posted: January 11, 2021
• Last Verified: December 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:

FX06; Pulmonary vascular hyperpermeability

Additional relevant MeSH terms:

Pneumonia; Respiratory Distress Syndrome, Newborn; Respiratory Distress Syndrome, Adult; Acute Lung Injury; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury