Add-on Reparixin in Adult Patients With ARDS

Acute Respiratory Distress Syndrome, Adult Clinical Trial

Official title:

Phase 2, Randomized, Double-blinded, Placebo-controlled, Multicenter Study to Assess Efficacy and Safety of Reparixin as add-on Therapy to SoC in Acute Respiratory Distress Syndrome (RESPIRATIO)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05496868
• Other study ID #: REP0122
• Secondary ID: 2022-001612-25
• Status: Recruiting
• Phase: Phase 2
• Start date: February 7, 2023
• Est. completion date: May 2025

Study information

• Verified date: June 2024
• Source: Dompé Farmaceutici S.p.A
• Contact: Sophie Toya, MD
• Phone: +1 219 427 2474
• Email: sophie.toya[@]dompe.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Study objectives

1. To characterize the efficacy of reparixin in ameliorating lung injury and systemic inflammation and expediting clinical recovery and liberation from mechanical ventilation in adult patients with moderate to severe ARDS (PaO2/FIO2 ratio ≤ 200).

2. To evaluate the safety of reparixin vs. placebo in patients enrolled in the study.

Description:

Phase 2, randomized, double-blinded, placebo controlled, multicenter study. All patients will receive therapy in line with current standard-of-care as it pertains to ARDS management (protocolized ventilator management will be made available to all sites in accordance with currently accepted standard of care). Patients will be randomized (1:1) to either reparixin or placebo. Duration of treatment will be 14 days.

The study will consist of 4 study periods:

Screening Randomization and Baseline assessments, Treatment (14 days with discretionary extension up to 21 days), Follow-up (up to 28 days or hospital discharge, whichever occurs first, and then up to day-60).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 66
• Est. completion date: May 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Signed Informed Consent, according to local guidelines and regulation.

2. Male and female adults (>18 years old).

3. Mechanically ventilated (invasive) patients with PaO2/FIO2 ratio =200 in the presence of PEEP of =5 cmH20.

4. Respiratory failure not fully explained by cardiac failure or fluid overload (if acute Congestive Heart Failure exacerbation is identified as part of the clinical picture this should be addressed effectively and as soon as possible before the patient can be enrolled).

5. Bilateral radiologic opacities consistent with pulmonary edema on the frontal chest x-ray (CXR), or bilateral ground glass opacities on a chest computerized tomography (CT) scan.

6. =48 hours from fulfilling above ARDS criteria.

7. =7 days from hospital admission.

8. Females of child-bearing potential who are sexually active must be willing not to get pregnant within 30 days after the last Investigational Medicinal Product (IMP) dose and must agree to at least one of the following reliable methods of contraception:

1. Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives from at least 2 months before the screening visit until 30 days after the last IMP dose;

2. A sterile sexual partner;

3. Abstinence.

Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all female subjects with child-bearing potential, pregnancy test result must be negative before first drug intake.

Exclusion Criteria:

1. Moderate-severe chronic hepatic disease (as verified by relevant history, imaging, if pre-existent, and Child-Pugh score B-C).

2. Severe chronic renal dysfunction: eGFR (MDRD) < 30 mL/min/1.73m2 or End Stage Renal Disease on renal replacement therapy.

3. Participation in another interventional clinical trial.

4. Patients that are clinically determined to have a high likelihood of death within the next 24 hours based on PI's estimation.

5. Evidence of anoxic brain injury

6. Currently receiving ECMO or high frequency oscillatory ventilation.

7. Anticipated extubation within 24 hours of enrollment.

8. Active malignancy (with the exception of non-melanotic skin cancers).

9. Hemodynamic instability (>30% increase in vasopressor in the last 6 hours or norepinephrine > 0.5 mcg/Kg/min).

10. Evidence of gastrointestinal (GI) dysmotility e.g., due to acute pancreatitis or immediate post-op state, as demonstrated by persistent gastric distention, enteral feeding intolerability and/or persistent gastric residuals >500 ml).

11. Anticipated discharge from the hospital or transfer to another hospital within 72 hours of screening.

12. Decision to withhold or withdraw life-sustaining treatment (patients may still be eligible however if they are committed to full support except cardiopulmonary resuscitation if cardiac arrest occurs).

13. History of:

1. Documented allergy/hypersensitivity to more than one medication belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib (hypersensitivity to sulphanilamide antibiotics alone, e.g., sulfamethoxazole does not qualify for exclusion), and to the study product and/or its excipients.

2. Lactase deficiency, galactosemia or glucose-galactose malabsorption.

3. History of GI bleeding or perforation due to previous Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) therapy or recurrent peptic ulcer/haemorrhage.

4. Hypersensitive to ibuprofen.

14. Active bleeding (excluding menses) or bleeding diathesis including patients on chronically high doses of NSAIDs.

15. Pregnant or lactating women.

16. Women of childbearing potential and fertile men who do not agree to use at least one primary form of contraception during the study and up to 30 days after the last IMP dose.

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

Drug:
• Reparixin 600mg
Reparixin will be administered through a nasogastric tube at the dose of 1200 mg (2 x 600 mg tablets) TID every 8 hours (6 tablets daily) for 14 days. All patients will receive therapy in line with current standard-of-care as it pertains to ARDS management (protocolized ventilator management will be made available to all sites in accordance with currently accepted standard of care).

Other:
• Matching Placebo
Placebo will be administered through a nasogastric tube at the dose of 1200 mg (2 x 600 mg tablets) TID every 8 hours (6 tablets daily) for 14 days. All patients will receive therapy in line with current standard-of-care as it pertains to ARDS management (protocolized ventilator management will be made available to all sites in accordance with currently accepted standard of care).

Locations

Country	Name	City	State
Germany	Universitaetsmedizin Goettingen	Göttingen	Niedersachsen
Germany	Berufsgenossenschaftliche Kliniken Bergmannstrost	Halle	Sachsen Anhalt
Germany	Universitaetsklinikum Heidelberg	Heidelberg	Baden Wuerttemberg
Germany	University Hospital of Schleswig-Holstein	Kiel	Schleswig Holstein
Germany	Universitaetsklinikum Leipzig	Leipzig	Sachsen
Germany	Herzzentrum Muenster	Muenster	Nordrhein Westfalen
Italy	Ospedale San Raffaele	Milano	Lombardia
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Baptist Hospitals of Southeast Texas	Beaumont	Texas
United States	The University of Alabama at Birmingham Hospital	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	NYU Langone Brooklyn	Brooklyn	New York
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	University of Missouri Health Care	Columbia	Missouri
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Cardiovoyage	Denison	Texas
United States	Denver Health	Denver	Colorado
United States	Detroit Medical Center	Detroit	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	Methodist Hospitals of Northwest Indiana	Gary	Indiana
United States	Hackensack Meridian Health	Hackensack	New Jersey
United States	Houston Methodist Hospital	Houston	Texas
United States	Jackson Pulmonary Associates	Jackson	Mississippi
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	University of Southern California	Los Angeles	California
United States	MyMichigan Medical Center Midland	Midland	Michigan
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	New York University Langone Health	New York	New York
United States	Newton Wellesley Hospital	Newton	Massachusetts
United States	University of Oklahoma Medical Center	Oklahoma City	Oklahoma
United States	University of California Irvine Health	Orange	California
United States	Banner - University Medical Center Phoenix	Phoenix	Arizona
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University Health System	Richmond	Virginia
United States	William Beaumont Hospital	Royal Oak	Michigan
United States	Unversity of California Davis Medical Center	Sacramento	California
United States	University of Utah Hospitals & Clinics	Salt Lake City	Utah
United States	Baystate Health	Springfield	Massachusetts
United States	University of South Florida	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Dompé Farmaceutici S.p.A

Countries where clinical trial is conducted

United States,  Germany,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in oxygenation index (OI) from baseline to day 7 of treatment	The OI is defined as: % mean airway pressure x FIO2/PaO2	to day 7
Primary	Ventilator free days (VFD) at day 28	Number of days from successfully weaning to day 28; patients who died before weaning have no ventilator-free days	at day 28
Secondary	Change in oxigenation index (OI) from baseline to day 4	The lower the OI the better the outcome	to day 4
Secondary	Acute lung injury score [composite of PaO2/FIO2 ratio, PEEP, lung compliance (plateau airway pressure minus PEEP/TV) and extent of pulmonary infiltrates] at 2, 3, 7, 14 days (if still intubated)		at 2, 3, 7, 14 days
Secondary	Sequential Organ Failure Assessment (SOFA) score at 2, 3, 7, 14 days (if still intubated)		at 2, 3, 7, 14 days
Secondary	Ventilatory ratio (product of minute ventilation and PaCO2) at 2, 3, 7, 14 days (if still intubated)		at 2, 3, 7, 14 days
Secondary	Incidence of Extracorporeal Membrane Oxygenation (ECMO) by day 14		by day 14
Secondary	Use of vasoactive medications by day 14		by day 14
Secondary	Chest X-Rays assessment of pulmonary edema by "radiographic assessment of lung edema" (RALE) score at 2, 3, 7, 14 days		at 2, 3, 7, 14 days
Secondary	Percentage of patients achieving pressure support ventilation equal to 5 cmH20 with PEEP equal to 5 cmH20 for 2 hours (measure of weaning) by day 28 and at hospital discharge		by day 28
Secondary	Intensive Care Unit free days by day 28 and at hospital discharge		by day 28
Secondary	Hospital-free days by day 28 and at hospital discharge		by day 28
Secondary	Incidence of tracheostomies by day 28 and at hospital discharge		by day 28
Secondary	Incidence of transfer to long term acute care (LTAC) facility by day 28 and at hospital discharge		by day 28
Secondary	All-cause mortality by day 28		by day 28
Secondary	All-cause mortality by day 60		by day 60
Secondary	Change from baseline to day 3, 7 and 14 days in plasma levels of IL-6, IL-8, PAI-1, TNFr-1, ICAM-1 RAGE		to day 3, 7 and 14 day
Secondary	Plasma levels (free and bound) of DF1681Y (acidic form of reparixin) and relevant metabolites (DF2188Y, DF2243Y, and ibuprofen (DF1674Y))	Plasma levels (free and bound) of DF1681Y (acidic form of reparixin) and relevant metabolites (DF2188Y, DF2243Y, and ibuprofen (DF1674Y)) are measured in a subset of about 24 (10-12 per group) patients selected at pre-defined sites.	day 1, day 2, day 7, day 14
Secondary	Incidence of Treatment Emergent AEs (TEAEs) and SAEs (TESAEs) from the beginning of study treatment to up to the end of study participation.		from the date of First Patient First Visit (FPFV) to the date of Last Patient Last Visit (LPLV)
Secondary	eGFR, absolute value and change from screening to day 3(±8h), day 7±1, day 14±2, day 21±2 (if still receiving reparixin), day 28±2		to day 3(±8h), 7±1 day, 14±2 day, 21±2 day, 28±2 day
Secondary	Incidence of secondary infections defined as new by day 28±2	Secondary infections defined as new (occurring after the first IMP intake) infection in a previously known to be sterile site, including blood, body fluid or tissue, or new pathogen isolated from cultures of biological samples known to be previously infected by day 28±2	by day 28±2