Add-on Reparixin in Adult Patients With ARDS

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Distress Syndrome, Adult
• Intervention / Treatment: Drug: Reparixin 600mg; Other: Matching Placebo

Detailed 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).

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sophie Toya, MD; Phone Number: +1 219 427 2474; Email: sophie.toya@dompe.com
• Study Contact Backup: Name: Enrico Minnella, MD; Phone Number: +39 02 583831; Email: enrico.minnella@dompe.com

Study Locations

• Germany
  • Baden Wuerttemberg
    • Heidelberg, Baden Wuerttemberg, Germany, 69120
      • Recruiting
      • Universitaetsklinikum Heidelberg
      • Contact: Thorsten Brenner, MD
  • Niedersachsen
    • Göttingen, Niedersachsen, Germany, 37075
      • Recruiting
      • Universitaetsmedizin Goettingen
      • Contact: Moerer Onnen, MD
  • Nordrhein Westfalen
    • Muenster, Nordrhein Westfalen, Germany, 48149
      • Recruiting
      • Herzzentrum Muenster
      • Contact: Alexander Zarbock, MD
  • Sachsen
    • Leipzig, Sachsen, Germany, 4103
      • Recruiting
      • Universitaetsklinikum Leipzig
      • Contact: Maria Theresa Voelker, MD
  • Sachsen Anhalt
    • Halle, Sachsen Anhalt, Germany, 6112
      • Recruiting
      • Berufsgenossenschaftliche Kliniken Bergmannstrost
      • Contact: Hermann Wrigge, MD
  • Schleswig Holstein
    • Kiel, Schleswig Holstein, Germany, 24105
      • Recruiting
      • University Hospital of Schleswig-Holstein
      • Contact: Dirk Schaedler, MD
• Italy
  • Lombardia
    • Milano, Lombardia, Italy, 20132
      • Recruiting
      • Ospedale San Raffaele
      • Contact: Giovanni Landoni, MD
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • The University of Alabama at Birmingham Hospital
      • Contact: Peter Morris, MD
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Recruiting
      • Banner - University Medical Center Phoenix
      • Contact: Esa Rayyan, MD
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • University of Southern California
      • Contact: Luis Huerta, MD
    • Orange, California, United States, 92868
      • Recruiting
      • University of California Irvine Health
      • Contact: Timmy Cheng, MD
    • Sacramento, California, United States, 95817
      • Recruiting
      • Unversity of California Davis Medical Center
      • Contact: Timothy Albertson, MD
  • Colorado
    • Denver, Colorado, United States, 80204
      • Recruiting
      • Denver Health
      • Contact: Ivor Douglas, MD
  • Florida
    • Tampa, Florida, United States, 33606
      • Not yet recruiting
      • University of South Florida
      • Contact: Brenda Juan Guardela, MD
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Not yet recruiting
      • Emory Saint Joseph's Hospital
      • Contact: Ishan Mehta, MD
  • Indiana
    • Gary, Indiana, United States, 46404
      • Recruiting
      • Methodist Hospitals of Northwest Indiana
      • Contact: Olusegun Apata, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Contact: Alon Dagan, MD
    • Newton, Massachusetts, United States, 02462-1607
      • Not yet recruiting
      • Newton Wellesley Hospital
      • Contact: Harry Schrager, MD
    • Springfield, Massachusetts, United States, 01107
      • Recruiting
      • Baystate Health
      • Contact: Mark Tidswell, MD
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Recruiting
      • Henry Ford Hospital
      • Contact: Daniel Ouellette, MD
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Detroit Medical Center
      • Contact: Wael Saasouh, MD
    • Midland, Michigan, United States, 48670
      • Recruiting
      • MyMichigan Medical Center Midland
      • Contact: John Blamoun, MD
    • Royal Oak, Michigan, United States, 48073
      • Recruiting
      • William Beaumont Hospital
      • Contact: Girish Nair, MD
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • Recruiting
      • Jackson Pulmonary Associates
      • Contact: Maria Rappai, MD
  • Missouri
    • Columbia, Missouri, United States, 65212
      • Not yet recruiting
      • University of Missouri Health Care
      • Contact: Dima Dandachi, MD
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Not yet recruiting
      • Hackensack Meridian Health
      • Contact: Keith Rose, MD
  • New York
    • Brooklyn, New York, United States, 11220
      • Not yet recruiting
      • NYU Langone Brooklyn
      • Contact: Ioannis Zacharioudakis, MD
    • New York, New York, United States, 10016
      • Recruiting
      • New York University Langone Health
      • Contact: David Kaufman, MD
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Not yet recruiting
      • The Cleveland Clinic Foundation
      • Contact: Marcelo Gama De Abreu, MD
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • The Ohio State University Wexner Medical Center
      • Contact: Sonal Pannu, MD
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma Medical Center
      • Contact: Tony Abdo, MD
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Oregon Health and Science University
      • Contact: Akram Khan, MD
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Recruiting
      • University of Tennessee Medical Center
      • Contact: Isaac Biney, MD
  • Texas
    • Beaumont, Texas, United States, 77701
      • Recruiting
      • Baptist Hospitals of Southeast Texas
      • Contact: Juan Iribarren, MD
    • Dallas, Texas, United States, 75390-8894
      • Recruiting
      • University of Texas Southwestern Medical Center
      • Contact: Christopher Choi, MD
    • Denison, Texas, United States, 75020
      • Recruiting
      • CardioVoyage
      • Contact: Aditi Swami, MD
    • Houston, Texas, United States, 77030
      • Recruiting
      • Houston Methodist Hospital
      • Contact: Asma Zainab, MD
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • Recruiting
      • University of Utah Hospitals & Clinics
      • Contact: Estelle Harris, MD
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Not yet recruiting
      • Virginia Commonwealth University Health System
      • Contact: Alan Dow, MD
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Not yet recruiting
      • Medical College of Wisconsin
      • Contact: Rahul Nanchal, MD

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reparixin + Standard of care; Reparixin tablets 1200 mg TID (2 tablets x 600 mg TID) as add-on to the standard of care (SoC).	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 Names: REP
Placebo Comparator: Placebo + Standard of care; Placebo tablets with the same schedule of reparixin, as add-on to the standard of care (SoC)	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).; Other Names: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in oxigenation index (OI) from baseline to day 4	The lower the OI the better the outcome	to day 4
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
Sequential Organ Failure Assessment (SOFA) score at 2, 3, 7, 14 days (if still intubated)		at 2, 3, 7, 14 days
Ventilatory ratio (product of minute ventilation and PaCO2) at 2, 3, 7, 14 days (if still intubated)		at 2, 3, 7, 14 days
Incidence of Extracorporeal Membrane Oxygenation (ECMO) by day 14		by day 14
Use of vasoactive medications by day 14		by day 14
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
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
Intensive Care Unit free days by day 28 and at hospital discharge		by day 28
Hospital-free days by day 28 and at hospital discharge		by day 28
Incidence of tracheostomies by day 28 and at hospital discharge		by day 28
Incidence of transfer to long term acute care (LTAC) facility by day 28 and at hospital discharge		by day 28
All-cause mortality by day 28		by day 28
All-cause mortality by day 60		by day 60
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
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
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)
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
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

Collaborators and Investigators

• Sponsor: Dompé Farmaceutici S.p.A
• Investigators: Principal Investigator: Moerer Onnen, MD, Universitaetsmedizin Goettingen

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2023
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: August 4, 2022
• First Submitted That Met QC Criteria: August 9, 2022
• First Posted (Actual): August 11, 2022

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: ARDS; Reparixin
• 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
• Other Study ID Numbers: REP0122; 2022-001612-25 (EudraCT Number)

Drug and device information, study documents

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