Clinical trial NCT05496868: Add-on Reparixin in Adult Patients With ARDS
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Respiratory Distress Syndrome, Adult
Keywords: ARDS
Reparixin
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2022-08-11
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 assess the effect of reparixin on systemic biomarkers linked to a hyper-inflammatory ARDS phenotype.
3. To evaluate the safety of reparixin vs. placebo in patients enrolled in the study.

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. In this study the IMP will be either reparixin or matched placebo, which will be provided in the form of tablets to be disintegrated for naso-gastric tube administration or administered orally after extubation and between extubation and day 14 should the patient be able to swallow. In such cases the IMP may be administered either intact or crushed and mixed with a vehicle as per speech swallow evaluation.

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).

Eligibility criteria: 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 (if a patient is transferred from a non-participating hospital to a participating site a 12-hour period beyond the 48 hours is allowed)
7. 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. In patients non able to personally consent to above due to complications of acute illness and/or its treatment assurances for the above must be given by LR and reiterated by patient when/if she is able to do so.

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 a previously known Child-Pugh score ≥7). If baseline Child-Pugh score is not known it should not be calculated while the patient is acutely ill. In that case the patient is excluded on the basis of: ALT/AST ≥ 3x ULN and total bilirubin \> 2x ULN or ALT/AST ≥ 5x ULN
2. Severe chronic renal dysfunction: eGFR (2021 CKD-EPI) \< 30 mL/min/1.73m2. If baseline (chronic) renal function is not known the patient is only excluded if in need of acute renal replacement therapy (currently on RRT or to be imminently placed on RRT)
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. Currently receiving ECMO or high frequency oscillatory ventilation.
6. Anticipated extubation within 24 hours of screening. (In such cases re-screening is allowed if the patient is within the enrollment window).
7. Evidence of GI dysmotility as demonstrated by presence of all the following: persistent gastric distention and enteral feeding intolerability and persistent gastric residuals \>500 ml).
8. Anticipated transfer to a hospital not participating in the trial within 72 hours of screening.
9. 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).
10. History of:

    1. Documented allergy/hypersensitivity to sulfonamides, ibuprofen and other COX-1 and 2 inhibitors, and to the study product and/or its excipients.
    2. Lactase deficiency, galactosemia or glucose-galactose malabsorption.
    3. History of peptic ulcer, GI bleeding or perforation due to previous NSAID therapy.
11. Active bleeding (excluding menses) from uncontrolled site that cannot be definitively resolved prior to enrollment.
12. Pregnant or lactating women.
13. 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. For patients non able to personally consent to above due to complications of acute illness and/or its treatment assurances for the above must be given by LR and reiterated by patient when/if he/she is able to do so.

Primary outcomes:
measure: Change in oxygenation index (OI) from baseline to day 7 of treatment
timeFrame: to day 7
measure: Ventilator free days (VFD) at day 28
timeFrame: at day 28
Secondary outcomes:
measure: Change in oxigenation index (OI) from baseline to day 4
timeFrame: to day 4
measure: Acute lung injury score at 2, 3, 7, 14 days (if still intubated)
timeFrame: at days 2, 3, 7, 14 (if still intubated)
measure: Sequential Organ Failure Assessment (SOFA) score at 2, 3, 7, 14 days
timeFrame: at Days 2, 3, 7, 14 days (if still intubated)
measure: Ventilatory ratio at 2, 3, 7, 14 days
timeFrame: at days 2, 3, 7, 14 days (if still intubated)
measure: Incidence of Extracorporeal Membrane Oxygenation (ECMO) by day 14
timeFrame: At day 14
measure: Use of vasoactive medications by day 14
timeFrame: At day 14
measure: Chest X-Rays assessment of pulmonary edema by "radiographic assessment of lung edema" (RALE) score at 2, 3, 7, 14 days
timeFrame: at days 2, 3, 7, 14
measure: 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
timeFrame: by day 28
measure: Intensive Care Unit free days by day 28 and at hospital discharge
timeFrame: by day 28
measure: Hospital-free days by day 28 and at hospital discharge
timeFrame: by day 28
measure: Incidence of tracheostomies by day 28 and at hospital discharge
timeFrame: by day 28
measure: Incidence of transfer to long term acute care (LTAC) facility by day 28 and at hospital discharge
timeFrame: by day 28
measure: All-cause mortality by day 28 and 60
timeFrame: by days 28 and 60
measure: 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
timeFrame: Days 3, 7 and 14
measure: Hospital discharge by day 28
timeFrame: by day 28
measure: Incidence of Treatment Emergent AEs (TEAEs) and SAEs (TESAEs) from the beginning of study treatment to up to the end of study participation.
timeFrame: from the date of First Patient First Visit (FPFV) to the date of Last Patient Last Visit (LPLV)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The University of Alabama at Birmingham Hospital
state: Alabama
city: Phoenix
country: United States
facility: Banner - University Medical Center Phoenix
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Orange
country: United States
facility: University of California Irvine Health
state: California
city: Sacramento
country: United States
facility: Unversity of California Davis Medical Center
state: California
city: Denver
country: United States
facility: Denver Health
state: Colorado
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital
state: Georgia
city: Gary
country: United States
facility: Methodist Hospitals of Northwest Indiana
state: Indiana
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Newton
country: United States
facility: Newton Wellesley Hospital
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Health
state: Massachusetts
city: Detroit
country: United States
facility: Detroit Medical Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Midland
country: United States
facility: MyMichigan Medical Center Midland
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Jackson
country: United States
facility: Jackson Pulmonary Associates
state: Mississippi
city: Columbia
country: United States
facility: University of Missouri Health Care
state: Missouri
city: Hackensack
country: United States
facility: Hackensack Meridian Health
state: New Jersey
city: Brooklyn
country: United States
facility: NYU Langone Brooklyn
state: New York
city: New York
country: United States
facility: New York University Langone Health
state: New York
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Medical Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
city: Beaumont
country: United States
facility: Baptist Hospitals of Southeast Texas
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Denison
country: United States
facility: Cardiovoyage
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospitals & Clinics
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University Health System
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
state: Baden Wuerttemberg
city: Göttingen
country: Germany
facility: Universitaetsmedizin Goettingen
state: Niedersachsen
city: Muenster
country: Germany
facility: Herzzentrum Muenster
state: Nordrhein Westfalen
city: Halle
country: Germany
facility: Berufsgenossenschaftliche Kliniken Bergmannstrost
state: Sachsen Anhalt
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig
state: Sachsen
city: Kiel
country: Germany
facility: University Hospital of Schleswig-Holstein
state: Schleswig Holstein
city: Milano
country: Italy
facility: Ospedale San Raffaele
state: Lombardia
Study officials:
affiliation: Universitaetsmedizin Goettingen
name: Moerer Onnen, MD
role: PRINCIPAL_INVESTIGATOR
References: