Add-on Reparixin in Adult Patients With ARDS

Dompé Farmaceutici S.p.A66 enrolled

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Acute Respiratory Distress Syndrome, Adult

Interventions

Reparixin 600mgDRUG

Reparixin 600 mg tablets, administered crushed through nasogastric tube at the dose of 1200 mg TID (2 tablets TID administered approximately about every 8 hours) as add-on to the standard of care. After extubation and if the patient can swallow, reparixin may be administered orally. Total duration of the treatment: 14 days

Matching PlaceboOTHER

Placebo tablets. Administered crushed through nasogastric tube with the same schedule as reparixin as add-on to the standard of care. After extubation and if the patient can swallow placebo may be administered orally. Total duration of the treatment: 14 days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (40)

Outcomes

Primary Outcomes

Change in Oxygenation Index (OI) From Baseline to Day 7 of Treatment

Oxygenation Index is defined as Mean Airway Pressure multiplied by (Fraction of Inspired Oxygen\[FiO2\]) x (100)/(Partial Pressure of Oxygen\[PaO2\]). It is a measure of efficiency of oxygen utilization in the body, with lower values indicating better oxygenation. OI values can range from 0 to 1000, with values below 25 generally associated with more favorable clinical outcomes. OI at Day 7 was derived according to estimand definition. If a participant died before or at Day 7 and OI was missing, an unfavorable value was imputed. If a participant was extubated at Day 7 and OI was not evaluable, a favorable value was imputed. In all other cases, OI at Day 7 was considered missing. Baseline was defined as last measurement collected prior to investigational medicinal product intake. Change from baseline was defined as post-baseline assessment minus baseline value. Adjusted means and 95% confidence interval from an ANOVA model with multiple imputation (MI) for missing data have been presented.

Time frame: Baseline to Day 7

Ventilator-Free Days (VFD)

Ventilator free days (VFDs) through Day 28 were defined as the number of days from the first IMP intake during which the participant was alive and free of invasive mechanical ventilation. Participants who died before or at Day 28 were assigned a value of 0 ventilator-free days, in accordance with the estimand definition. Adjusted means and 95% confidence interval from an ANOVA model with MI for missing data have been presented.

Time frame: At Day 28

Secondary Outcomes

Change in Oxygenation Index (OI) From Baseline to Day 4

Oxygenation Index (OI) is defined as Mean Airway Pressure multiplied by (FiO2) x (100) / (PaO2). It is a measure of the efficiency of oxygen utilization in the body, with lower values indicating better oxygenation. OI values can range from 0 to 1000, with values below 25 generally associated with more favorable clinical outcomes. OI at Day 7 was derived according to the estimand definition. If a participant died before or at Day 7 and OI was missing, an unfavorable value was imputed. If a participant was extubated at Day 7 and OI was not evaluable, a favorable value was imputed. In all other cases, OI at Day 7 was considered missing. For Day 4, no imputation or adjusted means were applied; only observed data from participants with available measurements were used. Baseline was defined as the last measurement collected prior to IMP intake. Change from baseline was defined as the difference between the value at each post-baseline assessment and the baseline value.

Data from ClinicalTrials.gov

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The University of Alabama at Birmingham Hospital

Birmingham, Alabama, United States

Banner - University Medical Center Phoenix

Phoenix, Arizona, United States

University of Southern California

Los Angeles, California, United States

University of California Irvine Health

Orange, California, United States

Unversity of California Davis Medical Center

Sacramento, California, United States

Denver Health

Denver, Colorado, United States

University of South Florida

Tampa, Florida, United States

Emory Saint Joseph's Hospital

Atlanta, Georgia, United States

Methodist Hospitals of Northwest Indiana

Gary, Indiana, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

...and 30 more locations

Time frame: Baseline to Day 4

Change From Baseline of Acute Lung Injury (ALI) Score

Acute Lung Injury (ALI) Score is a composite 4-point scoring system validated by the National Heart, Lung, and Blood Institute (NHLBI) acute respiratory distress syndrome (ARDS) Network that considers PaO2/FiO2, the level of positive end-expiratory pressure (PEEP), lung/respiratory compliance \[plateau airway pressure minus PEEP/Tidal Volume (TV)\], and the extent of pulmonary infiltrates on the chest radiograph. Each criterion was scored from 0-4 based on the severity of the condition. The final score was calculated by dividing the total score by the number of criteria used. A score of 0 indicates no lung injury, a score between 0.1 to 2.5 indicates mild to moderate lung injury and a score of \>2.5 indicates severe lung injury (ARDS). Baseline was defined as the last measurement collected prior to IMP intake, regardless of the visit at which it was obtained. Change from baseline was defined as the difference between the value at each post-baseline assessment and the baseline value.

Time frame: Baseline and at Days 2, 3, 7 and 14

Change From Baseline of Sequential Organ Failure Assessment (SOFA) Score

The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). The score ranges for each system organ classes range from 0 to 4. SOFA score was calculated every 24 hours using (for each organ system) the worst variable recorded within the same 24 hours. The best possible score corresponds to 0 whereas the worst score corresponds to 24. Baseline was defined as the last measurement collected prior to IMP intake, regardless of the visit at which it was obtained. Change from baseline was defined as the difference between the value at each post-baseline assessment and the baseline value.

Time frame: Baseline and at Days 2, 3, 7 and 14

Change From Baseline of Ventilatory Ratio

The Ventilatory Ratio (VR) is a simple, non-invasive bedside index used to monitor the efficiency of carbon dioxide (CO2) clearance in mechanically ventilated participants, particularly those with ARDS. VR = \[minute ventilation (ml/min) × PaCO2 (mm Hg)\] / \[predicted body weight × 100 (ml/min) × 37.5 (mm Hg)\] VR is a unitless ratio, and a value approximating 1 would represent normal ventilating lungs. An elevated value of VR would represent either increased pulmonary dead space, increased VCO2 or both. Baseline was defined as the last measurement collected prior to IMP intake, regardless of the visit at which it was obtained. Change from baseline was defined as the difference between the value at each post-baseline assessment and the baseline value.

Time frame: Baseline and at Days 2, 3, 7 and 14

Number of Participants Requiring Extracorporeal Membrane Oxygenation (ECMO) at Day 14

Extracorporeal Membrane Oxygenation (ECMO) is an advanced form of temporary life support used for participants with life-threatening heart or lung failure that has not responded to conventional treatments. It functions as a modified heart-lung bypass machine, circulating blood outside the body to add oxygen and remove carbon dioxide before returning it to the participants. Use of ECMO between first investigational medicinal product intake and Day 14 was counted.

Time frame: At Day 14

Percentage of Participants Using Vasoactive Medications at Day 14

Use of vasoactive medication is defined as the percentage of participants who received ≥1 vasoactive medication at any time from first IMP intake (Day 1) up to and including Day 14 (inclusive window), divided by the number of participants in the analysis population. Use of Vasoactive Medications is collected in "Ventilation - Specific Information" CRF Daily assessments through extubation. An event is recorded as "Yes" if vasoactive medication use is reported at any daily assessment performed between the date/time of first IMP intake (Day 1) and Day 14 (Day 1 + 13 days), inclusive. If no use is reported during this period, the event is recorded as "No" provided the last available assessment occurs on or after Day 12 (allowing a ±2-day window for the Day 14 visit). The event is recorded as missing if the last available assessment occurs before Day 12.

Time frame: At Day 14

Change From Baseline of Chest X-ray (CXR) Assessment of Pulmonary Edema by Radiographic Assessment of Lung Edema (RALE) Score

Radiographic Assessment of Lung Edema (RALE) score is a validated, semi-quantitative tool for quantifying pulmonary edema and ARDS severity using chest X-rays (CXR). It is calculated by dividing the lung fields on the chest radiograph into four quadrants. Each quadrant was assigned a number, and the extent of alveolar opacities (the consolidation score, from 0 to 4) and density of alveolar opacities (the density score, from 1 to 3) was determined. If the consolidation score was 0, the density score was 0. The final RALE score was the sum of the product of the consolidation and density score for each quadrant. Thus, the final RALE score ranged from minimum 0 to maximum 48. Higher RALE scores indicate more severe edema and poorer outcomes. Baseline was defined as the last measurement collected prior to IMP intake, regardless of the visit at which it was obtained. Change from baseline was defined as the difference between the value at each post-baseline assessment and the baseline value.

Time frame: Baseline and at Days 2, 3, 7 and 14

Percentage of Participants Achieving Pressure Support Ventilation Equal to 5 cm H20 With PEEP Equal to 5 cm H20 for 2 Hours (Measure of Weaning)

Continuous Positive Airway Pressure (CPAP) is defined as use of pressure support ventilation equal to 5 cmH2O with PEEP equal to 5 cmH2O for 2 hours. Each qualifying CPAP trial recorded in the Ventilation Specific Information CRF is counted as one weaning attempt. By Day 28: An event is recorded as "Yes" if at least one CPAP weaning attempt (\>0) is reported between Day 1 (first IMP intake) and Day 28 (Day 1 + 27 days). The event is "No" if all available assessments during this period are present and equal to 0; otherwise, the event is missing. By Hospital Discharge: An event is recorded as "Yes" if at least one CPAP weaning attempt (\>0) is reported between Day 1 and hospital discharge. The event is "No" if all available assessments during this period are present and equal to 0; otherwise, the event is missing. Hospital discharge date is obtained from EOS or, if missing, from the Hospital Discharge visit date; if unavailable, hospitalization is assumed ongoing.

Time frame: At Day 28 and Hospital Discharge (Up to Day 30)

Intensive Care Unit (ICU)-Free Days

Intensive Care Unit (ICU) free days were defined as number of calendar days from first IMP intake during which a participant was alive and not hospitalized in an ICU. ICU-free days at Day 28 were calculated as 28 minus total number of ICU days up to Day 28, with negative values set to 0. Participants who died on or before Day 28 were assigned 0 ICU-free days. If a participant was discharged before Day 28 and died after discharge but before Day 28, ICU-free days at Day 28 equaled ICU-free days at discharge. Endpoint was set to missing if participant was alive but followed for fewer than 26 days or if required data were missing. ICU-free days at hospital discharge were calculated as (discharge date - first IMP intake date + 1) minus total ICU days up to discharge, with negative values set to 0. Participants who died during hospitalization were assigned 0 ICU-free days. If discharge did not occur and death occurred after Day 28, ICU-free days at discharge equaled ICU-free days at Day 28.

Time frame: At Day 28 and Hospital Discharge (Up to Day 30)

Hospital-free Days

Hospital-free days are a participant-centered metric defining the number of days a participant stays alive outside an acute-care hospital. If the participant was alive at Day 28 (last available day ≥26), hospital-free days were calculated as 28 minus total hospital days up to Day 28. If the participant died on or before Day 28, hospital-free days were set to 0.

Time frame: Up to Day 28

Percentage of Participants With Tracheostomies

Percentage of participants who underwent a tracheostomy between Day 1 and Day 28 or hospital discharge, has been presented. The event is recorded as "Yes" if a tracheostomy occurred during this period, "No" if no procedure occurred and the visit/discharge date is available and missing if both the procedure date and visit/discharge date are unavailable.

Time frame: At Day 28 and Hospital Discharge (Up to Day 30)

Percentage of Participants Transferred to a Long-Term Acute Care (LTAC) Facility

An LTAC is a Long Term Acute Care Hospital, a facility that specializes in the treatment of participants with serious medical conditions, including patients with ongoing needs for mechanical ventilation, but who no longer require intensive care or extensive diagnostic procedures. The participants in LTAC are transferred there directly from the intensive care unit because they require more care than they can receive in a rehabilitation center, skilled care facility or at home.

Time frame: From Day 1 of first IMP intake through Day 28 and Hospital Discharge (Up to Day 30)

Percentage of Participants Who Died by Day 28 and Day 60

Percentage of death by Day 28 and Day 60 has been reported. The event is recorded as "Yes" if death occurred within the period, "No" if the participant was alive with last available assessment at or beyond Day 28 or Day 60.

Time frame: Up to Day 28 and 60

Hospital Discharge by Day 28

A participant was considered discharged alive by Day 28 if hospital discharge occurred on or before Day 28, regardless of vital status after discharge. Participants were considered not discharged alive by Day 28 if they died without a recorded discharge date, were discharged after Day 28, had a missing discharge date with sufficient follow-up (last available day ≥26), or had a discharge date equal to the date of death. The endpoint was set to missing if the discharge date was missing and the participant was alive but followed for fewer than 26 days. Percentage of participants discharged from hospital by Day 28 has been presented.

Time frame: Day 28

Change From Baseline in Plasma Biomarkers: Interleukin-6 (IL-6), IL-8, and Plasma Tumor Necrosis Factor Receptor 1 (TNFr-1)

Plasma biomarker levels for Interleukin -6 (IL-6), IL-8 and plasma Tumor Necrosis Factor Receptor 1 (TNFr-1) were measured using validated laboratory methods. Baseline was defined as the last measurement collected prior to IMP intake, regardless of the visit at which it was obtained. Change from baseline was calculated as the post-baseline plasma concentration minus the baseline concentration.

Time frame: Baseline and at Days 3, 7 and 14

Change From Baseline in Plasma Biomarkers: PAI-1, ICAM-1, and RAGE

Plasma biomarker levels of plasminogen activator inhibitor-1 (PAI-1), intercellular adhesion molecule-1 (ICAM-1), and receptor for advanced glycation end products (RAGE) were measured using validated laboratory methods. Baseline was defined as the last measurement collected prior to IMP intake, regardless of the visit at which it was obtained. Change from baseline was calculated as the post-baseline plasma concentration minus the baseline concentration.

Time frame: Baseline and at Days 3, 7 and 14

Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Treatment Emergent Adverse Events (Serious TEAEs)

An Adverse Event (AE) is any untoward medical occurrence in a participant, which does not necessarily have a causal relationship with the trial intervention. A TEAE is defined as any untoward medical occurrence that begins or worsens in intensity or frequency after the initiation of a treatment (e.g., drug, device, or procedure) in a clinical study. A Serious TEAE is defined as any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization.

Time frame: Up to 26 Months