Reparixin add-on Therapy to Standard Care to Limit Progression in Pts With COVID19 & Other Community Acquired Pneumonia

Reparixin 1200 mg TID as add-on to SoC to Limit Disease Progression in Hospitalised Patients With COVID-19 and Other Community-Acquired Pneumonia. A Multicentre, Randomized, Double-blinded, Placebo-controlled, Phase III Trial (REPAVID-22)

Primary objective:

- To compare the efficacy of reparixin vs. placebo in the proportion of patients dead or requiring IMV (or ECMO) by Day 28.

Key secondary objectives:

• To compare the efficacy of reparixin vs placebo in all-cause mortality at day 180.
• To compare the efficacy of reparixin vs placebo in proportion of patients alive and discharged at day 28
• To compare the efficacy of reparixin vs placebo in ventilatory-free days at day 28.
• To compare the efficacy of reparixin vs placebo in proportion of patients with IMV (or ECMO) by day 28.
• To compare the efficacy of reparixin vs placebo in length of primary hospital stay.

Other efficacy objectives

- To compare the efficacy of reparixin vs placebo on several disease severity/progression measures including recovery, ventilatory free days and mortality.

Safety objectives:

- To evaluate safety and tolerability of oral reparixin versus placebo in the specific clinical setting.

Study Overview

• Status: Terminated
• Conditions: Severe COVID-19; Infectious Pneumonia
• Intervention / Treatment: Drug: Reparixin; Other: Placebo

Detailed Description

Multinational, multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III trial.

This study was conducted at 101 sites across 7 countries (Argentina, Australia, Austria, Germany, Italy, Turkey, and the United States [US]) that enrolled 414 male and female patients > 18 years of age, hospitalized for CAP (including COVID-19). Please note that of these 101 sites, only 74 had enrolled patients and, hence, have been reported on CT.gov.

The maximum study duration for a participant was 180 days, which included screening (day -1 or 1), treatment (up to day 21), and follow-up period (up to day 180).

Of the 414 patients enrolled, 409 (98.8%) were randomized 1:1 to receive investigational products (oral reparixin [N = 205] or matched placebo [N = 204], three times a day (TID), for up to 21 days. Randomization was stratified according to disease severity and site.

Actually, 394 participants (96.3%)(oral reparixin [N = 201] or matched placebo [N = 193]) received at least 1 dose of the investigational product and hence were included in the FAS population.

All the patients received the Standard of Care (SoC) based on their clinical need, including COVID-19 and CAP medications, as per local standard therapy at the trial site and in line with international guidelines.

Of the randomized population (N = 409), 186 participants (45.5%) completed the study; 223 (54.5%) discontinued the study prematurely.

The primary outcome was evaluated at day 28, while the secondary outcomes were scheduled to be evaluated from day 3 to day 180.

An independent external data monitoring committee (DMC) oversaw the study and evaluated unblinded interim data for efficacy, futility, and safety.

The interim efficacy analysis met the pre-specified criteria for futility and the DMC recommended early termination of the study. Based on the recommendation of the DMC, Dompé decided to terminate the study earlier than planned. The decision was not related to any safety concerns.

Due to the early study termination and not reaching the planned enrollment target, the outcome measure analyses were conducted for descriptive purposes only.

• Study Type: Interventional
• Enrollment (Actual): 414
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1430
    • Clinica Adventista Belgrano
  • Buenos Aires, Argentina, C1425 EOE
    • Sanatorio Agote
  • Ciudad Autonoma Buenos Aires, Argentina, 1280
    • Hospital Britanico de Buenos Aires
  • Córdoba, Argentina, 5000
    • Nuevo Hospital San Roque
  • Córdoba, Argentina, 5000
    • Sanatorio Privado de la Canada - Cordoba
  • Córdoba, Argentina, 5000
    • Sanatorio Privado Duarte Quiroz De Clinica Colombo SA
  • Buenos Aires
    • Bahía Blanca, Buenos Aires, Argentina, 8001
      • Hospital Interzonal General de Agudos Dr Jose Penna
    • Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, 1181
      • Hospital Italiano de Buenos Aires
    • La Plata, Buenos Aires, Argentina, 1900
      • Hospital Italiano de La Plata
    • La Plata, Buenos Aires, Argentina, 1900
      • Instituto Medico Platense
    • Munro, Buenos Aires, Argentina, 1605
      • Clinica Independencia
  • Buenos Aires F.D.
    • Ciudad Autonoma de Buenos Aire, Buenos Aires F.D., Argentina, 1187
      • Sanatorio Finochietto
  • Córdoba Province
    • Villa María, Córdoba Province, Argentina, 5900
      • Sanatorio de la Canada
  • Santa Fe Province
    • Rosario, Santa Fe Province, Argentina, 2000
      • Sanatorio Britanico S.A.
• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Mater Hospital Brisbane
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
• Austria
  • Linz, Austria, 4020
    • KH der Barmherzigen Brüder Linz
  • Linz, Austria, 4020
    • Kepler Universitätsklinikum Med Campus III
  • Vienna, Austria, 1090
    • Medizinische Universitaet Wien, Medizinische Klinik I, Abteilung für Infektionskrankheiten und Tropenmedizin
  • Vienna, Austria, 1100
    • Klinik Favoriten (Sozialmedizinisches Zentrum Sued - Kaiser-Franz-Josef-Spital mit Gottfried von Preyer'schem Kinderspital)
• Germany
  • Bavaria
    • Dachau, Bavaria, Germany, 85221
      • Helios Hamper-Klinikum Dachau
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Universitaetsklinikum Carl Gustav Carus TU Dresden
  • Südniedersachsen
    • Göttingen, Südniedersachsen, Germany, 37075
      • Universitatsmedizin Gottingen
• Italy
  • Bergamo, Italy, 24127
    • ASST - Ospedale Papa Giovanni XXIII - UOC Pneumologia
  • Bologna, Italy, 40138
    • Azienda Ospedaliera Universitaria di Bologna - Ospedale Sant'Orsola
  • Catanzaro, Italy, 88100
    • Campus Universitario "Salvatore Venuta", Complesso Clinico, Padiglione B, 8° livello, Pneumologia
  • Genova, Italy, 16132
    • University Of Genoa - Ospedale Policlinico IRCCS San Martino di Genova
  • Milan, Italy, 20142
    • ASST SANTI PAOLO E CARLO Ospedale San Paolo Struttura Complessa Malattie Infettive
  • Milan, Italy, 20089
    • IRCCS Istituto Clinico Humanitas U.O. Medicina D'Urgenza
  • Milan, Italy, 20132
    • IRCCS Ospedale San Raffaele Centro di Ricerca Anestesia e Rianimazione
  • Milan, Italy, 20157
    • Università degli Studi di Milano-Ospedale "L.Sacco" Polo Universitario - ASST Fatebenefratelli Sacco
  • Milan, Italy, 20162
    • ASST Grande Ospedale Metropolitano Niguarda Dipartimento Malattie Infettive
  • Monza, Italy, 20900
    • ASST-Monza Ospedale San Gerardo Malattie Infettive
  • Napoli, Italy, 80131
    • Clinica Pneumologica "L. Vanvitelli" - Osp Monaldi
  • Palermo, Italy, 90127
    • AOUP "P.Giaccone" - UOC Pneumologia
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo - UOC Pneumologia, Dipartimento di Scienze Mediche e Malattie Infettive
  • Reggio Emilia, Italy, 42123
    • Struttura semplice di terapia demi-intensiva respiratoria S.C. di pneumologia AO IRCCS Santa Maria Nuova
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06800
    • Ankara City Hospital
  • Diyarbakır, Turkey (Türkiye), 21280
    • Dicle University, Medical Faculty
  • Gaziantep, Turkey (Türkiye), 27310
    • Gaziantep Universitesi Sahinbey Arastirma ve Uygulama Hastanesi
  • Istanbul, Turkey (Türkiye), 34303
    • Acibadem Atakent Hospital
  • Izmir, Turkey (Türkiye), 35340
    • Dokuz Eylul University Faculty of Medicine
  • Kayseri, Turkey (Türkiye), 38039
    • Kayseri State Hospital
  • Kocaeli, Turkey (Türkiye), 41380
    • Kocaeli Universitesi Tip Fakultesi
  • Malatya, Turkey (Türkiye), 44100
    • Inonu Uni.Med.Faculty
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • MD Banner University Medical Center /Arizona University
  • California
    • Orange, California, United States, 92868
      • UCI Health
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • MedStar Health Research Institute-Hyatteville, Maryland
  • Florida
    • Clearwater, Florida, United States, 33756
      • Research Alliance Inc.
    • Jacksonville, Florida, United States, 32209
      • University of Florida-Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Emory Johns Creek Hospital
    • Augusta, Georgia, United States, 30912
      • Augusta University Health - Augusta University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University, Feinberg School of Medicine
  • Indiana
    • Gary, Indiana, United States, 46404
      • Methodist Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Newton, Massachusetts, United States, 02462
      • Newton-Wellesley Hospital
  • Michigan
    • Midland, Michigan, United States, 48670
      • MidMichigan Medical Center - Midland
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University Hospital - MU Healthcare
    • St Louis, Missouri, United States, 63110
      • Washington University, School of Medicine
    • St Louis, Missouri, United States, 63141
      • Mercy Research St Louis
  • New York
    • Brooklyn, New York, United States, 11220
      • NYU Langone Hospital-Brooklyn
    • New York, New York, United States, 10016
      • New York University Langone Health
  • North Carolina
    • Durham, North Carolina, United States, 27708
      • Duke University Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University (OHSU) - Pulmonary Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson University Hospital
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center
  • Texas
    • Beaumont, Texas, United States, 77701
      • Baptist Hospitals of Southeast Texas
    • Denison, Texas, United States, 75020
      • Texoma Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Hospitals & Clinics
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Medical Center
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Health

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Informed consent signed
2. Male and female ≥18 years old;

3. Patients hospitalized for clinically suspected CAP, defined as the occurrence of (within 48h from hospital admission):

   1. at least 1 of the following signs/symptoms: dyspnea, cough, purulent sputum, crackles (rales) and/or rhonchi
   2. body temperature > 38°C or <36°C (before or during admission) or leucocytosis (> local ULN)
   3. new/increased pulmonary infiltrate(s) by chest imaging
4. Need for non-invasive supplemental oxygen (NIAID-OS 5-6);
5. SpO2 <92% at room air, or PaO2/FiO2 (or SpO2/FiO2) <300;

6. Females of child-bearing potential and with an active sexual life must not wish to get pregnant within 30 days after the end of the study and must be using at least one of the following reliable methods of contraception:

   1. Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit until 30 days after the last IMP dose
   2. A non-hormonal intrauterine device [IUD] or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit until 30 days after the last IMP dose
   3. A male sexual partner who agrees to use a male condom with spermicide
   4. A sterile sexual partner

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. Treatment with IMV or ECMO (NIAID-OS 7);
2. Hepatic dysfunction: ALT or AST > 5 ULN; history of chronic hepatic disease (defined with Child-Pugh score B or C);
3. Renal dysfunction: estimated glomerular filtration rate (eGFR, MDRD) <50 mL/min/1.73 m2, or need for haemodialysis or hemofiltration;
4. Current use of >2 immunosuppressive medications or immunosuppression status (AIDS, aplastic anaemia, asplenia, systemic chemotherapy within the past 3 months, neutropenia (ANC < local LLN), solid organ or bone marrow transplant recipients)
5. Treatment with prohibited medication within 5 half-lives, and inability to stop during treatment period;
6. Anticipated discharge from the hospital or transfer to another hospital within 72 hours of screening

7. History of:

   1. intolerance or hypersensitivity to ibuprofen 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)
   2. lactase deficiency, galactosemia or glucose-galactose malabsorption
   3. gastrointestinal bleeding or perforation due to previous NSAIDs therapy or recurrent peptic ulcer/haemorrhage
   4. allergy to reparixin or any component of the IMP formulation
8. Active bleeding or bleeding diathesis (excluding menses), prior intracranial haemorrhage
9. Participation in other interventional clinical trials
10. Clinical condition not compatible with oral administration of the study drug

11. Pregnancy:

    1. positive or missing pregnancy test before first drug intake or day 1;
    2. pregnant or lactating women;
    3. women of childbearing potential and fertile men who do not agree to use at least one primary form of contraception for the duration of the study
12. Current hospital stay >72h
13. Complicated CAP-associated conditions, such as fungal pulmonary infection, tuberculosis infection, abscess, empyema, significant bilateral pleural effusion, massive pulmonary embolism

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reparixin + standard of care (SoC); Reparixin was administered orally at the dose of 1200 mg (2 x 600 mg tablets) TID (6 tablets daily) for up to 21 days. The three daily doses were administered maintaining an interval between doses of about 8 hours.	Drug: Reparixin; Reparixin 600 mg tablets, administered orally at the dose of 1200 mg TID (2 tablets TID) as add-on therapy to standard of care up to 21 days. IMP was taken with a glass of water (about 250 mL) and a light meal or snack, as it was preferable that reparixin was taken with food. However, If the patient was unwilling or unable to administer oral tablets, investigator could decide a nasogastric tube as an alternative route.; Other Names: Repertaxin L-lysine salt
Placebo Comparator: Placebo + standard of care (SoC); Placebo tablets are identical in appearance to the active formulation. Placebo was administered with the same treatment schedule.	Other: Placebo; Administered orally three times a day (TID) as add-on therapy to standard of care (SoC) up to 21 days. Placebo was taken with a glass of water (about 250 mL) and a light meal or snack, as it was preferable that placebo was taken with food. However, if the patient was unwilling or unable to administer oral tablets, investigator could decide a nasogastric tube as an alternative route.; Other Names: Matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Dead or Requiring Invasive Mechanical Ventilation (IMV) or Extracorporeal Membrane Oxygenation (ECMO) by Day 28 [NIAID-OS 7].	The primary endpoint was based on NIAID-OS ordinal scale (National Institute of Allergy and Infectious Disease) with score OS 7 which means patients "hospitalized, on invasive mechanical ventilation or ECMO". The scores on this scale of Disease severity range from OS 1 (best outcome) to OS 8 (worst outcome). NIAID-OS (National Institute of Allergy and Infectious Disease Ordinal Scale) SCORE Descriptor: OS 1 Not hospitalized, no limitations on activities;; OS 2 Not hospitalized, limitation on activities and/or requiring home O2;; OS 3 Hospitalized, no supplemental O2 - no longer requires ongoing medical care;; OS 4 Hospitalized, no supplemental O2 - requiring ongoing medical care;; OS 5 Hospitalized, requiring supplemental O2;; OS 6 Hospitalized, on non-invasive ventilation or high-flow oxygen devices;; OS 7 Hospitalized, on invasive mechanical ventilation or ECMO;; OS 8 Death;	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality by Day 180	Key secondary endpoint. All-cause mortality is a measurement of the total number of deaths from any cause within a specific population over a defined period. It is a broad metric used in medical research and public health to assess overall population health, identify risk factors for premature death, and evaluate the effectiveness of interventions. The number of participants (in the form of unadjusted proportion) who met the endpoint is reported.	Day 180
Proportion of Patients Alive and Discharged From the Hospital by Day 28	Key secondary endpoint. The number of participants alive or discharged, expressed in the form of unadjusted proportion, who met the endpoint at the final analysis at day 28 is provided.	Day 28
Ventilatory-free Days (VFD) by Day 28	Key secondary endpoint. Number of days from Day 0 to Day 28 when the patient was alive and free of invasive ventilation is reported. In case of multiple periods of IMV during the first 28 days, the total duration of ventilation considered all periods of ventilation during the index admission. Patients who died within 28 days or who still were on invasive ventilation after 28 days were scored 0 VFDs.	Day 28
Proportion of Patients With IMV (or ECMO) by Day 28	Key secondary endpoint.The number of participants, expressed in the form of unadjusted proportion, who met the endpoint at the final analysis is reported.	Day 28
Length of Primary Hospital Stay (in Days)	Key secondary endpoint. The duration of primary hospital stay, expressed in days, are reported. This parameter is included in the set of final evaluation, which comprises: no. of days of hospitalization, etiologic agents (if identified), ICU admission and total days in ICU, occurrence, and duration of IMV and/or ECMO, if any.	Day 180
Clinical Failure by Day 3 and Day 7	Clinical failure was defined as the occurrence of IMV/ECMO or vasopressor, or death. IMV= invasive mechanical ventilation. ECMO=extracorporeal membrane oxygenation.	Day 3 and Day 7
28-day ICU-free Days	ICU-free days = days of hospitalization out of the Intensive Care Unit. Death within Day 28 was handled as an unfavorable event and ICU-free days were set at 0.	Day 28
Days Free of IMV or ECMO (Number of Days With NIAID-OS 1-6) by Day 28	These parameters are expressed as number of days with NIAID-OS score not equal to 7 or 8, where NIAID-OS is the National Institute of Allergy and Infectious Disease Ordinal Scale; a scale ranging from 1 to 8, where the lower the score, the better the outcome. The IMV/ECMO-free days at Day 28 were analyzed according to MI approach and ANOVA model. Death due to progression of the respiratory disease within Day 28 was handled as an unfavorable event and IMV/ECMO-free days at Day 28 was set at 0.	Day 28
Duration of Antibiotic Therapy (Days) by Day 28	A descriptive summary of duration of antibiotic therapy (days) at day 28 for the FAS is reported.	Day 28
Hospital Free Days	Results for hospital-free days at day 28 in the FAS are presented through an unadjusted descriptive summary.	Day 28
Proportion of Patients Recovered	Results for the proportion of participants recovered at fixed timepoints in the FAS are presented. Recovering was defined as a downward shift from screening of ≤2 points on the NIAID-OS or live discharge from hospital. Unadjusted proportion is reported.	days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41)
Proportion of Patients Worsening	Results for the proportion of participants worsening at fixed timepoints in the FAS are presented. Worsening was expressed as upward shift from screening of at least >1 point of the NIAID-OS or if patient died before X Visit Day. An unadjusted proportion is reported.	days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41)
Change From Baseline in the Arterial Partial Pressure of Oxygen (PaO2)	Descriptive statistics for the change from baseline in arterial partial pressure of oxygen (PaO2) at fixed timepoints are reported.	days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41)
Change From Baseline in Pulse Oximetry (SpO2)	Descriptive statistics for the change from baseline in pulse oximetry, measured as peripheral arterial oxygen saturation (SpO2), at fixed timepoints are reported.	days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41)
Change From Baseline in Inspired Oxygen (FiO2) Levels	FiO2 is a parameter of lung function representing the fraction of oxygen in the inspired air, ranging from 0.21 (room air) to 1.00 (100% oxygen). The endpoint assesses the change from baseline in FiO2 levels at predefined timepoints during the study.	days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41)
Change From Baseline in PaO2/FiO2 Ratio	The PaO2/FiO2 ratio is a parameter of lung function that reflects the efficiency of oxygen transfer from the lungs to the blood. It is calculated as the ratio between the arterial partial pressure of oxygen (PaO2, measured in mmHg) and the fraction of inspired oxygen (FiO2, expressed as a fraction ranging from 0.21 to 1.00). This endpoint assesses the change from baseline in the PaO2/FiO2 ratio at predefined timepoints during the study.	days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41)
Change From Baseline in SpO2/FiO2 Ratio	The SpO2/FiO2 ratio is a noninvasive indicator of lung function and oxygenation efficiency, calculated as the ratio between peripheral oxygen saturation (SpO2, expressed as a percentage) and the fraction of inspired oxygen (FiO2, expressed as a fraction ranging from 0.21 to 1.00). This endpoint assesses the change from baseline in the SpO2/FiO2 ratio at predefined timepoints during the study.	Days 3, 7, 14, 21, and 28
All-cause Mortality	Results for all-cause mortality rates in the FAS are reported, at day 28, day 60, and day 90. Analysis was based on logistic regression model with Multiple Imputation using retrieve dropouts with proportion of patients died up to Day 28 as dependent variable, treatment, disease severity at baseline (NIAID-OS <=5 vs. NIAID-OS 6), age class (<65, >= 65 years), sex and presence of concomitant disease at baseline as qualitative independent variables.	Days 28, 60 and 90
Hospital Re-admission by Day 90 and 180	Hospital Re-admission by Day 90 and 180 in the FAS is presented. The number of participants is expressed as unadjusted proportion.	Days 90 and 180
Time to Discharge or to a NEWS (National Early Warning Score) of ≤ 2 (for 24 Hours), Whichever Occurs First	The median time to discharge or to a NEWS (National Early Warning Score) of ≤ 2 (for 24 hours), whichever occurs first, was expressed using a "time to event" approach, and measured in days. NIAID-OS, National Early Warning Score (NEWS) was evaluated daily until day 28 (or hospital discharge). In a scored system standardizing the assessment of acute-illness severity in the NHS, NEWS includes Blood Pressure (BP), Heart Rate (HR), Respiratory Rate (RR), body temperature, level of consciousness (A, V, P, U), peripheral arterial oxygen saturation (SpO2) and supplemental oxygen. Time to discharge or to a NEWS of <= 2 (for 24 hours) = Min(Date of discharge, Date of NEWS of <= 2 (for 24 hours)) - Day 1 date + 1. Date of NEWS of <= 2 (for 24 hours): Given two consecutive days with NEWS of <= 2, the date of the first assessment has been considered.	Day 28
Change in Quality of Life Using EuroQol-5-dimensions-5 Levels (EQ-5D-5L) Questionnaire From Hospital Discharge to Day 90 and Day 180	The EQ-5D-5L asks patients to indicate whether they have no, slight, moderate, severe, extreme problems on each of 5 dimensions of health: mobility; self-care; usual activities; pain/discomfort; anxiety/depression.The count of patients of each level (1 - no problems, 2 - slight problems, 3 - moderate problems, 4 - severe problems, 5 - extreme problems) for each of the 5 dimensions were reported. The higher the score for each dimension (range 1-5), the worse the outcome.	Days 90±7 and 180±14
Duration of IMV and/or ECMO by Days 90 and 180	The summary of IMV/ECMO duration by day 90 and day 180 for the FAS is presented. The duration of IMV/ECMO use by day 90 was calculated as the total number of days between day 1 and the last available assessment day (≥ day 83) during which the participant was either receiving IMV/ECMO or had a NIAID-OS score of 7. Participants with less than 83 days of follow-up were considered non-evaluable for this endpoint. Similarly, the duration of IMV/ECMO by day 180 was calculated using the same methodology.	Days 90 and 180
Proportion of Participants Requiring ICU Admission by Days 90 and 180	Unadjusted proportion of ICU admission is reported as number and percentage of participants requiring ICU admission by day 90 and day 180.	Days 90 and 180
ICU Length of Stay by Days 90 and 180	Results for the Intensive Care Unit length of stay (days) by day 90 and day 180 in the FAS are reported.	Days 90 and 180
Hospital Length of Stay by Days 90 and 180	Results for hospital length of stay (days) by day 90 and 180 in the FAS are reported.	Days 90 and 180
Occurrence of Infections by Days 90 and 180	Occurrence of infections was expressed as the unadjusted proportion of participants with at least one infection by days 90 and 180 in the FAS.	Days 90 and 180
Number of Patients With at Least One Treatment-emergent Adverse Event (TEAE)	A TEAE is defined as any adverse event reported in the study having a possible, probable, or highly probable relationship to investigational product. A serious AE is defined as any untoward medical occurrence that at any dose: results in death.; is life-threatening (i.e. the patient was at risk of death at the time of the event. It does not refer to an event which hypothetically might have caused death if it were more severe),; requires inpatient hospitalization or prolongation of existing hospitalization,; results in persistent or significant disability/incapacity,; is a congenital anomaly/birth defect; is a medically significant or important medical condition, i.e. an important medical event that based upon appropriate medical judgment, may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed above.	Throughout the study till Day 180 (± 14) or end of treatment

Collaborators and Investigators

• Sponsor: Dompé Farmaceutici S.p.A
• Investigators: Principal Investigator: Giovanni Landoni, MD, IRCCS Ospedale San Raffaele Centro di Ricerca Anestesia e Rianimazione

Publications and helpful links

General Publications

• Truwit JD, Fleming K, Nanchal RS. Empowering Respiratory Therapists to Restrict Nebulized 3% Saline and N-Acetylcysteine During Mechanical Ventilation. Respir Care. 2025 Aug;70(8):937-945. doi: 10.1089/respcare.12586. Epub 2025 Feb 24.

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2022
• Primary Completion (Actual): July 29, 2024
• Study Completion (Actual): September 27, 2024

Study Registration Dates

• First Submitted: February 22, 2022
• First Submitted That Met QC Criteria: February 23, 2022
• First Posted (Actual): February 24, 2022

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 18, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; Infectious pneumonia acquired in the community (CAP)
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; reparixin
• Other Study ID Numbers: REP0321; 2021-006951-32 (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