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

Phase 3TerminatedNCT05254990

Dompé Farmaceutici S.p.A414 enrolled

Overview

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.

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.

Interventions

ReparixinDRUG

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.

PlaceboOTHER

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (74)

MD Banner University Medical Center /Arizona University

Tucson, Arizona, United States

UCI Health

Orange, California, United States

Denver Health

Denver, Colorado, United States

MedStar Health Research Institute-Hyatteville, Maryland

Washington D.C., District of Columbia, United States

Research Alliance Inc.

Clearwater, Florida, United States

Outcomes

Primary Outcomes

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;

Time frame: Day 28

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Day 28

Hospital Free Days

Results for hospital-free days at day 28 in the FAS are presented through an unadjusted descriptive summary.

Time frame: 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.