Reparixin as add-on Therapy to Standard of Care to Limit Disease Progression in Adult Patients With COVID-19 and Other Community-Acquired Pneumonia.

Study Overview
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Brief Summary
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Primary objective: - To evaluate the efficacy of oral reparixin versus standard care alone in limiting disease progression in adult patients hospitalised for infectious pneumonia acquired in the community (CAP), including COVID-19. Secondary objectives: - To determine the effect of reparixin on several disease severity/progression measures including recovery, ventilatory free days and mortality. Safety objectives: - To evaluate the safety of oral reparixin versus placebo in the specific clinical setting.

Detailed Description
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Multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase III trial. It will enrol 526 male and female patients >18 years, hospitalised for CAP (including COVID-19), assigned (1:1) to receive either oral reparixin (treatment group) or matched placebo (control group) three times a day (TID) for up to 21 days. Randomisation will be stratified according to disease severity and site. All the patients will receive the standard of care 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. The primary outcome will be evaluated at day 28, secondary will be evaluated from day 3 to day 180. An independent external data monitoring committee (DMC) will oversee the study and evaluate unblinded interim data for efficacy, futility, and safety.

Official Title
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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, Randomised, Double-blinded, Placebo-controlled, Phase III Trial (REPAVID-22)

Conditions
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Infectious Pneumonia, Severe COVID-19

Intervention / Treatment
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* Drug: Reparixin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent signed Male and female ≥18 years old; Patients hospitalized for clinically suspected CAP, defined as the occurrence of (within 48h from hospital admission): at least 1 of the following signs/symptoms: dyspnea, cough, purulent sputum, crackles (rales) and/or rhonchi body temperature > 38°C or <36°C (before or during admission) or leucocytosis (> local ULN) new/increased pulmonary infiltrate(s) by chest imaging Need for non-invasive supplemental oxygen (NIAID-OS 5-6; Appendix 14.4.1); SpO2 <92% at room air, or PaO2/FiO2 (or SpO2/FiO2) <300; 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: 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 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 A male sexual partner who agrees to use a male condom with spermicide 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: Treatment with IMV or ECMO (NIAID-OS 7); Hepatic dysfunction: ALT or AST > 5 ULN; history of chronic hepatic disease (defined with Child-Pugh score B or C); Renal dysfunction: estimated glomerular filtration rate (eGFR, MDRD) <50 mL/min/1.73 m2, or need for haemodialysis or hemofiltration; 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) Treatment with prohibited medication within 5 half-lives, and inability to stop during treatment period (see section 5.5.2); Anticipated discharge from the hospital or transfer to another hospital within 72 hours of screening History of: 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) lactase deficiency, galactosemia or glucose-galactose malabsorption gastrointestinal bleeding or perforation due to previous NSAIDs therapy or recurrent peptic ulcer/haemorrhage allergy to reparixin or any component of the IMP formulation Active bleeding or bleeding diathesis (excluding menses), prior intracranial haemorrhage Participation in other interventional clinical trials Clinical condition not compatible with oral administration of the study drug Pregnancy: positive or missing pregnancy test before first drug intake or day 1; pregnant or lactating women; 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 Current hospital stay >72h Complicated CAP-associated conditions, such as fungal pulmonary infection, tuberculosis infection, abscess, empyema, significant bilateral pleural effusion, massive pulmonary embolism

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: male and female patients >18 years, hospitalised for COVID-19, will be assigned (1:1) to receive either oral reparixin (treatment group) or matched placebo (control group) three times a day (TID) for up to 21 days.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reparixin + standard of care<br>Reparixin will be 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 will be administered maintaining an interval between doses of about 8 hours. | Drug: Reparixin<br>* 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 can be taken with a glass of water (about 250 mL) and a light meal or snack, as it is preferable that reparixin is taken with food. However, if the patient is unable to eat, the study drug may still be administered without concomitant food ingestion.<br>* Other names: Repertaxin L-lysine salt;|
| Placebo Comparator: Placebo + standard of care<br>Placebo tablets are identical in appearance to the active formulation. Placebo will be administered with the same treatment schedule. | Other: Placebo<br>* Administered orally three times a day (TID) as add-on therapy to standard of care up to 21 days. Placebo can be taken with a glass of water (about 250 mL) and a light meal or snack, as it is preferable that placebo is taken with food. However, if the patient is unable to eat, the placebo may still be administered without concomitant food ingestion.<br>* Other names: Matched placebo;|

What is the study measuring?
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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]. | NIAID-OS = National Institute of Allergy and Infectious Disease - Ordinal Scale | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality at day 180 |  | Day 180 | 
| Proportion of patients alive and discharged at day 28 |  | Day 28 | 
| Ventilatory-free days (VFD) at day 28 | Number of days from Day 0 to Day 28 when the patient will alive and free of invasive ventilation. 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 will die within 28 days or will be still on invasive ventilation after 28 days will score zero VFDs18 | Day 28 | 
| Occurrence of IMV (or ECMO) by day 28 |  | Day 28 | 
| Length of primary hospital stay |  | Throughout the trial | 
| Clinical failure by day 3 and day 7 | Clinical failure will be defined as the occurrence of IMV/ECMO or vasopressor, or death | day 3 and day 7 | 
| 28-day ICU-free days |  | Day 28 | 
| Days free of IMV/ECMO (number of days with NIAID-OS 1-6) at day 28 |  | Day 28 | 
| Duration of antibiotic therapy (days) at day 28 |  | Day 28 | 
| Hospital free days |  | Day 28 | 
| Proportion of patients recovered | downward shift from screening of ≤2 points on the NIAID-OS or live discharge from hospital) | days 3, 7±1, 14±2, 21±2, 28 ±2 or at hospital discharge | 
| Proportion of patients worsening | upward shift from screening of at least >1 point of the NIAID-OS) | days 3, 7±1, 14±2, 21±2, 28 ±2 or at hospital discharge | 
| PO2/FiO2 |  | days 3, 7±1, 14±2, 21±2, 28 ±2 or at hospital discharge | 
| All-cause mortality |  | Days 28 and 90 | 
| Hospital re-admission by day 90 and 180 |  | Days 90 and 180 | 
| Time to discharge or to a NEWS of ≤ 2 (for 24 hours), whichever occurs first |  | Day 28 | 
| Change in inflammatory markers (LDH, CRP, ferritin; D-dimer, PCT) and cytokines |  | Days 3, 7±1, 14±2, 21±2, 28±2 or at hospital discharge] | 
| Change in quality of life using EuroQol-5-dimensions-5 levels (EQ-5D-5L) questionnaire | The EQ-5D-5L asks patients to indicate whether they have no, slight, moderate, severe, extreme problems on each of five dimensions of health: mobility; self-care; usual activities; pain/discomfort; anxiety/depression. | 90±7 and 180±14 days | 
| Duration of IMV and/or ECMO at 90 and 180 days |  | Days 90 and 180 | 
| ICU admission at 90 and 180 days |  | Days 90 and 180 | 
| ICU length of stay at 90 and 180 days |  | Days 90 and 180 | 
| Hospital length of stay at 90 and 180 days |  | Days 90 and 180 | 
| Occurrence of infections at 90 and 180 days |  | Days 90 and 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-CoV-2, Infectious pneumonia acquired in the community (CAP)