A randomised, double-blinded, placebo-controlled, parallel-group phase III trial (REPAVID-22)

Official Title

Reparixin 1200 mg three times a day as add-on therapy to standard of care to limit disease progression in hospitalised adult patients with community-acquired pneumonia. A multinational, multicentre, randomised, double-blinded, placebo-controlled, parallel-group phase III trial

Details

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.

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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):
   • 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
4. Need for non-invasive supplemental oxygen (NIAID-OS 5-6; Appendix 14.4.1);
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:
   • 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:

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 (see section 5.5.2);
6. Anticipated discharge from the hospital or transfer to another hospital within 72 hours of screening
7. 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
   • strointestinal bleeding or perforation due to previous NSAIDs therapy or recurrent peptic ulcer/haemorrhage
   • 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: