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

Phase 3

Terminated

• Conditions: Severe COVID-19; Infectious Pneumonia
• Interventions: Other: Placebo; Drug: Reparixin

• Registration Number: NCT05254990
• Lead Sponsor: Dompé Farmaceutici S.p.A

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2022-02-22
• Study First Submitted QC: 2022-02-23
• Study First Posted: 2022-02-24
• Study Start: 2022-04-27
• Primary Completion: 2024-09-27
• Study Completion: 2024-09-27
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-22
• Last Update Posted: 2024-10-24

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 409

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; 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:

   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 (see section 5.5.2);

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + standard of care	Placebo	Placebo tablets are identical in appearance to the active formulation. Placebo will be administered with the same treatment schedule.
Reparixin + standard of care	Reparixin	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.

Primary Outcome Measures

Name	Time	Method
Proportion of patients dead or requiring Invasive Mechanical Ventilation (IMV) or Extracorporeal Membrane Oxygenation (ECMO) by day 28 [NIAID-OS 7].	Day 28	NIAID-OS = National Institute of Allergy and Infectious Disease - Ordinal Scale

Secondary Outcome Measures

Name	Time	Method
28-day ICU-free days	Day 28
Proportion of patients alive and discharged at day 28	Day 28
Length of primary hospital stay	Throughout the trial
Clinical failure by day 3 and day 7	day 3 and day 7	Clinical failure will be defined as the occurrence of IMV/ECMO or vasopressor, or death
Hospital re-admission by day 90 and 180	Days 90 and 180
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]
All-cause mortality at day 180	Day 180
Ventilatory-free days (VFD) at day 28	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
Occurrence of IMV (or ECMO) by day 28	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
PO2/FiO2	days 3, 7±1, 14±2, 21±2, 28 ±2 or at hospital discharge
All-cause mortality	Days 28 and 90
Time to discharge or to a NEWS of ≤ 2 (for 24 hours), whichever occurs first	Day 28
Duration of IMV and/or ECMO at 90 and 180 days	Days 90 and 180
Hospital length of stay at 90 and 180 days	Days 90 and 180
Proportion of patients recovered	days 3, 7±1, 14±2, 21±2, 28 ±2 or at hospital discharge	downward shift from screening of ≤2 points on the NIAID-OS or live discharge from hospital)
Proportion of patients worsening	days 3, 7±1, 14±2, 21±2, 28 ±2 or at hospital discharge	upward shift from screening of at least \>1 point of the NIAID-OS)
ICU admission at 90 and 180 days	Days 90 and 180
ICU length of stay at 90 and 180 days	Days 90 and 180
Occurrence of infections at 90 and 180 days	Days 90 and 180
Change in quality of life using EuroQol-5-dimensions-5 levels (EQ-5D-5L) questionnaire	90±7 and 180±14 days	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.
Hospital free days	Day 28

Trial Locations

Locations (101)

Azienda Ospedaliera Universitaria Arcispedale Sant'Anna; 🇮🇹 Ferrara, Italy

Azienda Ospedaliera Universitaria Federico II.; 🇮🇹 Napoli, Italy

Università degli Studi della Campania "Luigi Vanvitelli"; 🇮🇹 Napoli, Italy

MD Banner University Medical Center /Arizona University; 🇺🇸 Tucson, Arizona, United States

UC Davis Medical Center - UC Davis Medical Group - Davis; 🇺🇸 Davis, California, United States

University of Southern California; 🇺🇸 Los Angeles, California, United States

UCI Health; 🇺🇸 Orange, California, United States

Denver Health; 🇺🇸 Denver, Colorado, United States

Nuvance Health; 🇺🇸 Danbury, Connecticut, United States

MedStar Health Research Institute-Hyatteville, Maryland; 🇺🇸 Washington, District of Columbia, United States

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