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

Dompé

Status and phase: Terminated; Phase 3

Conditions: Infectious Pneumonia; Severe COVID-19

Treatments: Other: Placebo; Drug: Reparixin

Study type: Interventional

Funder types: Industry

Identifiers

NCT05254990

REP0321

2021-006951-32 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 414 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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414 participants in 2 patient groups, including a placebo group

Reparixin + standard of care (SoC)

Experimental group

Description:

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.

Treatment:

Drug: Reparixin

Placebo + standard of care (SoC)

Placebo Comparator group

Description:

Placebo tablets are identical in appearance to the active formulation. Placebo was administered with the same treatment schedule.

Treatment:

Other: Placebo