Phase 2, randomized, double-blinded, placebo-controlled, multicenter study to assess efficacy and safety of reparixin as additional therapy in adult patients with Acute Respiratory Distress Syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Dompe' Farmaceutici S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

6 Dec 2022 → 18 Apr 2025

Decision date (initial)

2024-08-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Dompé farmaceutici s.p.a.

External identifiers

EU CT number

2024-512621-88-00

EudraCT number

2022-001612-25

ClinicalTrials.gov

NCT05496868

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy, Pharmacokinetic

To characterize the efficacy of reparixin in ameliorating lung injury and systemic inflammation and expediting clinical recovery and liberation from mechanical ventilation in adult patients with moderate to severe ARDS (PaO2/FIO2 ratio ≤ 200). Furthermore, to assess the effect of reparixin on systemic biomarkers linked to a hyper-inflammatory ARDS phenotype.
Safety objectives: To evaluate the safety of reparixin vs. placebo in patients enrolled in the study.

Secondary objectives 1

1. To characterize the pharmacokinetics (PK) of reparixin in the same population of acutely ill patients enrolled in the study

Conditions and MedDRA coding

Acute Respiratory Distress Syndrome

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Signed Informed Consent, according to local guidelines and regulations.
2. Male and female adults (>18 years old).
3. Mechanically ventilated (invasive) patients with PaO2/FIO2 ratio ≤ 200 in the presence of PEEP of ≥5 cm H2O.
4. Respiratory failure not fully explained by cardiac failure or fluid overload (if acute Congestive Heart Failure exacerbation is identified as part of the clinical picture this should be addressed effectively and as soon as possible before the patient can be enrolled).
5. Bilateral radiologic opacities consistent with pulmonary edema on the frontal chest x-ray (CXR) radiograph, or bilateral ground glass opacities on a chest CT scan.
6. ≤48 hours from fulfilling above ARDS criteria (if a patient is transferred from a non-participating hospital to a participating site, a 12-hour period beyond the 48 hours is allowed)
7. Females of child-bearing potential who are sexually active must be willing not to get pregnant within 30 days after the last Investigational Medicinal Product (IMP) dose and must agree to at least one of the following reliable methods of contraception: • Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives from at least2 months before the screening visit until 30 days after the last IMP dose; • A sterile sexual partner; • Abstinence. For patients unable to personally consent to the above, due to complications of acute illness and/or its treatment, assurances for the above must be given by LR and reiterated by the patient when/if she is able to do so. Female participants of non-child-bearing potential or in postmenopausal status for at least 1 year will be admitted. For all female subjects with child-bearing potential, pregnancy test results must be negative before first drug intake.

Exclusion criteria 13

1. Moderate-Severe chronic hepatic disease (as verified by a previously known Child-Pugh score ≥7). If baseline Child-Pugh score is not known, it should not be calculated while the patient is acutely ill. In that case, the patient is excluded on the basis of: ALT/AST ≥ 3x ULN and total bilirubin > 2x ULN or ALT/AST ≥ 5x ULN.
2. Severe chronic renal dysfunction: eGFR (2021 CKD-EPI) < 30 mL/min/1.73m2 . If baseline (chronic) renal function is not known, the patient is only excluded if in need of acute renal replacement therapy (currently on RRT or to be imminently placed on RRT).
3. Participation in another interventional clinical trial.
4. Patients that are clinically determined to have a high likelihood of death within the next 24 hours based on PI's estimation.
5. Currently receiving ECMO or high frequency oscillatory ventilation.
6. Anticipated extubation within 24 hours of screening. (In such cases, re-screening is allowed if the patient is within the enrollment window).
7. Evidence of GI dysmotility as demonstrated by presence of all the following: persistent gastric distention and enteral feeding intolerability and persistent gastric residuals >500 ml).
8. Anticipated transfer to a hospital not participating in the trial within 72 hours of screening.
9. Decision to withhold or withdraw life-sustaining treatment (patients may still be eligible however if they are committed to full support except cardiopulmonary resuscitation if cardiac arrest occurs).
10. History of: a) Documented allergy/hypersensitivity to sulfonamides, ibuprofen and other COX-1 and 2 inhibitors, and to the study product and/or its excipients. b) Lactase deficiency, galactosemia or glucose-galactose malabsorption. c) History of peptic ulcer, GI bleeding or perforation due to previous NSAID therapy.
11. Active bleeding (excluding menses) from an uncontrolled site that cannot be definitively resolved prior to enrollment.
12. Pregnant or lactating women.
13. Women of childbearing potential and fertile men who do not agree to use at least one primary form of contraception during the study and up to 30 days after the last IMP dose. For patients unable to personally consent to above due to complications of acute illness and/or its treatment, assurances for the above must be given by LR and reiterated by the patient when/if he/she is able to do so.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Change in oxygenation index (OI) from baseline to day 7 of treatment. The OI is defined as: % mean airway pressure x FIO2/PaO2
2. Ventilator free days (VFD) at day 28

Secondary endpoints 16

1. Change in OI from baseline to day 4
2. Acute lung injury score [composite of PaO2/FIO2 ratio, PEEP, lung compliance (plateau airway pressure minus PEEP/TV) and extent of pulmonary infiltrates] at 2, 3, 7, 14 days (if still intubated)
3. SOFA scores at 2, 3, 7, 14 days (if still intubated)
4. Ventilatory ratio (product of minute ventilation and PaCO2) at 2, 3, 7, 14 days (if still intubated)
5. Incidence of ECMO at day 14
6. Use of vasoactive medications at day 14
7. CXR assessment of pulmonary edema by "radiographic assessment of lung edema" (RALE) score at 2, 3, 7, 14 days
8. Percentage of patients achieving pressure support ventilation equal to 5 cm H20 with PEEP equal to 5 cm H20 for 2 hours (measure of weaning) by day 28 and hospital discharge
9. ICU-free days by day 28 and hospital discharge
10. Hospital-free days by day 28 and hospital discharge
11. Incidence of tracheostomies by day 28 and hospital discharge
12. Incidence of LTAC facility by day 28 and hospital discharge
13. All-cause mortality by day 28
14. Hospital discharge by day 28
15. All-cause mortality by day 60
16. Change from baseline to day 3, 7 and 14 in plasma levels of Il-6, IL-8, PAI-1, Plasma TNFr-1, ICAM-1 RAGE

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dompe' Farmaceutici S.p.A.

Sponsor organisation

Dompe' Farmaceutici S.p.A.

Address

Via Santa Lucia 6

City

Milan

Postcode

20122

Country

Italy

Scientific contact point

Organisation

Dompe' Farmaceutici S.p.A.

Contact name

Clinical Trial Manager

Public contact point

Organisation

Dompe' Farmaceutici S.p.A.

Contact name

Clinical Trial Manager

Third parties 11

Locations

2 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications