Efficacy and Safety of Reparixin as Adjunctive Therapy in Adult Patients with Acute Respiratory Distress Syndrome: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2024-512621-88-00
Protocol: REP0122
Sponsor: Dompe' Farmaceutici S.p.A.

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Diseases & Conditions

Acute respiratory distress syndrome

Objectives

The primary objective of this Phase 2, randomized, double-blinded, placebo-controlled, multicenter study is to evaluate the **efficacy** of reparixin as an add-on therapy in adult patients with moderate to severe **Acute Respiratory Distress Syndrome (ARDS)**. The study aims to determine the potential of reparixin in ameliorating lung injury, reducing systemic inflammation, and expediting clinical recovery, including liberation from mechanical ventilation. Additionally, the study will assess the impact of reparixin on systemic biomarkers associated with a hyper-inflammatory ARDS phenotype. The safety of reparixin compared to placebo will also be evaluated in the enrolled patient population.

Secondary objectives include characterizing the pharmacokinetics (PK) of reparixin in the same population of acutely ill patients participating in the study. Understanding the PK profile is crucial for optimizing dosing regimens and ensuring therapeutic efficacy while minimizing potential adverse effects.

Participants

The clinical trial involves a total of **51 participants** diagnosed with **Acute Respiratory Distress Syndrome** (ARDS). The study population comprises both male and female adults over the age of 18, who are mechanically ventilated with a PaO2/FIO2 ratio of ≤ 200, indicating moderate to severe ARDS. Participants were selected based on specific inclusion criteria, including the presence of bilateral radiologic opacities consistent with pulmonary edema and respiratory failure not fully explained by cardiac failure or fluid overload. The trial includes a vulnerable population, as it involves individuals with acute illness requiring mechanical ventilation. Lifestyle considerations such as diet and physical activity are not specified, but female participants of child-bearing potential must adhere to reliable contraception methods. The trial aims to evaluate the efficacy and safety of reparixin in ameliorating lung injury and systemic inflammation in this patient group.

Plans and Procedures

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of **reparixin** as an add-on therapy to the standard of care in adult patients with **Acute Respiratory Distress Syndrome** (ARDS). The trial aims to assess the impact of reparixin on lung injury, systemic inflammation, and clinical recovery, including liberation from mechanical ventilation. The study will also evaluate the safety profile of reparixin compared to placebo. The trial is expected to last until August 2025, with recruitment having commenced in February 2023.

Participants will be randomly assigned to receive either reparixin or a placebo, both administered in tablet form orally. The maximum daily dose of reparixin is 3600 mg, with a total treatment period not exceeding 21 days. The trial includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, mechanical ventilation status, and specific respiratory parameters; follow-up visits to monitor changes in oxygenation index, ventilator-free days, and other secondary endpoints; and an end-of-study visit to assess overall outcomes and safety.

The expected duration of participant involvement is up to 28 days, with the possibility of early termination if safety concerns arise or if the participant withdraws consent. Primary endpoints include changes in the oxygenation index from baseline to day 7 and the number of ventilator-free days by day 28. Secondary endpoints encompass a range of clinical and biochemical measures, including acute lung injury scores, SOFA scores, and changes in systemic biomarkers. The trial is conducted under strict adherence to ethical guidelines, ensuring informed consent and the safety of all participants throughout the study duration.

Treatment

The clinical trial involves the administration of **Reparixin**, an experimental medication, in the form of a **tablet**. Reparixin is chemically synthesized and is provided by Dompé Farmaceutici S.p.A. The active substance in Reparixin is also referred to as Repertaxin. The medication is administered **orally** with a maximum daily dose of 3600 mg, and the total dose over the treatment period should not exceed 75600 mg. The treatment duration is set for a maximum of 21 days. The primary objective of the trial is to evaluate the efficacy of Reparixin in improving lung injury and systemic inflammation in patients with moderate to severe Acute Respiratory Distress Syndrome (ARDS), as well as to assess its safety profile.

In addition to Reparixin, a **placebo** is used as a comparator in this double-blinded, placebo-controlled study. The placebo is also administered in the form of a tablet for oral use. The placebo is designed to match the experimental medication in appearance and administration route to ensure blinding. The use of a placebo allows for the assessment of Reparixin's efficacy and safety against a control group receiving no active treatment. Compliance with the dosing schedule and administration is monitored throughout the study to ensure adherence to the protocol.

Efficacy

The efficacy of Reparixin as an add-on therapy to standard care in adult patients with **Acute Respiratory Distress Syndrome (ARDS)** will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change in oxygenation index (OI) from baseline to day 7 of treatment, and the number of ventilator-free days (VFD) at day 28. The oxygenation index is calculated as the percentage of mean airway pressure multiplied by the fraction of inspired oxygen (FIO2) divided by the partial pressure of arterial oxygen (PaO2).

Secondary endpoints will evaluate various parameters over different time points, including changes in the OI from baseline to day 4, acute lung injury scores, Sequential Organ Failure Assessment (SOFA) scores, and ventilatory ratios at days 2, 3, 7, and 14, if the patient remains intubated. Additional assessments include the incidence of extracorporeal membrane oxygenation (ECMO) use, vasoactive medication use, and radiographic assessment of lung edema (RALE) scores at specified intervals. The study will also measure the percentage of patients achieving specific ventilation criteria, ICU-free days, hospital-free days, incidence of tracheostomies, and long-term acute care (LTAC) facility admissions by day 28 and at hospital discharge.

Furthermore, the trial will monitor all-cause mortality at days 28 and 60, hospital discharge rates by day 28, and changes in plasma levels of biomarkers such as IL-6, IL-8, PAI-1, Plasma TNFr-1, ICAM-1, and RAGE from baseline to days 3, 7, and 14. These efficacy parameters will be collected and analyzed using validated scales and laboratory tests at the specified time points to determine the impact of Reparixin on lung injury, systemic inflammation, and clinical recovery in ARDS patients.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed Informed Consent, according to local guidelines and regulations.
Male and female adults (>18 years old).
Mechanically ventilated (invasive) patients with PaO2/FIO2 ratio ≤ 200 in the presence of PEEP of ≥5 cm H2O.
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).
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.
≤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)
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.

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Exclusion Criteria

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.
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).
Participation in another interventional clinical trial.
Patients that are clinically determined to have a high likelihood of death within the next 24 hours based on PI's estimation.
Currently receiving ECMO or high frequency oscillatory ventilation.
Anticipated extubation within 24 hours of screening. (In such cases, re-screening is allowed if the patient is within the enrollment window).
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).
Anticipated transfer to a hospital not participating in the trial within 72 hours of screening.
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).
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.
Active bleeding (excluding menses) from an uncontrolled site that cannot be definitively resolved prior to enrollment.
Pregnant or lactating women.
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.