Overview
This is a multicentre, double-blind, placebo-controlled Phase III randomized clinical trial designed to evaluate the efficacy and safety of inhaled aprotinin in adult patients with moderate or severe acute respiratory distress syndrome (ARDS). A total of 156 critically ill patients admitted to intensive care units will be randomized to receive either inhaled aprotinin or placebo in addition to standard supportive care. The primary objective is to determine whether aprotinin improves clinical outcomes based on a composite endpoint of ventilator-free days at 28 days.
Description
This study is a nation-wide, multicentre, double-blind, placebo-controlled, Phase III randomized clinical trial designed to investigate the efficacy and safety of inhaled aprotinin in adult patients diagnosed with moderate or severe acute respiratory distress syndrome (ARDS). ARDS is a heterogeneous acute inflammatory lung syndrome characterized by diffuse alveolar damage, increased vascular permeability, alveolar and interstitial edema, and severe hypoxemic respiratory failure. Despite advances in supportive care, no specific pharmacological therapy has demonstrated proven benefit.
Aprotinin is a broad-spectrum serine protease inhibitor that targets the kallikrein-kinin system and attenuates systemic inflammatory responses, including reductions in pro-inflammatory cytokines and matrix metalloproteinases (MMPs). Experimental and clinical data suggest that MMP overexpression contributes to tissue damage, coagulation abnormalities, and impaired lung repair, representing a potential therapeutic target in ARDS. Inhaled aprotinin has been used clinically in patients with respiratory conditions, including COVID-19 and chronic pulmonary disease, with no reported adverse events via this route of administration.
In this trial, 156 ICU patients with moderate or severe ARDS will be enrolled and randomized in a 1:1 ratio to receive either inhaled aprotinin or placebo, both administered alongside standard supportive care. The aprotinina dosing regimen will be four inhaled doses of 500 KIU every six hours (total 2,000 KIU/day), selected to achieve effective local pulmonary concentrations while minimizing systemic exposure. The primary endpoint is a composite of ventilator-free days at 28 days among survivors. Secondary outcomes include ICU and hospital mortality, duration of mechanical ventilation, and other clinically relevant respiratory and functional endpoints. Detailed study procedures, dosing, and administration are described in the study protocol.
All study procedures will be conducted under a double-blind design. Patients will be prospectively followed for clinical outcomes during their ICU and hospital stay according to prespecified assessment timepoints. A Data Monitoring Committee (DMC) composed of independent clinical experts will periodically review safety and efficacy data, ensuring the protection of participants and the scientific validity of the study. The estimated study duration is four years, from September 2025 to September 2029.
Eligibility
Inclusion Criteria:
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
- Diagnosed with moderate or severe Acute Respiratory Distress Syndrome (ARDS) according to the Berlin definition (ARDS Definition Task Force 2012):
- Acute onset of respiratory failure within 1 week of a known clinical insult or new/worsening respiratory symptoms.
- Respiratory failure not fully explained by cardiac failure or fluid overload; objective evaluation of cardiac failure or fluid overload is required if ARDS risk factors are absent.
- Radiographic abnormalities on chest X-ray or CT scan: bilateral opacities not fully explained by effusions, nodules, masses, or lobar/segmental collapse.
- Hypoxemia:
- Moderate ARDS: PaO₂/FiO₂ \>100 mmHg and ≤200 mmHg with Positive End-Expiratory Pressure (PEEP) ≥5 cmH₂O.
- Severe ARDS: PaO₂/FiO₂ ≤100 mmHg with PEEP ≥5 cmH₂O.
- Radiographic and hypoxemia criteria must occur within the same 24-hour period. ARDS onset is defined as the time when the last of these two criteria is met.
- First dose of study drug planned within 48 hours of moderate or severe ARDS diagnosis.
- Intubated and receiving mechanical ventilation.
- Age ≥18 years.
- Women of childbearing potential must have a negative serum pregnancy test during screening and a negative urine pregnancy test at study start. Female subjects of childbearing potential and male subjects with partners of childbearing potential must agree to use an effective contraceptive method from consent until 30 days after study drug administration.
Exclusion Criteria:
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
- Pregnant or lactating women, or positive/indeterminate pregnancy test (serum or urine).
- Simultaneous participation in another pharmacotherapy protocol.
- Life expectancy \<24 hours.
- Clinical condition in which, in the investigator's opinion, ventilator withdrawal is extremely unlikely (e.g., motor neuron disease, Duchenne muscular dystrophy, rapidly progressive interstitial lung disease).
- Severe chronic obstructive pulmonary disease requiring long-term home oxygen or mechanical ventilation (noninvasive or tracheostomy), except Continuous Positive Airway Pressure (CPAP) or Bilevel Positive Airway Pressure (BiPAP) used solely for sleep-related respiratory disorders.
- Congestive heart failure defined as New York Heart Association (NYHA) class IV.
- Acute left ventricular failure.
- Severe hepatic impairment (Child-Pugh class C).
- Prior interferon therapy.
- Known hypersensitivity to natural or recombinant IFN beta or any excipients.
- Receiving renal dialysisfor chronic renal failure.
- Receiving extracorporeal membrane oxygenation (ECMO), high-frequency oscillatory ventilation, or any form of extracorporeal pulmonary support.
- Mechanical ventilation, (invasive or noninvasive, excluding CPAP alone), for more than 48 hours before ARDS diagnosis. Noninvasive ventilation must be applied continuously for at least 12 hours/day during those 48 hours.
- Burns covering ≥15% total body surface.
- Women with positive pregnancy test at screening (serum) or study start (urine); lactating subjects; subjects planning pregnancy within 1 month after the study (including male partners).
