Safety and Preliminary Efficacy of Sequential Multiple Ascending Doses of Solnatide to Treat Pulmonary Permeability Oedema in Patients With Moderate-to-severe ARDS

Study Overview
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Brief Summary
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This phase IIb, randomized, placebo-controlled, double-blind, dose escalation study will assess the local and systemic safety of 7 days orally inhaled sequential multiple ascending doses of solnatide in patients with pulmonary permeability oedema and moderate-to-severe ARDS and review potential efficacy endpoints for a future phase III pivotal trial.

Official Title
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Safety and Preliminary Efficacy of Sequential Multiple Ascending Doses of Solnatide to Treat Pulmonary Permeability Oedema in Patients With Moderate-to-severe ARDS - a Randomised, Placebo-controlled, Double-blind Trial

Conditions
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ARDS

Intervention / Treatment
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* Drug: Solnatide 25 mg powder for reconstitution for solution for inhalation
* Drug: 0.9% Saline Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent Male or female ≥18 years of age. Patient has been admitted to an ICU, is mechanically ventilated (according to the ventilation and weaning protocol in Appendix I) and stable in this condition for at least 8 hours. Moderate-to-severe ARDS diagnosis as defined by the Berlin Definition: Onset of ARDS within 1 week of a known clinical insult or new or worsening respiratory symptoms. Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules. Respiratory failure not fully explained by cardiac failure or fluid overload (origin of oedema). PaO2/FiO2 ≤ 200 mm Hg with Positive End-Expiratory Pressure (PEEP) ≥5 cm H2O. ARDS diagnosis not older than 48 hours. Extravascular lung water index (EVLWI) ≥ 10 ml/PBW as assessed with a validated bedside measurement (single indicator transpulmonary thermodilution measurement with the PiCCO® system). Patient who meets criteria for extensive hemodynamic monitoring as per international intensive care medicine standards. For patients that are temporarily unable to consent (e.g. comatose patients) a subsequent informed consent has to be provided. Male and Female (WOCBP) patients using adequate contraception. Exclusion Criteria: History of clinically relevant allergies or idiosyncrasies to solnatide. Known use of any other investigational or non-registered drug within 30 days prior to study enrolment. Severe state of septic shock with a Mean Arterial Pressure (MAP) ≤ 65 mm Hg and a serum lactate level > 4 mmol/L (36 mg/dL) despite adequate volume resuscitation. An underlying clinical condition that, in the opinion of the Investigator, would make it very unlikely for the patient to be successfully weaned from ventilation due to severe underlying diseases (e.g. severe malnutrition, severe neurological diseases, pulmonary fibrosis or COPD). Extra-corporeal membrane oxygenation, high-frequency oscillatory ventilation or any form of extra-corporeal lung support. In no way are patients to be denied or delayed these procedures to avoid exclusion from the study. Neutrophil count < 0.3 x 109/L. Cancer treatment (chemotherapy or biological) or therapy with other immunosuppressive agents for organ transplantation within 2 weeks. Cachexia (BMI < 18.5 kg/m2). Cardiogenic pulmonary oedema diagnosed by echocardiography or pulmonary artery catheter. Severe skin burns involving more than 15% of body surface. Subjects who are extremely unlikely to survive more than 48 hours due to the acute conditions of the patient in the opinion of the Investigator. Subjects transferred from a hospital not participating in this study who are already planned to be re-transferred during the observation period. Subjects who are not expected to survive the next month because of an underlying uncorrectable medical condition or a do not resuscitate order. Women known to be pregnant, lactating or having a positive or indeterminate pregnancy test.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Solnatide 5mg<br>Solnatide 25 mg powder for reconstitution for solution for inhalation. 5mg administered | Drug: Solnatide 25 mg powder for reconstitution for solution for inhalation<br>* Inhalation of an aerosol every 12 hours (± 30 min), for a total of 7 days.<br>* Other names: AP301;|
| Experimental: Solnatide 60mg<br>Solnatide 25 mg powder for reconstitution for solution for inhalation. 60mg administered | Drug: Solnatide 25 mg powder for reconstitution for solution for inhalation<br>* Inhalation of an aerosol every 12 hours (± 30 min), for a total of 7 days.<br>* Other names: AP301;|
| Experimental: Solnatide 125mg<br>Solnatide 25 mg powder for reconstitution for solution for inhalation. 125mg administered | Drug: Solnatide 25 mg powder for reconstitution for solution for inhalation<br>* Inhalation of an aerosol every 12 hours (± 30 min), for a total of 7 days.<br>* Other names: AP301;|
| Placebo Comparator: Placebo<br>0,9% saline solution | Drug: 0.9% Saline Solution<br>* Inhalation of an aerosol every 12 hours (± 30 min), for a total of 7 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety endpoint: Any cause death | Primary Safety Endpoint: Composite endpoint including any cause death at day 28 | Randomisation - day 28 | 
| Safety endpoint: Drug-related adverse events | Primary Safety Endpoint: Composite endpoint including drug-related adverse events through day 14 | Randomisation - day 14 | 
| Safety endpoint: All adverse events | Primary Safety Endpoint: Composite endpoint including all adverse events through day 28 | Randomisation - day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EVLWI | Change in extravascular lung water index (EVLWI) as assessed with a validated bedside measurement (measurement with the PiCCO® system) | baseline - day 7 | 
| PVPI | Change in pulmonary vascular permeability index (PVPI) as assessed with a validated bedside measurement (measurement with the PiCCO® system) | baseline - day 7 | 
| Change of ventilatory settings | Composite endpoint including ventilation mode, ventilation pressures (ventilatory plateau pressure, positive end expiratory pressure, peak inspiratory pressure, mean airway pressure, peak airway pressure, driving pressure), tidal volume | baseline - day 14 | 
| Murray lung injury score | Murray lung injury score is composed of four components: 1) chest radiograph; 2) hypoxaemia score; 3) PEEP and 4) static compliance of respiratory system. The values of the total score may range from 0 to 4. Lower values indicate a better outcome. | baseline - day 7 | 
| Oxygenation ratio (PaO2 / FiO2 ratio) |  | baseline - day 7 | 
| Time to extubation |  | baseline - day 28 | 
| Ventilator-free days (VFD) |  | baseline - day 28 | 
| Days of hospitalization and in ICU |  | baseline - day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peptide