Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate-to-severe ARDS\u2014a randomized, placebo-controlled, double-blind trial

Benedikt Schmid,Markus Kredel,Rudolf Lucas,Sandra Frank,Patrick Meybohm,Bernhard Fischer,And The Solnatide Collaborators Group ,Roman Ullrich,Bernhard Zwißler,Klaus Markstaller,Peter Kranke,Katharina Krenn

doi:10.1186/s13063-021-05588-9

Abstract

BackgroundAcute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible etiologies. One common feature, however, is pulmonary permeability edema, which leads to an increased alveolar diffusion pathway and, subsequently, impaired oxygenation and decarboxylation. A novel inhaled peptide agent (AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to administer to healthy humans in a Phase I clinical trial. Here, we present the protocol for a Phase IIB clinical trial investigating the safety and possible future efficacy endpoints in ARDS patients.MethodsThis is a randomized, placebo-controlled, double-blind intervention study. Patients with moderate to severe ARDS in need of mechanical ventilation will be randomized to parallel groups receiving escalating doses of solnatide or placebo, respectively. Before advancing to a higher dose, a data safety monitoring board will investigate the data from previous patients for any indication of patient safety violations. The intervention (application of the investigational drug) takes places twice daily over the course of 7 days, ensued by a follow-up period of another 21 days.DiscussionThe patients to be included in this trial will be severely sick and in need of mechanical ventilation. The amount of data to be collected upon screening and during the course of the intervention phase is substantial and the potential timeframe for inclusion of any given patient is short. However, when prepared properly, adherence to this protocol will make for the acquisition of reliable data. Particular diligence needs to be exercised with respect to informed consent, because eligible patients will most likely be comatose and/or deeply sedated at the time of inclusion.Trial registrationThis trial was prospectively registered with the EU Clinical trials register (clinicaltrialsregister.eu). EudraCT Number: 2017-003855-47.

Highlights

IntroductionBackground and rationale {6a} Acute respiratory distress syndrome (ARDS) ARDS is a common pathology seen in intensive care units globally, with associated significant mortality and even long-term morbidity
When prepared properly, adherence to this protocol will make for the acquisition of reliable data
Background and rationale {6a} Acute respiratory distress syndrome (ARDS) ARDS is a common pathology seen in intensive care units globally, with associated significant mortality and even long-term morbidity

Summary

Introduction

Background and rationale {6a} Acute respiratory distress syndrome (ARDS) ARDS is a common pathology seen in intensive care units globally, with associated significant mortality and even long-term morbidity. A recent systematic review regarding the endpoint “return to work after critical illness” reported that approximately two-thirds, two-fifths, and one-third of previously employed intensive care unit survivors are jobless up to 3, 12, and 60 months following hospital discharge [1]. Acute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible etiologies. A novel inhaled peptide agent (AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to administer to healthy humans in a Phase I clinical trial. We present the protocol for a Phase IIB clinical trial investigating the safety and possible future efficacy endpoints in ARDS patients

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