Therapeutic iloprost for the treatment of acute respiratory distress syndrome (ARDS) (the ThIlo trial): a prospective, randomized, multicenter phase II study

Helene Haeberle, Stefanie Prohaska, Peter Martus, Andreas Straub, Alexander Zarbock, Gernot Marx, Manola Zago, Martin Giera, Michael Koeppen, Peter Rosenberger, Helene Haeberle, Stefanie Prohaska, Peter Martus, Andreas Straub, Alexander Zarbock, Gernot Marx, Manola Zago, Martin Giera, Michael Koeppen, Peter Rosenberger

Abstract

Background: Acute respiratory distress syndrome (ARDS) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. The treatment of ARDS to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. Therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ARDS.

Methods: The Therapeutic Iloprost during ARDS trial (ThIlo trial) is a multicenter, randomized, single blinded, clinical phase II trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ARDS in critically ill patients. One hundred fifty critically ill patients suffering from acute ARDS will be treated either by nebulized iloprost or NaCl 0.9% for 5 days. Blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. Mechanical ventilation will be standardized. In follow-up visits at days 28 and 90 as well as 6 months after enrollment, functional status according to the Barthel Index and a health care-related questionnaire, and frailty (Vulnerable Elders Survey) will be evaluated. The primary endpoint is the improvement of oxygenation, defined as the ratio of PaO2/FiO2. Secondary endpoints include 90-day all-cause mortality, Sequential Organ Failure Assessment scores during the study period up to day 90, the duration of mechanical ventilation, the length of intensive care unit (ICU) stay, ventilator-associated pneumonia, delirium, ICU-acquired weakness, and discharge localization. The study will be conducted in three university ARDS centers in Germany.

Discussion: The results of the ThIlo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ARDS, resulting in the improvement of outcome parameters in patients with ARDS.

Trial registration: EUDRA-CT: 2016-003168-37. Registered on 12 April 2017. ClinicalTrials.gov: NCT03111212. Registered on 4 June 2017.

Keywords: ARDS; Iloprost; Inflammation; Intensive care; Ventilation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Trial protocol and intervention scheme. After screening and determination of eligibility, patients will be included after a maximum of 48 h after the onset of ARDS. Within this time period, screening, consent, and randomization will be initialized. In addition, lung-protective ventilation will be instituted. After randomization, iloprost 3 × 20 μg (intervention) or NaCl 0.9% (control) will be administered for 5 days through a standard ultrasound nebulizer. Daily recordings will be made with respect to the development of the PaO2/FiO2 ratio and the severity of ARDS, organ failure, lung injury, and potential adverse events. The treatment with iloprost or NaCl (0.9%) will be stopped after 5 days. The follow-up period will then continue up to 90 days and 6 months to determine the outcome, quality of life, and pulmonary/secondary organ function

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