Clinical trial NCT02550600: Extracorporeal Lung Assist Device in Acute Lung Impairment
Official title: EXODUS: Extracorporeal Lung Assist Device in Acute Lung Impairment: A Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Acute Respiratory Distress Syndrome
Keywords: ARDS
Acute lung impairment
Extracorporeal lung assist
ECMO
ECLA
Murray-score
SOFA-score
Lead sponsor: Technical University of Munich
Sponsor class: OTHER
Collaborators: name: Novalung GmbH, Heilbronn, Germany
name: Studiensekretariat Intensivmedizin; II. Medizinische Klinik; Klinikum rechts der Isar; Munich
First posted: 2015-09-15
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the effect of interventional Lung Assist iLA activve to standard therapy in mechanically ventilated patients with severe acute lung impairment. Hypothesis: iLA(active) reduces the incidence of an increase in SOFA-Score of ≥3 points (or death) within 28 days compared to standard treatment.

Detailed description: Background:

Mechanical ventilation in patients with acute lung impairment further injures the lungs by inspiration forces and inflammatory response. Large efforts have been invested in reducing ventilator-associated lung damage by lower tidal volumes. However, benefits are limited by potential harms of permissive hypercapnia.

Therefore, extracorporeal membrane oxygenation (ECMO) and CO2-removal have been studied for more than 40 years. However, ECMO remained restricted to few specialized centres capable to provide extensive resources. Transfer of patients implicates loss of time and risks of transportation. Therefore, less invasive devices have been developed, including "pump-less "extracorporeal lung assist" (pECLA) and pump-driven ECLA (e.g. iLA activve). Despite pilot trials supporting feasibility, safety and efficient oxygenation and decarboxylation by pump-driven ECLA, there are no randomized controlled trials (RCT) proving a benefit regarding long-term endpoints.

Objectives:

Therefore, the aim of this multicentre RCT is to compare the outcome of 150 patients with early (after ≤96h of mechanical ventilation) acute lung impairment treated by pump-driven ECLA with iLA activve with a blood flow of at least 1L/min vs. 150 controls with standard intensive care including low tidal volume ventilation.

Main inclusion and exclusion criteria:

While most trials on ECMO and (p)ECLA included patients in a rescue scenario with severe and persisting ARDS, earlier inclusion also implicates modified inclusion criteria: A cumulative Murray score of ≥6 points without radiological points is the most important inclusion criterion. At least four points must result from pO2/FiO2 (mandatory pO2/FiO2\<300mmHg) and PEEP criteria of the Murray score. In order to provide sufficient time for conservative attempts to optimize ventilation, inclusion criteria can be fulfilled for a maximum of 48h before inclusion as long as the patient can be included within a maximum of 96h of mechanical ventilation.

Primary efficacy endpoint:

Incidence of an increase in SOFA-Score ≥3 points or death within 28 days.

Statistical analyses:

Generalized linear mixed model (logit link function) will be used to compare the primary efficacy endpoint, the proportion of patients with an increase in SOFA of ≥3 points or death within 28d, between the two groups. In this analysis the random factor variable study centre and anticoagulation therapy will be considered as adjustment variables. The test of group effect estimated by the multivariable mixed logistic model will be conducted at a two-sided 0.05 level of significance.

The primary efficacy analysis will be based on the intention-to-treat population. Missing values of SOFA score will be replaced by last-value carry forward approach.

Survival status of lost to follow-up patients will be replaced conservatively: missing survival status will be replaced by attribute "death" for patients in the verum arm and replaced by attribute "alive" for patients in the standard treatment arm.

A supportive complete case and per-protocol analysis will be conducted for purpose of sensitivity analysis of the primary endpoint. Further sensitivity analyses will be provided to evaluate robustness of results in regard to unexpected circumstances (e.g. impact of 'cross-over' patients who are not treated as randomized but are required to be analyzed as randomized (ITT-principle)). Secondary endpoints will be analyzed in an exploratory manner.

Chi-Square test or Fisher-exact test will be used to compare categorical data. For comparisons of continuous data between groups non-parametric tests (Kruskal-Wallis test, Mann-Whitney-U test) will be performed. 95% confidence intervals will be calculated for relevant measurements. SAS software (version 4.9 or future follow-up version).

Eligibility criteria: Inclusion Criteria:

* Potentially reversible lung failure AND
* Cumulative Murray score ≥6 points without radiological points for a maximum of 48h AND
* Cumulative Murray score ≥4 points for pO2/FiO and PEEP AND
* Cumulative Murray score ≥1 point for pO2/FiO
* Mechanical ventilation for ≤96h AND
* Age ≥ 18 years.

Exclusion Criteria:

* SOFA-Score \>20
* Life expectancy \<24h
* mechanical ventilation \>96h
* Heparin-induced thrombopenia
* Intracranial bleeding

Primary outcomes:
measure: Incidence of an increase in SOFA-Score ≥3 points or death within 28 days
timeFrame: 28 days
Secondary outcomes:
measure: Death or severe disability after 6 months defined as confinement to bed and inability to wash or dress alone
timeFrame: 6 months
measure: Mortality
timeFrame: 28 days, 60 days, ICU-stay
measure: Ventilator free days
timeFrame: 28 days, ICU stay
measure: Single organ failures as assessed by SOFA
timeFrame: 28 days, ICU stay
measure: Prediction of outcome (Primary endpoint: Incidence of an increase in SOFA-Score ≥3 points or death within 28 days)
timeFrame: 28 days
measure: Safety analysis assessed by documentation of complications and side effects potentially related to iLA activve and/or conventional therapy including complications associated to cannulation and extracorporeal circuit,
timeFrame: 6 months
measure: Meta-analysis
timeFrame: 6 months
measure: Resource use and economic outcomes
timeFrame: 6 months
measure: Early vs. late intervention
timeFrame: 6 months
measure: Prediction of outcome (Death or severe disability after 6 months defined as confinement to bed and inability to wash or dress alone)
timeFrame: 6 months
measure: Association of the fluid balance to the primary endpoint (Incidence of an increase in SOFA-Score ≥3 points or death within 28 days)
timeFrame: 28 days
measure: Association of the fluid balance to the secondary endpoint "death or severe disability after 6 months defined as confinement to bed and inability to wash or dress alone)"
timeFrame: 6 months
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna/General Hospital of Vienna
city: Hamburg
country: Germany
facility: Klinik für Intensivmedizin; Universitätsklinikum Hamburg-Eppendorf (UKE)
city: Munich
country: Germany
facility: Abteilung für Intensivmedizin; Krankenhaus Barmherzige Brüder; München
city: Munich
country: Germany
facility: I. Medizinische Klinik; Klinikum rechts der Isar; Technische Universität München
city: München
country: Germany
facility: II. Medizinische Klinik; Klinikum rechts der Isar; Technische Universität München
city: München
country: Germany
facility: Klinik für Anästhesiologie; Klinikum rechts der Isar; Technische Universität München
city: Szeged
country: Hungary
facility: Department of Anaesthesiology and Intensive Therapy; University of Szeged
city: London
country: United Kingdom
facility: St. Bartholomew's & London Chest Hospitals
Study officials:
affiliation: II. Medizinische Klinik; Klinikum rechts der Isar; Ismaningerstrasse 22; D-81675 München; Germany
name: Wolfgang Huber, MD
role: PRINCIPAL_INVESTIGATOR
References: