Comparison of Corticosteroids vs Placebo on Duration of Ventilatory Support During Severe Acute Exacerbations of COPD Patients in the ICU

Study Overview
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Brief Summary
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The main objective of this study is to determine if the systemic (intravenous) administration of corticosteroids, as compared to placebo, increases the number of ventilator-free days (VFD) and alive at day 28 in COPD patients admitted to an ICU, a step-up unit or a respiratory care unit for an ACRF requiring ventilatory support, either invasive or non-invasive.

Official Title
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Comparison of Corticosteroids Versus Placebo on Duration of Ventilatory Support During Severe Acute Exacerbations of COPD Patients in the Intensive Care Unit: a Multicentre Randomized Controlled Trial

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Methylprednisolone
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged ≥ 40 years Strongly suspected or documented COPD, defined by the presence of the following criterias: Persistent respiratory symptoms (dyspnoea, chronic cough or sputum) History of exposure to a risk factor such as tobacco smoke If available, pulmonary function tests showing airflow limitation not fully reversible (post-bronchodilator ratio of FEV1/ FVC ratio < 0.7) ACRF, defined by the presence of the two following criteria: COPD exacerbation defined by a change in the patient baseline respiratory symptoms at least 24 hours and requiring a change in regular respiratory medication Acute respiratory failure <24h (polypnea ≥ 30 breaths.min-1 or use of accessory respiratory muscles) requiring ventilatory support, either invasive (implemented because of respiratory distress) or NIV (implemented because of hypercapnic acidosis with PaCO2 ≥ 45 mmHg and pH ≤ 7.35). Admission to an ICU, a step-up unit or a respiratory care unit Inform consent from the patient or his surrogates. In patients who are not able to consent on admission an emergency inclusion procedure will be allowed, with a mandatory delayed consent. Affiliation to (or benefit from) French health insurance system Exclusion Criteria: Previous diagnostic of asthma, according to GINA international guidelines (40) Recent use of systemic corticosteroids, defined by systemic corticosteroids use in the past 7 days Contra-indication of systemic corticosteroids treatment: allergy to corticosteroids, uncontrolled severe arterial hypertension, uncontrolled diabetes mellitus, gastro-intestinal ulcer bleeding Pneumothorax at randomization Extracorporeal life support (ECMO or ECCO2R) at inclusion Moribund patient life expectancy < 3 months Pregnancy Patients protected by law Exclusion period due to other interventional clinical trial enrolment which can influence primary outcome Previous inclusion in the present study

Ages Eligible for Study
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Minimum Age: 40 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: cortisteroids arm<br> | Drug: Methylprednisolone<br>* In the experimental group, methylprednisolone will be administered intravenously for 5 days at a dose of 1 mg/kg/day. Methylprednisolone will be provided for reconstitution and dilution in 50 ml of NaCl 0.9% solution and administered over 15 minutes, once a day.<br>|
| Placebo Comparator: placebo arm<br> | Drug: Placebos<br>* in the control group, placebo will be administered intravenously for 5 days. Placebo will be identical (color and aspect) to experimental substance, will be provide as a 50 mL of NaCl 0.9% solution and administered intravenously over 15 minutes, once a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the number of ventilator-free days (VFD) and alive at day 28. | To determine if the systemic administration of corticosteroids, as compared to placebo, increases the number of ventilator-free days (VFD) and alive at day 28 in COPD patients admitted to an ICU, a step-up unit or a respiratory care unit for an ACRF requiring ventilatory support, either invasive or non-invasive. | day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NIV failure rate | NIV failure rate, defined by intubation within day 7 | day 7 | 
| Duration of NIV and of invasive mechanical ventilation | Duration of Non Invasive Ventilation and of invasive mechanical ventilation | at day 90 | 
| Circulatory and renal support-free days and alive at day 28 | Circulatory and renal support-free days and alive at day 28 | at day 28 | 
| Severe hyperglycemia requiring intravenous insulin during the five first days | Severe hyperglycemia requiring intravenous insulin during the five first days | during the five first days | 
| Gastro-intestinal bleeding | acute loss of 2 g/dL of hemoglobin requiring red blood cell transfusion or gastroscopic evaluation | between inclusion and day 28 | 
| Uncontrolled arterial hypertension | unusual hypertension requiring to introduce/add antihypertensive medication (compared to usual medications) | between inclusion and day 28 | 
| ICU acquired weakness (MRC-score < 48/60) assessed on day 28 or at the time of ICU discharge | Intensive Care Unit acquired weakness (MRC-score < 48/60) assessed on day 28 or at the time of ICU discharge | at day 28 | 
| ICU-acquired infections (especially Ventilator-Associated Pneumonia) | Intensive Care Unit -acquired infections (especially Ventilator-Associated Pneumonia) | at the time of ICU discharge or day 90 | 
| Length of ICU and hospital stay | Length of ICU and hospital stay | at day 90 | 
| ICU and hospital mortality | ICU and hospital mortality | between inclusion and day 28 or day 90 | 
| Day 28 and Day 90 mortality | Day 28 and Day 90 mortality | at Day 28 and Day 90 | 
| Standardized mortality ratio (SMR) | Standardized mortality ratio (SMR) | between inclusion and day 90 | 
| Number of new exacerbation(s)/hospitalization(s) between hospital discharge and Day 90 | Number of new exacerbation(s)/hospitalization(s) between hospital discharge and Day 90 | at day 90 | 
| Dyspnea (patient reported outcome) at Day 90 evaluated by clinical assessment test and dyspnea mMRC score | Dyspnea (patient reported outcome) at Day 90 evaluated by clinical assessment test and dyspnea mMRC score | at day 90 | 
| respiratory comfort (patient reported outcome) at Day 90 evaluated by clinical assessment test and dyspnea mMRC score | respiratory comfort (patient reported outcome) at Day 90 evaluated by clinical assessment test and dyspnea mMRC score | at day 90 |