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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02517489
Other study ID # PHRN14-PFD/CAPE COD
Secondary ID
Status Completed
Phase Phase 3
First received
Last updated
Start date October 28, 2015
Est. completion date August 28, 2020

Study information

Verified date January 2023
Source University Hospital, Tours
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

Mortality of severe Community-Acquired Pneumonia (CAP) has not declined over time and is between 25 and 30% in sub-groups of patients. Corticosteroids (CTx) could down-regulate pulmonary and systemic inflammation, accelerate clinical resolution and decrease the rate of inflammation-associated systemic complications. Two recent meta-analyses suggest a positive effect on severe CAP day 28 survival when CTx are added to standard therapy. However they are based on only four trials gathering less than 300 patients, of which only one was positive. Recently published guidelines do not recommend CTx as part of CAP treatment. Therefore a well-powered trial appears necessary to test the hypothesis that CTx - and more specifically hydrocortisone - could improve day 28 survival of critically-ill patients with severe CAP, severity being assessed either on a Pulmonary Severity Index ≥ 130 (Fine class V) or by the use of mechanical ventilation or high-FiO2 high-flow oxygen therapy. A phase-III multicenter add-on randomized controlled double-blind superiority trial assessing the efficacy of hydrocortisone vs. placebo on Day 28 all-causes mortality, in addition to antibiotics and supportive care, including the correction of hypoxemia. Randomization will be stratified on: (i) centers; (ii) use of mechanical ventilation at the time of inclusion.


Description:

Patients will receive state-of-the-art standard therapy for severe Community-Acquired Pneumonia (CAP), including antibiotics and supportive care. Correction of hypoxemia will use standard low-flow oxygen therapy, high-flow oxygen therapy, non-invasive-ventilation or invasive ventilation with endotracheal tube, as required. Patients in the treatment group will receive intra-venous hydrocortisone. Patients of the control group will receive an intravenous placebo by intravenous route at the same frequency. Hydrocortisone or placebo will be given in a double-blind fashion for 8 or 14 full days. The intravenous route will be used. The treatment course will include 4 or 7 days of full dose (200 mg/day by continuous infusion), 2 or 4 days of half dose (100 mg/day by continuous infusion), and 2 or 3 days of tapering dose (50 mg/day by continuous infusion). Duration of treatment is chosen upon patient initial improvement. A substantial amendment to the CAPE COD study has been submitted to the Competent Authorities in order to conduct a specific analysis on the sub-group of patients included with COVID19 (coronavirus disease 2019), in order to get a quick response in this specific population and in the context of an epidemic emergency. The aim is to answer as quickly as possible a therapeutic question of major importance in the treatment of severe respiratory infections with CoV-2 SARS (severe acute respiratory syndrome coronavirus 2). Modifications made to the original study for patients with COVID (coronavirus disease) include some inclusion criteria, the primary endpoint, and secondary endpoints.


Recruitment information / eligibility

Status Completed
Enrollment 952
Est. completion date August 28, 2020
Est. primary completion date July 19, 2020
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Age = 18 years - Patients affiliated to social security scheme - Admission to an Intensive Care Unit (ICU) or intermediate care unit participating to the trial - Diagnosis of Community- Acquired Pneumonia (CAP) suggested by at least two of the following: cough, purulent sputum, chest pain and dyspnea - Focal shadowing/infiltrate on chest X-ray or CT-scan - Diagnosis of Community- Acquired Pneumonia (CAP) during the 48 hours post-hospital admission - Study drug infusion initiated no longer than 24 hours post first severity criterion - Severity defined by at least one of the following: - Pneumonia Severity Index (PSI) > 130 (Fine class V) - Patient placed on mechanical ventilation (invasive or not) for acute respiratory failure, with a PEEP level of 5 cm of water or more - Patient treated by high-flow oxygen therapy with a FiO2 of 50% or more and a P/F ratio less than 300 - Patient treated by oxygen therapy with a partial rebreathing-mask with a reservoir bag, provided that the PaO2 is less than (cf. table): Oxygen flow (L/min) 6 7 8 9 10 or more PaO2 (mmHg) less than 180 210 240 270 300 - Patient already treated by antibiotics (at least one dose since admission to hospital) - Informed consent signed by the patient, its relatives or emergency procedure On the sub-group of patients included with COVID19 : - Diagnosis of COVID19 either as certain (PCR) or probable (evocative clinical and radiological features AND epidemic context AND absence of other microbiological documentation). - Study drug infusion initiated no longer than 24 hours post first severity criterion ; in case of transfer from another hospital, this period will be prolonged to 48 hours - Patient receiving the best available treatment as define by up-to-date scientific knowledge Exclusion Criteria: - Patient treated by vasopressors for septic shock at the time of inclusion - Clinical history suggesting of aspiration of gastric content - Patient treated by invasive mechanical ventilation within 14 days before current hospital admission - Patient treated by antibiotics for a respiratory infection for more than seven days at the admission to the hospital (except if a pathogen resistant to this antibiotics is isolated) - History of cystic fibrosis - Post-obstructive pneumonia - Patients in which rapid PCR-test is positive for flu - Active tuberculosis or fungal infection - Active viral hepatitis or active infection with herpes viruses - Myelosuppression - Decision of withholding mechanical ventilation or endotracheal intubation - Hypersensitivity to corticosteroids - Patient needing anti-inflammatory corticosteroids or substitutive hydrocortisone for any reason - Patients under treatment by more than 15 mg/d of prednisone (or equivalent) for more than 30 days - Patient already enrolled in another drug trial with mortality as an end-point. If the patient is already participating in another therapeutic trial with a different endpoint, the investigator must verify that inclusion in CAPE COD can not prejudice it. - Pregnant or breastfeeding woman - Patient on judicial protection

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Hydrocortisone
Hydrocortisone will be given in a double-blind fashion for 8 or 14 full days. The intravenous route will be used. The treatment course will include 4 or 7 days of full dose (200 mg/day by continuous infusion), 2 or 4 days of half dose (100 mg/day by continuous infusion), and 2 or 3 days of tapering dose (50 mg/day by continuous infusion). Duration of treatment is chosen upon patient initial improvement.
Placebo
Placebo will be given in a double-blind fashion for 8 or 14 full days. The intravenous route will be used. The treatment course will include 4 or 7 days of full dose (200 mg/day by continuous infusion), 2 or 4 days of half dose (100 mg/day by continuous infusion), and 2 or 3 days of tapering dose (50 mg/day by continuous infusion). Duration of treatment is chosen upon patient initial improvement.

Locations

Country Name City State
France Service de Réanimation - Unité de Soins Continus, CH d'Angoulême 'Angoulême
France Service de Réanimation Polyvalente, CH d'Argenteuil Argenteuil
France Service de Réanimation, CHR Metz-Thionville Ars-Laquenexy
France Service de Réanimation Aulnay-sous-Bois
France Service de Réanimation Belfort
France Service de Réanimation Bourg-en-Bresse
France Service de Réanimation HIA Clermont-Tonnerre Brest
France Service de Réanimation Médicale, CHU de Brest Brest
France Service de Réanimation, CHU Côte de Nacre Caen
France Service de Réanimation Médicale, Hôpital Louis Pasteur, Chartres Chartres
France Service de Réanimation Médicale Polyvalente, Hôpital G Montpied Clermont Ferrand
France Service de Réanimation, Hôpital Louis Mourier Colombes
France Service de Réanimation Médicale, CHU de Dijon Dijon
France Service de Réanimation Médico-Chirurgicale, Hôpital Raymond Poincarré, APHP Garches
France Service de Réanimation Médicale, CHU de Grenoble Grenoble
France Service de Réanimation Polyvalente, CHD La Roche sur Yon La Roche sur Yon
France Service de Réanimation, CH Le Mans Le Mans
France Service de Réanimation Polyvalente, Hôpital Salengro, CHU de Lille Lille
France Service de Réanimation Polyvalente, CHU de Limoges Limoges
France Service de Réanimation Médicale, Hôpital Nord Marseille
France Service de Réanimation Polyvalente - Surveillance Continue, CH de Montauban Montauban
France Service de Réanimation Médicale, CHU de Nancy Nancy
France Service de Réanimation Polyvalente, Hôpital Hôtel Dieu, CHU de Nantes Nantes
France Service de Réanimation Médicale, CHR d'Orléans Orléans
France Service de Réanimation et USC médico-chirurgicale, Hôpital Tenon, APHP Paris
France Service de Réanimation Médicale, Hôpital Cochin, APHP Paris
France Service de Réanimation Médicale et Médecine Interne, CHU de Poitiers Poitiers
France Service des Maladies Infectieuses et Réanimation Médicale, CHU de Rennes Rennes
France Service de Réanimation Polyvalente, CH de Saint Malo Saint Malo
France Service de Réanimation Saint-Brieuc
France Service de Réanimation Médicale, Hôpital de Hautepierre, CHU de Strasbourg Strasbourg
France Service de Réanimation Médicale, Nouvel Hôpital Civil, CHU de Strasbourg Strasbourg

Sponsors (1)

Lead Sponsor Collaborator
University Hospital, Tours

Country where clinical trial is conducted

France, 

Outcome

Type Measure Description Time frame Safety issue
Other P/F ratio measured daily from Day1 to Day7, at Day 14 and at Day 21 and/or at the end of ICU-stay Sub-group of patients included with COVID19 from day 1 to day 7, at day 14 and day 21 and/or at the end of ICU-stay
Other Proportion of patients needing endotracheal intubation Sub-group of patients included with COVID19 at day 21
Other Proportion of patients experiencing secondary infection during their ICU-stay Sub-group of patients included with COVID19 From baseline to day 21
Primary Day 28 all causes mortality at day 28
Primary Day 21 failure For the sub-group of patients included with COVID19, failure is defined as death or need of respiratory support (mechanical ventilation or high-flow oxygen therapy); at day 21
Secondary In patients non-invasively ventilated at inclusion, proportion of patients needing endotracheal intubation Participants will be followed for the duration of hospital stay, for a maximum of 28 days
Secondary In patients non-ventilated at inclusion, proportion of patients requiring non-invasive ventilation Participants will be followed for the duration of hospital stay, for a maximum of 28 days
Secondary In patients non-ventilated at inclusion, proportion of patients needing endotracheal intubation Participants will be followed for the duration of hospital stay, for a maximum of 28 days
Secondary Day 28 ventilator-free-days between 0 and day 28
Secondary Number of patients with vasopressor therapy initiation from inclusion to day 28 between 0 and day 28
Secondary Day 28 vasopressor-free-days between 0 and day 28
Secondary ICU and/or intermediate care unit LOS Participants will be followed for the duration of hospital stay, for a maximum of 28 days
Secondary All-causes mortality at day 90 at day 90
Secondary SF-36 Health Survey at day 90 at day 90
Secondary Biomarkers: procalcitonin at baseline, day 3 and day 7 at inclusion, day 3 and day 7
Secondary Biomarkers: C-reactive protein at baseline, day 3 and day 7 at inclusion, day 3 and day 7
Secondary Biomarkers: plasmatic concentration of pro-inflammatory cytokines (IL-6, IL-20, IL-22, IL-22BP, HBD2, TNF) at baseline, day 3 and day 7 at inclusion, day 3 and day 7
Secondary P/F ratio measured daily from baseline to day 7, at the end of treatment, at the end of ICU-stay and/or day 28 measured daily from baseline to day 7, at the end of treatment i.e 14 days after the start of treatment, at the end of ICU-stay (for a maximum of 28 days) and/or day 28
Secondary SOFA calculated daily from baseline to day 7, at the end of treatment, at the end of ICU-stay and/or day 28 calculated daily from baseline to day 7, at the end of treatment (i.e 14 days after the start of treatment), at the end of ICU-stay (for a maximum of 28 days) and/or day 28
Secondary Proportion of patients experiencing secondary infection during their ICU-stay Participants will be followed for the duration of hospital stay, for a maximum of 28 days
Secondary Proportion of patients experiencing gastrointestinal bleeding during their ICU-stay Participants will be followed for the duration of hospital stay, for a maximum of 28 days
Secondary Daily amount of insulin administered to the patient from day 1 to day 7 Patients will be followed from day 1 to day 7
Secondary Weight-gain at baseline and day 7 Patients will be followed at baseline and day 7
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