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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
952
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 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.
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
Day 28 all causes mortality
Time frame: at day 28
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);
Time frame: at day 21
In patients non-invasively ventilated at inclusion, proportion of patients needing endotracheal intubation
Time frame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
In patients non-ventilated at inclusion, proportion of patients requiring non-invasive ventilation
Time frame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
In patients non-ventilated at inclusion, proportion of patients needing endotracheal intubation
Time frame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
Day 28 ventilator-free-days
Time frame: between 0 and day 28
Number of patients with vasopressor therapy initiation from inclusion to day 28
Time frame: between 0 and day 28
Day 28 vasopressor-free-days
Time frame: between 0 and day 28
ICU and/or intermediate care unit LOS
Time frame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
All-causes mortality at day 90
Time frame: at day 90
SF-36 Health Survey at day 90
Time frame: at day 90
Biomarkers: procalcitonin at baseline, day 3 and day 7
Time frame: at inclusion, day 3 and day 7
Biomarkers: C-reactive protein at baseline, day 3 and day 7
Time frame: at inclusion, day 3 and day 7
Biomarkers: plasmatic concentration of pro-inflammatory cytokines (IL-6, IL-20, IL-22, IL-22BP, HBD2, TNF) at baseline, day 3 and day 7
Time frame: at inclusion, day 3 and day 7
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
Time frame: 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
SOFA calculated daily from baseline to day 7, at the end of treatment, at the end of ICU-stay and/or day 28
Time frame: 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
Proportion of patients experiencing secondary infection during their ICU-stay
Time frame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
Proportion of patients experiencing gastrointestinal bleeding during their ICU-stay
Time frame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
Daily amount of insulin administered to the patient from day 1 to day 7
Time frame: Patients will be followed from day 1 to day 7
Weight-gain at baseline and day 7
Time frame: Patients will be followed at baseline and day 7
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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
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