Community-Acquired Pneumonia : Evaluation of Corticosteroids (CAPE_COD)

Effects of Low-dose Corticosteroids on Survival of Severe Community-acquired Pneumonia

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.

Study Overview

• Status: Completed
• Conditions: Community Acquired Pneumonia
• Intervention / Treatment: Drug: Hydrocortisone; Drug: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 952
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • 'Angoulême, France, 16959
    • Service de Réanimation - Unité de Soins Continus, CH d'Angoulême
  • Argenteuil, France, 95107
    • Service de Réanimation Polyvalente, CH d'Argenteuil
  • Ars-Laquenexy, France, 57530
    • Service de Réanimation, CHR Metz-Thionville
  • Aulnay-sous-Bois, France, 93602
    • Service de réanimation
  • Belfort, France, 90015
    • Service de réanimation
  • Bourg-en-Bresse, France
    • Service de réanimation
  • Brest, France, 29240
    • Service de Réanimation HIA Clermont-Tonnerre
  • Brest, France, 29609
    • Service de Réanimation Médicale, CHU de Brest
  • Caen, France, 14033
    • Service de Réanimation, CHU Côte de Nacre
  • Chartres, France, 28000
    • Service de Réanimation Médicale, Hôpital Louis Pasteur, Chartres
  • Clermont Ferrand, France, 63003
    • Service de Réanimation Médicale Polyvalente, Hôpital G Montpied
  • Colombes, France, 92700
    • Service de Réanimation, Hopital Louis Mourier
  • Dijon, France, 21079
    • Service de Réanimation Médicale, CHU de Dijon
  • Garches, France, 92380
    • Service de Réanimation Médico-Chirurgicale, Hôpital Raymond Poincarré, APHP
  • Grenoble, France, 38043
    • Service de Réanimation Médicale, CHU de Grenoble
  • La Roche sur Yon, France, 85925
    • Service de Réanimation Polyvalente, CHD La Roche sur Yon
  • Le Mans, France, 72037
    • Service de Réanimation, CH Le Mans
  • Lille, France, 59037
    • Service de Réanimation Polyvalente, Hôpital Salengro, CHU de Lille
  • Limoges, France, 87042
    • Service de Réanimation Polyvalente, CHU de Limoges
  • Marseille, France, 13015
    • Service de Réanimation Médicale, Hôpital Nord
  • Montauban, France, 82013
    • Service de Réanimation Polyvalente - Surveillance Continue, CH de Montauban
  • Nancy, France, 54511
    • Service de Réanimation Médicale, CHU de Nancy
  • Nantes, France, 44093
    • Service de Réanimation Polyvalente, Hôpital Hôtel Dieu, CHU de Nantes
  • Orléans, France, 45067
    • Service de Réanimation Médicale, CHR d'Orléans
  • Paris, France, 75014
    • Service de Réanimation Médicale, Hôpital Cochin, APHP
  • Paris, France, 75020
    • Service de Réanimation et USC médico-chirurgicale, Hôpital Tenon, APHP
  • Poitiers, France, 86021
    • Service de Réanimation Médicale et Médecine Interne, CHU de Poitiers
  • Rennes, France, 35033
    • Service des Maladies Infectieuses et Réanimation Médicale, CHU de Rennes
  • Saint Malo, France, 35403
    • Service de Réanimation Polyvalente, CH de Saint Malo
  • Saint-Brieuc, France, 22000
    • Service de réanimation
  • Strasbourg, France, 67091
    • Service de Réanimation Médicale, Nouvel Hôpital Civil, CHU de Strasbourg
  • Strasbourg, France, 67098
    • Service de Réanimation Médicale, Hôpital de Hautepierre, CHU de Strasbourg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydrocortisone; Patients in the treatment group will receive intra-venous hydrocortisone (in addition to the standard treatment of severe Community-Acquired Pneumonia (CAP)	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 Comparator: Placebo; Patients of the control group will receive an intravenous placebo by intravenous route (in addition to the standard treatment of severe Community-Acquired Pneumonia (CAP)	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Day 28 all causes mortality		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);	at day 21

Secondary Outcome Measures

Outcome Measure	Time Frame
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
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
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
Day 28 ventilator-free-days	between 0 and day 28
Number of patients with vasopressor therapy initiation from inclusion to day 28	between 0 and day 28
Day 28 vasopressor-free-days	between 0 and day 28
ICU and/or intermediate care unit LOS	Participants will be followed for the duration of hospital stay, for a maximum of 28 days
All-causes mortality at day 90	at day 90
SF-36 Health Survey at day 90	at day 90
Biomarkers: procalcitonin at baseline, day 3 and day 7	at inclusion, day 3 and day 7
Biomarkers: C-reactive protein at baseline, day 3 and day 7	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	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	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	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	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	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	Patients will be followed from day 1 to day 7
Weight-gain at baseline and day 7	Patients will be followed at baseline and day 7

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Proportion of patients needing endotracheal intubation	Sub-group of patients included with COVID19	at day 21
Proportion of patients experiencing secondary infection during their ICU-stay	Sub-group of patients included with COVID19	From baseline to day 21

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Investigators: Principal Investigator: Pierre-François DEQUIN, MD-PhD, CHRU De Tours

Publications and helpful links

General Publications

• Dequin PF, Heming N, Meziani F, Plantefeve G, Voiriot G, Badie J, Francois B, Aubron C, Ricard JD, Ehrmann S, Jouan Y, Guillon A, Leclerc M, Coffre C, Bourgoin H, Lengelle C, Caille-Fenerol C, Tavernier E, Zohar S, Giraudeau B, Annane D, Le Gouge A; CAPE COVID Trial Group and the CRICS-TriGGERSep Network. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1298-1306. doi: 10.1001/jama.2020.16761.

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2015
• Primary Completion (Actual): July 19, 2020
• Study Completion (Actual): August 28, 2020

Study Registration Dates

• First Submitted: July 31, 2015
• First Submitted That Met QC Criteria: August 4, 2015
• First Posted (Estimate): August 7, 2015

Study Record Updates

• Last Update Posted (Estimate): January 10, 2023
• Last Update Submitted That Met QC Criteria: January 9, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Hydrocortisone; Corticosteroids; Community-Acquired Pneumonia (CAP); COronaVIrus Disease
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia; Anti-Inflammatory Agents; Hydrocortisone
• Other Study ID Numbers: PHRN14-PFD/CAPE COD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No