Clinical trial NCT02517489: Community-Acquired Pneumonia : Evaluation of Corticosteroids
Official title: Effects of Low-dose Corticosteroids on Survival of Severe Community-acquired Pneumonia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Community Acquired Pneumonia
Keywords: Community-Acquired Pneumonia (CAP)
Hydrocortisone
Corticosteroids
COronaVIrus Disease
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
First posted: 2015-08-07
Enrollment: 952
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: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Day 28 all causes mortality
timeFrame: at day 28
measure: Day 21 failure
timeFrame: at day 21
Secondary outcomes:
measure: In patients non-invasively ventilated at inclusion, proportion of patients needing endotracheal intubation
timeFrame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
measure: In patients non-ventilated at inclusion, proportion of patients requiring non-invasive ventilation
timeFrame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
measure: In patients non-ventilated at inclusion, proportion of patients needing endotracheal intubation
timeFrame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
measure: Day 28 ventilator-free-days
timeFrame: between 0 and day 28
measure: Number of patients with vasopressor therapy initiation from inclusion to day 28
timeFrame: between 0 and day 28
measure: Day 28 vasopressor-free-days
timeFrame: between 0 and day 28
measure: ICU and/or intermediate care unit LOS
timeFrame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
measure: All-causes mortality at day 90
timeFrame: at day 90
measure: SF-36 Health Survey at day 90
timeFrame: at day 90
measure: Biomarkers: procalcitonin at baseline, day 3 and day 7
timeFrame: at inclusion, day 3 and day 7
measure: Biomarkers: C-reactive protein at baseline, day 3 and day 7
timeFrame: at inclusion, day 3 and day 7
measure: Biomarkers: plasmatic concentration of pro-inflammatory cytokines (IL-6, IL-20, IL-22, IL-22BP, HBD2, TNF) at baseline, day 3 and day 7
timeFrame: at inclusion, day 3 and day 7
measure: 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
timeFrame: 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
measure: SOFA calculated daily from baseline to day 7, at the end of treatment, at the end of ICU-stay and/or day 28
timeFrame: 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
measure: Proportion of patients experiencing secondary infection during their ICU-stay
timeFrame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
measure: Proportion of patients experiencing gastrointestinal bleeding during their ICU-stay
timeFrame: Participants will be followed for the duration of hospital stay, for a maximum of 28 days
measure: Daily amount of insulin administered to the patient from day 1 to day 7
timeFrame: Patients will be followed from day 1 to day 7
measure: Weight-gain at baseline and day 7
timeFrame: Patients will be followed at baseline and day 7
Other outcomes:
measure: P/F ratio measured daily from Day1 to Day7, at Day 14 and at Day 21 and/or at the end of ICU-stay
timeFrame: from day 1 to day 7, at day 14 and day 21 and/or at the end of ICU-stay
measure: Proportion of patients needing endotracheal intubation
timeFrame: at day 21
measure: Proportion of patients experiencing secondary infection during their ICU-stay
timeFrame: From baseline to day 21
Locations:
city: 'Angoulême
country: France
facility: Service de Réanimation - Unité de Soins Continus, CH d'Angoulême
city: Argenteuil
country: France
facility: Service de Réanimation Polyvalente, CH d'Argenteuil
city: Ars-Laquenexy
country: France
facility: Service de Réanimation, CHR Metz-Thionville
city: Aulnay-sous-Bois
country: France
facility: Service de Réanimation
city: Belfort
country: France
facility: Service de Réanimation
city: Bourg-en-Bresse
country: France
facility: Service de Réanimation
city: Brest
country: France
facility: Service de Réanimation HIA Clermont-Tonnerre
city: Brest
country: France
facility: Service de Réanimation Médicale, CHU de Brest
city: Caen
country: France
facility: Service de Réanimation, CHU Côte de Nacre
city: Chartres
country: France
facility: Service de Réanimation Médicale, Hôpital Louis Pasteur, Chartres
city: Clermont Ferrand
country: France
facility: Service de Réanimation Médicale Polyvalente, Hôpital G Montpied
city: Colombes
country: France
facility: Service de Réanimation, Hôpital Louis Mourier
city: Dijon
country: France
facility: Service de Réanimation Médicale, CHU de Dijon
city: Garches
country: France
facility: Service de Réanimation Médico-Chirurgicale, Hôpital Raymond Poincarré, APHP
city: Grenoble
country: France
facility: Service de Réanimation Médicale, CHU de Grenoble
city: La Roche sur Yon
country: France
facility: Service de Réanimation Polyvalente, CHD La Roche sur Yon
city: Le Mans
country: France
facility: Service de Réanimation, CH Le Mans
city: Lille
country: France
facility: Service de Réanimation Polyvalente, Hôpital Salengro, CHU de Lille
city: Limoges
country: France
facility: Service de Réanimation Polyvalente, CHU de Limoges
city: Marseille
country: France
facility: Service de Réanimation Médicale, Hôpital Nord
city: Montauban
country: France
facility: Service de Réanimation Polyvalente - Surveillance Continue, CH de Montauban
city: Nancy
country: France
facility: Service de Réanimation Médicale, CHU de Nancy
city: Nantes
country: France
facility: Service de Réanimation Polyvalente, Hôpital Hôtel Dieu, CHU de Nantes
city: Orléans
country: France
facility: Service de Réanimation Médicale, CHR d'Orléans
city: Paris
country: France
facility: Service de Réanimation Médicale, Hôpital Cochin, APHP
city: Paris
country: France
facility: Service de Réanimation et USC médico-chirurgicale, Hôpital Tenon, APHP
city: Poitiers
country: France
facility: Service de Réanimation Médicale et Médecine Interne, CHU de Poitiers
city: Rennes
country: France
facility: Service des Maladies Infectieuses et Réanimation Médicale, CHU de Rennes
city: Saint Malo
country: France
facility: Service de Réanimation Polyvalente, CH de Saint Malo
city: Saint-Brieuc
country: France
facility: Service de Réanimation
city: Strasbourg
country: France
facility: Service de Réanimation Médicale, Nouvel Hôpital Civil, CHU de Strasbourg
city: Strasbourg
country: France
facility: Service de Réanimation Médicale, Hôpital de Hautepierre, CHU de Strasbourg
Study officials:
affiliation: CHRU de TOURS
name: Pierre-François DEQUIN, MD-PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.