Community-Acquired Pneumonia : Evaluation of Corticosteroids

Community Acquired Pneumonia Clinical Trial

— CAPE_COD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02517489
• Other study ID #: PHRN14-PFD/CAPE COD
• Status: Completed
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Community Acquired Pneumonia
• Pneumonia

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