CAPE_COD: Community-Acquired Pneumonia : Evaluation of Corticosteroids

Sponsor

University Hospital, Tours (Other)

Overall Status

Recruiting

CT.gov ID

NCT02517489

Collaborator

(none)

1,200

Enrollment

Locations

Arms

76.1

Anticipated Duration (Months)

37.5

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Community Acquired Pneumonia	Drug: Hydrocortisone Drug: Placebo	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

1200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 28, 2015

Anticipated Primary Completion Date :

Jan 1, 2022

Anticipated Study Completion Date :

Mar 1, 2022

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Day 28 all causes mortality [at day 28]
Day 21 failure [at day 21]
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);

Secondary Outcome Measures

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

P/F ratio measured daily from Day1 to Day7, at Day 14 and at Day 21 and/or at the end of ICU-stay [from day 1 to day 7, at day 14 and day 21 and/or at the end of ICU-stay]
Sub-group of patients included with COVID19
Proportion of patients needing endotracheal intubation [at day 21]
Sub-group of patients included with COVID19
Proportion of patients experiencing secondary infection during their ICU-stay [From baseline to day 21]
Sub-group of patients included with COVID19

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Service de Réanimation - Unité de Soins Continus, CH d'Angoulême	'Angoulême	France	16959
2	Service de Réanimation Polyvalente, CH d'Argenteuil	Argenteuil	France	95107
3	Service de Réanimation, CHR Metz-Thionville	Ars-Laquenexy	France	57530
4	Service de Réanimation	Aulnay-sous-Bois	France	93602
5	Service de Réanimation	Belfort	France	90015
6	Service de Réanimation	Bourg-en-Bresse	France
7	Service de Réanimation HIA Clermont-Tonnerre	Brest	France	29240
8	Service de Réanimation Médicale, CHU de Brest	Brest	France	29609
9	Service de Réanimation, CHU Côte de Nacre	Caen	France	14033
10	Service de Réanimation Médicale, Hôpital Louis Pasteur, Chartres	Chartres	France	28000
11	Service de Réanimation Médicale Polyvalente, Hôpital G Montpied	Clermont Ferrand	France	63003
12	Service de Réanimation, Hôpital Louis Mourier	Colombes	France	92700
13	Service de Réanimation Médicale, CHU de Dijon	Dijon	France	21079
14	Service de Réanimation Médico-Chirurgicale, Hôpital Raymond Poincarré, APHP	Garches	France	92380
15	Service de Réanimation Médicale, CHU de Grenoble	Grenoble	France	38043
16	Service de Réanimation Polyvalente, CHD La Roche sur Yon	La Roche sur Yon	France	85925
17	Service de Réanimation, CH Le Mans	Le Mans	France	72037
18	Service de Réanimation Polyvalente, Hôpital Salengro, CHU de Lille	Lille	France	59037
19	Service de Réanimation Polyvalente, CHU de Limoges	Limoges	France	87042
20	Service de Réanimation Médicale, Hôpital Nord	Marseille	France	13015
21	Service de Réanimation Polyvalente - Surveillance Continue, CH de Montauban	Montauban	France	82013
22	Service de Réanimation Médicale, CHU de Nancy	Nancy	France	54511
23	Service de Réanimation Polyvalente, Hôpital Hôtel Dieu, CHU de Nantes	Nantes	France	44093
24	Service de Réanimation Médicale, CHR d'Orléans	Orléans	France	45067
25	Service de Réanimation Médicale, Hôpital Cochin, APHP	Paris	France	75014
26	Service de Réanimation et USC médico-chirurgicale, Hôpital Tenon, APHP	Paris	France	75020
27	Service de Réanimation Médicale et Médecine Interne, CHU de Poitiers	Poitiers	France	86021
28	Service des Maladies Infectieuses et Réanimation Médicale, CHU de Rennes	Rennes	France	35033
29	Service de Réanimation Polyvalente, CH de Saint Malo	Saint Malo	France	35403
30	Service de Réanimation	Saint-Brieuc	France	22000
31	Service de Réanimation Médicale, Nouvel Hôpital Civil, CHU de Strasbourg	Strasbourg	France	67091
32	Service de Réanimation Médicale, Hôpital de Hautepierre, CHU de Strasbourg	Strasbourg	France	67098