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Community-Acquired Pneumonia : Evaluation of Corticosteroids (CAPE_COD)

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ClinicalTrials.gov Identifier: NCT02517489
Recruitment Status : Recruiting
First Posted : August 7, 2015
Last Update Posted : April 15, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospital, Tours

Tracking Information
First Submitted Date  ICMJE July 31, 2015
First Posted Date  ICMJE August 7, 2015
Last Update Posted Date April 15, 2020
Actual Study Start Date  ICMJE October 28, 2015
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 13, 2020)
  • Day 28 all causes mortality [ Time Frame: at day 28 ]
  • Day 21 failure [ Time Frame: 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);
Original Primary Outcome Measures  ICMJE
 (submitted: August 4, 2015)
Day 28 all causes mortality [ Time Frame: at day 28 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 4, 2015)
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 13, 2020)
  • P/F ratio measured daily from Day1 to Day7, at Day 14 and at Day 21 and/or at the end of ICU-stay [ Time Frame: 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 [ Time Frame: at day 21 ]
    Sub-group of patients included with COVID19
  • Proportion of patients experiencing secondary infection during their ICU-stay [ Time Frame: From baseline to day 21 ]
    Sub-group of patients included with COVID19
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Community-Acquired Pneumonia : Evaluation of Corticosteroids
Official Title  ICMJE Effects of Low-dose Corticosteroids on Survival of Severe Community-acquired Pneumonia
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Community Acquired Pneumonia
Intervention  ICMJE
  • 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.
  • 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.
Study Arms  ICMJE
  • Experimental: Hydrocortisone
    Patients in the treatment group will receive intra-venous hydrocortisone (in addition to the standard treatment of severe Community-Acquired Pneumonia (CAP)
    Intervention: Drug: Hydrocortisone
  • 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)
    Intervention: Drug: Placebo
Publications * Dequin PF, Heming N, Meziani F, Plantefève G, Voiriot G, Badié J, François B, Aubron C, Ricard JD, Ehrmann S, Jouan Y, Guillon A, Leclerc M, Coffre C, Bourgoin H, Lengellé C, Caille-Fénérol 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 4, 2015)
1200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pierre-François DEQUIN, MD-PhD 02.47.47.38.55 ext +33 pierre-françois.dequin@univ-tours.fr
Contact: Marie LECLERC 02.47.47.46.64 ext +33 m.leclerc@chu-tours.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02517489
Other Study ID Numbers  ICMJE PHRN14-PFD/CAPE COD
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University Hospital, Tours
Study Sponsor  ICMJE University Hospital, Tours
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Pierre-François DEQUIN, MD-PhD CHRU de TOURS
PRS Account University Hospital, Tours
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP