Corticosteroid Therapy for Glucocorticoid Insufficiency Related to Traumatic Brain Injury (Corti-TC)

This study has been completed.
Sponsor:
Collaborator:
Société Française d'Anesthésie et de Réanimation
Information provided by (Responsible Party):
Karim ASEHNOUNE, Nantes University Hospital
ClinicalTrials.gov Identifier:
NCT01093261
First received: March 23, 2010
Last updated: December 12, 2012
Last verified: December 2012
  Purpose

Traumatic brained injured (TBI) patients frequently suffered from glucocorticoid insufficiency that is associated with a raise in the rate of pneumonia.

In a placebo-controlled, multi-center, double-blinded trial, treatment of glucocorticoid insufficiency (hydrocortisone associated with fludrocortisone) will be assessed for prevention of post trauma pneumonia in a population of severe TBI patients.


Condition Intervention Phase
Traumatic Brain Injury
Trauma
Adrenal Insufficiency
Pneumonia
Drug: Placebo
Drug: Hydrocortisone Fludrocortisone
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 3 Study of Hydrocortisone and Fludrocortisone in Glucocorticoid Insufficiency Related to Traumatic Brain Injury

Resource links provided by NLM:


Further study details as provided by Nantes University Hospital:

Primary Outcome Measures:
  • rate of hospital acquired pneumonia [ Time Frame: day-28 ] [ Designated as safety issue: No ]
    Presence of at least two signs (body fever greater than 38°C; leukocytosis greater than 12000/ml or leukopenia below 4000/ml, purulent pulmonary secretions) associated with the appearance of a new infiltrate or modification of an existing infiltrate on chest-X-ray. Confirmation by a lower respiratory tract sample using a quantitative culture with a predefined positive threshold. Hospital-acquired pneumonia was defined as a pneumonia that occurs 48 hours after admission, which was not incubating at time of admission (Am J Respir Crit Care Med 2005; 171, 388-416).


Secondary Outcome Measures:
  • Neurological recovery [ Time Frame: 1-year ] [ Designated as safety issue: No ]
    in adapated and insufficient glucocorticoid function (Glasgow Outcome Scale, Barthel index, MIF) (Ancillary study)

  • other infections [ Time Frame: day-28 ] [ Designated as safety issue: No ]
    Tracheobronchitis 1: Association of at least two signs (fever above 38.0°C, Leucocytosis above 12000/ml or purulent pulmonary secretions) with isolation of bacteria in a lower respiratory tract sample without modification of chest-X-Ray; Urinary tract infection : Fever above 38.2°C associated with leucocyturia (>10000/ml) and bacteriuria (>103 UFC/ml) without other infection; Bacteriemia : One positive blood culture (two positive blood cultures for Staphiloccocus coagulase negative); Surgical wound infection : sputum from surgical incision or scare dehiscence associated with fever.

  • Organ failures [ Time Frame: day-28 ] [ Designated as safety issue: Yes ]
    Acute Lung Injury or Acute Respiratory Distress Syndrom: PaO2/FiO2 below 300 with bilateral infiltrates on chest-X-ray without elevation of left atrial pressure; Acute kydney injury: oliguria (<0.3 ml/kg/hour for 24 hours or more) or raise in basal creatinemia of more than 300%; Myocardial insufficiency: indexed cardiac output below 2 l/min/m2; Hematologic insufficiency: platelet count below 50 000/ml; Hepatic insufficiency: bilirubinemia (<50 mmol.l-1) with a prothrombin (<40%), SOFA score (First week)

  • Length of ICU stay [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    in adapated and insufficient glucocorticoid function

  • Duration of mechanical ventilation support [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    in adapated and insufficient glucocorticoid function

  • Mortality from all causes [ Time Frame: day-28 ] [ Designated as safety issue: No ]
    in adapated and insufficient glucorticoid function

  • Mortality from all causes [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    in adapated and insufficient glucorticoid function

  • Time to amines withdrawal [ Time Frame: day-28 ] [ Designated as safety issue: No ]
  • Post traumatic stress disorder [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Assessment of psychological status (ancillary study)

  • Glucocorticoid function [ Time Frame: on day 11-12 ] [ Designated as safety issue: No ]
    Short corticotropin test


Enrollment: 336
Study Start Date: August 2010
Study Completion Date: December 2012
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Hydrocortisone and fludrocortisone
Patients with glucocorticoid insufficiency
Drug: Hydrocortisone Fludrocortisone
HYDROCORTISONE: 200 mg.day-1 for 7 days, 100 mg.day-1 on day 8 and 9, 50 mg on day-10 (continuous intravenous infusion) FLUDROCORTISONE: 50 microg.day-1 for 10 days (per os)
Placebo Comparator: Placebo
Patients with glucocorticoid insufficiency
Drug: Placebo

Placebo:

continuous intra venous infusion of placebo n°1 for 10 days. enteral administration of placebo n°2 for 10 days.

No Intervention: Controlled
Adapted glucocorticoid function

Detailed Description:

Treatment of glucocorticoid insufficiency in TBI patients remains controversial.

The purpose of this study is to determine whether hydrocortisone associated with fludrocortisone decreases rate of hospital-acquired pneumonia on day-28 in TBI patients with glucocorticoid insufficiency. Glucocorticoid function will be assessed by a corticotropin test (ACTH 0.25 mg). The study treatment will be started before reception of the results of these test. Patients with glucocorticoid insufficiency (basal cortisolemia < 15 mcg/dl or post ACTH raise < or = 9 mcg/dl) will be treated for 10 days. Patients with adapted glucocorticoid function will no longer be treated till the results of corticotropin test are known.

The primary end point will be rate of HAP on day-28 in patients with glucocorticoid insufficiency. Secondary endpoints will be neurological recovery (on day-28, -6 and -12), mortality (on day-28 and day-365), rate of other infections (on day-28), rate of organ failures (on day-28), mechanical ventilation weaning time, ICU length of stay.

In a double-blinded fashion (randomized on a 1:1 basis), 326 patients receive 200 mg intravenously for 10 days. After 7 days, treatment will be tapered with 100 mg given intravenously for days 8-9, then 50 mg for day 10, and then stopped.

All concomitant treatments, including antibiotics, fluids, vasopressors and ancillary therapies will be given at the discretion of the primary care physician. Evidence-based guidelines for the management of severe trauma brain injury (J Neurotrauma 2007; 24 Suppl 1, S1-106.) are encouraged to be followed. All institution are level I trauma center and university hospital.

Clinical assessments were performed twice a day in the ICU. When HAP was suspected after clinical examination, a new infiltrate was checked on a chest X-ray. The study protocol stated that antibiotic therapy should not be modified before a bacteriological sample was performed

All serious adverse events (SAE) which occur between days 0 and 28, which are unexpected and/or considered possibly or probably related to the study medication, must be documented and reported within 24 hours to the Safety and Efficacy Monitoring Committee. Non-serious adverse events will be listed on the case report form if they are unexpected and believed to be related to the study drug during days 0 to 14.

Specific adverse events which will be monitored closely because of their relationship to corticosteroids and trauma are: Use of corticosteroids, i.e. gastrointestinal bleeding and superinfection; hyperglycemia, hypernatremia, muscular weakness, etc.

In addition, substudies will include radiological assessment of hypothalamus and hypophyses,immune and neuro-endocrine interactions, post stress disorder assessment.

  Eligibility

Ages Eligible for Study:   15 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Trauma brain injury (Glasgow score below 8 and lesion on scanner)
  • Informed consent
  • Time to inclusion inferior to 24 hours

Exclusion Criteria:

  • Tetraplegia
  • Administration of chronic corticosteroids in the last 6 months or acute steroid therapy (any dose) within 4 weeks (excluding inhaled steroids). Topical steroids are not exclusions
  • Drug-induced immunosuppression, including chemotherapy or radiation therapy within 4 weeks before the study
  • Antibiotherapy for active sepsis at the time of inclusion
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01093261

Locations
France
University hospital
Amiens, France
University Hospital
Angers, France
University Hospital
Beaujon, France
University hospital
Bordeaux, France, 33000
University Hospital
Brest, France
Universtiy Hospital
Caen, France
University Hospital
Clermont Ferrand, France
University Hospital
Creteil, France
University hospital
Creteil, France, 94000
University Hospital
Grenoble, France
University Hospital
Montpellier, France
University Hospital
Nantes, France
University Hospital
Nimes, France
European Hospital Georges Pompidou
Paris, France, 75000
Saint Louis Hospital
Paris, France, 75000
University hospital
Poitiers, France, 86000
University Hospital
Strasbourg, France
University Hospital
Toulouse, France
Sponsors and Collaborators
Nantes University Hospital
Société Française d'Anesthésie et de Réanimation
Investigators
Study Chair: Karim ASEHNOUNE Nantes University Hospital
Principal Investigator: Antoine ROQUILLY Nantes University Hospital
Study Director: Pierre François Perrigault CHU de Montpellier
Study Director: Pierre Albaladejo University Hospital, Grenoble
Study Director: Marc Leonne CHU de Marseille
Study Director: Olivier Langeron Assistance Publique - Hôpitaux de Paris
  More Information

Publications:
Responsible Party: Karim ASEHNOUNE, Asehnoune, Nantes University Hospital
ClinicalTrials.gov Identifier: NCT01093261     History of Changes
Other Study ID Numbers: CHU de Nantes, SFAR
Study First Received: March 23, 2010
Last Updated: December 12, 2012
Health Authority: France: Agence Française de Sécurité Sanitaire des Produits de Santé

Keywords provided by Nantes University Hospital:
trauma
trauma brain injury
multiple trauma
head trauma
hydrocortisone
fludrocortisone
glucocorticoid insufficiency related to ICU
adrenal Insufficiency
pneumonia
intensive care unit
shock
neurological recovery

Additional relevant MeSH terms:
Pneumonia
Brain Injuries
Adrenal Insufficiency
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Wounds and Injuries
Adrenal Gland Diseases
Endocrine System Diseases
Hydrocortisone acetate
Hydrocortisone 17-butyrate 21-propionate
Cortisol succinate
Hydrocortisone
Fludrocortisone
Hydrocortisone-17-butyrate
Glucocorticoids
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Dermatologic Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 18, 2014