Corticosteroid Therapy for Glucocorticoid Insufficiency Related to Traumatic Brain Injury

Condition(s) targeted: Traumatic Brain Injury; Trauma; Adrenal Insufficiency; Pneumonia

Intervention: Placebo (Drug); Hydrocortisone Fludrocortisone (Drug); No treatment (Other)

Phase: Phase 3

Status: Recruiting

Sponsored by: Nantes University Hospital

Official(s) and/or principal investigator(s):
Karim ASEHNOUNE, Study Chair, Affiliation: Nantes University Hospital
Antoine ROQUILLY, Principal Investigator, Affiliation: Nantes University Hospital
Samir Jaber, Study Director, Affiliation: CHU de Montpellier
Pierre Albaladejo, Study Director, Affiliation: University Hospital, Grenoble
Marc Leonne, Study Director, Affiliation: CHU de Marseille
Olivier Langeron, Study Director, Affiliation: Assistance Publique - Hôpitaux de Paris

Overall contact:
Christelle Dibon, Phone: (+33)253432852, Email: christelle.dibon@chu-nantes.fr

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.

Official title: Phase 3 Study of Hydrocortisone and Fludrocortisone in Glucocorticoid Insufficiency Related to Traumatic Brain Injury

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: rate of hospital acquired pneumonia

Secondary outcome:

Neurological recovery

other infections

Organ failures

Length of ICU stay

Duration of mechanical ventilation support

Mortality from all causes

Mortality from all causes

Time to amines withdrawal

Post traumatic stress disorder

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.

Minimum age: 15 Years. Maximum age: 65 Years. Gender(s): Both.

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

Christelle Dibon, Phone: (+33)253432852, Email: christelle.dibon@chu-nantes.fr

University hospital, Amiens, France; Recruiting
Hervé DUPONT, M.D.;Ph.D.
Patrick Jeanjean, M.D.
Hervé Dupont, M.D.;Ph.D., Principal Investigator

University Hospital, Angers, France; Recruiting
Sigismond lasocki, MD, Email: sigismond@lasocki.com
Sigismond Lasocki, MD, Principal Investigator

University Hospital, Beaujon, France; Recruiting
Jean Mantz, MD, Email: jean.mantz@idb.aphp.fr
Jeremy Allary, MD, Sub-Investigator
Jean Mantz, MD, Principal Investigator
Tobiass Gauss, MD, Sub-Investigator

University hospital, Bordeaux 33000, France; Recruiting
Philippe Nevel, M.D., Principal Investigator
Mathieu Biais, MD, Principal Investigator
Francois sztark, MD, Principal Investigator

University Hospital, Brest, France; Recruiting
Herve FLOCH, M.D.
Charles Arvieux, M.D;Ph.D., Principal Investigator

Universtiy Hospital, Caen, France; Recruiting
Sophie Ramakers, M.D.
Jean Luc Hanouz, M.D.;Ph.D., Principal Investigator

University Hospital, Clermont Ferrand, France; Recruiting
Thierry Gillart, M.D.
Thierry Gillart, M.D.;Ph.D., Principal Investigator

University Hospital, Creteil, France; Recruiting
Jean Mantz, M.D;Ph.D., Principal Investigator

University hospital, Creteil 94000, France; Recruiting
Benoit Plaud, M.D;Ph.D.
Benoit Plaud, M.D.;Ph.D., Principal Investigator
Fabrice Cook, MD, Principal Investigator
Coralie Vigne, MD, Sub-Investigator

University Hospital, Dijon, France; Active, not recruiting

University Hospital, Grenoble, France; Not yet recruiting
Jean Francois Payen, MD
Jean Francois Payen, MD, Principal Investigator

University Hospital, Lyon, France; Active, not recruiting

University Hospital, Montpellier, France; Recruiting
Pierre Francois PERRIGAULT, M.D.
Pierre Francois PERRIGAULT, M.D., Principal Investigator

University Hospital, Montpellier, France; Recruiting
Xavier Capdevilla, M.D.
Priscilla Amaru, M.D., Sub-Investigator

University Hospital, Montpellier, France; Recruiting
Priscilla AMARU, M.D.
Xavier CAPDEVILLA, M.D.;Ph.D., Principal Investigator

University Hospital, Nancy, France; Not yet recruiting
Gerard Audibert, MD
Gerard Audibert, MD, Principal Investigator

University Hospital, Nantes, France; Recruiting
Antoine Roquilly, MD
Mahe, M.D., Sub-Investigator
Antoine Roquilly, M.D., Principal Investigator

University Hospital, Nimes, France; Recruiting
Jean Yves Lefranc, MD, Email: jean-yves.lefrant@chu-nimes.fr
Jean Yves Lefranc, MD, Principal Investigator
Sophie Lloret, MD, Sub-Investigator

Saint Louis Hospital, Paris 75000, France; Not yet recruiting
Elie Azoulay, M.D.;Ph.D., Principal Investigator

European Hospital Georges Pompidou, Paris 75000, France; Recruiting
Journois, M.D.,Ph.D.
Didier Journois, M.D;Ph.D., Principal Investigator
Alix Lagrange, MD, Sub-Investigator

University hospital, Poitiers 86000, France; Recruiting
Claire Dahyot, M.D.
Olivier Mimoz, M.D.;Ph.D., Principal Investigator

University Hospital, Strasbourg, France; Recruiting
Thierry Pottecher, M.D.;Ph.D., Principal Investigator
Bartholomeus Calon, MD, Sub-Investigator

University Hospital, Toulouse, France; Active, not recruiting

University hospital, Tours 37000, France; Not yet recruiting
Jacques Fusciardi, M.D.;Ph.D., Principal Investigator

Starting date: August 2010
Last updated: October 4, 2011