Clinical trial NCT01093261: Corticosteroid Therapy for Glucocorticoid Insufficiency Related to Traumatic Brain Injury
Official title: Phase 3 Study of Hydrocortisone and Fludrocortisone in Glucocorticoid Insufficiency Related to Traumatic Brain Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Traumatic Brain Injury
Trauma
Adrenal Insufficiency
Pneumonia
Keywords: trauma
trauma brain injury
multiple trauma
head trauma
hydrocortisone
fludrocortisone
glucocorticoid insufficiency related to ICU
adrenal Insufficiency
pneumonia
intensive care unit
shock
neurological recovery
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
Collaborators: name: Société Française d'Anesthésie et de Réanimation
First posted: 2010-03-25
Enrollment: 336
Sex: ALL
Minimum age (years): 15
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: rate of hospital acquired pneumonia
timeFrame: day-28
Secondary outcomes:
measure: Neurological recovery
timeFrame: 1-year
measure: other infections
timeFrame: day-28
measure: Organ failures
timeFrame: day-28
measure: Length of ICU stay
timeFrame: 6 months
measure: Duration of mechanical ventilation support
timeFrame: 6 months
measure: Mortality from all causes
timeFrame: day-28
measure: Mortality from all causes
timeFrame: 1 year
measure: Time to amines withdrawal
timeFrame: day-28
measure: Post traumatic stress disorder
timeFrame: 12 months
measure: Glucocorticoid function
timeFrame: on day 11-12
Other outcomes:
Locations:
city: Amiens
country: France
facility: University hospital
city: Angers
country: France
facility: University Hospital
city: Beaujon
country: France
facility: University Hospital
city: Bordeaux
country: France
facility: University hospital
city: Brest
country: France
facility: University Hospital
city: Caen
country: France
facility: Universtiy Hospital
city: Clermont Ferrand
country: France
facility: University Hospital
city: Creteil
country: France
facility: University hospital
city: Creteil
country: France
facility: University Hospital
city: Grenoble
country: France
facility: University Hospital
city: Montpellier
country: France
facility: University Hospital
city: Nantes
country: France
facility: University Hospital
city: Nimes
country: France
facility: University Hospital
city: Paris
country: France
facility: European Hospital Georges Pompidou
city: Paris
country: France
facility: Saint Louis Hospital
city: Poitiers
country: France
facility: University hospital
city: Strasbourg
country: France
facility: University Hospital
city: Toulouse
country: France
facility: University Hospital
Study officials:
affiliation: Nantes University Hospital
name: Karim ASEHNOUNE
role: STUDY_CHAIR
affiliation: Nantes University Hospital
name: Antoine ROQUILLY
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Montpellier
name: Pierre François Perrigault
role: STUDY_DIRECTOR
affiliation: University Hospital, Grenoble
name: Pierre Albaladejo
role: STUDY_DIRECTOR
affiliation: CHU de Marseille
name: Marc Leonne
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Olivier Langeron
role: STUDY_DIRECTOR
References:
citation: Asehnoune K, Roquilly A, Sebille V; Corti-TC trial group. Corticotherapy for traumatic brain-injured patients--the Corti-TC trial: study protocol for a randomized controlled trial. Trials. 2011 Oct 14;12:228. doi: 10.1186/1745-6215-12-228.
citation: Asehnoune K, Seguin P, Allary J, Feuillet F, Lasocki S, Cook F, Floch H, Chabanne R, Geeraerts T, Roger C, Perrigault PF, Hanouz JL, Lukaszewicz AC, Biais M, Boucheix P, Dahyot-Fizelier C, Capdevila X, Mahe PJ, Le Maguet P, Paugam-Burtz C, Gergaud S, Plaud B, Constantin JM, Malledant Y, Flet L, Sebille V, Roquilly A; Corti-TC Study Group. Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial. Lancet Respir Med. 2014 Sep;2(9):706-16. doi: 10.1016/S2213-2600(14)70144-4. Epub 2014 Jul 24.