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

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

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.

Study Overview

• Status: Completed
• Conditions: Pneumonia; Trauma; Traumatic Brain Injury; Adrenal Insufficiency
• Intervention / Treatment: Drug: Hydrocortisone Fludrocortisone; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 336
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • University Hospital
  • Angers, France
    • University Hospital
  • Beaujon, France
    • University Hospital
  • Bordeaux, France, 33000
    • University Hospital
  • Brest, France
    • University Hospital
  • Caen, France
    • Universtiy Hospital
  • Clermont Ferrand, France
    • University Hospital
  • Creteil, France, 94000
    • University Hospital
  • Creteil, France
    • University Hospital
  • Grenoble, France
    • University Hospital
  • Montpellier, France
    • University Hospital
  • Nantes, France
    • University Hospital
  • Nimes, France
    • University Hospital
  • Paris, France, 75000
    • European Hospital Georges Pompidou
  • Paris, France, 75000
    • Saint Louis Hospital
  • Poitiers, France, 86000
    • University Hospital
  • Strasbourg, France
    • University Hospital
  • Toulouse, France
    • University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 61 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate of hospital acquired pneumonia	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).	day-28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurological recovery	in adapated and insufficient glucocorticoid function (Glasgow Outcome Scale, Barthel index, MIF) (Ancillary study)	1-year
other infections	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.	day-28
Organ failures	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)	day-28
Length of ICU stay	in adapated and insufficient glucocorticoid function	6 months
Duration of mechanical ventilation support	in adapated and insufficient glucocorticoid function	6 months
Mortality from all causes	in adapated and insufficient glucorticoid function	day-28
Mortality from all causes	in adapated and insufficient glucorticoid function	1 year
Time to amines withdrawal		day-28
Post traumatic stress disorder	Assessment of psychological status (ancillary study)	12 months
Glucocorticoid function	Short corticotropin test	on day 11-12

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Collaborators: 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

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: Lancet Respir Med. 2014 Sep;2(9):e15.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: March 23, 2010
• First Submitted That Met QC Criteria: March 24, 2010
• First Posted (Estimate): March 25, 2010

Study Record Updates

• Last Update Posted (Actual): September 14, 2017
• Last Update Submitted That Met QC Criteria: September 13, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: trauma; intensive care unit; shock; pneumonia; hydrocortisone; multiple trauma; head trauma; fludrocortisone; trauma brain injury; glucocorticoid insufficiency related to ICU; adrenal Insufficiency; neurological recovery
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Endocrine System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Adrenal Gland Diseases; Brain Injuries; Pneumonia; Wounds and Injuries; Brain Injuries, Traumatic; Adrenal Insufficiency; Anti-Inflammatory Agents; Hydrocortisone; Fludrocortisone
• Other Study ID Numbers: BRD/10/01-L; SFAR (Other Identifier: Societe francaise d'Anesthesie Reanimation)