Corticosteroid Therapy for Glucocorticoid Insufficiency Related to Traumatic Brain Injury

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Traumatic Brain Injury, Trauma, Adrenal Insufficiency, Pneumonia

Intervention / Treatment
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* Drug: Placebo
* Drug: Hydrocortisone Fludrocortisone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydrocortisone and fludrocortisone<br>Patients with glucocorticoid insufficiency | Drug: Hydrocortisone Fludrocortisone<br>* 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)<br>|
| Placebo Comparator: Placebo<br>Patients with glucocorticoid insufficiency | Drug: Placebo<br>* Placebo: continuous intra venous infusion of placebo n°1 for 10 days. enteral administration of placebo n°2 for 10 days.<br>|
| No Intervention: Controlled<br>Adapted glucocorticoid function | |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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trauma, trauma brain injury, multiple trauma, head trauma, hydrocortisone, fludrocortisone, glucocorticoid insufficiency related to ICU, adrenal Insufficiency, pneumonia, intensive care unit, shock, neurological recovery