Neuroendocrine Dysfunction in Traumatic Brain Injury: Effects of Testosterone Therapy

Study Overview
=================
Brief Summary
-----------------
The purpose of this study was to address 3 short term objectives; (1) Determine the effects of physiologic testosterone (T) therapy on neurological function and functional independence following traumatic brain injury (TBI) in hypogonadal men during inpatient rehabilitation; (2) Document the natural history of neuroendocrine dysfunction and recovery in men during inpatient rehabilitation after TBI; (3) Obtain data to validate the NIH toolbox, a novel assessment of neurological function for use in the TBI population; and 2 long-term objectives: (1) Utilize study findings to design a multicenter trial to further assess the impact of T therapy in hypogonadal men following TBI and (2) Impact TBI practice management with new information about neuroendocrine dysfunction after TBI and hormone treatments to improve outcomes.

Detailed Description
-----------------
This randomized, double blind, placebo-controlled pilot study assessed the hormonal status of men on admission to an inpatient TBI rehabilitation program. 498 consecutively admitted men for TBI rehabilitation were screened for participation in the study. 22 participants with low T who met all criteria were randomized into placebo (n=10), or physiologic T therapy (n=12). Of those with normal T who met all criteria, 24 were randomized into a follow up group. All participants were evaluated every two weeks for up to 12 weeks: hormone levels, FIM ratings and NIH Toolbox testing as able. There was participant drop out over time as participants were discharged from the hospital. The final analysis examined differences between the normal T, low T Treatment and low T placebo groups on hormone levels, FIM ratings and NIH Toolbox results at baseline and weeks 2, 4 and 6.

Official Title
-----------------
Neuroendocrine Dysfunction in Traumatic Brain Injury: Effects of Testosterone Therapy

Conditions
-----------------
Endocrine Dysfunction, Trauma, Brain Injury

Intervention / Treatment
-----------------
* Drug: Androgel (Testosterone Gel)
* Other: Placebo gel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: History of TBI as defined as damage to brain tissue caused by an external mechanical force as evidenced by loss of consciousness or post traumatic amnesia (PTA) due to brain trauma or by objective neurological findings that can be reasonably attributed to TBI on physical examination or mental status examination;82 Moderate to severe TBI as indicated by a Glasgow Coma Scale (GCS) score of less than or equal to 12 at emergency department admission, or post traumatic amnesia (PTA) of greater than or equal to seven days post-injury, or radiographic evidence of intracranial injury; Continuously hospitalized from time of injury until admission for rehabilitation; Enrolled in study within 6 months of TBI; Receiving inpatient rehabilitation for TBI at Craig Hospital; Males between the ages of 16 to 65 (inclusive); Approval by attending physician; Testosterone level below the assay normal range; Consent to study participation Exclusion Criteria: History of any conditions that would prohibit testing contained in the NIH toolbox; Non-English or non-Spanish speaking (to the extent that would limit the ability to complete study measures); History of prior psychiatric illness requiring hospitalization; Prior testosterone therapy; History of or current or suspected hormonally dependent cancer , including carcinoma of the breast or prostate cancer; Known hypersensitivity to any T gel ingredients including alcohol and soy products; Hematocrit (HCT) greater than 55% (normal range in Colorado is up to 52) or transaminase elevation >4x upper limit of the normal range. Abnormal finding on digital rectal examination such as nodule, asymmetry, or induration (Does not include enlarged prostate or abnormal rectal tone) PSA>4.0 BMI <16 or >40kg/m2 History of untreated prolactinoma History of severe heart failure or uncontrolled medical problem that would interfere with the participant's safety in the study as determined by the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low T Intervention - Androgel Treatment<br>Men with TBI meeting study criteria with Low Testosterone levels were randomly assigned to the Androgel treatment group. They underwent hormonal assays, FIM ratings and NIH Toolbox testing at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. | Drug: Androgel (Testosterone Gel)<br>* 2.5 gram stickpacks administered with starting dosage of 5g increasing to a max of 10g.<br>|
| Placebo Comparator: Low T Intervention - Placebo Treatment<br>Men with TBI meeting study criteria with Low Testosterone levels were randomly assigned to the Placebo gel treatment group. They underwent hormonal assays, FIM ratings and NIH Toolbox testing at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. | Other: Placebo gel<br>* 2.5 gram stickpacks with starting dose of 5g increasing to max of 10g.<br>|
| No Intervention: Normal T<br>A subset of men with TBI meeting study criteria with normal T at screening were assessed at all data collection time points to provide a control group. Thirty-eight men obtained normal T levels at screening of which 24 were followed. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Restricted Functional Independence Measure (FIM) | The FIM is the most widely accepted functional assessment measure in use in the rehabilitation community in the US. It is an 18-item ordinal clinician rating scale that is useful for assessment of functional skills progress during inpatient rehabilitation. It measures levels of independent/dependent performance of 13 motor functions and 5 cognitive functions. By adding the points for each item, the possible total score ranges from 18 to 126, with higher numbers indicating better performance. A restricted FIM total score that eliminated the toileting, bladder management and bowel management items was computed and used in the final analysis with scores ranging from 14-105). The restricted FIM total score was used as the primary outcome measure. | Administered at baseline and every other week for up to 12 weeks with 7 total possible administrations. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Traumatic Brain Injury, Hypogonadism, Testosterone, Endocrine Dysfunction, Low Testosterone in men with new Traumatic Brain Injury