Neuroendocrine Dysfunction in Traumatic Brain Injury: Effects of Testosterone Therapy

• Sponsor: Craig Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01201863
• Collaborator: University of Colorado, Denver (Other)
• Enrollment: 46
• Location: 1
• Arms: 3
• Duration (Months): 46
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Endocrine Dysfunction; Trauma; Brain Injury	Drug: Androgel (Testosterone Gel); Other: Placebo gel	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Neuroendocrine Dysfunction in Traumatic Brain Injury: Effects of Testosterone Therapy
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low T Intervention - Androgel Treatment 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); 2.5 gram stickpacks administered with starting dosage of 5g increasing to a max of 10g.
Placebo Comparator: Low T Intervention - Placebo Treatment 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; 2.5 gram stickpacks with starting dose of 5g increasing to max of 10g.
No Intervention: Normal T 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.

Outcome Measures

Primary Outcome Measures

1. Restricted Functional Independence Measure (FIM) [Administered at baseline and every other week for up to 12 weeks with 7 total possible administrations.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 65 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 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

2. 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;

3. Continuously hospitalized from time of injury until admission for rehabilitation;

4. Enrolled in study within 6 months of TBI;

5. Receiving inpatient rehabilitation for TBI at Craig Hospital;

6. Males between the ages of 16 to 65 (inclusive);

7. Approval by attending physician;

8. Testosterone level below the assay normal range;

9. Consent to study participation

Exclusion Criteria:

1. History of any conditions that would prohibit testing contained in the NIH toolbox;

2. Non-English or non-Spanish speaking (to the extent that would limit the ability to complete study measures);

3. History of prior psychiatric illness requiring hospitalization;

4. Prior testosterone therapy;

5. History of or current or suspected hormonally dependent cancer , including carcinoma of the breast or prostate cancer;

6. Known hypersensitivity to any T gel ingredients including alcohol and soy products;

7. Hematocrit (HCT) greater than 55% (normal range in Colorado is up to 52) or transaminase elevation >4x upper limit of the normal range.

8. Abnormal finding on digital rectal examination such as nodule, asymmetry, or induration (Does not include enlarged prostate or abnormal rectal tone)

9. PSA>4.0

10. BMI <16 or >40kg/m2

11. History of untreated prolactinoma

12. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Craig Hospital	Englewood	Colorado	United States	80113

Sponsors and Collaborators

• Craig Hospital
• University of Colorado, Denver

Investigators

• Principal Investigator: David Ripley, MD, Rehab Institute of Chicago

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Pubmed link to Testosterone replacement in hypogonadal men during inpatient rehabilitation following traumatic brain injury

Publications

None provided.

• Responsible Party: Cynthia Harrison-Felix, PhD, Director of Research, Craig Hospital
• ClinicalTrials.gov Identifier: NCT01201863
• Other Study ID Numbers: 10 IHA 11650
• First Posted: Sep 15, 2010
• Last Update Posted: Jul 27, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by Cynthia Harrison-Felix, PhD, Director of Research, Craig Hospital: Testosterone; Traumatic Brain Injury; Hypogonadism; Endocrine Dysfunction; Low Testosterone in men with new Traumatic Brain Injury
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries; Testosterone

Study Results

Participant Flow

Recruitment Details	Male in-patients with TBI at Craig Hospital meeting study criteria were screened from November 1, 2010 through July 24, 2014:
Pre-assignment Detail	A total of 46 participants meeting all criteria were enrolled and randomized of which 22 had low testosterone levels, and 24 who had normal T were followed as controls. The total number who started and were followed was 46.

Arm/Group Title	Intervention - Treatment	Intervention Placebo	Normal - No Intervention
Arm/Group Description	Men with TBI meeting study criteria with Low Testosterone levels will be randomly assigned to either a treatment or placebo group. They will participate in blood assays at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. They will also be scored on the FIM (primary outcome measure) and the NIH Toolbox (Secondary Outcome Measure. Androgel (Testosterone Gel): 2.5 gram stickpacks administered with starting dosage of 5g increasing to a max of 10g.	Men with TBI meeting study criteria with Low Testosterone levels will be randomly assigned to either a treatment or placebo group. They will participate in blood assays at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. They will also be scored on the FIM (primary outcome measure) and the NIH Toolbox (Secondary Outcome Measure. Androgel Placebo: 2.5 gram stickpacks with starting dose of 5g increasing to max of 10g.	Enrolled participants with normal T
Period Title: Overall Study
STARTED	12	10	24
COMPLETED	11	6	18
NOT COMPLETED	1	4	6

Baseline Characteristics

Arm/Group Title	Low T Intervention - Treatment	Low T Intervention - Placebo	Normal T No Intervention - Followed	Total
Arm/Group Description	Men with TBI meeting study criteria with Low Testosterone levels were randomly assigned to either a treatment or placebo group. They will participate in blood assays at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. They will also be scored on the FIM (primary outcome measure) and the NIH Toolbox (Secondary Outcome Measure. Androgel (Testosterone Gel): 2.5 gram stickpacks administered with starting dosage of 5g increasing to a max of 10g.	Men with TBI meeting study criteria with Low Testosterone levels were randomly assigned to either a treatment or placebo group. They will participate in blood assays at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. They will also be scored on the FIM (primary outcome measure) and the NIH Toolbox (Secondary Outcome Measure. Androgel Placebo: 2.5 gram stickpacks with starting dose of 5g increasing to max of 10g.	A subset of men with TBI meeting study criteria with Normal Testosterone levels were assessed at all data collection time points. They will participate in blood assays at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. They will also be scored on the FIM (primary outcome measure) and the NIH Toolbox (Secondary Outcome Measure.	Total of all reporting groups
Overall Participants	12	10	24	46
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	12 100%	10 100%	24 100%	46 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	12 100%	10 100%	24 100%	46 100%

Outcome Measures

1. Primary Outcome

Title	Restricted Functional Independence Measure (FIM)
Description	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.
Time Frame	Administered at baseline and every other week for up to 12 weeks with 7 total possible administrations.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention - Treatment	Intervention Placebo	No Intervention
Arm/Group Description	Men with TBI meeting study criteria with Low Testosterone levels were randomly assigned to either a treatment or placebo group. They participated in blood assays at baseline and every other week for up to 12 weeks during inpatient rehabilitation hospitalization. At the same assessment points, they were also scored on the FIM (primary outcome measure) and were administered the NIH Toolbox (Secondary Outcome Measure). Androgel (Testosterone Gel): 2.5 gram stickpacks administered with starting dosage of 5g increasing to a max of 10g.	Men with TBI meeting study criteria with Low Testosterone levels were randomly assigned to either a treatment or placebo group. They participated in blood assays at baseline and every other week for up to 12 weeks during inpatient rehabilitation hospitalization. At the same assessment points, they were also scored on the FIM (primary outcome measure) and were administered the NIH Toolbox (Secondary Outcome Measure). Androgel Placebo: 2.5 gram stickpacks with starting dose of 5g increasing to max of 10g.	Men with TBI and normal T were followed for assessments only. They participated in blood assays at baseline and every other week for up to 12 weeks during inpatient rehabilitation hospitalization. At the same assessment points, they were also scored on the FIM (primary outcome measure) and were administered the NIH Toolbox (Secondary Outcome Measure).
Measure Participants	11	6	18
Baseline	34	16	21
Six Week	52	31	36

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intervention - Treatment, Intervention Placebo
	Comments	To investigate a difference in change in outcome over time between treatment and control, a trend analysis was used in place of a profile analysis, where both control and treatment arms are described more parsimoniously i.e. by a slope (change in outcome over time) (Fitzmaurice 2011).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.9540
	Comments
	Method	comparison of slopes
	Comments	Slopes by group and slope difference
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.07816
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.3315
	Estimation Comments

Adverse Events

Arm/Group Title	Low T Intervention - Treatment		Low T Intervention - Placebo		Normal T - No Intervention
Arm/Group Description	Men with TBI meeting study criteria with Low Testosterone levels will be randomly assigned to either a treatment or placebo group. They will participate in blood assays at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. They will also be scored on the FIM (primary outcome measure) and the NIH Toolbox (Secondary Outcome Measure). Androgel (Testosterone Gel): 2.5 gram stickpacks administered with starting dosage of 5g increasing to a max of 10g.		Men with TBI meeting study criteria with Low Testosterone levels will be randomly assigned to either a treatment or placebo group. They will participate in blood assays at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. They will also be scored on the FIM (primary outcome measure) and the NIH Toolbox (Secondary Outcome Measure). Androgel Placebo: 2.5 gram stickpacks with starting dose of 5g increasing to max of 10g.		A subset of men with TBI meeting study criteria with Normal Testosterone levels will participate in blood assays at baseline and every other week for 12 weeks during inpatient rehabilitation hospitalization. They will also be scored on the FIM (primary outcome measure) and the NIH Toolbox (Secondary Outcome Measure).
All Cause Mortality
	Low T Intervention - Treatment		Low T Intervention - Placebo		Normal T - No Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Low T Intervention - Treatment		Low T Intervention - Placebo		Normal T - No Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/10 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Low T Intervention - Treatment		Low T Intervention - Placebo		Normal T - No Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)		3/10 (30%)		0/24 (0%)
Endocrine disorders
greater than 100 ng/dl total testosterone change from screen to baseline	1/13 (7.7%)	1	2/10 (20%)	2	0/24 (0%)	0
Hepatobiliary disorders
Elevated ALT	1/13 (7.7%)	1	0/10 (0%)	0	0/24 (0%)	0
Renal and urinary disorders
Elevated PSA	0/13 (0%)	0	1/10 (10%)	1	0/24 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.