Testosterone Replacement in Hypogonadal Men Following Traumatic Brain Injury: Results From a Double-Blind, Placebo Controlled Pilot Study.

David L Ripley MD MS1,2 , Maggie Wierman MD3,4, Don Gerber PsyD5, Chris Pretz PhD4,5, Micol Rothman MD4, Alan Weintraub MD5, Robert Kowalski MD5

1. Rehabilitation Institute of Chicago

2. Northwestern University Feinberg School of Medicine

3. Denver Veterans Administration Medical Center

4. University of Colorado School of Medicine

5. Craig Hospital

SUPPORT

Funding for study provided by the Colorado Traumatic Brain Injury Trust Fund

DISCLOSURES

Drug and matching placebo for the study were provided by AbbVie Pharmaceuticals.

None of the authors have any financial conflicts to disclose

BACKGROUND

5.6 Million with TBI in the US TBI Results in significant morbidity Neuroendocrine dysfunction is prevalent in this

population, may affect outcomes and functional performance

IMPACT OF NEUROENDOCRINE DYSFUNCTION

Neuroendocrine Dysfunction

TRAUMATIC BRAIN INJURY

Suppression of HPG Axis

Activation of HPA Axis

NeurocognitiveImpairment

FunctionalImpairment

POTENTIAL IMPACT OF TESTOSTERONE DEFICIENCY

Testosterone deficiency associated with impaired strength

Testosterone deficiency potentially associated with impaired cognition• attention• memory and learning • executive function• language and communication• visual-spatial skills• processing speed

Testosterone may be related to neurological recovery

IMPACT OF T DEFICIENCY ON FUNCTION IN REHAB

Hypogonadism is present in 33% of TBI inpatient rehab patients.

Hypogonadism has been shown to be correlated with lower functional status in rehab

Total FIM

0

20

40

60

80

100

120

Admission* Discharge Change

Low Total T (<250 ng/dL)

High Total T( >250 ng/dL)

Carlson NE, Brenner LA, Wierman ME, Harrison-Felix C, Morey C, Gallagher S, Ripley D. Brain Inj. 2009 Apr;23(4):336-44.

OBJECTIVE

To determine the safety, feasibility, and efficacy of testosterone replacement therapy in men with hypogonadism following traumatic brain injury.

9/2/112 A Neural Interface for Artificial Limbs: Targeted Muscle Reinnervation

All male patients

Low T

Normal T

RandomizationT replacement

No T replacement

Inpatient

Eval

Eval

Eval

Q 2 wks

Q 2 wks

Q 2 wks

Eval

Eval

Eval

Final outcome

Final outcome

Final outcome

Outpatient

Study Design

INTERVENTION

Testosterone gel 1% (AbbVie Pharmaceuticals) or placebo in identical gel packs

Application by nursing staff at 0800 daily Serum T levels are monitored by study endocrinologist

who has no contact with patients to make sure that levels reach therapeutic levels

ASSESSMENTS AND OUTCOME MEASURES

FUNCTIONAL

Functional Independence Measure – FIM Modified FIM

• Eliminated items not expected to be affected by testosterone

• Utilized in Preliminary study

ASSESSMENTS AND OUTCOME MEASURES

NEUROLOGICAL• The NIH toolbox is a measure designed to be a

comprehensive measure of neurological function that is useful for longitudinal assessment of neurological outcomes.

• It measures four domains of neurological function; Motor Function, Sensory Function, Cognitive Function, and Emotional Function

Outcome Measures – Adverse Reactions

Adverse Reactions Checklist Restless, Agitated, or Aggressive Behavior Records

ENROLLMENT - CONSORT DIAGRAM

BASELINE CHARACTERISTICS

RESULTS OF RANDOMIZATION

RESULTS OF TESTOSTERONE REPLACEMENT

baseline week 0 week 2 week 4 week 60

50

100

150

200

250

300

350

400

450

Low T Placebo

Low T Treatment

Normal T

ADVERSE EVENTS

RESTLESS AGITATED OR AGGRESSIVE BEHAVIOR

FIM CHANGE BY GROUP

week 0 week 2 week 4 week 60

10

20

30

40

50

60

Low T Placebo

Low T Treatment

Normal T

Analytic Approach

As a consequence of not being able to capture the sample size projected by the original power analysis, the design of the study was altered so that a similar, but more powerful approach was adopted.

Specifically, 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 an intercept (baseline status) and slope (change in outcome over time) (Fitzmaurice 2011).

Additional advantages of profile analysis include the ability to handle staggered time points and missing data.

In the original study design it was indented that information regarding outcome be captured every other week for 12 weeks, but, due to drop out, sufficient longitudinal data was only captured through week 6. As a result, the focus of the analysis revolves around the six week time frame, though, because of the ability of the analytic approach to handle missing data, a twelve week “sensitivity” analysis was also performed (Molenberghs and Kenward 2007).

To account for potential heteroscedasticity and the association between repeated measures collected in a temporal setting, various variance-covariance matrices were investigated, where, the structure that fits the data best was determined by comparison of the Akaike information criterion.

Additionally, a full battery of model diagnostics was performed.Fitzmaurice G., Laird N., Ware J. (2011) Applied Longitudinal Analysis, Second Edition. John Wiley & Sons, Inc., Hoboken NJMolenberghs, G. and Kenward, M. (2007) Missing Data in Clinical Studies. John Wiley & Sons, Ltd., West Sussex P019 8SQ, England

Study Results

Even with a more robust evaluation method, the study remained underpowered with the drug arm consisting of 13 participants and the placebo arm containing 10.

Even though this study is not powered to detect a less pronounced change, if testosterone exerts an appreciable influence on recovery as measured by the modified FIMTM, this analysis should detect such an influence.

Examination of the data suggested a linear function defined by an intercept and slope appropriately fit the data for each arm.

Data did not appear to exhibit a ceiling (or floor) effect, where, at baseline, ample room for change exists as suggested by each group intercept.

Several candidate variance-covariance matrices were used to compensate for the temporal nature of the data, where, for the analysis based on the six week timeframe an unstructured matrix was most suitable, and, for the analysis based on the 12 week data, an ante-dependence configuration fit the data best.

STUDY RESULTS

The crux of providing evidence of drug efficacy lies in comparing the slopes between the drug and placebo arms while making sure intercepts for each group are statistically equivalent as this establishes successful randomization. Specifically, if the slope related to the drug group indicates a significant increase in the rate of change as comparted to that of the placebo group, this provides evidence of treatment effect. Likewise, if there are no group differences between the intercepts and slopes, this is an indication both arms follow the same path over time implying treatment is not effective.

Although the focus of our analysis was on the 6 week timeframe, the 12 week timeframe was examined in the spirit of a sensitivity analysis i.e. to examine the degree to which results are (or are not) consistent.

RESULTS

Information given in Table 1 provides evidence that randomization was successful as there is no difference between the intercepts for either the 6 or 12 week data. However, Table 1 also indicates that treatment was not effective as the slopes for the treatment and placebo arms for do not differ significantly regardless of timeframe. Additionally, the estimates in Table 2 suggest that, although participants improve over time, they do so consistently and independent of group assignment. Thus, the overall conclusion is that participants do improve over time, but, testosterone treatment does not significantly increase the rate of improvement when compared to placebo

FIM CHANGE

GRIP STRENGTH AND TESTOSTERONE

CORRELATIONS WITH TOTAL TESTOSTERONE

CORRELATIONS OF GRIP SCORE WITH TESTOSTERONE

Summary

498 patients were screened of which 61 were enrolled and followed per protocol. 38% had low T levels (< 260ng/dl) at screening and were randomized into placebo (n=10) or physiologic T gel therapy (n=13). No significant differences were found among the two low T and normal groups in the rate of improvement on the FIM over six weeks (intercepts t = -0.31, p=0.7593, slopes t= 0.61, p = 0.5472). The low T treatment group demonstrated greater absolute FIM improvement than placebo or normal T groups (Normal T = 17.5, Placebo = 19.5, Treatment = 30). A similar pattern was found for grip strength. There was no difference in adverse events per patient between groups. Percentage of time with agitated and aggressive behaviors was highest in the Placebo group.

Conclusions

Although there was no difference in recovery rate, the Treatment group had greater functional improvement than the Placebo and the Normal T groups.

Testosterone-supplemented patients had less frequent agitated and aggressive behavior than the Placebo group.

Testosterone replacement to low normal levels was safe and well tolerated.

Recruitment for this study was extremely difficult Small sample size limited the study’s power.

ACKNOWLEDGEMENTS

Colorado TBI Trust Fund Research Team

Maggie Wierman, MD, Co Principal Investigator Don Gerber, PsyD, Study Director, Co-Investigator Chris Pretz, PhD, Study Statistician Micol Rothman, MD, Co Investigator Alan Weintraub MD, Co Investigator Melissa Sendroy Terrell, MA, Study Coordinator Jody Newman, MS CCC-SLP, Study Coordinator Robert Kowalski, MD, Co Investigator Dominick Zaccardi, Study Phlebotomist Tammie Nakamura, MS, Research Assistant Staff at Craig Hospital

University of Colorado CTRC Core Laboratory AbbVie Pharmaceuticals Gale Whiteneck, PhD, Cindy Harrison-Felix, PhD