Impact of GHRH on Sleep Promotion and Endocrine Regulation in Service Members Who Sustained a Traumatic Brain Injury and Have Current Insomnia

Objective: Traumatic brain injury (TBI) is the hallmark injury of deployment in Iraq and
Afghanistan. Up to one-third of service members who sustain a TBI are diagnosed with a sleep
disorder; insomnia being one of the most common. Currently, over half of TBI-associated
insomnia cases remain untreated due to poor efficacy of available pharmacologic agents.
Neuroendocrine dysfunction is an important mechanism linking TBI and disordered sleep, thus
pharmacological agents that address this dysfunction may be effective in treating
TBI-related insomnia. The neuroendocrine system is essential for regulating sleep and
circadian function. Decreased neuroendocrine function, including the hypothalamus and the
somatotrophic cells of the anterior pituitary, which regulate growth hormone secretion,
likely contributes to insomnia. This assertion is supported by previous studies that
demonstrated the sleep-promoting effects of growth hormone releasing hormone (GHRH)
administration in healthy controls, the elderly, and participants with depression.
Therefore, we propose that administration of GHRH will address the underlying mechanisms of
insomnia in service members and veterans who sustained a TBI, and provide a pharmacological
agent more robust than currently available treatments.

Study population: This study will recruit 50 active duty service members and veterans with a
documented TBI to participate in one of two study groups. The insomnia group (n=25) will
include participants that have a current clinical diagnosis of insomnia without obstructive
sleep apnea. The no-insomnia group (n=25) will include participants with no current clinical
diagnosis of insomnia or obstructive sleep apnea. Withdrawals/dropouts will be replaced to
obtain 20 participants per group who complete the study.

Design: A double-blind, randomized, crossover design will be used to examine the impact of
tesamorelin (GHRH (1-44) analog) or placebo on total non-rapid eye movement (NREM) time
evaluated during two polysomnography visits, scheduled 1-3 weeks apart. Serial blood draws
will be obtained during the polysomnography to examine endocrine function and neuropeptide
release.

Outcome measures: The primary outcome is change in NREM time following tesamorelin
administration compared to placebo. The secondary outcomes are (1) within and between group
differences in plasma concentration levels of neuroendocrine proteins following tesamorelin
administration compared to placebo and (2) within and between group differences in urinary
concentration levels of growth hormone following tesamorelin administration compared to
placebo.

- INCLUSION CRITERIA:

Both groups may be eligible for this research study if they:

1. Are between 18 and 45 years of age (on Visit 1)

2. Are active duty service members or veterans who were active duty within the past 10
years (on Visit 1)

3. Are able to provide medical records documenting a TBI, which occurred within the past
6 months to 10 years (on Visit 1)

4. Are able to provide their own consent

5. Are able to understand the study, as shown by scoring a 6 out of 6 on a consent quiz

6. (For women only) agree not to breastfeed from the time of enrollment in the study
until 1 month after the last exposure to tesamorelin

7. (For women of childbearing potential only) have a negative urine pregnancy test and
agree to use two effective methods of contraception from the time of enrollment in
the study until 1 month after the last exposure to tesamorelin

The insomnia group may be eligible for this research study if they:

1. Have a current clinical diagnosis of insomnia determined by polysomnography

2. Have a PSQI score greater than 10

The no-insomnia group may be eligible for this research study if they:

1. Have no current clinical diagnosis of insomnia determined by self-report

2. Have a PSQI score less than or equal to 5

EXCLUSION CRITERIA:

Both groups may not be eligible for this research study if they:

1. Have obstructive sleep apnea determined by polysomnography (insomnia group) or
selfreport (no-insomnia group)

2. Have a known hypersensitivity to tesamorelin and/or mannitol

3. Have taken any of the following medications within the past 30 days: benzodiazepines
(e.g., Valium, Ativan, etc.); benzodiazepine receptor agonists (e.g., Ambien,
Lunesta, etc.); opiates (e.g., Codeine, Percocet, etc.); or sedatives (e.g., Amytal,
Numbutal, etc.)

4. Cannot abstain from using stimulants such as amphetamines (e.g., Adderall, Ritalin,
etc.); caffeine (e.g., coffee, cola, etc.); ephedrine (e.g., diet pills, energy
drinks, etc.); and eugeroics (e.g., Modafinil, Provigil, etc.) from at least 9:00 AM
on Visits 2 and 3

5. Are under treatment for a major injury (e.g., amputation, burns, eye injury, skeletal
injury, severe infection, etc.)

6. Have a major medical illness (e.g., active malignancy, cardiovascular disease,
diabetes mellitus, HIV, etc.)

7. Are at risk for self-harm determined by a licensed independent practitioner

8. Have indications of recreational substance use determined by a urine drug test

9. Have an abnormal lab value that may indicate major medical illness, which was not
cleared by a licensed independent practitioner

10. Have an abnormal lab value that may indicate endocrine dysfunction, which was not
cleared by a licensed independent practitioner

11. Have adrenal insufficiency determined by the ACTH stimulation test

12. Have a current bipolar disorder determined by the SCID-IV-TR

13. Have a current psychotic disorder determined by the SCID-IV-TR

14. Have current alcohol dependence determined by the SCID-IV-TR

15. Have current drug dependence determined by the SCID-IV-TR