Evaluation of the Efficacy of Sodium Oxybate (Xyrem®) in Treatment of Post-traumatic Narcolepsy and Post-traumatic Hypersomnia

Post-traumatic narcolepsy and post-traumatic hypersomnia are under-recognized clinical
conditions in post-TBI patients.

Considering the high prevalence of hypersomnia, treatment difficulty, and sparse clinical
studies for treatment of sleep problems in TBI patients, additional clinical trials need to
be performed to provide more therapeutic options for patients and physicians. Sodium oxybate
(Xyrem®) could be potentially one such option given its high efficacy in idiopathic
narcolepsy patients.

From the results of animal research, as well as from cerebrospinal fluid (CSF) and autopsy
findings from TBI patients, hypothalamic injury and hypocretin pathology seem to play a role
in the pathogenesis of post-traumatic narcolepsy and hypersomnia. Despite lack of clear
understanding of the exact mechanism of action of sodium oxybate in patients with idiopathic
narcolepsy, the shared pathophysiology of the hypocretin system in post-traumatic hypersomnia
and narcolepsy would suggest the possible efficacy of sodium oxybate (Xyrem®) on excessive
daytime sleepiness (EDS) and prolonged sleep in patients with TBI.

In this Pilot Clinical Trial, we will test whether sodium oxybate (Xyrem®, approved for the
treatment of improve wakefulness in adult patients with excessive sleepiness associated with
narcolepsy) is effective in improving the sleep-wake symptoms, global functioning and quality
of life of post-TBI patients with hypersomnia and narcolepsy.

Inclusion Criteria:

- History of first-ever primary TBI 12 or more months ago;

- Mild to severe TBI (GCS 3-15);

- Either a) or b):

1. Presence of subjective daytime sleepiness (ESS ≥ 10) lasting 3 months or more,
and not present prior to the TBI;

2. Long sleep duration (mean TST ≥ 9hours/24hrs or increased sleep need of at least
1-2 h per 24 h compared to pre-TBI), documented by actigraphy, lasting 3 months
or more;

- Objectively demonstrated EDS (MSLT mean of 5 naps: SL ≤ 8min);

- Age: 18 - 64;

- Ability to read and understand consent form, complete questionnaires and daily sleep
diary, and provide informed consent. The Folstein MMSE will be used to assess
cognitive function.

Exclusion Criteria:

- Current neurologic deficit (weakness, dysarthria or dysphagia, aphasia or dysphasia);
Participants with a score of <27 on Folstein MMSE will be excluded.

- History of neurologic or psychiatric disease prior to TBI;

- Epilepsy or history of seizure (whether related or unrelated to TBI);

- Body mass index (BMI) ≥ 32;

- Sleep apnea (Apnea Hypopnea Index, AHI > 15/h); -Chronic sleep restriction (≥ 2hour
sleep extension on weekends from self- report, diary, or at least 14 days of
actigraphy);

- Sleep-wake disturbance other than long sleep duration or sleepiness (DSPD, ASPD,
Shift-work Sleep Disorder);

- Diagnosis of narcolepsy or other sleep disorder prior to TBI;

- Unwillingness to follow physician instructions relating to the concomitant use of
alcohol and sodium oxybate during the study;

- History of or current substance abuse;

- Current regular CNS-affecting medication use;

- History of depression, suicidal thoughts, and/or post-traumatic stress disorder
(PTSD);

- Current depression assessed by a structured clinical interview and Beck Depression
Inventory (BDI);

- Abnormal liver function (LFT more than twice the upper limit of normal or serum
bilirubin more than 1.5 times the upper limit of normal);

- Hypertension, heart failure, history of myocardial infarction, or abnormal EKG
demonstrating clinically significant arrhythmia;

- Kidney disease (Serum creatinine >2.0mg/dl);

- Lung disease (COPD, ILD, asthma);

- On a low salt diet for medical reasons;

- An occupation that requires variable shift work or routine night shifts (work hours
between 11pm and 6am);

- Pregnant, intention to become pregnant;

- Breast-feeding or plans to breastfeed;

- Succinic semialdehyde dehydrogenase deficiency.