Sildenafil for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

The goal of this Phase II study is to generate pilot data that will allow for the design of
a clinical trial of sildenafil (Viagra®) to treat patients with traumatic vascular injury in
the chronic state after traumatic brain injury (TBI). Injury to small and medium-sized blood
cerebral blood vessels is a well-recognized consequence of traumatic brain injury (TBI).
Non-invasive imaging with positron emission tomography (PET) and single photon emission
computerized tomography (SPECT) have long demonstrated deficits in cerebral blood flow in
TBI, including in symptomatic patients years after mild TBI (mTBI). Recently, magnetic
resonance imaging (MRI) methods have been developed which allow reliable and non-invasive
measurement of cerebrovascular reactivity (CVR) to vasodilatory stimuli such as hypercapnia
in humans. These techniques have never been applied to symptomatic patients in the chronic
stage after mTBI. These methods are particularly promising due to the recent discovery that
phosphodiesterase-5 (PDE5) inhibitors improve cerebral blood flow, induce angiogenesis and
neurogenesis, and improve functional recovery in animals after experimental stroke and
cryoinjury. This pilot study will use novel MRI methods (Blood Oxygen Level Dependent (BOLD)
response to hypercapnia) to noninvasively measure cerebrovascular reactivity in the chronic
stage after TBI, and the first to use sildenafil in patients with chronic TBI.

The study has one primary objective and 10 secondary objectives:

Primary objective:

1. Single dose treatment with sildenafil (50 mg orally) is effective in increasing the
global BOLD response to hypercapnia in symptomatic patients in the chronic stage after
TBI.

Secondary objective (Safety and Tolerability):

2. Sildenafil therapy (25 mg orally twice daily) is well tolerated in symptomatic patients
in the chronic stage after TBI, with few adverse effects and treatment discontinuations
in less than 10% of patients.

Tertiary (Exploratory) objectives:

3. Single dose treatment with sildenafil (50 mg orally) is effective in increasing the
regional BOLD response to hypercapnia in symptomatic patients in the chronic stage
after TBI.

4. Patients with persistent symptoms in the chronic stage after TBI have deficits in
cerebrovascular reactivity compared to uninjured healthy controls.

5. Patients with persistent symptoms in the chronic stage after TBI have deficits in
cerebrovascular reactivity compared to asymptomatic patients after TBI.

6. Patients with persistent symptoms in the chronic stage after TBI have reduced numbers
of circulating EPCs compared to uninjured healthy controls.

7. Patients with persistent symptoms in the chronic stage after TBI have reduced numbers
of circulating EPCs compared to asymptomatic patients after TBI.

8. The effect on cerebrovascular reactivity of single dose treatment with sildenafil
persists after 8 weeks of chronic therapy (25 mg orally, twice daily).

9. Treatment with sildenafil for 8 weeks (25 mg orally twice daily) increases the number
of circulating endothelial progenitor cells (EPCs) in symptomatic chronic TBI patients.

10. Treatment with sildenafil for 8 weeks (25 mg orally twice daily) reduces the prevalence
of post-concussive symptoms, compared to placebo treatment.

11. Treatment with sildenafil for 8 weeks (25 mg orally twice daily) improves performance
in neuropsychometric tests, compared to placebo treatment.

Inclusion Criteria:

Inclusion Criteria applied to all participants

In order to be included in this study, all participants must meet the following minimum
criteria:

1. Age 18 - 55 years, inclusive

2. Ability to undergo MRI scanning.

3. Ability to read, write, and speak English.

4. Stable doses of concomitant medications for at least 2 weeks prior to enrollment.

5. Likelihood of completing 18 weeks of study procedures. Likelihood of ability to
complete the study procedures means that the person has 1) a low probability of being
deployed during the 18-week period 2) verbalizes intent to complete the study.

Inclusion Criteria for Group 1 (symptomatic TBI)

In order to be included in the symptomatic TBI Group, study participants must meet the
following criteria:

1. A history of having sustained a TBI > 6 months and < 10 years prior to enrollment.
Evidence will be any one of the following 3 criteria:

1. GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record)

2. Post-traumatic amnesia > 24 hours

3. TBI-related abnormality on neuroimaging (either CT or MRI). (Some missing
information about the initial injury (i.e. documentation of initial GCS) is not
necessarily exclusionary if the bulk of the available history is indicative that
the patient suffered a TBI and meets the inclusion criteria)

2. Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for
Post-Concussional Disorder, including:

1. Evidence from neuropsychological testing of difficulty in attention or memory.
(refers to neuropsychological testing done as a part of the patient's hospital
or rehabilitation care not as a part of screening for this study)

2. Three or more of the following symptoms, which started shortly after the trauma
and persist for at least three months:

i) Fatigability ii) Disordered sleep iii) Headache iv) Vertigo or dizziness v)
Irritability or aggression vi) Anxiety, depression, or affective instability vii)
Changes in personality (e.g. social or sexual inappropriateness) viii) Apathy or lack
of spontaneity c) Symptoms in criteria (a) and (b) must have their onset after
trauma, or there was a significant worsening of pre-existing symptoms after trauma.

d) Disturbance from these symptoms causes significant impairment of social or
occupational functioning and represents a significant decline from previous level of
functioning.

Inclusion Criteria Group 2—Healthy controls In order to be included in this study,
participants must meet the inclusion criteria for all participants listed in 4.2.

3.2.3 Inclusion Criteria Group 3—Recovered TBI

1. History of having sustained a TBI > 6 months and < 10 years prior to enrollment. This
evidence will be any one of the following:

a) GCS 3 - 12 (GCS obtained in Emergency Room after injury and noted in medical record) b)
Post-traumatic amnesia > 24 hours c) TBI-related abnormality on neuroimaging (either CT or
MRI) 2. Does not meet criteria for persistent post-concussive symptoms, according to the
DSM-IV Research Criteria for Post-concussional Disorder defined by the following:

1. No evidence from neuropsychological testing of difficulty in attention or memory.

2. No more than 1 of the following symptoms, which started shortly after the trauma and
persists for at least three months:

i) Fatigability ii) Disordered sleep iii) Headache iv) Vertigo or dizziness v)
Irritability or aggression vi) Anxiety, depression, or affective instability vii) Changes
in personality (e.g. social or sexual inappropriateness) viii) Apathy or lack of
spontaneity c) No impairment of social or occupational functioning or a significant
decline from previous level of functioning.

Exclusion Criteria:

Exclusion Criteria for all Groups:

1. Contraindication to sildenafil which includes the following:

1. Current use of organic nitrate vasodilators

2. use of ritonavir (HIV-protease inhibitor)

3. Current use of erythromycin, ketoconazole, or itraconazole

4. Current use of cimetidine

5. Alpha-blockers such as doxazosin (Cardura), tamsulosin (Flomax), and terazosin
(Hytrin) prazosin (Minipres). These medications are usually used for the
treatment of enlarged prostate.

6. Current resting hypotension (BP < 90/50 mm Hg)

7. Current severe renal insufficiency (Creatinine Clearance < 30 mL/min)

8. Current hepatic cirrhosis

9. Current cardiac failure or coronary artery disease causing unstable angina

10. Retinitis pigmentosa

11. Known hypersensitivity or allergy to sildenafil or any component of the tablet

2. Evidence of penetrating injury

3. Daily therapy with a PDE5 inhibitor within the past 2 months

4. History or evidence of pre-existing neurological or psychiatric disorder not related
to TBI, such as:

1. Multiple sclerosis, pre- or co-existing

2. Stroke (other than stroke at the time of TBI)

3. Pre-existing developmental disorder

4. Pre-existing epilepsy

5. Pre-existing major depressive disorder

6. Pre-existing schizophrenia

5. Women who are pregnant or breast-feeding.

Exclusion for Healthy Control Group Any evidence or history of a TBI or concussion is
exclusionary for the Control Group.