Sildenafil for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.
Condition: Traumatic Brain Injury; Post-concussive Syndrome
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Post-Concussion Syndrome; Wounds and Injuries
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine whether sildenafil (Viagra®) is effective in
      improving cerebral blood flow and cerebrovascular reactivity inpatients who have persistent
      symptoms at least 6 months after a traumatic brain injury (TBI).
    

Detailed description: 
      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.
    

Intervention name(s): Sildenafil
Intervention type(s): Drug
Other intervention name(s): Viagra
Intervention MeSH terms: Sildenafil Citrate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Magnetic resonance imaging; Blood oxygen level dependent signal; Hypercapnia; Endothelial progenitor cells