A Dose Titration of Droxidopa in Patients With Spinal Cord Injury
Condition: Spinal Cord Injury; Hypotension
MeSH terms: Spinal Cord Injuries; Hypotension
Study type: Interventional
Phase: Phase 1

Summary: 
      The investigators seek to determine the efficacy, duration of action and safety of escalating
      dose of droxidopa on systemic blood pressure, cerebral blood flow and vasoactive hormones and
      catecholamines during upright seated posture.

      Primary Question:

      1. What is the lowest dose of droxidopa that increases seated SBP to 115±5 mmHg in men and
      105±5 mmHg in women?

        -  When does the defined increase in SBP occur after oral ingestion of droxidopa?

        -  How long does this dose of droxidopa sustain SBP at these levels?

        -  What are the vital signs and the subjective symptomology following droxidopa
           administration?

      Secondary Question:

      1. What is the MFV response to droxidopa administration in hypotensive individuals with SCI?

        -  Does an increase in SBP correspond to an increase in MCA MFV?

      Tertiary Question:

      1. What is the vasoactive hormone and catecholamine response to droxidopa administration in
      hypotensive individuals with SCI?

        -  Does droxidopa administration result in a change in APR, Aldo or NE in hypotensive
           individuals with SCI?
    

Detailed description: 
      Persons with spinal cord injury (SCI), due to partial to complete interruption of sympathetic
      pathways from the brainstem to the cardiovascular system are prone to blood pressure
      dysregulation including hypotension which is worsened during orthostasis. It is well
      established that orthostatic hypotension (OH) hinders the rehabilitation process during the
      acute phase of SCI but also may hamper the resumption of independence and activity in persons
      with chronic SCI. Surprisingly, only a few reports exist on the use and efficacy of an alpha
      receptor agonist (midodrine hydrochloride) to restore blood pressure to more normal levels in
      persons with tetraplegia. Our group has recently reported normalization of supine blood
      pressure with a relatively low dose of the nitric oxide synthase inhibitor (NOSi),
      nitro-L-arginine methyl ester (L-NAME). In addition to an alpha agonist and a NOSi, the use
      of a norepinephrine (NE) precursor, droxidopa, may be safe and efficacious for the treatment
      of orthostatic hypotension in a human model of SCI.

      It has been demonstrated that the blood pressure-raising effect of
      3,4-threo-dihydroxyphenylserine (droxidopa) occurs independently of the central nervous
      system in human models of neurologic OH by conversion to norepinephrine (NE) in neuronal and
      non-neuronal tissue. Oral droxidopa is taken up by the more peripheral sympathetic neurons,
      converted to NE, stored and released appropriately during postural stress. Droxidopa has been
      used for the effective treatment of OH in several human models of neurologically caused
      autonomic disorders, such as familial amyloid polyneuropathy, autoimmune autonomic
      neuropathy, pure autonomic failure, and multiple system atrophy . The effectiveness of
      droxidopa at improving orthostatic blood pressure in persons with SCI has not been studied.
      To date, only a single case on the use of the drug in a person with SCI has been reported and
      the use droxidopa in that case was successful. The purpose of this proposal is to determine
      the dose effectiveness, duration of action and any adverse events following droxidopa
      administration in hypotensive individuals with SCI.

      To determine the efficacy, duration of action and safety of escalating dose of droxidopa on
      systemic blood pressure, cerebral blood flow and vasoactive hormones and catecholamines
      during upright seated posture.

      Primary Question:

      1. What is the lowest dose of droxidopa that increases seated SBP to 115±5 mmHg in men and
      105±5 mmHg in women?

        -  When does the defined increase in SBP occur after oral ingestion of droxidopa?

        -  How long does this dose of droxidopa sustain SBP at these levels?

        -  What are the vital signs and the subjective symptomology following droxidopa
           administration?

      Secondary Question:

      1. What is the MFV response to droxidopa administration in hypotensive individuals with SCI?

        -  Does an increase in SBP correspond to an increase in MCA MFV?

      Tertiary Question:

      1. What is the vasoactive hormone and catecholamine response to droxidopa administration in
      hypotensive individuals with SCI?

        -  Does droxidopa administration result in a change in APR, Aldo or NE in hypotensive
           individuals with SCI?
    

Intervention name(s): Droxidopa
Intervention type(s): Drug
Intervention description(s): Dose titration of placebo, 100mg, 200mg, 400mg of Droxidopa will be given to assess the effects of Droxidopa on blood pressure and cerebral blood flow.
Other intervention name(s): L-DOPs
Intervention MeSH terms: Droxidopa
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment