Dose Response to the Norepinephrine Precursor Droxidopa in Hypotensive Individuals With Spinal Cord Injury
Condition: Hypotension, Orthostatic; Hypotension; Spinal Cord Injuries
MeSH terms: Spinal Cord Injuries; Hypotension, Orthostatic; Hypotension; Wounds and Injuries
Study type: Interventional
Phase: Phase 4

Summary: 
      The goal of this study is to determine the efficacy of the drug Droxidopa (Northera) in
      increasing blood pressure in subject with hypotension, low blood pressure, which is
      classified as blood pressure less than 110/70 in males and 100/70 in females. The first aim
      is to determine the proportion of subject with Spinal Cord Injury (SCI) who have a
      normotensive response to Droxidopa. The second is to determine the proportion of subject with
      SCI who express a hypertensive response to Droxidopa. A Normal blood pressure ranges from
      111-139 in males and 101-139 in females and a hypertensive blood pressure is anything higher
      than 140 in males and females.

      The study would take place in James J. Peters VA Medical Center (JJPVAMC) and The Icahn
      School of Medicine at Mount Sinai (ISMMS) in Manhattan, New York.
    

Detailed description: 
      Interruption of sympathetic cardiovascular autonomic regulation following spinal cord injury
      (SCI) is associated with significantly reduced plasma norepinephrine (NE) levels, hypotension
      and orthostatic hypotension (OH), particularly in individuals with high cord lesions.
      Although the incidence of hypotension is reported to be as high as 70% in persons with
      cervical lesions (i.e., tetraplegia), the vast majority of these individuals remains
      asymptomatic and, therefore, does not raise clinical concern, or prompt intervention. While
      it is appreciated that clinicians are faced with substantial challenges in managing blood
      pressure (BP) in persons with SCI, contrary to the prevailing belief, asymptomatic
      hypotension and OH are not benign conditions. Reports suggest that asymptomatic hypotensive
      individuals with SCI may have subclinical cognitive dysfunction affecting memory and
      attention processing and increased incidence of fatigue and depression compared to
      normotensive individuals with SCI. It must be appreciated that to date, there are no FDA
      approved pharmaceutical options proven to be safe and effective for treatment of hypotension
      and OH in the SCI population. Until 2014, midodrine hydrochloride was the only agent with FDA
      approval for treatment of symptomatic neurogenic OH (NOH). Midodrine, an alpha-agonist, is
      the most commonly prescribed agent used to treat symptomatic hypotension in the SCI
      population despite a lack of convincing evidence of safety or efficacy. In 2014 droxidopa
      (L-threo-3,4-dihydroxyphenylserine - NORTHERA; Chelsea Therapeutics, Charlotte, NC) was
      approved by the FDA for treatment of symptomatic NOH based on data collected in conditions of
      autonomic dysfunction. Droxidopa is a NE precursor that is stored in neuronal and
      non-neuronal tissue and has been shown to increase standing BP and reduce symptoms of
      orthostatic intolerance in individuals with symptomatic NOH. We recently reported preliminary
      evidence of a mean increase in seated BP in individuals with SCI following oral
      administration of 400 mg of droxidopa; however, this dose was effective in only 5 of the 10
      subjects tested and the BP effect waned over a 4-hour observation. Because of its unique
      pharmacokinetic profile, droxidopa is a highly promising agent to treat hypotension in
      persons with SCI. As such; there exists a pressing imperative to determine the clinical value
      and safety of droxidopa in hypotensive individuals with SCI.
    

Intervention name(s): Northera; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.; Study 2 is blinded placebo controlled trial using the individualized optimal dose of droxidopa determined by study 1.
Other intervention name(s): Droxidopa
Intervention MeSH terms: Droxidopa
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Hypotension; Spinal Cord Injury; Droxidopa; Northera; Neurogenic Orthostatic Hypotension