Dose Response to the Norepinephrine Precursor Droxidopa in Hypotensive Individuals With Spinal Cord Injury

Phase 4

Completed

Conditions: Hypotension
Spinal Cord Injuries
Hypotension, Orthostatic

Interventions: Drug: Northera
Other: Placebo

Registration Number: NCT03602014

Lead Sponsor: James J. Peters Veterans Affairs Medical Center

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Study 1:

Male or Female, age 18 to 89 with traumatic SCI.
SCI Subjects (n=40):
1. Any level of injury;
2. Any American Spinal Injury Association Impairment Scale (AIS) grade of SCI;
3. Non-ventilator dependent
4. Primarily wheelchair dependent for mobility;
5. Duration of injury < 1 year
Low Blood Pressure:
1. Systolic BP less than 110 mmHg and/or diastolic BP less than 70 mmHg for males.
2. Systolic BP less than 100 mmHg and/or diastolic BP less than 70 mmHg for females.
Primary Language is English.
Able to provide informed consent

Study 2:
Male or Female, age 18 to 89 with traumatic SCI.
SCI Subjects (n=40):
1. Any level of injury;
2. Any AIS grade of SCI;
3. Non-ventilator dependent
4. Primarily wheelchair dependent for mobility
5. Duration of injury < 1 year
Low Blood Pressure:
1. Systolic BP less than 110 mmHg and/or diastolic BP less than 70 mmHg for males.
2. Systolic BP less than 100 mmHg and/or diastolic BP less than 70 mmHg for females.
Primary Language is English.
Able to provide informed consent
Showed a normotensive blood pressure in response to Droxidopa during study 1.

Exclusion Criteria

Current illness or infection
Individuals with frequent or severe autonomic dysreflexia:
1. More than 3 symptomatic events per week
2. BP ≥140/90 mmHg
3. Significant adverse subjective symptoms reporting
Hypertension
Any neurological condition other than SCI (Alzheimer's disease, dementia, stroke, multiple sclerosis, Parkinson's disease, etc.)
History of epilepsy or other seizure disorder
History of traumatic brain injury (TBI)
Liver or kidney disease
Bladder problems including blockage of the urine and/or weak urine stream.
Diagnosis of a psychiatric disorder such as schizophrenia or bipolar disorder
Known artery disease, heart failure, Atrio-ventricular block, and irregular heartbeat
Any allergies to droxidopa, asprin, polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide
Major surgery in the last 30 days
Illicit drug abuse in the past 6 months
Pregnant
Your prescription medications will be reviewed by the study investigators and research staff. If you are currently taking medications to treat any of the following please make the investigators aware:

d. Depression, Schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD) e. Pain (opioids) f. Infection or illness (antibiotics) g. Erectile dysfunction (Viagra, Cialis, etc.) h. Overactive bladder i. High or low blood pressure j. Migraine headaches k. Malaria l. asthma

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Study 2: Blinded Placebo & Northera	Placebo	Participants will then be administered either oral optimal dose of Northera (Droxidopa) or matching placebo in a double-blinded manner and will remain in the supine position for 60 minutes. Subjects will remain in their wheelchair for instrumentation, which will include: 1) ECG, 2) brachial BP, 3) finger arteriolar BP and 4) Cerebral Blood Flow velocity (CBFv).
Study 1: Dose Optimization of Northera	Northera	Subjects will be administered oral droxidopa in a dose escalation, open-label manner beginning with 200 mg. The dose will be adjusted upwards by 100 mg on subsequent visits until average Systolic Blood Pressure (SBP) recorded 60-120 minutes after dose administration is 111-139 mmHg in males and 101-139 mmHg in females, sustained elevation (≥ 30 consecutive minutes) in seated SBP ≥ 140/100 mmHg, maximum dose of 800 mg is reached without adequate SBP response. Subjects will visit the testing laboratory on as few as 1 (200 mg) and as many as 7 (800 mg) days. Seated cardiovascular assessments will be monitored and recorded at 15-minute intervals for 4-hours, and the side effects questionnaire will be administered hourly during the 4-hour study. Each study visit will take about 5 hours.
Study 2: Blinded Placebo & Northera	Northera	Participants will then be administered either oral optimal dose of Northera (Droxidopa) or matching placebo in a double-blinded manner and will remain in the supine position for 60 minutes. Subjects will remain in their wheelchair for instrumentation, which will include: 1) ECG, 2) brachial BP, 3) finger arteriolar BP and 4) Cerebral Blood Flow velocity (CBFv).

Primary Outcome Measures

Name	Time	Method
Proportion of Systolic BP Within a Normotensive Range	up to 240 minutes following administration of droxidopa	To determine the proportion (%) of normotensive systolic blood pressure for males=(110-120 mmHg); and females=(101-120 mmHg) following administration of droxidopa.

Secondary Outcome Measures

Name	Time	Method
Supine Systolic Blood Pressure	within 60 minutes of administration of droxidopa or placebo	To measure supine systolic blood pressure following administration of droxidopa compared to placebo in hypotensive participants with SCI
Orthostatic Systolic Blood Pressure	60-90 minutes following administration of droxidopa or placebo	To document systolic blood pressure responses to head-up tilt to 70 degrees following administration of droxidopa compared to placebo in hypotensive participants with SCI.
Orthostatic Cerebral Blood Flow	60-90 minutes following administration of droxidopa or placebo	To compare cerebral blood flow velocity in the middle cerebral artery following administration of placebo compared to administration of Northera (Droxidopa)

Trial Locations

Locations (2): James J. Peters Veteran's Affair Medical Center
🇺🇸
Bronx, New York, United States
The Icahn School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States