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

Spinal Cord Injuries Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03602014
• Other study ID #: WEC-17-042
• Status: Completed
• Phase: Phase 4
• Start date: June 1, 2018
• Est. completion date: December 31, 2021

Study information

• Verified date: June 2023
• Source: James J. Peters Veterans Affairs Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: December 31, 2021
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 89 Years

Eligibility

Inclusion Criteria:

Study 1:

1. Male or Female, age 18 to 89 with traumatic SCI.

2. 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

3. 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.

4. Primary Language is English.

5. Able to provide informed consent

Study 2:

6. Male or Female, age 18 to 89 with traumatic SCI.

7. 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

8. 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.

9. Primary Language is English.

10. Able to provide informed consent

11. 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

Related Conditions & MeSH terms

• Hypotension
• Hypotension, Orthostatic
• Spinal Cord Injuries
• Wounds and Injuries

Intervention

Drug:
• Northera
Study 1 is a dose optimization, open-label trial of Northera from a dose range of 200mg up to 800mg.

Other:
• Placebo
Study 2 is blinded placebo controlled trial using the individualized optimal dose of droxidopa determined by study 1.

Locations

Country	Name	City	State
United States	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

Sponsors (2)

Lead Sponsor	Collaborator
James J. Peters Veterans Affairs Medical Center	New York State Department of Health

Country where clinical trial is conducted

United States, 

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* Note: There are 119 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of subjects with normotensive systolic blood pressure	To determine the proportion (%) of hypotensive participants with SCI who have a normotensive systolic blood pressure (males=111-139 mmHg; females=101-139 mmHg) following administration of droxidopa.	60 to 120 minutes following administration of droxidopa
Secondary	Supine systolic blood pressure	To measure supine systolic blood pressure following administration of droxidopa compared to placebo in hypotensive participants with SCI	within 60 minutes of administration of droxidopa or placebo
Secondary	Orthostatic systolic Blood Pressure	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.	60-90 minutes following administration of droxidopa or placebo
Secondary	Change in cerebral blood flow	To document change (from supine to 70 degrees head-up tilt) in cerebral blood flow velocity in the middle cerebral artery following administration of droxidopa compared to placebo in hypotensive participants with SCI.	60-90 minutes following administration of droxidopa or placebo