Northera Improves Postural Tachycardia Syndrome (POTS) and Postural Vasovagal Syncope (VVS)

• ClinicalTrials.gov Identifier: NCT02558972
• Recruitment Status: Recruiting
• First Posted: September 24, 2015
• Last Update Posted: July 16, 2019
• Sponsor: New York Medical College
• Collaborator: Lundbeck LLC
• Information provided by (Responsible Party): Julian Stewart, New York Medical College

Study Description

Brief Summary:

Vasovagal syncope (VVS, simple faint) is the most common cause of transient loss of consciousness and represents the acute episodic form of orthostatic intolerance (OI). Postural tachycardia syndrome (POTS) is the common chronic form of OI. Both are defined by debilitating symptoms and signs while upright relieved by recumbency. Northera should therefore improve both sympathetic splanchnic arterial vasoconstriction and sympathetic splanchnic venoconstriction in POTS and VVS, and may represent an ideal drug to improve the orthostatic response in POTS and VVS.

Condition or disease	Intervention/treatment	Phase
Postural Tachycardia Syndrome (POTS); Vasovagal Syncope (VVS); Fainting	Drug: Northera (Droxidopa); Drug: Placebo	Phase 2

Detailed Description:

Vasovagal syncope (VVS, simple faint) is the most common cause of transient loss of consciousness and represents the acute episodic form of orthostatic intolerance (OI). Postural tachycardia syndrome (POTS) is the common chronic form of OI. Both are defined by debilitating symptoms and signs while upright relieved by recumbency. Pathophysiological mechanisms have remained elusive. Most POTS patients and all VVS patients have normal supine resting hemodynamics but excessively redistribute blood flow and blood volume from the central pool to the splanchnic vasculature because of defective splanchnic arterial vasoconstriction and venoconstriction. While peripheral and splanchnic arterial vasoconstriction depend primarily on post-junctional alpha-1 adrenergic receptors, splanchnic venoconstriction also depends on post-junctional alpha-2 adrenergic receptors. Consequently, selective alpha-1 agonists such as midodrine may not produce sufficient splanchnic venoconstriction to compensate for splanchnic pooling in POTS and VVS. Such alpha adrenergic subtype restrictions do not apply to Northera (droxidopa) because it is a norepinephrine (NE) prodrug and therefore increases the amount of synaptic NE that can then bind to both alpha-2 and alpha-1 receptors. Northera should therefore improve both sympathetic splanchnic arterial vasoconstriction and sympathetic splanchnic venoconstriction in POTS and VVS, and may represent an ideal drug to improve the orthostatic response in POTS and VVS. We will test the hypothesis that Northera, in appropriate dose, improves the splanchnic adrenergic deficits that initiate POTS and postural VVS and in sufficient daily dose improves quality of life in these patients. To accomplish this, the investigator will recruit 10 POTS patients aged 18-30 years, 10 similarly aged patients with 2 or more episodes of VVS in the past year (thus defining recurrent VVS) and 10 age and gender matched healthy volunteer control subjects with the following specific aims:

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Northera Improves Postural Tachycardia Syndrome (POTS) and Postural
• Study Start Date: September 2015
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: December 2019

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Northera-single dose; Study #1 -Does single large dose (600mg) of Northera improve upright hemodynamics and orthostatic intolerance in POTS and VVS	Drug: Northera (Droxidopa); Study #1 -Supine monitoring is performed for 30 minutes before administration of a single 600mg oral dose of Northera or placebo assigned randomly, After 2 hours supine a 70 degree upright tilt will performed for 10 minutes. On another day, subjects previously given Northera will receive placebo and vice versa and studies repeated.; Drug: Placebo; Study #1 -Supine monitoring is performed for 30 minutes before administration of a single 600mg oral dose of Northera or placebo assigned randomly, After 2 hours supine a 70 degree upright tilt will performed for 10 minutes. On another day, subjects previously given Northera will receive placebo and vice versa and studies repeated.
Placebo Comparator: Northera- chronic administration; Study #2 -Patients will randomized to receive Northera or placebo for two weeks after which they will return for instrumented tilt studies as in Study 1. Doses of Northera will be titrated upwards by 100mg/dose every 48 hours from a starting dose of 100mg three times a day to a maximum of 600mg three times a day.	Drug: Northera (Droxidopa); Study #2 -Patients will randomized to receive Northera or placebo for two weeks after which they will return for instrumented tilt studies as in Study 1. Doses of Northera will be titrated upwards by 100mg/dose every 48 hours from a starting dose of 100mg three times a day to a maximum of 600mg three times a day. Doses will be reduced to the preceding dose if systolic BP>140mmHg or diastolic BP>80mmHg measured in the seated position at home using an automated ambulatory blood pressure cuff 2 hours after receiving an oral dose. Doses will also be reduced if supine BP measured with the head of the bed elevated upon awakening in the morning exceeds 150/90 mmHg. Following a 1 week wash out period, subjects will receive the alternative treatment for 2 additional weeks and instrumented laboratory studies repeated.; Drug: Placebo; Study #2 -Patients will randomized to receive Northera or placebo for two weeks after which they will return for instrumented tilt studies as in Study 1. Doses of Northera will be titrated upwards by 100mg/dose every 48 hours from a starting dose of 100mg three times a day to a maximum of 600mg three times a day. Doses will be reduced to the preceding dose if systolic BP>140mmHg or diastolic BP>80mmHg measured in the seated position at home using an automated ambulatory blood pressure cuff 2 hours after receiving an oral dose. Doses will also be reduced if supine BP measured with the head of the bed elevated upon awakening in the morning exceeds 150/90 mmHg. Following a 1 week wash out period, subjects will receive the alternative treatment for 2 additional weeks and instrumented laboratory studies repeated.

Outcome Measures

Primary Outcome Measures :

1. Study #1 and Study #2 - Splanchnic and lower extremity pooling (physiological parameter) [ Time Frame: 2 weeks ]
   Splanchnic and lower extremity pooling will be measured before, during, and after upright tilt. The investigators will use both venous occlusion plethysmography and impedance plethysmography. Venous occlusion plethysmography are made in ml/min by rapidly inflating cuffs to a pressure of 45mmHg and then computing the slope of the time dependent increase in cross limb section. During impedance plethysmography, a Tetrapolar High Resolution Impedance monitor 4-channel digital IPG is used to detect changes in regional blood volume and blood flow in ml/min
2. Study #2 -Quality of Life measured by self reporting questionnaire (RAND-36) [ Time Frame: 6 weeks ]
   The investigators will test whether chronic administration of Northera (Droxidopa) in escalating dose improves quality of life. Quality of life will be measured by the RAND-36 questionnaire. The RAND-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. The RAND 36-Item Health Survey (Version 1.0) taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. (2-4)
3. Study #2 -Quality of Life measured by self reporting questionnaire (COMPASS 31) [ Time Frame: 6 weeks ]
   The investigators will test whether chronic administration of Northera (Droxidopa) in escalating dose improves quality of life. Quality of life will be measured by the RAND-36 questionnaire (as shown in the above primary outcome) as well as the COMPASS 31 questionnaire. The COMPASS 31 "was developed as a self-assessment instrument of autonomic symptoms and function that is up-to-date, broadly applicable, easy to administer in a short amount of time, and based on a scientific approach. It was designed to provide a global autonomic severity score and domain scores that are both clinically and scientifically meaningful." "COMPASS 31 is based on the well-established ASP [Autonomic Symptom Profile], a comprehensive questionnaire assessing autonomic symptoms across multiple domains." (1)

Secondary Outcome Measures :

1. Study #1 and Study #2 -Blood pressure (BP) [ Time Frame: 2 weeks ]
   During laboratory testing, blood pressure will be continuously monitored in mmHg
2. Study #1 and Study #2 -Heart rate (HR) [ Time Frame: 2 weeks ]
   During laboratory testing, heart rate will be continuously monitored in beats/minute.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 35 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Both male and female participants are being studied
• Ages 18-30 years old
• POTS cases will be referred for day-to-day Orthostatic Intolerance (OI) with ≥3 symptoms for >6 months.
• POTS will be confirmed by medical history indicating chronic OI, and by a prior 700 tilt table test or standing test showing excessive tachycardia and symptoms OI in the absence of hypotension.
• VVS (fainting) subjects will have at least 2 episodes of postural VVS during the past calendar year.
• Healthy volunteers will be included for Study #1

Exclusion Criteria:

• Only those free from all systemic illnesses will be eligible to participate. This excludes patients with illnesses associated with autonomic dysfunction such as diabetes, renal disease, congestive heart failure, systemic hypertension, acute and chronic inflammatory diseases, neoplasm, immune mediated disease, trauma, obesity, cancer, supine or upright hypertension, and peripheral vascular disease.
• No subjects will be taking neurally active, or vasoactive drugs. Prior medication will be stopped for at least 2 weeks.

Contacts and Locations

Contacts

Contact: Courtney Terilli, RN, BSN; 914-593-8888; courtney_terilli@nymc.edu

Contact: Marvin S. Medow, Ph.D.; 914-593-8888; marvin_medow@nymc.edu

Locations

United States, New York

New York Medical College/Bradhurst building; Recruiting

Hawthorne, New York, United States, 10532

Contact: Courtney R Terilli, RN, BSN 914-593-8888 courtney_terilli@nymc.edu

Contact: Julian M Stewart, MD, PhD 914-593-8888 julian_stewart@nymc.edu

Principal Investigator: Julian M Stewart, MD, PhD

Sub-Investigator: Marvin S. Medow, PhD

Sponsors and Collaborators

New York Medical College

Lundbeck LLC

Investigators

• Principal Investigator: Julian M Stewart, M.D., Ph.D.; New York Medical College

More Information

Additional Information:

The Center for Hypotension 

Publications:

Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. 2012 Dec;87(12):1196-201. doi: 10.1016/j.mayocp.2012.10.013.

http: and www.rand.org/health/surveys_tools/mos/mos_core_36item.html. 36-Item Short Form Survey from the RAND Medical Outcomes Study. 2014.

Hays RD, Shapiro MF. An overview of generic health-related quality of life measures for HIV research. Qual Life Res. 1992 Apr;1(2):91-7.

Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473-83.

• Responsible Party: Julian Stewart, Professor of Pediatrics and Physiology, New York Medical College
• ClinicalTrials.gov Identifier: NCT02558972 History of Changes
• Other Study ID Numbers: L-11,388
• First Posted: September 24, 2015
• Last Update Posted: July 16, 2019
• Last Verified: July 2019

Keywords provided by Julian Stewart, New York Medical College:

Postural Tachycardia Syndrome (POTS); Vasovagal Syncope (VVS); Fainting; Orthostatic Intolerance; Droxidopa; Northera

Additional relevant MeSH terms:

Syncope; Postural Orthostatic Tachycardia Syndrome; Syncope, Vasovagal; Tachycardia; Syndrome; Disease; Pathologic Processes; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Unconsciousness; Consciousness Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Orthostatic Intolerance; Primary Dysautonomias; Autonomic Nervous System Diseases; Droxidopa; Antiparkinson Agents; Anti-Dyskinesia Agents