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

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ClinicalTrials.gov Identifier: NCT02558972
Recruitment Status : Recruiting
First Posted : September 24, 2015
Last Update Posted : July 20, 2018
Sponsor:
Collaborator:
Lundbeck LLC
Information provided by (Responsible Party):
Julian Stewart, New York Medical College

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 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 : October 2018
Estimated Study Completion Date : October 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fainting
Drug Information available for: Droxidopa

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.




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.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02558972


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

Additional Information:
Publications:
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    Key Record Dates
Last Update Posted: July 20, 2018
Last Verified: July 2018

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:
Syndrome
Tachycardia
Postural Orthostatic Tachycardia Syndrome
Syncope
Syncope, Vasovagal
Disease
Pathologic Processes
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
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