Autonomic Determinants of POTS - Pilot 2

• ClinicalTrials.gov Identifier: NCT04140721
• Recruitment Status: Enrolling by invitation
• First Posted: October 28, 2019
• Last Update Posted: November 1, 2021
• Sponsor: Vanderbilt University Medical Center
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Andre' Diedrich, Vanderbilt University Medical Center

Study Description

Brief Summary:

Postural tachycardia syndrome (POTS) is a relatively common condition affecting mostly otherwise healthy young women. These patients have high heart rate and disabling symptoms during standing. Quality of life may be poor. The sympathetic nerves in the autonomic nervous system help to maintain normal blood pressures and heart rates during activities of daily life.

The purpose of this study is to determine the importance of sympathetic activation as a cause of orthostatic symptoms. The investigators will assess the effects of a blood pressure medication (Moxonidine) on the symptoms during standing. Moxonidine lowers sympathetic activity. The investigators believe patients with high resting sympathetic activity might benefit from Moxonidine. It might reduce high heart rate and improve symptoms during standing. This study should help clinicians and the growing population of patients with POTS gain a better understanding of this disorder and find more personalized treatment.

Condition or disease	Intervention/treatment	Phase
Postural Tachycardia Syndrome	Drug: Placebo oral tablet; Drug: Moxonidine Pill	Early Phase 1

Detailed Description:

Patients with POTS experience symptoms and an increase in heart rate≥30 beats/min with standing in the absence of orthostatic hypotension. As a result of considerable functional impairment, individuals with POTS are often unable to attend school or work. There is agreement that POTS is a heterogeneous disorder with multiple overlapping pathophysiologies proposed to underlie the clinical phenotype of patients. It would be important to define the underlying pathophysiological mechanisms in an individual patient to design optimal therapy. Our overarching hypothesis is that there is a subset of POTS patients (psPOTS) with a central sympathetic activation as the primary pathophysiology. We have characterized these patients by an increase in muscle sympathetic nerve activity (MSNA, a reflection of central sympathetic outflow) even at rest. In this project, we will focus on the role of primary sympathetic activation in the pathogenesis of POTS. Direct neural recordings of sympathetic activity, central sympathetic inhibition and extensive autonomic phenotyping will enable us to identify and correct the primary pathophysiology to optimally benefit psPOTS patients. This is a mechanistic study, designed to assess the effects of 4 weeks of central sympatholysis with moxonidine on orthostatic tachycardia and symptoms (Specific Aim 1), hypovolemia (Specific Aim 2) and central and peripheral baroreflex properties (Specific Aim 3) in a randomized, crossover design with POTS patients having elevated resting sympathetic nerve activity.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: randomized, double blind, crossover design
• Masking: Double (Participant, Investigator)
• Masking Description: Vanderbilt's Investigational Pharmacy will randomly assign participants to the moxonidine/placebo or placebo/moxonidine arm of the study. They will also provide the active drug and matching placebo. The medication distribution list will be kept by a dedicated person not involved in the study.
• Primary Purpose: Other
• Official Title: Autonomic Determinants of Postural Tachycardia Syndrome (Chronic Pilot Study 2)
• Actual Study Start Date: September 22, 2021
• Estimated Primary Completion Date: January 1, 2025
• Estimated Study Completion Date: December 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Moxonidine then Placebo; After 5 days of screening/baseline evaluations, patients will be discharged home on moxonidine 0.2-0.4 mg/day PO. On days 29, 30 and 31, the patients will be re-admitted for study testing while on moxonidine. At completion of this testing, patients will start taking matching placebo once daily PO to be continued at home. On days 58, 59 and 60, the patients will be re-admitted for study testing while on placebo.	Drug: Placebo oral tablet; Placebo pill identical to moxonidine administered for 4 weeks; Other Name: inactive pill; Drug: Moxonidine Pill; Moxonidine pill administered for 4 weeks; Other Name: Physiotens
Experimental: Placebo then Moxonidine; After 5 days of screening/baseline evaluations, patients will be discharged home on placebo identical to moxonidine once daily PO. On days 29, 30 and 31, the patients will be re-admitted for study testing while on placebo. At completion of this testing, patients will start taking moxonidine 0.2-0.4 mg/day PO to be continued at home. On days 58, 59 and 60, the patients will be re-admitted for study testing while on moxonidine.	Drug: Placebo oral tablet; Placebo pill identical to moxonidine administered for 4 weeks; Other Name: inactive pill; Drug: Moxonidine Pill; Moxonidine pill administered for 4 weeks; Other Name: Physiotens

Outcome Measures

Primary Outcome Measures :

1. Change in Orthostatic Symptom Burden [delta (delta VOSS)] [ Time Frame: after 30 min supine to after 15 min of 60 degrees upright tilt (delta VOSS), 2-3 hours after a dose of the treatment assigned for the previous 4 weeks. ]
   VOSS is a validated questionnaire that consists of 9 items: mental clouding, blurred vision, shortness of breath, rapid heartbeat, tremulousness, chest discomfort, headache, lightheadedness, and nausea. Each item is scored on a 0 to 10 scale (with 0 reflecting absence of symptoms), and the change of the total scores (range: 0-90) from supine to upright postures (delta VOSS) will be used as a measure of orthostatic symptom burden. The primary outcome measure will be the difference in orthostatic symptom burden [delta (delta VOSS)] following 4 weeks of placebo vs. moxonidine treatment.

Secondary Outcome Measures :

1. Change in Orthostatic Change in Heart Rate [delta (delta HR)] [ Time Frame: after 30 min supine to after 15 min of 60 degrees upright tilt (delta HR), 2-3 hours after a dose of the treatment assigned for the previous 4 weeks. ]
   Difference in heart rate change from supine to upright postures (delta HR) following 4 weeks of placebo vs. moxonidine treatment [delta (delta HR)].

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• meets criteria for postural tachycardia syndrome (POTS)

  1. a heart rate increase of ≥30 beats/min within 10 minutes of upright posture;
  2. lack of orthostatic hypotension (blood pressure fall ≥ 20/10 mmHg within 3 minutes of standing); and
  3. chronic symptoms during upright posture over at least 6 months, in the absence of any other acute cause.
• in the follicular phase of the menstrual cycle (days 5-13 of a 28-day cycle)
• POTS with primary central sympathetic activation (psPOTS) as defined as having resting MSNA ≥ 25 bursts/min
• able and willing to provide informed consent.

Exclusion Criteria:

• pregnancy,
• smoker,
• BMI>30 kg/m2,
• deconditioned status (if available VO2max<80% of predicted)
• unable to withdraw from medications known to affect autonomic function, blood pressure or blood volume
• systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathies, and autoimmune neuropathies.
• arteriosclerotic disease of carotid artery. History of neck surgery.
• conditions associated with inflammatory processes, such as coronary artery disease, hypertension, smoking, hypercholesterolemia (or on statin therapy), rheumatoid arthritis, diabetes,
• treatment with oral corticosteroids, current infections (e.g., urinary tract infection), or use of non-steroidal anti-inflammatory drugs.
• other factors which in the investigator's opinion would prevent the subject from completing the protocol including clinically significant abnormalities in clinical, mental or laboratory testing.

Contacts and Locations

Locations

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37221

Sponsors and Collaborators

Vanderbilt University Medical Center

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: André Diedrich, MD, PhD; Vanderbilt University Medical Center

More Information

• Responsible Party: Andre' Diedrich, Research Professor of Medicine, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT04140721
• Other Study ID Numbers: VANDERBILT_IRB_191749; R01HL142583 ( U.S. NIH Grant/Contract )
• First Posted: October 28, 2019
• Last Update Posted: November 1, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Andre' Diedrich, Vanderbilt University Medical Center:

postural tachycardia syndrome; hyperadrenergic; moxonidine; sympatholytic; orthostatic symptoms; POTS

Additional relevant MeSH terms:

Postural Orthostatic Tachycardia Syndrome; Tachycardia; Syndrome; Disease; Pathologic Processes; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Orthostatic Intolerance; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Moxonidine; Antihypertensive Agents