Hemodynamic Response of Neuropathic And Non-Neuropathic POTS Patients To Adrenoreceptor Agonist And Antagonist

NCT03070730 | Terminated Phase 1 Results

• 2 other identifiers: 2011P000246R01HL059459
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to test the hypothesis that patients with non-neuropathic POTS will have different responsiveness than patients with neuropathic POTS to direct alpha-1 adrenoreceptor agonist therapy (droxidopa) and to non-selective beta-adrenoreceptor antagonist therapy (atenolol). The specific goal of this protocol is to investigate the effect of atenolol and droxidopa on cardiovascular autonomic functions such as cardiovagal control, sympathetic nerve activity, and sympathetic vascular transduction, systemic hemodynamic response to orthostatic stress and on the quality of life in neuropathic and non-neuropathic patients with postural tachycardia syndrome (POTS). Standardized tests are used to assess cardiovagal control function, sympathetic nerve activity, sympathetic vascular transduction, systemic hemodynamic response to head-up tilt test and standardized questionnaires to assess the quality of life in patients with POTS. The cardiovagal, sympathetic and hemodynamic measurements are performed after and during drug administration. To control the effect of medications placebo is used on separate testing visits. The order of drugs and placebo is randomized.

Conditions

Postural Orthostatic Tachycardia Syndrome; Orthostatic Intolerance

Keywords

Tachycardia; orthostatic symptoms; autonomic reflex

Outcome Measures

Primary Outcomes (6)

• Change in Maximal Postural Tachycardia During Tilt

  Maximal postural tachycardia is the maximum heart rate during a 20-min tilt table test.

  Up to 3 days after randomization

• Change Maximal Postural Tachycardia During Tilt

  Maximal postural tachycardia is the maximum heart rate during a 20-min tilt table test.

  2 weeks after first intervention

• Change Maximal Postural Tachycardia During Tilt

  Maximal postural tachycardia is the maximum heart rate during a 20-min tilt table test.

  2 weeks after second intervention

• Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline

  A 14 item self-report questionnaire. Subjects respond on a continuum of 1 to 4 questions evaluating fatigue intensity while distinguishing physical from mental fatigue.

  up to 3 days after randomization

• Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline

  A 14 item self-report questionnaire. Subjects respond on a continuum of 1 to 4 questions evaluating fatigue intensity while distinguishing physical from mental fatigue.

  2 weeks after first intervention

• Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline

  A 14 item self-report questionnaire. Subjects respond on a continuum of 1 to 4 questions evaluating fatigue intensity while distinguishing physical from mental fatigue.

  2 weeks after second intervention

Secondary Outcomes (36)

• Change in Blood Pressure From Baseline

  1 week after first intervention

• Change in Blood Pressure From Baseline

  1 week after second intervention

• Change in Blood Pressure From Baseline

  1 week after third intervention

• Change in Heart Rate From Baseline

  1 week after first intervention

• Change in Heart Rate From Baseline

  1 week after second intervention

Study Arms (3)

Atenolol

OTHER

In this arm subjects are randomized to atenolol 50 mg qd, droxidopa 100 mg/300 mg tid and placebo tid. Atenolol is used to examine the effect of non-selective beta adrenoreceptor antagonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia patients. Droxidopa is used to examine the effect of direct alpha-1 adrenoreceptor agonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia (POTS) patients.

Drug: Droxidopa; Drug: Atenolol; Drug: Placebos

Placebos

OTHER

In this arm subjects are randomized to placebo tid. Placebo is used to control the administration effect.

Drug: Placebos

Droxidopa

OTHER

In this arm subjects are randomized to droxidopa 100 mg/300 mg tid, atenolol 50 mg qd, and placebo tid. Atenolol is used to examine the effect of non-selective beta adrenoreceptor antagonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia patients. Droxidopa is used to examine the effect of direct alpha-1 adrenoreceptor agonist on primary and secondary endpoints in neuropathic and non-neuropathic postural tachycardia (POTS) patients.

Drug: Droxidopa; Drug: Atenolol; Drug: Placebos

Interventions

Droxidopa DRUG

Droxidopa: 100 mg or 300 mg t.i.d

Also known as: Northera

Atenolol; Droxidopa

Atenolol DRUG

Atenolol: 50 mg Q.D.

Also known as: Tenormin

Atenolol; Droxidopa

Placebos DRUG

Placebo: t.i.d

Also known as: placebo

Atenolol; Droxidopa; Placebos

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• CDC criteria for chronic fatigue syndrome
• Evidence of postural tachycardia syndrome with symptoms of orthostatic intolerance

You may not qualify if:

• Pregnant or lactating females. The administration of droxidopa is harmful to the fetus
• Concomitant therapy with anticholinergic, alpha-, and beta-adrenergic antagonists or other medications that affect autonomic function
• Clinically significant coronary artery, cerebrovascular or peripheral vascular disease
• Cardiac arrhythmias
• Systemic illness that might affect autonomic function such as congestive heart failure, hypertension, renal, pulmonary, and hepatic disease, anemia, malignancies, thyroid disease, and alcoholism
• Severe depression, severe anxiety disorder (score of on the Beck Depression Inventory \> 29 or score on the Beck Anxiety Inventory of ≥ 36) or psychosis
• Antidepressant treatment by MAO inhibitors within 2 weeks before the study
• Glaucoma
• Liver disease
• Subjects with a history of reaction to local anesthetic will be excluded from the study
• Subjects who have a history of any bleeding disorders or significantly impaired wound healing will be excluded. Subjects who are using any medications such as Coumadin or Plavix will be also excluded
• Subjects who are currently enrolled in any other studies using investigational products

Sponsors & Collaborators

• Beth Israel Deaconess Medical Center: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (2)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Center for Autonomic and Peripheral Nerve Disorders - Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Related Publications (24)

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• Karas B, Grubb BP, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a potentially treatable cause of chronic fatigue, exercise intolerance, and cognitive impairment in adolescents. Pacing Clin Electrophysiol. 2000 Mar;23(3):344-51. doi: 10.1111/j.1540-8159.2000.tb06760.x.

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• Stewart JM. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res. 2000 Aug;48(2):218-26. doi: 10.1203/00006450-200008000-00016.

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MeSH Terms

Conditions

Postural Orthostatic Tachycardia Syndrome; Orthostatic Intolerance; Tachycardia

Interventions

Droxidopa; Atenolol

Condition Hierarchy (Ancestors)

Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Pathologic Processes

Intervention Hierarchy (Ancestors)

Norepinephrine; Catecholamines; Amines; Organic Chemicals; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols

Limitations and Caveats

The trial was terminated early due to difficulties in the recruitment process. Subjects were found to be ineligible, or decided not to participate in the study.

Results Point of Contact

• Title: Dr. Roy Freeman
• Organization: Beth Israel Deaconess Medical Center

rfreeman@bidmc.harvard.edu

617-632-8454

Study Officials

• Roy Freeman, MD

  Beth Israel Deaconess Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology

Model Details: The study design is a "double-dummy" design. While during two of the three trial arms the patients take an active study drug and a placebo, there is also an arm where patients take only placebo.

Study Record Dates

• First Submitted: February 27, 2012
• First Posted: March 6, 2017
• Study Start: August 15, 2011
• Primary Completion: December 18, 2012
• Study Completion: July 28, 2014
• Last Updated: May 18, 2017
• Results First Posted: May 18, 2017

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will share

Locations

US (2)