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

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ClinicalTrials.gov Identifier: NCT03070730
Recruitment Status : Terminated (Recruitment was slow and subjects declined participation after signing the ICF.)
First Posted : March 6, 2017
Results First Posted : May 18, 2017
Last Update Posted : May 18, 2017
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Roy Freeman, MD, Beth Israel Deaconess Medical Center

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.


Condition or disease Intervention/treatment Phase
Postural Orthostatic Tachycardia Syndrome Orthostatic Intolerance Drug: Droxidopa Drug: Atenolol Drug: Placebos Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: 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.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-Blinded, Placebo-Controlled Study To Assess Hemodynamic Changes, Orthostatic Tolerance, Out-Patient Fatigue And Quality Of Life In Neuropathic And Non-Neuropathic POTS Patients In Response To Adrenoreceptor Agonist And Antagonist
Actual Study Start Date : August 15, 2011
Actual Primary Completion Date : December 18, 2012
Actual Study Completion Date : July 28, 2014

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Atenolol

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
Droxidopa: 100 mg or 300 mg t.i.d
Other Name: Northera
Drug: Atenolol
Atenolol: 50 mg Q.D.
Other Name: Tenormin
Drug: Placebos
Placebo: t.i.d
Other Name: placebo
Placebos

In this arm subjects are randomized to placebo tid.

Placebo is used to control the administration effect.

Drug: Placebos
Placebo: t.i.d
Other Name: placebo
Droxidopa

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
Droxidopa: 100 mg or 300 mg t.i.d
Other Name: Northera
Drug: Atenolol
Atenolol: 50 mg Q.D.
Other Name: Tenormin
Drug: Placebos
Placebo: t.i.d
Other Name: placebo



Primary Outcome Measures :
  1. Change in Maximal Postural Tachycardia During Tilt [ Time Frame: Up to 3 days after randomization ]
    Maximal postural tachycardia is the maximum heart rate during a 20-min tilt table test.

  2. Change Maximal Postural Tachycardia During Tilt [ Time Frame: 2 weeks after first intervention ]
    Maximal postural tachycardia is the maximum heart rate during a 20-min tilt table test.

  3. Change Maximal Postural Tachycardia During Tilt [ Time Frame: 2 weeks after second intervention ]
    Maximal postural tachycardia is the maximum heart rate during a 20-min tilt table test.

  4. Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline [ Time Frame: up to 3 days after randomization ]
    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.

  5. Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline [ Time Frame: 2 weeks after first intervention ]
    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.

  6. Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline [ Time Frame: 2 weeks after second intervention ]
    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.


Secondary Outcome Measures :
  1. Change in Blood Pressure From Baseline [ Time Frame: 1 week after first intervention ]
  2. Change in Blood Pressure From Baseline [ Time Frame: 1 week after second intervention ]
  3. Change in Blood Pressure From Baseline [ Time Frame: 1 week after third intervention ]
  4. Change in Heart Rate From Baseline [ Time Frame: 1 week after first intervention ]
  5. Change in Heart Rate From Baseline [ Time Frame: 1 week after second intervention ]
  6. Change in Heart Rate From Baseline [ Time Frame: 1 week after third intervention ]
  7. Change in Vascular Resistance From Baseline [ Time Frame: 1 week after first intervention ]
  8. Change in Vascular Resistance From Baseline [ Time Frame: 1 week after second intervention ]
  9. Change in Vascular Resistance From Baseline [ Time Frame: 1 week after third intervention ]
  10. Change in Muscle Sympathetic Nerve Activity From Baseline [ Time Frame: 1 week after first intervention ]
  11. Change in Muscle Sympathetic Nerve Activity From Baseline [ Time Frame: 1 week after second intervention ]
  12. Change in Muscle Sympathetic Nerve Activity From Baseline [ Time Frame: 1 week after third intervention ]
  13. Change in Physical Functioning-SF-36 Q From Baseline [ Time Frame: 1 week after first intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the SF-36 questionnaire.

  14. Change in Physical Functioning-SF-36 Q From Baseline [ Time Frame: 1 week after second intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the SF-36 questionnaire.

  15. Change in Physical Functioning-SF-36 Q From Baseline [ Time Frame: 1 week after third intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the SF-36 questionnaire.

  16. Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline [ Time Frame: 1 week after first intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the 7 item patient global impression of change with items anchored by :very much better" to "very much worse".

  17. Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline [ Time Frame: 1 week after second intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the 7 item patient global impression of change with items anchored by :very much better" to "very much worse".

  18. Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline [ Time Frame: 1 week after third intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the 7 item patient global impression of change with items anchored by :very much better" to "very much worse".

  19. Change in Physical Functioning- HADS From Baseline [ Time Frame: 1 week after first intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Hospital Anxiety and Depression Scales.

  20. Change in Physical Functioning- HADS From Baseline [ Time Frame: 1 week after second intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Hospital Anxiety and Depression Scales.

  21. Change in Physical Functioning- HADS From Baseline [ Time Frame: 1 week after third intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Hospital Anxiety and Depression Scales.

  22. Change in Physical Functioning-CIS From Baseline [ Time Frame: 1 week after first intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Checklist Individual Strength (CIS).

  23. Change in Physical Functioning-CIS From Baseline [ Time Frame: 1 week after second intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Checklist Individual Strength (CIS).

  24. Change in Physical Functioning-CIS From Baseline [ Time Frame: 1 week after third intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Checklist Individual Strength (CIS).

  25. Change in Physical Functioning-MFI From Baseline [ Time Frame: 1 week after first intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Multidimensional Fatigue Inventory (MFI).

  26. Change in Physical Functioning-MFI From Baseline [ Time Frame: 1 week after second intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Multidimensional Fatigue Inventory (MFI).

  27. Change in Physical Functioning-MFI From Baseline [ Time Frame: 1 week after third intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Multidimensional Fatigue Inventory (MFI).

  28. Change in Physical Functioning-FSS From Baseline [ Time Frame: 1 week after first intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Fatigue Severity Scale.

  29. Change in Physical Functioning-FSS From Baseline [ Time Frame: 1 week after second intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Fatigue Severity Scale.

  30. Change in Physical Functioning-FSS From Baseline [ Time Frame: 1 week after third intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Fatigue Severity Scale.

  31. Change in Physical Functioning-EuroQOL From Baseline [ Time Frame: 1 week after first intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the EuroQOL.

  32. Change in Physical Functioning-EuroQOL From Baseline [ Time Frame: 1 week after second intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the EuroQOL.

  33. Change in Physical Functioning-EuroQOL From Baseline [ Time Frame: 1 week after third intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the EuroQOL.

  34. Change in Physical Functioning-OI From Baseline [ Time Frame: 1 week after first intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Orthostatic Intolerance Questionnaire.

  35. Change in Physical Functioning-OI From Baseline [ Time Frame: 1 week after second intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Orthostatic Intolerance Questionnaire.

  36. Change in Physical Functioning-OI From Baseline [ Time Frame: 1 week after third intervention ]
    Measures of follow up testing will be the scores on the physical functioning subscale of the Orthostatic Intolerance Questionnaire.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

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

Exclusion Criteria:

  • 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

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): NCT03070730


Locations
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Center for Autonomic and Peripheral Nerve Disorders - Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Roy Freeman, MD Beth Israel Deaconess Medical Center

Publications:

Responsible Party: Roy Freeman, MD, Professor of Neurology, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT03070730     History of Changes
Other Study ID Numbers: 2011P000246
R01HL059459 ( U.S. NIH Grant/Contract )
First Posted: March 6, 2017    Key Record Dates
Results First Posted: May 18, 2017
Last Update Posted: May 18, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NIH Grant Policy on Sharing of Unique Research Resources including the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources.

Keywords provided by Roy Freeman, MD, Beth Israel Deaconess Medical Center:
Tachycardia
orthostatic symptoms
autonomic reflex

Additional relevant MeSH terms:
Tachycardia
Orthostatic Intolerance
Postural Orthostatic Tachycardia Syndrome
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Atenolol
Droxidopa
Anti-Arrhythmia Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antiparkinson Agents
Anti-Dyskinesia Agents