Clinical trial NCT03070730: Hemodynamic Response of Neuropathic And Non-Neuropathic POTS Patients To Adrenoreceptor Agonist And Antagonist
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Postural Orthostatic Tachycardia Syndrome
Orthostatic Intolerance
Keywords: Tachycardia
orthostatic symptoms
autonomic reflex
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2017-03-06
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

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.

Detailed description: The pathophysiological basis of postural tachycardia syndrome (POTS) is not well elucidated. The most widely recognized primary cause of POTS is a "restricted" or "selective" peripheral neuropathy - neuropathic POTS. Several lines of evidence point to a restricted peripheral neuropathy, specifically sympathetic denervation in the lower hemibody, as a cause of POTS. These include venous denervation, impaired distal sudomotor dysfunction, lower norepinephrine spillover in the legs than the arms. However, not all POTS patients have peripheral neuropathy. Proposed pathogenic etiologies for non-neuropathic POTS include deconditioning, low-grade inflammation and oxidative stress. Neuropathic POTS is present in 33% of patients while non-neuropathic POTS is present in 67% of patients.

The most frequent neuropathic feature in the neuropathic POTS group is decreased sweat output measured by quantitative sudomotor axon reflex test. Headache and gastrointestinal symptoms (such as abdominal pain, bloating, nausea and constipation) are also more prevalent in the neuropathic than in the non-neuropathic POTS group, suggesting more global differences between the two populations.

In relation to the ambiguous pathophysiological basis, there is no definitive treatment for POTS. There are reports of improvements in hemodynamic measures and symptoms of orthostatic tolerance with pharmacologic agents that include intravenous saline, intravenous phenylephrine, midodrine, octreotide, erythropoietin, pyridostigmine, and betablockade. The therapy is however frequently disappointing. Furthermore, there are no reported long-term studies of medications to treat POTS and there are no reports of the effects of any intervention on fatigue or quality of life.

The most widely used agents to treat POTS, the alpha-adrenoreceptor agonist midodrine, and the beta blockers, paradoxically have agonistic and antagonistic effects on the autonomic nervous system. Responses to these drugs are inconsistent and there are no delineated predictors of the response in POTS patients.

The comparison of therapeutic interventions in this protocol are based on the rationale that while alpha-adrenoreceptor agonists are thought to be more effective in neuropathic POTS - a disorder characterized by a compensatory increase in sympathetic outflow in which sympatholysis may be counterproductive, beta-adrenoreceptor antagonists are thought to be more effective in non-neuropathic POTS - a disorder that could be characterized by increased central sympathetic outflow due to impaired sympathetic inhibition.

This protocol uses droxidopa, which is converted to direct adrenoreceptor agonist, norepinephrine. The protocol also uses beta-adrenoreceptor antagonist, the non-selective atenolol.

This is a randomized, double-blind, placebo-controlled, cross-over experimental study with three trial arms, according to the two medications (droxidopa and atenolol) and the placebo. The trial is performed in the Center for Autonomic and Peripheral Nerve Disorders at the Beth Israel Deaconess Medical Center.

The study consists of 10 visits:

* screening visit,
* testing days to define drug sensitivity
* classification day
* autonomic testing visits
* follow-up visits

Screening visit (Visit 1) includes

* Consenting procedure
* Review of medical history
* Review of all current medications, prescription and over the counter
* Physical and neurological examinations
* Measure height, weight, temperature and vital signs
* 12-lead ECG
* Baseline autonomic tests
* Blood labs
* Serum pregnancy testing for women of childbearing potential
* Patients are able to take PO medications

Drug Sensitivity Visit (Visit 2 and 3) On the first visit, patients receive one 100 mg droxidopa while on the second visit patients receive one 300 mg test dose of droxidopa to define their response to the drug. The drug administration is preceded and followed by heart rate and blood pressure measurements and side effect monitoring. The two consecutive visits are made within a period of 3 days. The goal of sensitivity visit is to determine if a patient has any sign of denervation supersensitivity in response to droxidopa. The patient is considered to have denervation supersensitivity if systolic blood pressure is greater than 180 mmHg or diastolic blood pressure is greater than 110 mmHg after 3 minutes of standing or after 5 minutes of sitting or the patient is unable to tolerate the side effects believed to be related to the drug.

Patient classification visit (Visit 4) includes

* Quantitative Direct and Indirect testing of Sudomotor Function (QDIRT)
* Quantitative Sudomotor Axon Reflex Testing (QSART)
* Quantitative Sensory Testing (QST)
* Punch skin biopsy
* Questionnaires (Chronic Fatigue Screening Form, Fatigue Severity Scale, Chalder Fatigue Questionnaire, etc., see Questionnaires section)

Autonomic Evaluation Visits (Visit 5, 7 and 9) include

* Urine pregnancy test for women of child-bearing potential
* Setup and instrumentation
* Blood draw for hormones and catecholamines (Visit 5 only)
* Microneurography procedure
* Drug/placebo administration
* Deep breathing test
* Paced breathing test
* Modified Oxford test
* Sympathetic transduction
* Static exercise
* Tilt table test

Primary outcome measure of autonomic evaluation visit is maximum postural tachycardia while secondary outcome measure of autonomic evaluation visit are blood pressure, heart rate, vascular resistance, muscle sympathetic nerve activity.

Follow-up testing visits (Visit 6, 8 and 10) include

* Medical history
* Physical examination
* Vital signs
* EKG
* Blood pressure measurement
* Tilt table test

Primary outcome measure of follow-up testing visits is the fatigue score on the Chalder Fatigue questionnaire while secondary outcome measures of follow-up testing visits are the scores on the physical functioning subscale of the SF-36 questionnaire, 7 item patient global impression of change, the Hospital Anxiety and Depression Scales, the Checklist Individual Strength (CIS), Multidimensional Fatigue Inventory (MFI), the Fatigue Severity Scale, the EuroQOL, the HADS and anxiety scores. The Orthostatic Intolerance Questionnaire - a unique validated questionnaire is used to assess orthostatic intolerance symptoms and quality of life-related to orthostatic intolerance.

Eligibility 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

Primary outcomes:
measure: Change in Maximal Postural Tachycardia During Tilt
timeFrame: Up to 3 days after randomization
measure: Change Maximal Postural Tachycardia During Tilt
timeFrame: 2 weeks after first intervention
measure: Change Maximal Postural Tachycardia During Tilt
timeFrame: 2 weeks after second intervention
measure: Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline
timeFrame: up to 3 days after randomization
measure: Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline
timeFrame: 2 weeks after first intervention
measure: Change in Fatigue Score on the Chalder Fatigue Questionnaire From Baseline
timeFrame: 2 weeks after second intervention
Secondary outcomes:
measure: Change in Blood Pressure From Baseline
timeFrame: 1 week after first intervention
measure: Change in Blood Pressure From Baseline
timeFrame: 1 week after second intervention
measure: Change in Blood Pressure From Baseline
timeFrame: 1 week after third intervention
measure: Change in Heart Rate From Baseline
timeFrame: 1 week after first intervention
measure: Change in Heart Rate From Baseline
timeFrame: 1 week after second intervention
measure: Change in Heart Rate From Baseline
timeFrame: 1 week after third intervention
measure: Change in Vascular Resistance From Baseline
timeFrame: 1 week after first intervention
measure: Change in Vascular Resistance From Baseline
timeFrame: 1 week after second intervention
measure: Change in Vascular Resistance From Baseline
timeFrame: 1 week after third intervention
measure: Change in Muscle Sympathetic Nerve Activity From Baseline
timeFrame: 1 week after first intervention
measure: Change in Muscle Sympathetic Nerve Activity From Baseline
timeFrame: 1 week after second intervention
measure: Change in Muscle Sympathetic Nerve Activity From Baseline
timeFrame: 1 week after third intervention
measure: Change in Physical Functioning-SF-36 Q From Baseline
timeFrame: 1 week after first intervention
measure: Change in Physical Functioning-SF-36 Q From Baseline
timeFrame: 1 week after second intervention
measure: Change in Physical Functioning-SF-36 Q From Baseline
timeFrame: 1 week after third intervention
measure: Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline
timeFrame: 1 week after first intervention
measure: Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline
timeFrame: 1 week after second intervention
measure: Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline
timeFrame: 1 week after third intervention
measure: Change in Physical Functioning- HADS From Baseline
timeFrame: 1 week after first intervention
measure: Change in Physical Functioning- HADS From Baseline
timeFrame: 1 week after second intervention
measure: Change in Physical Functioning- HADS From Baseline
timeFrame: 1 week after third intervention
measure: Change in Physical Functioning-CIS From Baseline
timeFrame: 1 week after first intervention
measure: Change in Physical Functioning-CIS From Baseline
timeFrame: 1 week after second intervention
measure: Change in Physical Functioning-CIS From Baseline
timeFrame: 1 week after third intervention
measure: Change in Physical Functioning-MFI From Baseline
timeFrame: 1 week after first intervention
measure: Change in Physical Functioning-MFI From Baseline
timeFrame: 1 week after second intervention
measure: Change in Physical Functioning-MFI From Baseline
timeFrame: 1 week after third intervention
measure: Change in Physical Functioning-FSS From Baseline
timeFrame: 1 week after first intervention
measure: Change in Physical Functioning-FSS From Baseline
timeFrame: 1 week after second intervention
measure: Change in Physical Functioning-FSS From Baseline
timeFrame: 1 week after third intervention
measure: Change in Physical Functioning-EuroQOL From Baseline
timeFrame: 1 week after first intervention
measure: Change in Physical Functioning-EuroQOL From Baseline
timeFrame: 1 week after second intervention
measure: Change in Physical Functioning-EuroQOL From Baseline
timeFrame: 1 week after third intervention
measure: Change in Physical Functioning-OI From Baseline
timeFrame: 1 week after first intervention
measure: Change in Physical Functioning-OI From Baseline
timeFrame: 1 week after second intervention
measure: Change in Physical Functioning-OI From Baseline
timeFrame: 1 week after third intervention
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Center for Autonomic and Peripheral Nerve Disorders - Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Roy Freeman, MD
role: PRINCIPAL_INVESTIGATOR
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