Postural Orthostatic Tachycardia SyndromePhase 1/2NCT03070730
Hemodynamic Response of Neuropathic And Non-Neuropathic POTS Patients To Adrenoreceptor Agonist And Antagonist
A Phase 1/2 study testing Droxidopa and Atenolol in people with Postural Orthostatic Tachycardia Syndrome and Orthostatic Intolerance, run by Beth Israel Deaconess Medical Center at 2 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Postural Orthostatic Tachycardia Syndrome, Orthostatic Intolerance
- What is being tested?
- Droxidopa and Atenolol
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 8 participants
- Where
- 2 sitesUnited States
- Study dates
- 15 Aug 2011to 28 Jul 2014
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- CDC criteria for chronic fatigue syndrome
- Evidence of postural tachycardia syndrome with symptoms of orthostatic intolerance
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Center for Autonomic and Peripheral Nerve Disorders - Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
About this study
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
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).
Read more
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.
Read the 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.
- Being tested
- Droxidopa, Atenolol, Placebos
- Keywords
- Tachycardia, orthostatic symptoms, autonomic reflex
- Medical subject headings
- Postural Orthostatic Tachycardia Syndrome, Orthostatic Intolerance, Tachycardia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DroxidopaDrug
Also called Northera
Droxidopa: 100 mg or 300 mg t.i.d
AtenololDrug
Also called Tenormin
Atenolol: 50 mg Q.D.
PlacebosDrug
Also called placebo
Placebo: t.i.d
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Droxidopa; Drug: Atenolol; Drug: Placebos |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Maximal Postural Tachycardia During Tilt
Maximal postural tachycardia is the maximum heart rate during a 20-min tilt table test.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 2 weeks after second intervention
Secondary outcomes (36)
Change in Blood Pressure From Baseline
Measured: 1 week after first intervention
Change in Blood Pressure From Baseline
Measured: 1 week after second intervention
Change in Blood Pressure From Baseline
Measured: 1 week after third intervention
Change in Heart Rate From Baseline
Measured: 1 week after first intervention
Change in Heart Rate From Baseline
Measured: 1 week after second intervention
Change in Heart Rate From Baseline
Measured: 1 week after third intervention
Change in Vascular Resistance From Baseline
Measured: 1 week after first intervention
Change in Vascular Resistance From Baseline
Measured: 1 week after second intervention
Change in Vascular Resistance From Baseline
Measured: 1 week after third intervention
Change in Muscle Sympathetic Nerve Activity From Baseline
Measured: 1 week after first intervention
Change in Muscle Sympathetic Nerve Activity From Baseline
Measured: 1 week after second intervention
Change in Muscle Sympathetic Nerve Activity From Baseline
Measured: 1 week after third intervention
Change in Physical Functioning-SF-36 Q From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the SF-36 questionnaire.
Measured: 1 week after first intervention
Change in Physical Functioning-SF-36 Q From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the SF-36 questionnaire.
Measured: 1 week after second intervention
Change in Physical Functioning-SF-36 Q From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the SF-36 questionnaire.
Measured: 1 week after third intervention
Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline
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".
Measured: 1 week after first intervention
Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline
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".
Measured: 1 week after second intervention
Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline
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".
Measured: 1 week after third intervention
Change in Physical Functioning- HADS From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Hospital Anxiety and Depression Scales.
Measured: 1 week after first intervention
Change in Physical Functioning- HADS From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Hospital Anxiety and Depression Scales.
Measured: 1 week after second intervention
Change in Physical Functioning- HADS From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Hospital Anxiety and Depression Scales.
Measured: 1 week after third intervention
Change in Physical Functioning-CIS From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Checklist Individual Strength (CIS).
Measured: 1 week after first intervention
Change in Physical Functioning-CIS From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Checklist Individual Strength (CIS).
Measured: 1 week after second intervention
Change in Physical Functioning-CIS From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Checklist Individual Strength (CIS).
Measured: 1 week after third intervention
Change in Physical Functioning-MFI From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Multidimensional Fatigue Inventory (MFI).
Measured: 1 week after first intervention
Change in Physical Functioning-MFI From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Multidimensional Fatigue Inventory (MFI).
Measured: 1 week after second intervention
Change in Physical Functioning-MFI From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Multidimensional Fatigue Inventory (MFI).
Measured: 1 week after third intervention
Change in Physical Functioning-FSS From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Fatigue Severity Scale.
Measured: 1 week after first intervention
Change in Physical Functioning-FSS From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Fatigue Severity Scale.
Measured: 1 week after second intervention
Change in Physical Functioning-FSS From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Fatigue Severity Scale.
Measured: 1 week after third intervention
Change in Physical Functioning-EuroQOL From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the EuroQOL.
Measured: 1 week after first intervention
Change in Physical Functioning-EuroQOL From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the EuroQOL.
Measured: 1 week after second intervention
Change in Physical Functioning-EuroQOL From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the EuroQOL.
Measured: 1 week after third intervention
Change in Physical Functioning-OI From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Orthostatic Intolerance Questionnaire.
Measured: 1 week after first intervention
Change in Physical Functioning-OI From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Orthostatic Intolerance Questionnaire.
Measured: 1 week after second intervention
Change in Physical Functioning-OI From Baseline
Measures of follow up testing will be the scores on the physical functioning subscale of the Orthostatic Intolerance Questionnaire.
Measured: 1 week after third intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Mar 2017
- Study start15 Aug 2011
- Primary completion18 Dec 2012
- Study completion28 Jul 2014
Why it stopped: Recruitment was slow and subjects declined participation after signing the ICF.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for Postural Orthostatic Tachycardia SyndromeStudies of the same condition, open and under way.
- More trials run by Beth Israel Deaconess Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- 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 blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Beth Israel Deaconess Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Principal investigator, Roy Freeman, MD, Beth Israel Deaconess Medical Center
- Investigators
- Roy Freeman, MD, Principal investigator, Beth Israel Deaconess Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03070730
- Sponsor's protocol ID
- 2011P000246
- Other IDs
- R01HL059459
- Status last verified
- Apr 2017
- First submitted
- 27 Feb 2012
- Last updated
- 18 May 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- Yes: 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.
Publications
Jacob G, Biaggioni I; New Collective Author. Idiopathic orthostatic intolerance and postural tachycardia syndromes. Am J Med Sci. 1999 Feb;317(2):88-101. doi: 10.1097/00000441-199902000-00003.
PubMed 10037112Karas 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.
PubMed 10750135Stewart 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.
PubMed 10926298Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology. 1993 Jan;43(1):132-7. doi: 10.1212/wnl.43.1_part_1.132.
PubMed 8423877Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M, Biaggioni I, Ertl A, Black B, Robertson D; New Collective Author. The neuropathic postural tachycardia syndrome. N Engl J Med. 2000 Oct 5;343(14):1008-14. doi: 10.1056/NEJM200010053431404.
PubMed 11018167Streeten DH. Pathogenesis of hyperadrenergic orthostatic hypotension. Evidence of disordered venous innervation exclusively in the lower limbs. J Clin Invest. 1990 Nov;86(5):1582-8. doi: 10.1172/JCI114878.
PubMed 2243132Low PA, Novak V, Spies JM, Novak P, Petty GW; New Collective Author. Cerebrovascular regulation in the postural orthostatic tachycardia syndrome (POTS). Am J Med Sci. 1999 Feb;317(2):124-33. doi: 10.1097/00000441-199902000-00007.
PubMed 10037116Freeman R, Lirofonis V, Farquhar WB, Risk M. Limb venous compliance in patients with idiopathic orthostatic intolerance and postural tachycardia. J Appl Physiol (1985). 2002 Aug;93(2):636-44. doi: 10.1152/japplphysiol.00817.2001.
PubMed 12133874Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, Robertson D; New Collective Author. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med. 2000 Feb 24;342(8):541-9. doi: 10.1056/NEJM200002243420803.
PubMed 10684912Al-Shekhlee A, Lindenberg JR, Hachwi RN, Chelimsky TC. The value of autonomic testing in postural tachycardia syndrome. Clin Auton Res. 2005 Jun;15(3):219-22. doi: 10.1007/s10286-005-0282-7.
PubMed 15944872Stewart JM, Munoz J, Weldon A. Clinical and physiological effects of an acute alpha-1 adrenergic agonist and a beta-1 adrenergic antagonist in chronic orthostatic intolerance. Circulation. 2002 Dec 3;106(23):2946-54. doi: 10.1161/01.cir.0000040999.00692.f3.
PubMed 12460877Gordon VM, Opfer-Gehrking TL, Novak V, Low PA; New Collective Author. Hemodynamic and symptomatic effects of acute interventions on tilt in patients with postural tachycardia syndrome. Clin Auton Res. 2000 Feb;10(1):29-33. doi: 10.1007/BF02291387.
PubMed 10750641Freitas J, Santos R, Azevedo E, Costa O, Carvalho M, de Freitas AF. Clinical improvement in patients with orthostatic intolerance after treatment with bisoprolol and fludrocortisone. Clin Auton Res. 2000 Oct;10(5):293-9. doi: 10.1007/BF02281112.
PubMed 11198485Gibbons CH, Vernino SA, Kaufmann H, Freeman R. L-DOPS therapy for refractory orthostatic hypotension in autoimmune autonomic neuropathy. Neurology. 2005 Oct 11;65(7):1104-6. doi: 10.1212/01.wnl.0000178980.83477.14.
PubMed 16217067Low PA, Opfer-Gehrking TL, Textor SC, Benarroch EE, Shen WK, Schondorf R, Suarez GA, Rummans TA. Postural tachycardia syndrome (POTS). Neurology. 1995 Apr;45(4 Suppl 5):S19-25.
PubMed 7746369
Study at a glance
From the registry record, last updated by the sponsor on 18 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03070730
- Acronym / sponsor ID
- 2011P000246
- Keywords
- Tachycardia, orthostatic symptoms, autonomic reflex
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Recruitment was slow and subjects declined participation after signing the ICF.
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Beth Israel Deaconess Medical CenterUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- 15 Aug 2011 (actual)
- Primary completion
- 18 Dec 2012 (actual)
- Study completion
- 28 Jul 2014 (actual)
- First posted
- 6 Mar 2017 (actual)
- Results
- Posted 18 May 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| Atenolol | Other | Drug: Droxidopa, Drug: Atenolol, Drug: PlacebosIn 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. |
| Placebos | Other | Drug: PlacebosIn this arm subjects are randomized to placebo tid. Placebo is used to control the administration effect. |
| Droxidopa | Other | Drug: Droxidopa, Drug: Atenolol, Drug: PlacebosIn 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. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- CDC criteria for chronic fatigue syndrome
- Evidence of postural tachycardia syndrome with symptoms of orthostatic intolerance
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DroxidopaAlso: NortheraDroxidopa: 100 mg or 300 mg t.i.d | Drug | Atenolol, Droxidopa |
| AtenololAlso: TenorminAtenolol: 50 mg Q.D. | Drug | Atenolol, Droxidopa |
| PlacebosAlso: placeboPlacebo: t.i.d | Drug | Atenolol, Droxidopa, Placebos |
Primary outcome
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.
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.
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.
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.
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.
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.
36 secondary outcomes
Change in Blood Pressure From Baseline
Time frame: 1 week after first intervention
Change in Blood Pressure From Baseline
Time frame: 1 week after second intervention
Change in Blood Pressure From Baseline
Time frame: 1 week after third intervention
Change in Heart Rate From Baseline
Time frame: 1 week after first intervention
Change in Heart Rate From Baseline
Time frame: 1 week after second intervention
Change in Heart Rate From Baseline
Time frame: 1 week after third intervention
Change in Vascular Resistance From Baseline
Time frame: 1 week after first intervention
Change in Vascular Resistance From Baseline
Time frame: 1 week after second intervention
Change in Vascular Resistance From Baseline
Time frame: 1 week after third intervention
Change in Muscle Sympathetic Nerve Activity From Baseline
Time frame: 1 week after first intervention
Change in Muscle Sympathetic Nerve Activity From Baseline
Time frame: 1 week after second intervention
Change in Muscle Sympathetic Nerve Activity From Baseline
Time frame: 1 week after third intervention
Change in Physical Functioning-SF-36 Q From Baseline
Time frame: 1 week after first intervention
Change in Physical Functioning-SF-36 Q From Baseline
Time frame: 1 week after second intervention
Change in Physical Functioning-SF-36 Q From Baseline
Time frame: 1 week after third intervention
Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline
Time frame: 1 week after first intervention
Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline
Time frame: 1 week after second intervention
Change in Physical Functioning- 7 Item Patient Global Impression of Change From Baseline
Time frame: 1 week after third intervention
Change in Physical Functioning- HADS From Baseline
Time frame: 1 week after first intervention
Change in Physical Functioning- HADS From Baseline
Time frame: 1 week after second intervention
Change in Physical Functioning- HADS From Baseline
Time frame: 1 week after third intervention
Change in Physical Functioning-CIS From Baseline
Time frame: 1 week after first intervention
Change in Physical Functioning-CIS From Baseline
Time frame: 1 week after second intervention
Change in Physical Functioning-CIS From Baseline
Time frame: 1 week after third intervention
Change in Physical Functioning-MFI From Baseline
Time frame: 1 week after first intervention
Change in Physical Functioning-MFI From Baseline
Time frame: 1 week after second intervention
Change in Physical Functioning-MFI From Baseline
Time frame: 1 week after third intervention
Change in Physical Functioning-FSS From Baseline
Time frame: 1 week after first intervention
Change in Physical Functioning-FSS From Baseline
Time frame: 1 week after second intervention
Change in Physical Functioning-FSS From Baseline
Time frame: 1 week after third intervention
Change in Physical Functioning-EuroQOL From Baseline
Time frame: 1 week after first intervention
Change in Physical Functioning-EuroQOL From Baseline
Time frame: 1 week after second intervention
Change in Physical Functioning-EuroQOL From Baseline
Time frame: 1 week after third intervention
Change in Physical Functioning-OI From Baseline
Time frame: 1 week after first intervention
Change in Physical Functioning-OI From Baseline
Time frame: 1 week after second intervention
Change in Physical Functioning-OI From Baseline
Time frame: 1 week after third intervention
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 May 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 10037112Jacob G, Biaggioni I; New Collective Author. Idiopathic orthostatic intolerance and postural tachycardia syndromes. Am J Med Sci. 1999 Feb;317(2):88-101. doi: 10.1097/00000441-199902000-00003.
- Background: PubMed 10750135Karas 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.
- Background: PubMed 10926298Stewart 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.
- Background: PubMed 8423877Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology. 1993 Jan;43(1):132-7. doi: 10.1212/wnl.43.1_part_1.132.
- Background: PubMed 11018167Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M, Biaggioni I, Ertl A, Black B, Robertson D; New Collective Author. The neuropathic postural tachycardia syndrome. N Engl J Med. 2000 Oct 5;343(14):1008-14. doi: 10.1056/NEJM200010053431404.
- Background: PubMed 2243132Streeten DH. Pathogenesis of hyperadrenergic orthostatic hypotension. Evidence of disordered venous innervation exclusively in the lower limbs. J Clin Invest. 1990 Nov;86(5):1582-8. doi: 10.1172/JCI114878.
- Background: PubMed 10037116Low PA, Novak V, Spies JM, Novak P, Petty GW; New Collective Author. Cerebrovascular regulation in the postural orthostatic tachycardia syndrome (POTS). Am J Med Sci. 1999 Feb;317(2):124-33. doi: 10.1097/00000441-199902000-00007.
- Background: PubMed 12133874Freeman R, Lirofonis V, Farquhar WB, Risk M. Limb venous compliance in patients with idiopathic orthostatic intolerance and postural tachycardia. J Appl Physiol (1985). 2002 Aug;93(2):636-44. doi: 10.1152/japplphysiol.00817.2001.
- Background: PubMed 10684912Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, Robertson D; New Collective Author. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med. 2000 Feb 24;342(8):541-9. doi: 10.1056/NEJM200002243420803.
- Background: PubMed 15944872Al-Shekhlee A, Lindenberg JR, Hachwi RN, Chelimsky TC. The value of autonomic testing in postural tachycardia syndrome. Clin Auton Res. 2005 Jun;15(3):219-22. doi: 10.1007/s10286-005-0282-7.
- Background: PubMed 12460877Stewart JM, Munoz J, Weldon A. Clinical and physiological effects of an acute alpha-1 adrenergic agonist and a beta-1 adrenergic antagonist in chronic orthostatic intolerance. Circulation. 2002 Dec 3;106(23):2946-54. doi: 10.1161/01.cir.0000040999.00692.f3.
- Background: PubMed 10750641Gordon VM, Opfer-Gehrking TL, Novak V, Low PA; New Collective Author. Hemodynamic and symptomatic effects of acute interventions on tilt in patients with postural tachycardia syndrome. Clin Auton Res. 2000 Feb;10(1):29-33. doi: 10.1007/BF02291387.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roy Freeman, MD principal investigator
Beth Israel Deaconess Medical Center
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Droxidopa and Atenolol in people with Postural Orthostatic Tachycardia Syndrome and Orthostatic Intolerance, run by Beth Israel Deaconess Medical Center at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 18 May 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 May 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Maximal Postural Tachycardia During Tilt (time frame: Up to 3 days after randomization). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03070730, which also lists 24 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 May 2017.