Norepinephrine Transporter Blockade as a Pathological Biomarker in Neurogenic Orthostatic Hypotension (6103)

• ClinicalTrials.gov Identifier: NCT01316666
• Recruitment Status: Completed
• First Posted: March 16, 2011
• Last Update Posted: January 6, 2017
• Sponsor: Vanderbilt University Medical Center
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Italo Biaggioni, Vanderbilt University

Study Description

Brief Summary:

The autonomic or automatic nervous system helps control blood pressure. Diseases of the autonomic nervous system may result in a drop in blood pressure on standing in many cases leading to fainting. Diseases that affect the autonomic nervous system include pure autonomic failure, multiple system atrophy and Parkinson's disease, and can present with very similar symptoms and it is sometimes difficult to determine an exact diagnosis. The purpose of the study is to find out if the blood pressure response from taking a single dose of the medication atomoxetine can help in the diagnosis of these diseases.

Condition or disease
Orthostatic Hypotension; Pure Autonomic Failure; Multiple System Atrophy; Parkinson's Disease

Detailed Description:

This is an observational, prospective three-year longitudinal study. The investigators will enroll participants with primary neurogenic orthostatic hypotension. All participants will undergo an extensive neurological and cardiovascular evaluation, including detailed autonomic testing and quality of life assessment. The investigators will then determine the magnitude of the pressor effect produced by 18 mg atomoxetine given orally, measured 1 hour after drug administration. Participants will be followed annually or more often if there is a significant change in their clinical condition. During follow up at year 3, the investigators will repeat the initial neurological, cardiovascular and autonomic evaluation. The primary endpoint would be the final diagnosis made at year 3 after the initial evaluation (at the end of the follow-up period) or if they develop significant worsening of symptoms during follow-up phone assessments, based on specific clinical criteria.

Study Design

• Study Type: Observational
• Actual Enrollment: 50 participants
• Time Perspective: Prospective
• Official Title: Norepinephrine Transporter Blockade as a Pathophysiological Biomarker in Neurogenic Orthostatic Hypotension
• Study Start Date: March 2011
• Actual Primary Completion Date: December 2016
• Actual Study Completion Date: December 2016

Groups and Cohorts

Group/Cohort
Neurogenic Hypotension; Patients with neurogenic hypotension, which includes those with Pure Autonomic Failure (PAF), Multiple System Atrophy (MSA) and Parkinson Disease (PD)

Outcome Measures

Primary Outcome Measures :

1. Final Diagnosis (pre vs post ganglionic autonomic failure) based on clinical criteria. [ Time Frame: 3 years ]

   Probable MSA - PAF with urinary incontinence or an orthostatic decrease of 30 mmHG in systolic blood pressure within 3 minutes of standing and poorly levodopa responsive parkinsonism or a cerebellar syndome.

   For Possible MSA - parkinsonism or a cerebellar syndrome and one additional feature.

   Probable PAF - orthostatic hypotension and impaired autonomic reflexes in the absence of clinical signs or symptoms of neurodegeneration.

   For Parkinson's Disease: diagnosed based on the United Kingdom Parkinson Disease Society Brain Bank clinical diagnostic criteria.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

participants with neurogenic orthostatic hypotension, which is a drop in systolic blood pressure of at least 30 mmHg within 5 minutes of standing with associated impaired autonomic reflexes.

Criteria

Inclusion Criteria:

• Age 18-80 years old with Neurogenic orthostatic hypotension, ≥30 mmHg drop in SBP within 5 minutes of standing
• Associated with impaired autonomic reflexes, as determined by absence of blood pressure overshoot during phase IV of the Valsalva maneuver
• Absence of other identifiable causes of autonomic neuropathy
• Able and willing to provide informed consent

Exclusion Criteria:

• Pregnancy
• Systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathy of unknown significance, and autoimmune neuropathies
• Known intolerance to atomoxetine, Pre-existing sustained severe hypertension (BP at least 180/110 mmHg in the sitting position)
• Clinically unstable coronary artery disease, or major cardiovascular or neurological event in the past 6 months
• Any other significant systemic, hepatic, cardiac or renal illness
• Use of MAO-I within 14 days
• Known closed-angle glaucoma or Life-threatening arrhythmias

Contacts and Locations

Locations

United States, Massachusetts

Beth Israel Deaconess Medical Center (Harvard)

Boston, Massachusetts, United States, 02215

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55902

United States, New York

New York University

New York, New York, United States, 10016

United States, Tennessee

Vanderbilt University

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University Medical Center

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Italo Biaggioni, MD; Vanderbilt University

More Information

Additional Information:

Beth Israel Deaconess Medical Center Department of Neurology 

New York University Dysautonomia Center 

Publications:

Birkenfeld AL, Schroeder C, Boschmann M, Tank J, Franke G, Luft FC, Biaggioni I, Sharma AM, Jordan J. Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation. 2002 Nov 5;106(19):2459-65. doi: 10.1161/01.cir.0000036370.31856.73.

Esler MD, Wallin G, Dorward PK, Eisenhofer G, Westerman R, Meredith I, Lambert G, Cox HS, Jennings G. Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans. Am J Physiol. 1991 Apr;260(4 Pt 2):R817-23. doi: 10.1152/ajpregu.1991.260.4.R817.

Gilman S, Low P, Quinn N, Albanese A, Ben-Shlomo Y, Fowler C, Kaufmann H, Klockgether T, Lang A, Lantos P, Litvan I, Mathias C, Oliver E, Robertson D, Schatz I, Wenning G. Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clin Auton Res. 1998 Dec;8(6):359-62. doi: 10.1007/BF02309628.

Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008 Aug 26;71(9):670-6. doi: 10.1212/01.wnl.0000324625.00404.15.

Goldstein DS, Holmes C. Metabolic fate of the sympathoneural imaging agent 6-[18F]fluorodopamine in humans. Clin Exp Hypertens. 1997 Jan-Feb;19(1-2):155-61. doi: 10.3109/10641969709080812.

Goldstein DS, Polinsky RJ, Garty M, Robertson D, Brown RT, Biaggioni I, Stull R, Kopin IJ. Patterns of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol. 1989 Oct;26(4):558-63. doi: 10.1002/ana.410260410.

Horimoto Y, Matsumoto M, Akatsu H, Ikari H, Kojima K, Yamamoto T, Otsuka Y, Ojika K, Ueda R, Kosaka K. Autonomic dysfunctions in dementia with Lewy bodies. J Neurol. 2003 May;250(5):530-3. doi: 10.1007/s00415-003-1029-9.

Kaufmann H, Nahm K, Purohit D, Wolfe D. Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology. 2004 Sep 28;63(6):1093-5. doi: 10.1212/01.wnl.0000138500.73671.dc.

• Responsible Party: Italo Biaggioni, MD, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT01316666
• Other Study ID Numbers: 101311; U54NS065736 ( U.S. NIH Grant/Contract )
• First Posted: March 16, 2011
• Last Update Posted: January 6, 2017
• Last Verified: January 2017

Keywords provided by Italo Biaggioni, Vanderbilt University:

orthostatic hypotension; Multiple System Atrophy; Pure Autonomic Failure; Parkinson's Disease

Additional relevant MeSH terms:

Parkinson Disease; Multiple System Atrophy; Shy-Drager Syndrome; Hypotension, Orthostatic; Pure Autonomic Failure; Hypotension; Atrophy; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Pathological Conditions, Anatomical; Vascular Diseases; Cardiovascular Diseases; Primary Dysautonomias; Autonomic Nervous System Diseases; Orthostatic Intolerance