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Clinical Laboratory Evaluation of Chronic Autonomic Failure

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ClinicalTrials.gov Identifier: NCT03648905
Recruitment Status : Recruiting
First Posted : August 28, 2018
Last Update Posted : June 10, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

Brief Summary:

Background:

The autonomic nervous system controls automatic body functions. Researchers want to improve the tests used to diagnose autonomic failure. Orthostatic hypertension is a drop in blood pressure when a person stands up. Researchers want to focus on this sign of autonomic failure.

Objective:

To improve testing for conditions that cause autonomic nervous system failure.

Eligibility:

People ages 18 and older in one of these categories:

  • Their blood pressure drops when they get up.
  • They have had a heart transplant or bilateral endoscopic thoracic sympathectomies or have had or will have renal sympathetic ablation

Design:

All participants will be screened with:

  • Medical history
  • Physical exam
  • Blood and urine tests

Some participants will be screened with:

  • Heart and breathing tests
  • IV placement into an arm vein
  • Tilt table testing: Participants lie on a table that tilts while an IV is used to draw their blood.

Participants may stay in the hospital for up to 1 week depending on their tests. Tests may include repeats of screening tests and:

  • Sweat testing: A drug is placed on the skin to cause sweating. Sensors on the skin measure moisture.
  • Lumbar puncture: A needle is inserted between the bones in the back to collect fluid.
  • MRI and PET/CT scan: Participants lie on a table that slides into a scanner. For the PET/CT, a small amount of a radioactive chemical will be injected with a small amount of a radioactive chemical.
  • Bladder catheter placement to collect urine
  • Skin biopsies: A punch tool removes a small skin sample.
  • Tests to see how the pupils react to light
  • Smelling tests
  • Thinking and memory tests
  • Questionnaires

Participants may have a visit about 2 years later to repeat tests.


Condition or disease
Parkinson's Disease Multiple System Atrophy Autonomic Failure

Detailed Description:

Objective:

In dysautonomias, altered functions of one or more components of the autonomic nervous system adversely affect health. A subset of dysautonomias consists of chronic autonomic failure (CAF) syndromes. A key sign of CAF is orthostatic hypotension (OH) due to sympathetic neurocirculatory failure (neurognic OH, or nOH). Primary CAF has been classified based on clinical manifestations into three forms-pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson s disease with OH (PD+OH). All three forms involve deposition of the protein, alpha-synuclein (AS), in neurons (PD, PAF) or glial cells (MSA) and therefore are called autonomic synucleinopathies. Clinical assessment alone often is inadequate for distinguishing among these conditions in individual patients. Dementia with Lewy bodies (DLB) is another form of autonomic synucleinopathy. This observational study continues and expands on Protocol 03-N-0004, Clinical Laboratory Evaluation of Primary Chronic Autonomic Failure. The objective is to conduct multi-modality testing of catecholaminergic and autonomic systems in patients with neurodegenerative chronic

autonomic failure (CAF). The goals are to: (a) build up rosters of well characterized patients for future experimental therapeutic trials; (b) test predictions derived from the catecholaldehyde hypothesis for the pathogenesis of autonomic synucleinopathies; (c) follow the natural history of neurodegenerative chronic autonomic failure (CAF); and (d) discover new clinical entities involving catecholaminergic neurodegeneration.

Study Population:

The study population consists of patients with neurodegenerative chronic autonomic failure (neurodegenerative CAF) identified by on site screening at the NIH Clinical Center. Comparison groups include a group on control patients with iatrogenic CAF (e.g., status-post cardiac transplantation, pre/post renal sympathetic ablation, pre/post bilateral thoracic sympathectomies) or PD and without OH (PD No OH), and a group of Healthy Volunteers (HVs), some of whom have genetic abnormalities known to increase the risk of developing PD. A group of MSA patients is included, to build up a subject roster for a planned clinical trial.

Design:

This is an observational pathophysiology/natural history study with a planned duration of 3 years. Descriptive statistics will be done in diagnostic groups with neurodegenerative CAF.

Outcome Measures:

The primary outcome measure is results of clinical laboratory research tests in neurodegenerative CAF patients. Neuroimaging data are from MRI and from 18F-DOPA and 18F-dopamine PET scanning. Neurochemical data are from assays of catechols in plasma and cerebrospinal fluid. Immunofluorescence microscopy data are from analyses of immunoreactive tyrosine hydroxylase and AS in skin biopsy samples. Neurobehavioral rating scale data are from the University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Uniform Parkinson s Disease Rating Scale (UPDRS). Correlation analyses will be done among individual values for outcome measures. A secondary outcome measure is estimated non-specific binding of 11C-methylreboxetine, based on studies of patients with iatrogenic CAF and desipraminetreated HVs.


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Study Type : Observational
Estimated Enrollment : 140 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Clinical Laboratory Evaluation of Chronic Autonomic Failure
Actual Study Start Date : September 6, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021


Group/Cohort
Control patients (iatrogenic CAF)
Patients with iatrogenic chronic autonomic failure (CAF) (e.g., status-post cardiac transplantation, pre/post renal sympathetic ablation, pre/post bilateral thoracic sympathectomies)
Control patients (PD No OH)
Patients with Parkinson's disease (PD) without orthostatic hypotension (PD no OH
Healthy Volunteers
Healthy Volunteers, includes people with genetic risk of PD
Patients with neurodegenerative chronic autonomic failure (CAF
Includes patients with orthostatic hypotension (OH) due to sympathetic neurocirculatory failure (nOH), and people with multiple system atrophy (MSA).



Primary Outcome Measures :
  1. Pathophysiological classification based on clinical laboratory test results [ Time Frame: Initial Visit and on an approximately biennial basis ]
    Neuroimaging data are from MRI and from 18F-DOPA and 18F-dopamine PET scanning. Neurochemical data are from assays of catechols in plasma and cerebrospinal fluid. Immunofluorescence microscopy data are from analyses of immunoreactive tyrosine hydroxylase and AS in skin biopsy samples. Neurobehavioral rating scale data are from the University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Uniform Parkinson s Disease Rating Scale (UPDRS).


Secondary Outcome Measures :
  1. Estimated non-specific binding of 11C-methylreboxetine [ Time Frame: Initial Visit ]
    Estimated non-specific binding of 11C-methylreboxetine is based on studies of patients with iatrogenic CAF and desipramine-treated HVs



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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
The study population consists of patients with neurodegenerative chronic autonomic failure (neurodegenerative CAF) identified by on-site screening at the NIH Clinical Center. Comparison groups include a group of control patients with iatrogenic CAF (e.g., status-post cardiac transplantation, pre/post renal sympathetic ablation, pre/post bilateral thoracic sympathectomies) or PD without OH (PD No OH), and a group of Healthy Volunteers (HVs), some of whom have genetic abnormalities known to increase the risk of developing PD. A group of MSA patients is included, to build up a subject roster for a planned clinical trial.@@@@@@
Criteria
  • INCLUSION CRITIERIA:

Inclusion Critieria: Patients referred for orthostatic hypotension. This is the main subject cohort.

  • Previously studied and diagnosed with one of the forms of nOH or else newly accrued with a referral diagnosis of orthostatic hypotension, and
  • 18 years or older, and
  • Able to provide own consent to participate or have an existing Legally Authorized Representative (LAR).

If a patient has already been diagnosed as having neurodegenerative CAF under NIH Clinical Protocol 03-N-0004, this satisfies the inclusion criteria for that patient. Previous enrollment in NIH Clinical Protocol 03-N-0004 is not required for enrollment in this study. We do plan to recruit participation intothis study from NIH Clinical Protocol 03-N-0004 which has been closed.

If a patient has been referred for OH, then the patient gives consent at the NIH Clinical Center (and therefore is accrued) and then has screening testing at the NIH Clinical Center to confirm that the OH is neurogenic. We anticipate that all patients referred for OH will be shown to have nOH upon screening testing at the NIH Clinical Center. At the time of screening, exclusionary abnormal laboratory test results (e.g., high serum creatinine indicating renal failure) may come to light, in which case they will be withdrawn from the study; however, the patient would have been accrued.

Inclusion criteria: Control patients with iatrogenic CAF

  • Patients with heart transplants, pre or post bilateral endoscopic thoracic sympathectomies, or pre or post-renal sympathetic ablation, and
  • 18 years or older, and
  • Able to provide own consent to participate.

Inclusion criteria: Cotrol patients with PD No OH:

-Patients with PD and no OH who have (a) already been evaluated under other protocols of the AMS and are undergoing follow-up; (b) have already been evaluated under another intramural NINDS protocol; or (c) have cardiac symptoms, signs, or laboratory findings that in the opinion of the PI make it likely there is a cardiac

sympathetic lesion, and

  • 18 years or older, and
  • Able to provide own consent to participate.

Inclusion criteria: Healthy Volunteers:

  • Age 18 years or older and
  • Able to provide own informed consent to participate

NIH employees may participate. There is no direct solicitation of employees/staff by supervisors. Co-workers will not solicit co-workers. NIH employees are required to abide by NIH Policy Manual 2300-630-3, Leave Policy for NIH Employees Participating in

NIH Medical Research Studies.

EXCLUSION CRITIERIA:

Patient Group Referred for Orthostatic Hypotension

  • A medical condition that in the judgment of the Principal Investigator would place the subject at substantially increased acute medical risk, or
  • A disqualifying condition such as: hepatic or renal failure, symptomatic congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, currently symptomatic coronary heart disease, cerebrovascular disease with current symptoms (e.g., recent transient ischemic attacks), diabetes or
  • Secondary form of CAF, such as diabetic autonomic neuropathy, or
  • Being treated currently (within 2 weeks of anticipated protocol participation) with a medication known to interfere with the cell membrane norepinephrine transporter, which would obviate obtaining scientifically valid results (e.g., tricyclic antidepressant).
  • Condition that may cause difficulty or inability to insert a catheter into a vein, or
  • Unable to tolerate lying still for up to 1 hour during the procedures, or
  • Refusal to undergo certain procedures. These include: (1) IV catheter and blood drawing; (2) DNA extraction, storage, and analysis; (3) PET scanning; and (4) skin biopsies, or
  • History of keloid, or
  • Unable to travel safely to the NIH CC, or
  • Lacking consent capacity, unless a Durable Power of Attorney (DPA) is in place.
  • Subordinates of study investigators or relatives of the PI or AIs.

Patient Control Group with Iatrogenic CAF or PD no OH

  • A medical condition which in the judgment of the Principal Investigator would place the subject at substantially increased acute medical risk, or
  • A disqualifying condition such as: hepatic or renal failure, symptomatic congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, currently symptomatic coronary heart disease, cerebrovascular disease with current symptoms (e.g., recent transient ischemic attacks), or diabetes or
  • Being treated currently (within 2 weeks of anticipated protocol participation) with a medication that would obviate obtaining scientifically valid results (e.g., tricyclic antidepressant).
  • Condition that may cause difficulty or inability to insert a catheter into a vein, or
  • Unable to tolerate lying still for up to 1 hour during the procedures, or
  • Refusal to undergo certain procedures. These include: (1) IV catheter and (2) PET scanning, or
  • Unable to travel safely to the NIH CC, or
  • Lacking consent capacity, or
  • Subordinates of study investigators or relatives of the PI or AIs.

Healthy Volunteer Group

  • A medical condition which in the judgment of the Principal Investigator would place the subject at substantially increased acute medical risk, or
  • A disqualifying condition such as: hepatic or renal failure, symptomatic congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, currently symptomatic coronary heart disease, cerebrovascular disease with current symptoms (e.g., recent transient ischemic attacks), diabetes or
  • Being treated currently (within 2 weeks of anticipated protocol participation) with a medication that would obviate obtaining scientifically valid results (e.g., tricyclic antidepressant).
  • Condition that may cause difficulty or inability to insert a catheter into a vein, or
  • Unable to tolerate lying still for up to 1 hour during the procedures, or
  • Refusal to undergo certain procedures. These include: (1) IV catheter and (2) PET scanning, or
  • Unable to travel safely to the NIH CC, or
  • Lacking consent capacity, or
  • Subordinates of study investigators or relatives of the PI or AIs.

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): NCT03648905


Contacts
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Contact: Janna Gelsomino, R.N. (301) 435-5166 janna.gelsomino@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: David S Goldstein, M.D. National Institute of Neurological Disorders and Stroke (NINDS)

Additional Information:
Publications:
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Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier: NCT03648905     History of Changes
Other Study ID Numbers: 180140
18-N-0140
First Posted: August 28, 2018    Key Record Dates
Last Update Posted: June 10, 2019
Last Verified: June 4, 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):
Autonomic Failure
Parkinson's Disease
Pure Autonomic Failure
Multiple System Atrophy
Lewy Body
Catecholamines

Additional relevant MeSH terms:
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Multiple System Atrophy
Shy-Drager Syndrome
Brain Diseases
Parkinson Disease
Atrophy
Pure Autonomic Failure
Parkinsonian Disorders
Basal Ganglia Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Pathological Conditions, Anatomical
Primary Dysautonomias
Autonomic Nervous System Diseases
Hypotension
Vascular Diseases
Cardiovascular Diseases