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Trial record 1 of 2 for:    premorbid functioning assessment | Parkinson Disease
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The Role of the Noradrenergic System in the Nonmotor Symptoms of Parkinson's Disease (NAinPD)

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ClinicalTrials.gov Identifier: NCT04346394
Recruitment Status : Recruiting
First Posted : April 15, 2020
Last Update Posted : February 22, 2022
Sponsor:
Information provided by (Responsible Party):
Nathaniel M. Robbins, Dartmouth-Hitchcock Medical Center

Brief Summary:

The purpose of the study is to learn about the role of noradrenergic system in the non-motor symptoms of Parkinson's disease. In particular, researchers hope to better understand what role the noradrenergic system may play in the regulation of blood pressure, cognition and mood symptoms in patients with Parkinson's disease. With this information, future research may explore treatments that target the noradrenergic system in order to better treat the non-motor symptoms of Parkinson's disease.

The experimental drug used in some of the study assessments, yohimbine hydrochloride, is not being tested as a potential treatment for Parkinson's disease. Yohimbine hydrochloride will be used to manipulate the noradrenergic system during some of the assessments. By measuring the amounts of hormones and neurotransmitters the body produces before and after yohimbine hydrochloride administration, researchers can assess how well the noradrenergic system is functioning.


Condition or disease Intervention/treatment Phase
Parkinson Disease Drug: Yohimbine HCl Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: The Role of the Noradrenergic System in the Nonmotor Symptoms of Parkinson's Disease: Orthostatic Hypotension and Other Nonmotor Symptoms
Actual Study Start Date : October 11, 2021
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : May 2023


Arm Intervention/treatment
Experimental: Yohimbine
The first visit in the study has no interventional drug. Yohimbine (5mg) is administered orally during visit two, during a head up tilt test, to manipulate the noradrenergic system to determine the association between OH and NP symptoms in those with PD. Yohimbine is not administered as a treatment in this study, but as a pharmacologic tool to study the adrenergic system.
Drug: Yohimbine HCl
Yohimbine hydrochloride will be used to manipulate the noradrenergic system during some of the assessments. By measuring the amounts of hormones the body produces before and after yohimbine hydrochloride administration, researchers can assess how well the noradrenergic system is functioning




Primary Outcome Measures :
  1. Difference in fatigue (measured with the self-reported Fatigue Severity Scale) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [ Time Frame: All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ]
    The Fatigue Severity Scale (FSS) measures average fatigue experienced over the previous week. The FSS questionnaire contains nine statements that rate the severity of fatigue symptoms. A low value indicates strong disagreement with the statement, a high value indicates strong agreement. A total score of 36 or more suggests presence of fatigue.


Secondary Outcome Measures :
  1. Difference in apathy (measured with the self-reported Apathy Evaluation Scale) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [ Time Frame: All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ]
    Apathy Evaluation Scale (AES) measures apathy over the previous month. The AES questionnaire contains 18 statements that each rAll measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ate the severity of apathy on a scale from 1 to 4. A total score ranges from 18 to 72, with higher scores indicating more apathy.

  2. Difference in self-reported depression (measured with the Geriatric Depression Scale - short form) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [ Time Frame: All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ]
    The Geriatric Depression Scale - short form measures depression over the previous week. This questionnaire contains 15 questions that are answered by either indicating "Yes" or "No" to the questions. The total score ranges from 0 to 15, with higher scores indicating more depression.

  3. Difference in self-reported anxiety (measured with the Geriatric Anxiety Inventory) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [ Time Frame: All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ]
    The Geriatric Anxiety Inventory measures anxiety over the previous week. This questionnaire contains 20 questions that are answered by indicating either "Yes" or "No" to the questions. The total score ranges from 0 to 20, with higher scores indicating more anxiety.

  4. Difference in neurocognition (measured with average composite z-score on a neurocognitive battery) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [ Time Frame: All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ]
    Neurocognition will be measured with the following battery, adjusting for age, gender, education level, and premorbid functioning. Digit Span subtest from the Wechsler Adult Intelligence Scale - IV; Symbol Digit Modalities Test; Trail Making Test; California Verbal Learning Test - II; Rey Complex Figure Test; DKEFS Color-Word Interference Test; Phonemic and Semantic Verbal Fluency; Behavior Rating Inventory of Executive Function - Adult Outcome. An average composite z-score will calculated and compared between groups.

  5. Difference in informant-reported anxiety (measured by an informant-reported Neuropsychiatric Inventory Questionnaire) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH). [ Time Frame: All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ]
    The NPI-Q measures 12 psychiatric symptoms, and each symptom (ie anxiety) is scored as absent or present.

  6. Difference in informant-reported apathy (measured by an informant-reported Neuropsychiatric Inventory Questionnaire) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [ Time Frame: All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ]
    The NPI-Q measures 12 psychiatric symptoms, and each symptom (ie apathy) is scored as absent or present.

  7. Difference in informant-reported depression (measured by an informant-reported Neuropsychiatric Inventory Questionnaire) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH). [ Time Frame: All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ]
    The NPI-Q measures 12 psychiatric symptoms, and each symptom (ie depression) is scored as absent or present

  8. Change in serum catecholamine levels (supine and orthostatic) before and after yohimbine administration [ Time Frame: Baseline (supine position), after 5 minutes of head-up tilt, 60 minutes after yohimbine administration (supine position), and 5 minutes after that with repeat head-up tilt. ]
    Change in serum catecholamine levels will be measured from blood samples collected from participants upon lying face up and 5 minutes after head-up tilt, before and after yohimbine administration

  9. Change in serum desmopressin levels (supine and orthostatic) before and after yohimbine administration [ Time Frame: Baseline (supine), after 15 minutes of head-up tilt, 60 minutes after yohimbine administration (supine position) and 15 minutes after that with repeat head-up tilt ]
    Change in serum desmopressin levels 15 minutes after head-up tilt before and after yohimbine administration


Other Outcome Measures:
  1. Between group (Parkinson patients with and without orthostatic hypotension (PD+OH v PD-OH) change in self-reported anxiety before and after yohimbine administration [ Time Frame: Baseline and 45 minutes after yohimbine administration ]
    Change in self-reported anxiety levels before and after yohimbine administration measured with an 11-point visual analogue scale (0-10), where a higher score indicate more anxiety and fatigue

  2. Between group (Parkinson patients with and without orthostatic hypotension (PD+OH v PD-OH) change in self-reported mood before and after yohimbine administration [ Time Frame: Baseline and 45 minutes after yohimbine administration ]
    Change in self-reported mood before and after yohimbine administration measured with an 11-point visual analogue scale (0-10), where a higher score indicate more anxiety and fatigue

  3. Between group (Parkinson patients with and without orthostatic hypotension (PD+OH v PD-OH) change in self-reported fatigue before and after yohimbine administration [ Time Frame: Baseline and 45 minutes after yohimbine administration ]
    Change in self-reported fatigue levels before and after yohimbine administration measured with an 11-point visual analogue scale (0-10), where a higher score indicate more anxiety and fatigue

  4. Between group (PD+OH v PD-OH) change in diastolic blood pressure before and after yohimbine [ Time Frame: Baseline (after resting 30 minutes supine) and 45 minutes after yohimbine administration ]
    Change in diastolic blood pressure (measured in mmHg, supine after 30 min rest) before and after yohimbine administration in Parkinson's patient with and without orthostatic hypotension

  5. Between group (PD+OH v PD-OH) change in time until pupillary redilation before and after yohimbine [ Time Frame: Baseline (after resting 30 minutes supine) and 45 minutes after yohimbine administration ]
    Change in time until pupillary redilation (measure in seconds after brief light stimulus using a NeuroOptics pupilometer) before and 45 minutes after yohimbine administration

  6. Between group (PD+OH v PD-OH) difference in change in time to recovery of BP after 60 degree head-up tilt before and after yohimbine administration [ Time Frame: Baseline tilt test before yohimbine and second tilt 60 minutes after yohimbine administration ]
    Change in time to recovery of systolic blood pressure (measured in seconds back to baseline) after 60 degree head-up tilt before and after yohimbine administration



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:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant able to provide informed consent
  2. Diagnosis of Parkinson's disease confirmed by a DH neurologist according to Movement Disorder Society criteria, with the exception that "Red flag" 5a will not be used (severe autonomic failure within five years of disease onset).
  3. All subjects must have CMP and CBC drawn within 6 months of study visit 1, with results in the normal range or with abnormal results not considered to be clinically significant in the investigator's opinion.
  4. Female patients must be post-menopausal (at least one year) or not planning to get pregnant and have negative pregnancy test.

Exclusion Criteria:

  1. Diagnosis or previous history of diabetes of any kind
  2. Known autonomic neuropathy unrelated to PD
  3. History of or current cardiac, liver or renal disease that, in the opinion of the investigator, may put the patient at risk because of participation in the study
  4. Known condition that in the investigator's opinion would be a contraindication to HUT testing or yohimbine challenge (e.g. decompensated cardiac disease, severe positional vertigo; severe anxiety, known panic disorder69)
  5. Current use of catecholaminergic medications (e.g. stimulants, droxidopa, midodrine) that cannot be held for at least three half-lives
  6. Inability to hold PD medications for at least 12 hours
  7. History of major depressive or bipolar disorder preceding the diagnosis of PD,69 or diagnosis or previous history of psychiatric illness that in the investigator's opinion would affect the subject's ability to successfully participate in the study.
  8. Any history (other than PD) that could significantly and adversely affect neurocognitive function, such as history of traumatic brain injury (head injury with loss of consciousness > 1 hour), known dementia unrelated to Parkinson's or related diseases; developmental delay, multiple sclerosis or epilepsy with cognitive impairment, intellectual deficit, diagnosed and untreated sleep apnea; untreated syphilis; HIV with HAND; or other conditions that, based on the investigators opinion, could interfere with neurocognitive evaluation.
  9. Known ophthalmologic disease such as untreated cataract, glaucoma, optic neuritis, orbital trauma, or other neuroretinal disease that might impact pupillary function
  10. Severe illness within 30 days prior to enrollment.
  11. Use of opiate, procholinergic, or other medications influencing pupillary function that cannot be held for three half-lives
  12. In the Investigator's opinion, subject would be unable to successfully participate in the study for any reason.

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): NCT04346394


Contacts
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Contact: Stephanie Langlois, BS 603-650-4646 Stephanie.E.Langlois@hitchcock.org

Locations
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United States, New Hampshire
Dartmouth-Hitchcock Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Stephanie Langlois, BS    603-650-4646    Stephanie.E.Langlois@hitchcock.org   
Sponsors and Collaborators
Nathaniel M. Robbins
Investigators
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Principal Investigator: Nathaniel M Robbins, MD Dartmouth-Hitchcock Medical Center
  Study Documents (Full-Text)

Documents provided by Nathaniel M. Robbins, Dartmouth-Hitchcock Medical Center:
Study Protocol  [PDF] November 14, 2019

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Responsible Party: Nathaniel M. Robbins, Physician, Assistant Professor of Neurology, Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT04346394    
Other Study ID Numbers: D19090
First Posted: April 15, 2020    Key Record Dates
Last Update Posted: February 22, 2022
Last Verified: February 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nathaniel M. Robbins, Dartmouth-Hitchcock Medical Center:
Parkinson's
Orthostatic Hypotension
Yohimbine
Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Synucleinopathies
Yohimbine
Mydriatics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic alpha-2 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Urological Agents