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The goal of this clinical trial is to learn about the role of noradrenergic system in the non-motor symptoms of Parkinson's disease. The main objectives it aims to answer are:
Participants will be asked to come onsite for two study visits.
Visit one will consist of:
Visit two will consist of :
Visit three will be a follow-up call from the Nurse Coordinator to discuss any adverse events.
This is a cross-sectional pilot study comparing 10 PD patients with Orthostatic hypertension (OH) to 10 PD patients without OH. OH is defined as a drop in blood pressure within 5 minutes of standing (measured at 1, 2, and 5 minutes). The study will include two clinical visits and a follow-up phone call 24-72 hours after the 2nd visit. Visits will last approximately 4-5 hours each. During visit two the participant will be given a 5 mg tablet of Yohimbine hydrochloride. Yohimbine hydrochloride will be administered orally during Visit 2 in order to manipulate the noradrenergic system to determine the association between OH and neuropsychiatric symptoms in those with PD. Yohimbine is not administered as a treatment in this study, but as a tool to study the noradrenergic system during some of the assessments. This will be done by measuring the amounts of hormones in the participants body produces before and after yohimbine hydrochloride administration. Yohimbine hydrochloride is not approved by the FDA for this use.
On the morning of Visit 1, the participant will be asked to not take their medications that contains dopamine, such as levodopa/carbidopa, as well as other medications that would interfere with testing. The study doctor will determine which medications need to be held for this visit. The participant will be asked to bring one dose of these medications to take during the visit, instead of at the normal time in the morning. During visit one eligibility criteria will be discussed and if participants meet the inclusion exclusion criteria the Informed Consent will be signed and Visit 1 procedures will follow.
Visit 2 will occur no more than 30 days after visit 1. Subjects will be asked to not eat, and not take morning medications containing dopamine or norepinephrine (such as levodopa/carbidopa), or any other medications that interfere with testing. The neurologist will determine which medications need to be held for this visit. An IV will be placed as per Head Up Tilt procedure. Head Up Tilt testing will be conducted twice, once prior to and once after yohimbine administration. The participant will complete a scale that measures anxiety, mood, and fatigue prior to and after yohimbine administration. Pupil testing will also be evaluated prior to yohimbine administration and after yohimbine administration. Blood will be drawn twice prior to yohimbine administration and twice after yohimbine administration. One draw will be in a lying down position, and the other will be during the head up tilt.
A follow up study phone call will be made by the study nurse coordinator 24-72 hours after study visit 2. Any adverse events which may have occurred since the study visit will be captured on the participants adverse event log.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Yohimbine | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Yohimbine HCl | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | 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. | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Between group (Parkinson patients with and without orthostatic hypotension (PD+OH v PD-OH) change in self-reported anxiety before and 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 | Baseline and 45 minutes after yohimbine administration |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nathaniel M Robbins, MD | Dartmouth-Hitchcock Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dartmouth-Hitchcock | Lebanon | New Hampshire | 03756 | United States |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Nov 14, 2019 | Jan 16, 2020 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| D007024 | Hypotension, Orthostatic |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D015016 | Yohimbine |
| ID | Term |
|---|---|
| D046948 | Secologanin Tryptamine Alkaloids |
| D026121 | Indole Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
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| 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 |
| 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) | 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. | 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 |
| 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) | 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. | 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 |
| 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) | 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. | 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 |
| 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). | The NPI-Q measures 12 psychiatric symptoms, and each symptom (ie anxiety) is scored as absent or present. | 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 |
| 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) | The NPI-Q measures 12 psychiatric symptoms, and each symptom (ie apathy) is scored as absent or present. | 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 |
| 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). | The NPI-Q measures 12 psychiatric symptoms, and each symptom (ie depression) is scored as absent or present | 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 |
| Change in serum catecholamine levels (supine and orthostatic) before and after yohimbine administration | 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 | 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 desmopressin levels (supine and orthostatic) before and after yohimbine administration | Change in serum desmopressin levels 15 minutes after head-up tilt before and after yohimbine administration | 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 |
| Between group (Parkinson patients with and without orthostatic hypotension (PD+OH v PD-OH) change in self-reported mood before and 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 | Baseline and 45 minutes after yohimbine administration |
| Between group (Parkinson patients with and without orthostatic hypotension (PD+OH v PD-OH) change in self-reported fatigue before and 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 | Baseline and 45 minutes after yohimbine administration |
| Between group (PD+OH v PD-OH) change in diastolic blood pressure before and after yohimbine | 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 | Baseline (after resting 30 minutes supine) and 45 minutes after yohimbine administration |
| Between group (PD+OH v PD-OH) change in time until pupillary redilation before and after yohimbine | Change in time until pupillary redilation (measure in seconds after brief light stimulus using a NeuroOptics pupilometer) before and 45 minutes after yohimbine administration | Baseline (after resting 30 minutes supine) and 45 minutes after yohimbine administration |
| 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 | 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 | Baseline tilt test before yohimbine and second tilt 60 minutes after yohimbine administration |
| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |
| D054971 | Orthostatic Intolerance |
| D054969 | Primary Dysautonomias |
| D001342 | Autonomic Nervous System Diseases |
| D007022 | Hypotension |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D007211 |
| Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D054836 | Indolizidines |
| D007212 | Indolizines |