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Noradrenergic and Stress-Related Etiologies of Chronic Fatigue Syndrome

Primary Purpose

Chronic Fatigue Syndrome

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Posture Study, Autonomic Function Tests, and a Stress Test
Sponsored by
Vanderbilt University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Chronic Fatigue Syndrome focused on measuring CFS, Stress, Norepinephrine Transporter (NET), Norepinephrine (NE), Healthy Controls, Fatigue

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

Chronic Fatigue Participants:

Inclusion Criteria:

  • Confirmed chronic fatigue with severity >50 on a scale of 1 to 100 that is not improving over time
  • Meet The Centers for Disease Control and Prevention (CDC) diagnostic criteria of CFS (self-reported persistent or relapsing fatigue lasting 6 or more consecutive months)

Exclusion Criteria:

  • Male and female subjects <18 or >60 years
  • Obesity, defined as a BMI of 30 or more
  • Presence of other medical or psychiatric conditions known to cause fatigue (alcohol/drug abuse, anorexia nervosa, bipolar disorder, bulimia nervosa, dementia, major depression, psychotic/delusional disorders, schizophrenia)
  • Presence of sleep disorder/disruption known to cause fatigue (sleep apnea, narcolepsy)
  • Cardiovascular, pulmonary, hepatic, or hematological disease by history or prior testing defined as significant by investigator (including but not limited to chronic hepatitis, chronic kidney disease, cirrhosis, emphysema, heart failure, HIV, lupus, multiple sclerosis, myasthenia gravis, rheumatoid arthritis)
  • History of hypertension defined as supine resting BP>145/95 mmHg off medications or needing antihypertensive medication
  • Patients taking medications that can affect autonomic function or plasma catecholamines (vasoactive drugs), stimulants, and/or are sedatives
  • Other factors which in the opinion of the investigator could potentially impact the study outcomes (e.g., underlying disease, medications, history)* or prevent the participant from completing the protocol (poor compliance or unpredictable schedule)
  • Inability to stand unassisted for 10 minutes
  • Patients who are bedridden or chair-ridden
  • Patients who are colorblind
  • Inability or refusal to give informed consent for any reason including a diagnosis of dementia or cognitive impairment
  • Patients who are pregnant or breastfeeding

Healthy Control Participants:

  • Participant with no significant reported conditions or medications.

Exclusion Criteria:

  • Male and female subjects <18 or >60 years
  • Obesity, defined as a BMI of 30 or more
  • Presence of any serious or chronic disease, or prescription medication as deemed by investigator including hypertension as defined by supine resting BP >145/95 mmHg off medications or needing antihypertensive medication
  • Other factors which in the investigator's opinion would prevent the participant from completing the protocol, including poor compliance during previous studies or an unpredictable schedule
  • Inability to stand unassisted for 10 minutes
  • Patients who are bedridden or chair-ridden
  • Patients who are colorblind
  • Inability or refusal to give informed consent for any reason including a diagnosis of dementia or cognitive impairment
  • Patients who are pregnant or breastfeeding
  • Stress Overload Score above 66

Sites / Locations

  • Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Chronic Fatigue Patients

Healthy Controls

Arm Description

Patients between 18-60 years of age with fatigue symptoms who meet preliminary chronic fatigue phenotype criteria and complete preliminary screening surveys. Participants will undergo a Posture Study, Autonomic Function Tests, and a Stress Test. Participants' blood will be drawn to measure markers of sympathetic nervous system function.

Patients between 18-60 years of age with no known conditions or prescription medications who meet preliminary screening criteria. Participants will undergo a Posture Study, Autonomic Function Tests, and a Stress Test. Participants' blood will be drawn to measure markers of sympathetic nervous system function.

Outcomes

Primary Outcome Measures

dihydroxyphenylglycol (DHPG)/norepinephrine (NE) Ratio (post stress)
Change in DHPG/NE Ratio from Baseline to post stress compared across arms

Secondary Outcome Measures

DHPG/NE Ratio (post Autonomic Function test)
Change in DHPG/NE Ratio from Baseline to post Autonomic Function test compared across arms
DHPG/NE Ratio (post Standing position)
Change in DHPG/NE Ratio from Baseline to post Standing position compared across arms
DHPG/NE Ratio (post Sitting position)
Change in DHPG/NE Ratio from Baseline to post Sitting position compared across arms
Absolute DHPG and NE Levels (post stress)
Change in absolute DHPG and NE Levels from Baseline to post stress compared across arms
Absolute DHPG and NE Levels (post Autonomic Function test)
Change in DHPG and NE levels from Baseline to post Autonomic Function test compared
Absolute DHPG and NE Levels (post Standing position)
Change in absolute DHPG and NE Levels from Baseline to post Standing position compared across arms
Absolute DHPG and NE Levels (post Sitting position)
Change in DHPG and NE levels from Baseline to post Sitting position compared across arms
Fatigue as assessed by Multidimensional Assessment of Fatigue Scale (MAF)
Mean values +/- standard deviation (SD) compared across arms
Mood as assessed by Hospital Anxiety and Depression Scale (HADS)
Mean values +/- SD compared across arms
Quality of Life as assessed by 36-Item Short Form Survey Instrument (SF-36)
Mean values +/- SD compared across arms
Stress as assessed by Stress Overload Scale
Mean values +/- SD compared across arms
Cytokines
Compared across arms

Full Information

First Posted
January 9, 2017
Last Updated
April 25, 2018
Sponsor
Vanderbilt University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03029377
Brief Title
Noradrenergic and Stress-Related Etiologies of Chronic Fatigue Syndrome
Official Title
Noradrenergic and Stress-Related Etiologies of Chronic Fatigue Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Completed
Study Start Date
January 2017 (Actual)
Primary Completion Date
February 23, 2018 (Actual)
Study Completion Date
February 23, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The objective of this study is to measure sympathetic nervous system function and stress responses in patients with clinically documented and self-reported chronic fatigue that is worsened by stress, compared to healthy controls. Baseline norepinephrine (NE) levels and stress-induced NE levels in patients who fulfill criteria for Chronic Fatigue Syndrome (CFS) and who self-identify with stress induced worsening fatigue, will be compared to data from normal individuals pre and post-stress.
Detailed Description
Symptoms of Chronic Fatigue Syndrome (CFS) are critically important to study as patients report that these symptoms are often profoundly debilitating and an impediment to effective daily functioning as well as effective vocational and social functioning, while also contributing to a significantly increased risk of psychiatric illness and diminished quality of life. Previous Phenome-Wide Association (PheWAS) studies revealed a link between a norepinephrine transporter (NET) genetic variant and CFS. Based on the potential function of the variant and published literature, elevated norepinephrine (NE) levels may underlie at least some cluster of fatigue symptoms. Some patients may experience chronic fatigue that is due to an excess of circulating NE, and fatigue symptoms are reported by our patient population to be commonly exacerbated by stress. This study will test the hypothesis that in a subset of people with severely debilitating fatigue of long duration (>6 months) that is worsened by stress identified through the Vanderbilt electronic health record phenotyping study, have chronic over-release of the hormone NE into the bloodstream/periphery over time that results in an overload of NE. This overload of NE causes a compensatory but deleterious effect on the brain and nervous system, including sympathetic effects and dysregulated physiologic response to stress. Thus, while numerous currently approved therapies that target NET inhibit the transporter, a drug with the opposite mechanism of action, a NET activator that would decrease circulating NE, may have efficacy in treating underlying pathophysiology of chronic fatigue. Baseline NE levels and stress-induced NE levels in patients who fulfill criteria for CFS and who self-identify with stress induced worsening fatigue, will be compared to data from normal individuals pre and post-stress. After all inclusion criteria has been confirmed, an IV will be placed for blood collection, a continuous electrocardiographic trace and blood pressure cuff will be placed on the subject's arm and finger. Subjects will undergo a posture study, autonomic reflex testing, and Stroop stress testing each followed by blood specimen collection. An optional blood draw for DNA analysis will occur after patients have been provided lunch. Questionnaires will be completed after study procedures and patients have been provided lunch. Study blood collection will total up to 28 milliliters (mL): 5 mL for cytokines, 20 mL for catecholamines, and optional 3 mL for DNA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Fatigue Syndrome
Keywords
CFS, Stress, Norepinephrine Transporter (NET), Norepinephrine (NE), Healthy Controls, Fatigue

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
55 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Chronic Fatigue Patients
Arm Type
Experimental
Arm Description
Patients between 18-60 years of age with fatigue symptoms who meet preliminary chronic fatigue phenotype criteria and complete preliminary screening surveys. Participants will undergo a Posture Study, Autonomic Function Tests, and a Stress Test. Participants' blood will be drawn to measure markers of sympathetic nervous system function.
Arm Title
Healthy Controls
Arm Type
Active Comparator
Arm Description
Patients between 18-60 years of age with no known conditions or prescription medications who meet preliminary screening criteria. Participants will undergo a Posture Study, Autonomic Function Tests, and a Stress Test. Participants' blood will be drawn to measure markers of sympathetic nervous system function.
Intervention Type
Other
Intervention Name(s)
Posture Study, Autonomic Function Tests, and a Stress Test
Intervention Description
Participants will undergo a Posture Study, Autonomic Function Tests, and a Stress Test. Participants' blood will be drawn to measure markers of sympathetic nervous system function at baseline, in three postural positions, after autonomic tests, and after a stress test.
Primary Outcome Measure Information:
Title
dihydroxyphenylglycol (DHPG)/norepinephrine (NE) Ratio (post stress)
Description
Change in DHPG/NE Ratio from Baseline to post stress compared across arms
Time Frame
Change from Baseline to post stress test (approximately 100 minutes post-baseline blood collection)
Secondary Outcome Measure Information:
Title
DHPG/NE Ratio (post Autonomic Function test)
Description
Change in DHPG/NE Ratio from Baseline to post Autonomic Function test compared across arms
Time Frame
Change from Baseline to post Autonomic Function test (approximately 30 minutes post-baseline blood collection)
Title
DHPG/NE Ratio (post Standing position)
Description
Change in DHPG/NE Ratio from Baseline to post Standing position compared across arms
Time Frame
Change from Baseline to post Standing position (approximately 40 minutes post-baseline blood collection)
Title
DHPG/NE Ratio (post Sitting position)
Description
Change in DHPG/NE Ratio from Baseline to post Sitting position compared across arms
Time Frame
Change from Baseline to post Sitting position (approximately 70 minutes post-baseline blood collection)
Title
Absolute DHPG and NE Levels (post stress)
Description
Change in absolute DHPG and NE Levels from Baseline to post stress compared across arms
Time Frame
Change from Baseline to post stress test (approximately 100 minutes post-baseline blood collection)
Title
Absolute DHPG and NE Levels (post Autonomic Function test)
Description
Change in DHPG and NE levels from Baseline to post Autonomic Function test compared
Time Frame
Change from Baseline to post Autonomic Function test (approximately 30 minutes post-baseline blood collection)
Title
Absolute DHPG and NE Levels (post Standing position)
Description
Change in absolute DHPG and NE Levels from Baseline to post Standing position compared across arms
Time Frame
Change from Baseline to post Standing position (approximately 40 minutes post-baseline blood collection)
Title
Absolute DHPG and NE Levels (post Sitting position)
Description
Change in DHPG and NE levels from Baseline to post Sitting position compared across arms
Time Frame
Change from Baseline to post Sitting position (approximately 70 minutes post-baseline blood collection)
Title
Fatigue as assessed by Multidimensional Assessment of Fatigue Scale (MAF)
Description
Mean values +/- standard deviation (SD) compared across arms
Time Frame
End of Study Visit (approximately 140 minutes post-baseline blood collection)
Title
Mood as assessed by Hospital Anxiety and Depression Scale (HADS)
Description
Mean values +/- SD compared across arms
Time Frame
End of Study Visit (approximately 140 minutes post-baseline blood collection)
Title
Quality of Life as assessed by 36-Item Short Form Survey Instrument (SF-36)
Description
Mean values +/- SD compared across arms
Time Frame
End of Study Visit (approximately 140 minutes post-baseline blood collection)
Title
Stress as assessed by Stress Overload Scale
Description
Mean values +/- SD compared across arms
Time Frame
Beginning of Study Visit (Approximately 15 minutes pre-baseline blood collection)
Title
Cytokines
Description
Compared across arms
Time Frame
At baseline (approximately 30 minutes after supine position start)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Chronic Fatigue Participants: Inclusion Criteria: Confirmed chronic fatigue with severity >50 on a scale of 1 to 100 that is not improving over time Meet The Centers for Disease Control and Prevention (CDC) diagnostic criteria of CFS (self-reported persistent or relapsing fatigue lasting 6 or more consecutive months) Exclusion Criteria: Male and female subjects <18 or >60 years Obesity, defined as a BMI of 30 or more Presence of other medical or psychiatric conditions known to cause fatigue (alcohol/drug abuse, anorexia nervosa, bipolar disorder, bulimia nervosa, dementia, major depression, psychotic/delusional disorders, schizophrenia) Presence of sleep disorder/disruption known to cause fatigue (sleep apnea, narcolepsy) Cardiovascular, pulmonary, hepatic, or hematological disease by history or prior testing defined as significant by investigator (including but not limited to chronic hepatitis, chronic kidney disease, cirrhosis, emphysema, heart failure, HIV, lupus, multiple sclerosis, myasthenia gravis, rheumatoid arthritis) History of hypertension defined as supine resting BP>145/95 mmHg off medications or needing antihypertensive medication Patients taking medications that can affect autonomic function or plasma catecholamines (vasoactive drugs), stimulants, and/or are sedatives Other factors which in the opinion of the investigator could potentially impact the study outcomes (e.g., underlying disease, medications, history)* or prevent the participant from completing the protocol (poor compliance or unpredictable schedule) Inability to stand unassisted for 10 minutes Patients who are bedridden or chair-ridden Patients who are colorblind Inability or refusal to give informed consent for any reason including a diagnosis of dementia or cognitive impairment Patients who are pregnant or breastfeeding Healthy Control Participants: Participant with no significant reported conditions or medications. Exclusion Criteria: Male and female subjects <18 or >60 years Obesity, defined as a BMI of 30 or more Presence of any serious or chronic disease, or prescription medication as deemed by investigator including hypertension as defined by supine resting BP >145/95 mmHg off medications or needing antihypertensive medication Other factors which in the investigator's opinion would prevent the participant from completing the protocol, including poor compliance during previous studies or an unpredictable schedule Inability to stand unassisted for 10 minutes Patients who are bedridden or chair-ridden Patients who are colorblind Inability or refusal to give informed consent for any reason including a diagnosis of dementia or cognitive impairment Patients who are pregnant or breastfeeding Stress Overload Score above 66
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gordon Bernard, MD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
21906029
Citation
Okamoto LE, Raj SR, Peltier A, Gamboa A, Shibao C, Diedrich A, Black BK, Robertson D, Biaggioni I. Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes. Clin Sci (Lond). 2012 Feb;122(4):183-92. doi: 10.1042/CS20110200.
Results Reference
background
PubMed Identifier
23580201
Citation
Shirey-Rice JK, Klar R, Fentress HM, Redmon SN, Sabb TR, Krueger JJ, Wallace NM, Appalsamy M, Finney C, Lonce S, Diedrich A, Hahn MK. Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome. Dis Model Mech. 2013 Jul;6(4):1001-11. doi: 10.1242/dmm.012203. Epub 2013 Apr 4.
Results Reference
background
PubMed Identifier
24534443
Citation
Danciu I, Cowan JD, Basford M, Wang X, Saip A, Osgood S, Shirey-Rice J, Kirby J, Harris PA. Secondary use of clinical data: the Vanderbilt approach. J Biomed Inform. 2014 Dec;52:28-35. doi: 10.1016/j.jbi.2014.02.003. Epub 2014 Feb 14.
Results Reference
background
Links:
URL
http://www.cdc.gov/cfs/
Description
CDC - Chronic Fatigue Syndrome (CFS)

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Noradrenergic and Stress-Related Etiologies of Chronic Fatigue Syndrome

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