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Autonomic Nervous System and Chronic Fatigue Syndrome (CFS&ANS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00580619
Recruitment Status : Completed
First Posted : December 27, 2007
Last Update Posted : January 18, 2017
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University

Tracking Information
First Submitted Date  ICMJE December 17, 2007
First Posted Date  ICMJE December 27, 2007
Last Update Posted Date January 18, 2017
Study Start Date  ICMJE April 2007
Actual Primary Completion Date January 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 20, 2007)
Heart rate [ Time Frame: Duration of the intervention ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2007)
Blood Pressure [ Time Frame: Duration of the intervention ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Autonomic Nervous System and Chronic Fatigue Syndrome
Official Title  ICMJE Autonomic Nervous System and Chronic Fatigue Syndrome
Brief Summary The investigators propose to test the hypothesis that the sympathetic nervous system contributes to the cardiovascular and inflammatory abnormalities present in the chronic fatigue syndrome (CFS) and, in particular in the subset of patients characterized by postural tachycardia syndrome (POTS). CFS and POTS are seen mostly in otherwise normal young women, and are the cause of significant disability. A substantial proportion of patients referred for evaluation of POTS met diagnostic criteria for CFS and, conversely, a subset of patients referred for treatment for CFS have POTS. The investigators hypothesize that sympathetic activation underlies the pathophysiology of patients in whom CFS and POTS overlap (CFS-P).
Detailed Description

In Specific Aim 1, the investigators will use state-of-the-art measurements of sympathetic activity (autonomic function tests, response to trimethaphan, direct nerve sympathetic traffic recordings with microneurography, plasma norepinephrine, and intraneuronal metabolites), inflammatory mediators (C-reactive protein, inflammatory cytokines), and oxidative stress (isoprostanes) in patients with CFS-P. It is important that appropriate control groups be included, and we will also study patients with CFS without orthostatic tachycardia, patients with POTS without CFS, and normal controls.

The investigators have documented abnormalities in volume regulation in POTS patients. Hypovolemia can contribute to sympathetic activation and, vice versa, sympathetic activation can contribute to hypovolemia. Interrupting this vicious circle with acute saline infusion is the most effective treatment to improve symptoms in POTS patients. Not surprisingly, many POTS patients followed by the investigators, and CFS patients followed by Dr. David Bell, are using saline pulse therapy as a way to alleviate symptoms. However, the efficacy and safety of this approach has not been proven. The investigators propose to validate this treatment in Specific Aim 2.

This group studies show that nitric oxide is arguably the most important metabolic factor involved in cardiovascular regulation. Abnormalities in nitric oxide have been proposed to contribute to CFS and POTS, but proving this has been challenging in part due to its interaction with the sympathetic nervous system. In Specific Aim 3, the investigators propose to investigate the importance of nitric oxide in CFS-P patients using an experimental approach developed in our laboratory to eliminate nitric oxide/autonomic interactions.

Finally, in Specific Aim 4, they propose a proof-of-concept study to test the hypothesis that sympathetic activation contributes to many of the abnormalities found in CFS patients. If our hypothesis is correct, inhibition of sympathetic tone will result in improvement of the abnormalities described in volume, inflammation, and oxidative stress. More importantly, it will result in symptomatic improvement in these patients. The investigators believe, therefore, that the studies proposed in this application will improve the understanding of the pathophysiology of CFS, and provide a rationale approach to the treatment of this disabling condition.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Condition  ICMJE
  • Chronic Fatigue Syndrome
  • Orthostatic Intolerance
  • Postural Tachycardia Syndrome
Intervention  ICMJE
  • Other: Autonomic Function Testing
    The autonomic function tests include asking the subject to breathe deeply for two minutes and breathing as fast and as hard as they can for 30 seconds, maintaining a handgrip for 3 minutes, breathing against pressure for 15 seconds, placing one hand in ice water for 1 minute and an orthostatic test. All these tests are meant to stimulate the autonomic nervous system to produce changes in blood pressure and heart rate of short duration that reflect how well the involuntary nervous system is working. In addition, a 24-hour blood pressure monitoring and exercise test may be also performed in some subjects.
  • Other: Saline infusions
    The effects of continuous IV infusion or pulse IV administration of saline in increasing total blood volume and fatigue score will be evaluated
  • Drug: L-NMMA trimethaphan
    Trimethaphan IV infusion for approximately 60 minutes at a dose of 4-6 mg/min L-NMMA IV infusion for approximately 45 minutes at 125, 250, and 500 mg/kg/min for 15 minutes each
  • Drug: methyldopa
    Aldomet oral twice a day for 12 weeks
    Other Name: Aldomet
Study Arms  ICMJE
  • Experimental: 1 (markers of sympathetic activity)
    To evaluate if the various indices of sympathetic activity (Autonomic Function Testing) differ between patients with chronic fatigue syndrome and postural tachycardia syndrome (CFS-P), and CFS without POTS.
    Intervention: Other: Autonomic Function Testing
  • Experimental: 2 (saline)
    To test the null hypothesis that there is no difference between two saline therapies (pulse saline vs. sham saline) in improving both the fatigue score and postural tachycardia syndrome.Saline infusions
    Intervention: Other: Saline infusions
  • Experimental: 3 (NO inhibition/ autonomic blockade)
    Response to nitric oxide inhibition in the presence and absence of an intact autonomic nervous system will be evaluated. L-NMMA trimethaphan will be used for NO inhibition and autonomic blockade, respectively.
    Intervention: Drug: L-NMMA trimethaphan
  • Active Comparator: 4 (methyldopa)
    The effects of chronic autonomic withdrawal on improving symptoms of chronic fatigue and postural tachycardia syndrome will be evaluated
    Intervention: Drug: methyldopa
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 16, 2017)
Original Estimated Enrollment  ICMJE
 (submitted: December 20, 2007)
Actual Study Completion Date  ICMJE January 2017
Actual Primary Completion Date January 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Meet CDC diagnostic criteria of CFS (Fukuda et al., 1994)
  • Meet diagnostic criteria of POTS (Raj et al., 2005)
  • Age between 18-65 years
  • Male and female are eligible (although the majority of patients with CFS-P are female)

Exclusion Criteria:

  • Presence of medical conditions that can explain postural tachycardia syndrome (e.g., dehydration, medications)
  • Presence of medical or psychiatric conditions known to cause fatigue (Fukuda et al., 1994). Inability to give, or withdrawal of, informed consent
  • Inability to acquire or maintain adequate long-term intravenous access (peripheral indwelling catheter, PIC)
  • Pregnancy
  • Other factors which in the investigator's opinion would prevent the subject from completing the protocol
  • Patients who are bedridden or chair-ridden
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00580619
Other Study ID Numbers  ICMJE 060662
CRC-1636 ( Other Identifier: Local CRC )
CRC-1705 ( Other Identifier: Local CRC )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Italo Biaggioni, Vanderbilt University
Study Sponsor  ICMJE Vanderbilt University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Italo Biaggioni, MD Vanderbilt University
PRS Account Vanderbilt University Medical Center
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP