Chronic Fatigue SyndromePhase 1CFS&ANSNCT00580619
Autonomic Nervous System and Chronic Fatigue Syndrome
A Phase 1 study testing Autonomic Function Testing, Saline infusions and L-NMMA trimethaphan in people with Chronic Fatigue Syndrome and Orthostatic Intolerance, run by Vanderbilt University at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Chronic Fatigue Syndrome, Orthostatic Intolerance, Postural Tachycardia Syndrome
- What is being tested?
- Autonomic Function Testing, Saline infusions and L-NMMA trimethaphan
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 170 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2007to Jan 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
About this study
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).
Read the 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.
- Being tested
- Autonomic Function Testing, Saline infusions, L-NMMA trimethaphan, methyldopa
- Keywords
- Chronic fatigue syndrome, Postural tachycardia syndrome, Autonomic nervous system
- Medical subject headings
- Fatigue Syndrome, Chronic, Orthostatic Intolerance, Postural Orthostatic Tachycardia Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Autonomic Function TestingOther
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.
Saline infusionsOther
The effects of continuous IV infusion or pulse IV administration of saline in increasing total blood volume and fatigue score will be evaluated
L-NMMA trimethaphanDrug
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
methyldopaDrug
Also called Aldomet
Aldomet oral twice a day for 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| 1 (markers of sympathetic activity) | Experimental | 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. Receives: Other: Autonomic Function Testing |
| 2 (saline) | Experimental | 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 Receives: Other: Saline infusions |
| 3 (NO inhibition/ autonomic blockade) | Experimental | 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. Receives: Drug: L-NMMA trimethaphan |
| 4 (methyldopa) | Active comparator | The effects of chronic autonomic withdrawal on improving symptoms of chronic fatigue and postural tachycardia syndrome will be evaluated Receives: Drug: methyldopa |
What is being measured
The primary outcome is the main question the study is designed to answer.
Heart rate
Measured: Duration of the intervention
Secondary outcomes (1)
Blood Pressure
Measured: Duration of the intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Dec 2007 (estimated)
- Study startApr 2007
- Primary completionJan 2017
- Study completionJan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Fatigue SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 170 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Italo Biaggioni, Vanderbilt University
- Investigators
- Italo Biaggioni, MD, Principal investigator, Vanderbilt University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00580619
- Sponsor's protocol ID
- 060662
- Other IDs
- CRC-1636, CRC-1705
- Acronym
- CFS&ANS
- Status last verified
- Jan 2017
- First submitted
- 17 Dec 2007
- Last updated
- 18 Jan 2017
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
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.
PubMed 21906029
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Autonomic Nervous System and Chronic Fatigue Syndrome
- ClinicalTrials.gov ID
- NCT00580619
- Acronym / sponsor ID
- CFS&ANS / 060662
- Keywords
- Chronic fatigue syndrome, Postural tachycardia syndrome, Autonomic nervous system
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 170 participants (actual)
- Lead sponsor
- Vanderbilt UniversityUniversity, hospital or other
- Study start
- Apr 2007
- Primary completion
- Jan 2017 (actual)
- Study completion
- Jan 2017 (actual)
- First posted
- 27 Dec 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| 1 (markers of sympathetic activity) | Experimental | Other: Autonomic Function TestingTo 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. |
| 2 (saline) | Experimental | Other: Saline infusionsTo 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 |
| 3 (NO inhibition/ autonomic blockade) | Experimental | Drug: L-NMMA trimethaphanResponse 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. |
| 4 (methyldopa) | Active comparator | Drug: methyldopaThe effects of chronic autonomic withdrawal on improving symptoms of chronic fatigue and postural tachycardia syndrome will be evaluated |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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)
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Autonomic Function TestingThe 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 | 1 (markers of sympathetic activity) |
| Saline infusionsThe effects of continuous IV infusion or pulse IV administration of saline in increasing total blood volume and fatigue score will be evaluated | Other | 2 (saline) |
| L-NMMA trimethaphanTrimethaphan 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 | 3 (NO inhibition/ autonomic blockade) |
| methyldopaAlso: AldometAldomet oral twice a day for 12 weeks | Drug | 4 (methyldopa) |
Primary outcome
Heart rate
Time frame: Duration of the intervention
1 secondary outcome
Blood Pressure
Time frame: Duration of the intervention
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2017.
- Results publication: PubMed 21906029Okamoto 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Italo Biaggioni, MD principal investigator
Vanderbilt University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Autonomic Function Testing, Saline infusions and L-NMMA trimethaphan in people with Chronic Fatigue Syndrome and Orthostatic Intolerance, run by Vanderbilt University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Heart rate (time frame: Duration of the intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00580619, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jan 2017.