The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
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ClinicalTrials.gov Identifier: NCT03674541 |
Recruitment Status :
Enrolling by invitation
First Posted : September 17, 2018
Last Update Posted : July 15, 2020
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Tracking Information | |||||||
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First Submitted Date ICMJE | September 11, 2018 | ||||||
First Posted Date ICMJE | September 17, 2018 | ||||||
Last Update Posted Date | July 15, 2020 | ||||||
Actual Study Start Date ICMJE | January 14, 2020 | ||||||
Estimated Primary Completion Date | June 1, 2021 (Final data collection date for primary outcome measure) | ||||||
Current Primary Outcome Measures ICMJE |
Maximal Oxygen Uptake (VO2max) [ Time Frame: 1 hour ] Define the response of oxygen uptake to pyridostigmine
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Original Primary Outcome Measures ICMJE |
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Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE |
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Current Other Pre-specified Outcome Measures | Not Provided | ||||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||||
Descriptive Information | |||||||
Brief Title ICMJE | The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome | ||||||
Official Title ICMJE | The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome | ||||||
Brief Summary | Myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS), otherwise known as Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME), is an under-recognized disorder whose cause is not yet understood. Suggested theories behind the pathophysiology of this condition include autoimmune causes, an inciting viral illness, and a dysfunctional autonomic nervous system caused by a small fiber polyneuropathy. Symptoms include fatigue, cognitive impairments, gastrointestinal changes, exertional dyspnea, and post-exertional malaise. The latter two symptoms are caused in part by abnormal cardiopulmonary hemodynamics during exercise thought to be due to a small fiber polyneuropathy. This manifests as low biventricular filling pressures throughout exercise seen in patients undergoing a level 3 CPET along with small nerve fiber atrophy seen on skin biopsy. After diagnosis, patients are often treated with pyridostigmine (off-label use of this medication) to enhance cholinergic stimulation of norepinephrine release at the post-ganglionic synapse. This is thought to improve venoconstriction at the site of exercising muscles, leading to improved return of blood to the heart and increasing filling of the heart to more appropriate levels during peak exercise. Retrospective studies have shown that noninvasive measurements of exercise capacity, such as oxygen uptake, end-tidal carbon dioxide, and ventilatory efficiency, improve after treatment with pyridostigmine. To date, there are no studies that assess invasive hemodynamics after pyridostigmine administration. It is estimated that four million people suffer from ME/CFS worldwide, a number that is thought to be a gross underestimate of disease prevalence. However, despite its potential for debilitating symptoms, loss of productivity, and worldwide burden, the pathophysiology behind ME/CFS remains unknown and its treatment unclear. By evaluating the exercise response to cholinergic stimulation, this study will shed further light on the link between the autonomic nervous system and cardiopulmonary hemodynamics, potentially leading to new therapeutic targets. |
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Detailed Description | The hypothesis of our study is that hemodynamic, ventilatory and oxygen exchange variables such biventricular filling pressures and systemic oxygen extraction can be improved by cholinergic stimulation in patients with ME/CFS. The objective of this study is to examine the exercise response to pharmacologic cholinergic stimulation in ME/CFS patients already undergoing a clinically indicated level 3 cardiopulmonary exercise test (CPET). This will be achieved by inhibiting acetylcholinesterase with pyridostigmine, thus increasing acetylcholine levels, downstream levels of norepinephrine, and enhancing vascular regulation. To test our hypothesis, we propose the following specific aims: Define the response of peak oxygen uptake (VO2) to pyridostigmine. Define the gas exchange responses, such as end-tidal CO2 and ventilatory efficiency to pyridostigmine. Define the hemodynamic responses, such as right atrial pressures, pulmonary artery pressure, pulmonary capillary wedge pressures, cardiac output, heart rate, stroke volume, pulmonary vascular resistance and systemic vascular resistance to pyridostigmine. Evaluate the response of skeletal muscle oxygen extraction and lactate to pyridostigmine. These determinations will occur during a clinically indicated level 3 CPET, which includes exercising on a stationary cycle with a right heart catheter (RHC) and a radial arterial line in place. To stimulate the cholinergic response, a single dose of an oral acetylcholinesterase inhibitor, pyridostigmine, versus placebo will be given after the level 3 CPET. Recovery cycling will be performed after a rest period of 50 minutes. This will be administered in a randomized, double-blind, placebo-controlled trial. |
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Study Type ICMJE | Interventional | ||||||
Study Phase ICMJE | Phase 2 | ||||||
Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Subjects will be assigned ramsomly to receive either pyridostigmine or placebo, both study participants and investigators will be blinded. Masking: Triple (Participant, Care Provider, Investigator)Primary Purpose: Treatment |
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Intervention ICMJE |
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Study Arms ICMJE |
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Publications * | Joseph P, Pari R, Miller S, Warren A, Stovall MC, Squires J, Chang CJ, Xiao W, Waxman AB, Systrom DM. Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest. 2022 May 6. pii: S0012-3692(22)00890-X. doi: 10.1016/j.chest.2022.04.146. [Epub ahead of print] | ||||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||||
Recruitment Status ICMJE | Enrolling by invitation | ||||||
Estimated Enrollment ICMJE |
50 | ||||||
Original Estimated Enrollment ICMJE |
25 | ||||||
Estimated Study Completion Date ICMJE | June 1, 2021 | ||||||
Estimated Primary Completion Date | June 1, 2021 (Final data collection date for primary outcome measure) | ||||||
Eligibility Criteria ICMJE | Inclusion Criteria:
Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years to 80 Years (Adult, Older Adult) | ||||||
Accepts Healthy Volunteers ICMJE | No | ||||||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||||
Listed Location Countries ICMJE | United States | ||||||
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Administrative Information | |||||||
NCT Number ICMJE | NCT03674541 | ||||||
Other Study ID Numbers ICMJE | 2018P001871 | ||||||
Has Data Monitoring Committee | No | ||||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Current Responsible Party | David Systrom, Brigham and Women's Hospital | ||||||
Original Responsible Party | Same as current | ||||||
Current Study Sponsor ICMJE | Brigham and Women's Hospital | ||||||
Original Study Sponsor ICMJE | Same as current | ||||||
Collaborators ICMJE | Not Provided | ||||||
Investigators ICMJE |
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PRS Account | Brigham and Women's Hospital | ||||||
Verification Date | July 2020 | ||||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |