The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

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 an invasive cardiopulmonary exercise test (iCPET) 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.

Study Overview

• Status: Completed
• Conditions: Fibromyalgia; Chronic Fatigue Syndrome; Orthostatic Hypotension; Postural Orthostatic Tachycardia Syndrome; Dysautonomia; Myalgic Encephalomyelitis; Exercise Intolerance; Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Low Ventricular Filling Pressures (Preload Failure)
• Intervention / Treatment: Drug: Pyridostigmine Bromide; Drug: Placebo

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 invasive cardiopulmonary exercise test (iCPET). 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 carbon dioxide(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 iCPET, 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 iCPET. Recovery cycling will be performed after a rest period of 50 minutes. This will be administered in a randomized, double-blind, placebo-controlled trial.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Meets the Institute of Medicine (IOM) criteria for ME/CFS
• Completing the clinically indicated invasive cardiopulmonary exercise test (iCPET)

Exclusion Criteria:

• Obesity (BMI > 30 kg/m2)
• Non-controlled asthma
• Anemia (Hb < 10 g/dl)
• Active or treated cancer
• History of interstitial lung disease (ILD)
• Chronic obstructive pulmonary disease (COPD)
• Pulmonary hypertension (PH)
• Congestive heart failure (CHF)
• Active arrhythmias
• Valvular heart disease
• Coronary artery disease (CAD)
• Other conditions that could predict a limitation or not completion of the study.
• Pregnancy
• Submaximal testing in clinically indicated iCPET
• Pulmonary mechanical limitation to exercise in clinically indicated iCPET.
• Pulmonary arterial hypertension in clinically indicated iCPET.
• Pulmonary venous hypertension in clinically indicated iCPET.
• Exercise induced pulmonary arterial hypertension in clinically indicated iCPET.
• Exercise induced pulmonary venous hypertension in clinically indicated iCPET.
• Persistent hypotension during or after the clinically indicated iCPET.
• Refractory arrhythmia during or after the clinically indicated level 3 CPET.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Study Drug - Pyridostigmine; Pyridostigmine 60 mg by mouth as a one time dose	Drug: Pyridostigmine Bromide; Pyridostigmine Bromide 60 mg capsule by mouth as a one time dose; Other Names: Mestinon
Placebo Comparator: Placebo; Placebo by mouth as a one time dose	Drug: Placebo; Placebo (Cellulose microcrystalline) capsule by mouth as a one time dose; Other Names: Cellulose microcrystalline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Peak Oxygen Uptake (Peak VO2) Between the First and Second iCPET	Define the response of oxygen uptake to pyridostigmine expressed both as mL/min and mL/min/kg. The difference in peak oxygen uptake from first iCPET to second iCPET. Research has shown that ME/CFS patients have inability to reproduce results on two consecutive cardiopulmonary exercise tests(CPET). Traditionally this is demonstrated with a two-day CPET protocol, but in this study we investigate the acute effects of pyridostigmine administration on the early stages of post exertional malaise(PEM).	First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak-Rest Oxygen Uptake (VO2)	Peak versus rest changes in oxygen uptake between first and second CPETs expressed as mL/min.	First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak Cardiac Output (Qc)	Arterial and mixed-venous blood gases and pH are measured at peak exercise and Qc is calculated using the direct Fick principle Qc=VO2/(Ca-Cv). Change in peak Qc between first and second iCPETs is measured in L/min.	First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak-Rest Cardiac Output (Qc)	Peak versus rest change in cardiac output expressed in L/min between first and second iCPETs. Cardiac output is determined using the direct Fick principle.	First iCPET up to 30 min, 50 minutes rest, second iCPET up to 30 minutes
Peak Right Atrial Pressure (RAP)	Difference in peak RAP between first and second iCPETs measured in mmHg.	First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak-Rest Right Atrial Pressure (RAP)	Peak versus rest changes in RAP between first and second iCPETs measured in mmHg	First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak Pulmonary Arterial Wedge Pressure (PAWP)	Difference in peak PAWP between first and second iCPETs measured in mmHg	First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak Stroke Volume (SV)	Difference in peak SV between first and second iCPETs measured in mL	First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak (Ca-vO2)/[Hgb]	Difference in peak arterial-venous oxygen content difference normalized to hemoglobin (Ca-vO2)/[Hgb] between first and second iCPETs	First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Ventilatory Efficiency (VE/VCO2)	Difference in ventilatory efficiency between first and second iCPETs	First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Borg Fatigue Scale	Difference in perception of fatigue at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).	First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Borg Dyspnea Scale	Difference in perceived dyspnea at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).	First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: David Systrom, MD, Brigham and Women's Hospital

Publications and helpful links

General 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 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest. 2022 Nov;162(5):1116-1126. doi: 10.1016/j.chest.2022.04.146. Epub 2022 May 6.

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2020
• Primary Completion (Actual): December 5, 2021
• Study Completion (Actual): December 20, 2021

Study Registration Dates

• First Submitted: September 11, 2018
• First Submitted That Met QC Criteria: September 14, 2018
• First Posted (Actual): September 17, 2018

Study Record Updates

• Last Update Posted (Actual): November 8, 2022
• Last Update Submitted That Met QC Criteria: October 14, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Pyridostigmine; Chronic fatigue syndrome; Myalgic encephalomyelitis; Exercise Intolerance; Myalgic encephalomyelitis/Chronic fatigue syndrome; Invasive Cardiopulmonary Exercise Test
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Central Nervous System Diseases; Nervous System Diseases; Virus Diseases; Infections; Pain; Neurologic Manifestations; Disease; Musculoskeletal Diseases; Rheumatic Diseases; Muscular Diseases; Neuromuscular Diseases; Musculoskeletal Pain; Central Nervous System Infections; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Autonomic Nervous System Diseases; Orthostatic Intolerance; Syndrome; Fatigue; Myalgia; Fibromyalgia; Tachycardia; Hypotension; Fatigue Syndrome, Chronic; Hypotension, Orthostatic; Postural Orthostatic Tachycardia Syndrome; Primary Dysautonomias; Encephalomyelitis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Anticonvulsants; Cholinesterase Inhibitors; Bromides; Pyridostigmine Bromide
• Other Study ID Numbers: 2018P001871

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after de-identification(text, tables, figures, and appendices) will be available for researchers who provide a methodologically sound proposal to achieve aims in the approved proposal.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: Proposals should be directed to jsquires1@bwh.harvard.edu. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes