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

• ClinicalTrials.gov Identifier: NCT03674541
• Recruitment Status: Completed
• First Posted: September 17, 2018
• Results First Posted: October 4, 2022
• Last Update Posted: November 8, 2022
• Sponsor: Brigham and Women's Hospital
• Information provided by (Responsible Party): David Systrom, Brigham and Women's Hospital

Study Description

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 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.

Condition or disease	Intervention/treatment	Phase
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Chronic Fatigue Syndrome; Myalgic Encephalomyelitis; Exercise Intolerance; Dysautonomia; Low Ventricular Filling Pressures (Preload Failure); Postural Orthostatic Tachycardia Syndrome; Orthostatic Hypotension; Fibromyalgia	Drug: Pyridostigmine Bromide; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects will be assigned randomly to receive either pyridostigmine or placebo, both study participants and investigators will be blinded.
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
• Actual Study Start Date: January 14, 2020
• Actual Primary Completion Date: December 5, 2021
• Actual Study Completion Date: December 20, 2021

Arms and Interventions

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 Name: 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 Name: Cellulose microcrystalline

Outcome Measures

Primary Outcome Measures :

1. Change in Peak Oxygen Uptake (Peak VO2) Between the First and Second iCPET [ Time Frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
   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).

Secondary Outcome Measures :

1. Peak-Rest Oxygen Uptake (VO2) [ Time Frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
   Peak versus rest changes in oxygen uptake between first and second CPETs expressed as mL/min.
2. Peak Cardiac Output (Qc) [ Time Frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
   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.
3. Peak-Rest Cardiac Output (Qc) [ Time Frame: First iCPET up to 30 min, 50 minutes rest, second iCPET up to 30 minutes ]
   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.
4. Peak Right Atrial Pressure (RAP) [ Time Frame: First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
   Difference in peak RAP between first and second iCPETs measured in mmHg.
5. Peak-Rest Right Atrial Pressure (RAP) [ Time Frame: First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
   Peak versus rest changes in RAP between first and second iCPETs measured in mmHg
6. Peak Pulmonary Arterial Wedge Pressure (PAWP) [ Time Frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
   Difference in peak PAWP between first and second iCPETs measured in mmHg
7. Peak Stroke Volume (SV) [ Time Frame: First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
   Difference in peak SV between first and second iCPETs measured in mL
8. Peak (Ca-vO2)/[Hgb] [ Time Frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
   Difference in peak arterial-venous oxygen content difference normalized to hemoglobin (Ca-vO2)/[Hgb] between first and second iCPETs
9. Ventilatory Efficiency (VE/VCO2) [ Time Frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
   Difference in ventilatory efficiency between first and second iCPETs
10. Borg Fatigue Scale [ Time Frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
    Difference in perception of fatigue at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).
11. Borg Dyspnea Scale [ Time Frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes. ]
    Difference in perceived dyspnea at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02215

Sponsors and Collaborators

Brigham and Women's Hospital

Investigators

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

  Study Documents (Full-Text)

Documents provided by David Systrom, Brigham and Women's Hospital:

Study Protocol and Statistical Analysis Plan  [PDF] September 3, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: David Systrom, Principal Investigator; Director, Dyspnea Center; Associate Professor of Medicine, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT03674541
• Other Study ID Numbers: 2018P001871
• First Posted: September 17, 2018
• Results First Posted: October 4, 2022
• Last Update Posted: November 8, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Beginning 9 months and ending 36 months following article publication.
• Access Criteria: Proposals should be directed to jsquires1@bwh.harvard.edu. To gain access, data requestors will need to sign a data access agreement.

• 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

Keywords provided by David Systrom, Brigham and Women's Hospital:

Myalgic encephalomyelitis/Chronic fatigue syndrome; Myalgic encephalomyelitis; Chronic fatigue syndrome; Pyridostigmine; Exercise Intolerance; Invasive Cardiopulmonary Exercise Test

Additional relevant MeSH terms:

Fatigue Syndrome, Chronic; Encephalomyelitis; Fibromyalgia; Myalgia; Hypotension, Orthostatic; Primary Dysautonomias; Postural Orthostatic Tachycardia Syndrome; Hypotension; Tachycardia; Syndrome; Fatigue; Disease; Pathologic Processes; Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Diseases; Cardiac Conduction System Disease; Virus Diseases; Infections; Central Nervous System Diseases; Orthostatic Intolerance; Autonomic Nervous System Diseases; Central Nervous System Infections; Musculoskeletal Pain