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

NCT ID: NCT03674541

Last Updated: 2022-11-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-14
• Study Completion Date: 2021-12-20

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.

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Study Drug - Pyridostigmine

Pyridostigmine 60 mg by mouth as a one time dose

Group Type: ACTIVE_COMPARATOR

Pyridostigmine Bromide

Intervention Type: DRUG

Pyridostigmine Bromide 60 mg capsule by mouth as a one time dose

Placebo

Placebo by mouth as a one time dose

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo (Cellulose microcrystalline) capsule by mouth as a one time dose

Interventions

Pyridostigmine Bromide

Pyridostigmine Bromide 60 mg capsule by mouth as a one time dose

Intervention Type: DRUG

Placebo

Placebo (Cellulose microcrystalline) capsule by mouth as a one time dose

Intervention Type: DRUG

Other Intervention Names

Mestinon; Cellulose microcrystalline

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

David Systrom

Principal Investigator; Director, Dyspnea Center; Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

David Systrom, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Brigham and Women's Hospital

Boston, Massachusetts, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 35526605 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2018P001871

Identifier Type: -

Identifier Source: org_study_id