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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

 No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

 Interventional
Eligible Ages 18 Years - 80 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - Meets the Institute of Medicine (IOM) criteria for ME/CFS.
  • - Completing the clinically indicated 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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

 NCT03674541
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

 Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

 Brigham and Women's Hospital
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

 David Systrom, MD
Principal Investigator Affiliation Brigham and Women's Hospital
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

 Other
Overall Status Enrolling by invitation
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

 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
Additional Details

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.

Arms & Interventions

Arms

Active Comparator: Study Drug - Pyridostigmine

Pyridostigmine 60 mg by mouth as a one time dose

Placebo Comparator: Placebo

Placebo by mouth as a one time dose

Interventions

Drug: - Pyridostigmine Bromide

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

Drug: - Placebo

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

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Brigham and Women's Hospital, Boston, Massachusetts

Status

Address

Brigham and Women's Hospital

Boston, Massachusetts, 02215

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