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

• ClinicalTrials.gov Identifier: NCT03674541
• Recruitment Status: Enrolling by invitation
• First Posted: September 17, 2018
• Last Update Posted: July 15, 2020
• Sponsor: Brigham and Women's Hospital
• Information provided by (Responsible Party): David Systrom, Brigham and Women's Hospital

Tracking Information

• First Submitted Date: September 11, 2018
• First Posted Date: September 17, 2018
• Last Update Posted Date: July 15, 2020
• Actual Study Start Date: January 14, 2020
• Estimated Primary Completion Date: June 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 13, 2020)

Maximal Oxygen Uptake (VO2max) [ Time Frame: 1 hour ]

Define the response of oxygen uptake to pyridostigmine

Original Primary Outcome Measures (submitted: September 14, 2018)

• Maximal Oxygen Uptake (VO2max) [ Time Frame: 1 hour ]
  Define the response of oxygen uptake to pyridostigmine
• End-tidal Carbon Dioxide (CO2) [ Time Frame: 1 hour ]
  Define the response of carbon dioxide production to pyridostigmine
• Ventilatory Efficiency (VE/VCO2) [ Time Frame: 1 hour ]
  Define the ventilatory efficiency response to pyridostigmine

Current Secondary Outcome Measures (submitted: July 13, 2020)

• End-tidal Carbon Dioxide (CO2) [ Time Frame: 1 hour ]
  Define the response of carbon dioxide production to pyridostigmine
• Ventilatory Efficiency (VE/VCO2) [ Time Frame: 1 hour ]
  Define the ventilatory efficiency response to pyridostigmine
• Right atrial pressure (RAP) [ Time Frame: 1 hour ]
  Define the right atrial pressure response to pyridostigmine
• Pulmonary artery pressure (PAP) [ Time Frame: 1 hour ]
  Define the pulmonary artery pressure response to pyridostigmine
• Pulmonary capillary wedge pressure (PCWP) [ Time Frame: 1 hour ]
  Define the pulmonary capillary wedge pressure response to pyridostigmine
• Cardiac output (CO) [ Time Frame: 1 hour ]
  Define the cardiac output response to pyridostigmine
• Heart rate (HR) [ Time Frame: 1 hour ]
  Define the heart rate response to pyridostigmine
• stroke Volume (SV) [ Time Frame: 1 hour ]
  Define the stroke volume response to pyridostigmine
• Pulmonary vascular resistance (PVR) [ Time Frame: 1 hour ]
  Define the pulmonary vascular resistance response to pyridostigmine
• Systemic vascular resistance (SVR) [ Time Frame: 1 hour ]
  Define the systemic vascular resistance response to pyridostigmine
• Arterial venous content difference (Ca-v O2 Difference) [ Time Frame: 1 hour ]
  Evaluate skeletal muscle oxygen extraction response to pyridostigmine
• Lactate [ Time Frame: 1 hour ]
  Evaluate the lactate response to pyridostigmine

Original Secondary Outcome Measures (submitted: September 14, 2018)

• Right atrial pressure (RAP) [ Time Frame: 1 hour ]
  Define the right atrial pressure response to pyridostigmine
• Pulmonary capillary wedge pressure (PCWP) [ Time Frame: 1 hour ]
  Define the pulmonary capillary wedge pressure response to pyridostigmine
• Cardiac output (CO) [ Time Frame: 1 hour ]
  Define the cardiac output response to pyridostigmine
• Arterial venous content difference (Ca-v O2 Difference) [ Time Frame: 1 hour ]
  Evaluate skeletal muscle oxygen extraction to pyridostigmine

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
• Official Title: 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.

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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

Condition

• 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

Intervention

• Drug: Pyridostigmine Bromide
  Pyridostigmine Bromide 60 mg capsule by mouth as a one time dose
  Other Name: Mestinon
• Drug: Placebo
  Placebo (Cellulose microcrystalline) capsule by mouth as a one time dose

Study Arms

• Active Comparator: Study Drug - Pyridostigmine
  Pyridostigmine 60 mg by mouth as a one time dose
  Intervention: Drug: Pyridostigmine Bromide
• Placebo Comparator: Placebo
  Placebo by mouth as a one time dose
  Intervention: Drug: Placebo

• 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]

Recruitment Information

• Recruitment Status: Enrolling by invitation
• Estimated Enrollment (submitted: July 13, 2020): 50
• Original Estimated Enrollment (submitted: September 14, 2018): 25
• Estimated Study Completion Date: June 1, 2021
• Estimated Primary Completion Date: June 1, 2021 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03674541
• Other Study ID Numbers: 2018P001871
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: David Systrom, Brigham and Women's Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Brigham and Women's Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Brigham and Women's Hospital
• Verification Date: July 2020