The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure

• ClinicalTrials.gov Identifier: NCT03674541
• Recruitment Status: Enrolling by invitation
• First Posted: September 17, 2018
• Last Update Posted: February 28, 2019
• Sponsor: Brigham and Women's Hospital
• Information provided by (Responsible Party): David Systrom, Brigham and Women's Hospital

Study Description

Brief Summary:

Chronic fatigue syndrome (CFS), otherwise known as 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 CFS/ME 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 CFS/ME 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
Preload Failure; Chronic Fatigue Syndrome; Myalgic Encephalomyelitis; Fibromyalgia; Dyspnea	Drug: Pyridostigmine	Phase 3

Detailed Description:

The hypothesis of the investigators' study is that small fiber polyneuropathy is a cause of low biventricular filling pressures/preload failure of the heart and poor oxygen extraction in the muscle bed, leading to symptoms of exertional intolerance and post-exertional malaise. The objective of this study is to examine the exercise response to pharmacologic cholinergic stimulation in 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 enhanced vascular regulation.

To test our hypothesis, the investigators propose the following specific aims:

1. Define the gas exchange responses, such as oxygen uptake, end-tidal carbon dioxide (CO2), and ventilatory efficiency to pyridostigmine
2. Define the hemodynamic responses, such as right atrial pressures, pulmonary capillary wedge pressures and cardiac output to pyridostigmine
3. Evaluate skeletal muscle oxygen extraction to pyridostigmine

These determinations will occur during a clinically indicated level 3 CPET, which includes exercising on a stationary bicycle 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 double-blind, randomized control trial.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure
• Estimated Study Start Date: March 8, 2019
• Estimated Primary Completion Date: October 15, 2019
• Estimated Study Completion Date: October 15, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Study Drug - Pyridostigmine; Pyridostigmine 60 mg by mouth as a one time dose	Drug: Pyridostigmine; Pyridostigmine 60 mg by mouth as a one time dose
Placebo Comparator: Placebo; Placebo by mouth as a one time dose	Drug: Pyridostigmine; Pyridostigmine 60 mg by mouth as a one time dose

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Low filling pressures during a clinically indicated invasive cardiopulmonary exercise test

Exclusion Criteria:

• Submaximal testing
• Exercise induced pulmonary arterial hypertension
• Exercise induced pulmonary venous hypertension
• Severe hypotension during or after test
• Refractory arrhythmia during or after test

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

More Information

• Responsible Party: David Systrom, Principal Investigator; Director, Dyspnea Center; Associate Professor of Medicine, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT03674541 History of Changes
• Other Study ID Numbers: 2018P001871
• First Posted: September 17, 2018
• Last Update Posted: February 28, 2019
• Last Verified: February 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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

Additional relevant MeSH terms:

Fatigue Syndrome, Chronic; Fibromyalgia; Dyspnea; Encephalomyelitis; Fatigue; Signs and Symptoms; Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Virus Diseases; Central Nervous System Diseases; Central Nervous System Infections; Cholinergic Agents; Pyridostigmine Bromide; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Cholinesterase Inhibitors; Enzyme Inhibitors