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

Tracking Information

• First Submitted Date: September 11, 2018
• First Posted Date: September 17, 2018
• Last Update Posted Date: February 28, 2019
• Estimated Study Start Date: March 8, 2019
• Estimated Primary Completion Date: October 15, 2019 (Final data collection date for primary outcome measure)

Current 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

• Original Primary Outcome Measures: Same as current

Current 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

• Original Secondary Outcome Measures: Same as current
• 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 Preload Failure
• Official Title: The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure

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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Preload Failure
• Chronic Fatigue Syndrome
• Myalgic Encephalomyelitis
• Fibromyalgia
• Dyspnea

Intervention

Drug: Pyridostigmine

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Enrolling by invitation
• Estimated Enrollment (submitted: September 14, 2018): 25
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 15, 2019
• Estimated Primary Completion Date: October 15, 2019 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (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

• Responsible Party: David Systrom, Brigham and Women's Hospital
• Study Sponsor: Brigham and Women's Hospital
• Collaborators: Not Provided

Investigators

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

• PRS Account: Brigham and Women's Hospital
• Verification Date: February 2019