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The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure

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

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.


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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

Resource links provided by the National Library of Medicine


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




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



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03674541


Locations
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United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
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Principal Investigator: David Systrom, MD Brigham and Women's Hospital

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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    Key Record Dates
Last Update Posted: February 28, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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:
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Fatigue Syndrome, Chronic
Fatigue
Fibromyalgia
Dyspnea
Encephalomyelitis
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