The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure

Learn more about:
Related Clinical Trial
Assessment of N-Acetylcysteine as Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Investigating the Role of Early Intravenous Immunoglobulin Treatment for Children With Encephalitis Complex Chronic Diseases Program Data Registry Cardiopulmonary Testing in ME/CFS to Improve Diagnostic Accuracy The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure Analysis of Post-exertional Malaise Using a Two-day CPET in People With ME/CFS The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial B-cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Very Severe Chronic Fatigue Syndrome B-cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome Pilot Study of Alternative Treatments of Unexplained Chronic Fatigue Survey and Cognitive Behavior Therapy for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Oral Melatonin Plus Zinc Supplementation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) The Study of the Safety and Efficacy of Ampligen in Chronic Fatigue Syndrome The Comeback Study New MRT Imaging Biomarkers and Treatment With Kinetic Oscillatory Stimulation (KOS) in Nasal Cavity for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Tumor Necrosis Factor-alpha Inhibition Using Etanercept in Chronic Fatigue Syndrome A Non-Interventional Pilot Study to Explore the Role of Gut Flora in ME/CFS

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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Maximal Oxygen Uptake (VO2max)

Secondary Outcome

 End-tidal Carbon Dioxide (CO2)

Condition

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Intervention

Pyridostigmine Bromide

Study Arms / Comparison Groups

 Study Drug - Pyridostigmine
Description:  Pyridostigmine 60 mg by mouth as a one time dose

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

50

Start Date

January 14, 2020

Completion Date

June 1, 2021

Primary Completion Date

June 1, 2021

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.
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

David Systrom, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03674541

Organization ID

2018P001871


Responsible Party

Principal Investigator

Study Sponsor

Brigham and Women's Hospital


Study Sponsor

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


Verification Date

July 2020