Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 17 of 42 for:    Mestinon

The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE September 11, 2018
First Posted Date  ICMJE September 17, 2018
Last Update Posted Date February 28, 2019
Estimated Study Start Date  ICMJE March 8, 2019
Estimated Primary Completion Date October 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Preload Failure
  • Chronic Fatigue Syndrome
  • Myalgic Encephalomyelitis
  • Fibromyalgia
  • Dyspnea
Intervention  ICMJE Drug: Pyridostigmine
Pyridostigmine 60 mg by mouth as a one time dose
Study Arms  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: September 14, 2018)
25
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 15, 2019
Estimated Primary Completion Date October 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03674541
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: Undecided
Responsible Party David Systrom, Brigham and Women's Hospital
Study Sponsor  ICMJE Brigham and Women's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: David Systrom, MD Brigham and Women's Hospital
PRS Account Brigham and Women's Hospital
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP