The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

NCT03674541 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 2018P001871
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

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 an invasive cardiopulmonary exercise test (iCPET) 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.

Conditions

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Chronic Fatigue Syndrome; Myalgic Encephalomyelitis; Exercise Intolerance; Dysautonomia; Low Ventricular Filling Pressures (Preload Failure); Postural Orthostatic Tachycardia Syndrome; Orthostatic Hypotension; Fibromyalgia

Keywords

Myalgic encephalomyelitis/Chronic fatigue syndrome; Myalgic encephalomyelitis; Chronic fatigue syndrome; Pyridostigmine; Exercise Intolerance; Invasive Cardiopulmonary Exercise Test

Outcome Measures

Primary Outcomes (1)

• Change in Peak Oxygen Uptake (Peak VO2) Between the First and Second iCPET

  Define the response of oxygen uptake to pyridostigmine expressed both as mL/min and mL/min/kg. The difference in peak oxygen uptake from first iCPET to second iCPET. Research has shown that ME/CFS patients have inability to reproduce results on two consecutive cardiopulmonary exercise tests(CPET). Traditionally this is demonstrated with a two-day CPET protocol, but in this study we investigate the acute effects of pyridostigmine administration on the early stages of post exertional malaise(PEM).

  First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.

Secondary Outcomes (11)

• Peak-Rest Oxygen Uptake (VO2)

  First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.

• Peak Cardiac Output (Qc)

  First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.

• Peak-Rest Cardiac Output (Qc)

  First iCPET up to 30 min, 50 minutes rest, second iCPET up to 30 minutes

• Peak Right Atrial Pressure (RAP)

  First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.

• Peak-Rest Right Atrial Pressure (RAP)

  First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.

Study Arms (2)

Study Drug - Pyridostigmine

ACTIVE COMPARATOR

Pyridostigmine 60 mg by mouth as a one time dose

Drug: Pyridostigmine Bromide

Placebo

PLACEBO COMPARATOR

Placebo by mouth as a one time dose

Drug: Placebo

Interventions

Pyridostigmine Bromide DRUG

Pyridostigmine Bromide 60 mg capsule by mouth as a one time dose

Also known as: Mestinon

Study Drug - Pyridostigmine

Placebo DRUG

Placebo (Cellulose microcrystalline) capsule by mouth as a one time dose

Also known as: Cellulose microcrystalline

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Meets the Institute of Medicine (IOM) criteria for ME/CFS
• Completing the clinically indicated invasive cardiopulmonary exercise test (iCPET)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Joseph P, Pari R, Miller S, Warren A, Stovall MC, Squires J, Chang CJ, Xiao W, Waxman AB, Systrom DM. Neurovascular Dysregulation and Acute Exercise Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest. 2022 Nov;162(5):1116-1126. doi: 10.1016/j.chest.2022.04.146. Epub 2022 May 6.

  PMID: 35526605 DERIVED

MeSH Terms

Conditions

Fatigue Syndrome, Chronic; Autonomic Nervous System Diseases; Postural Orthostatic Tachycardia Syndrome; Hypotension, Orthostatic; Fibromyalgia

Interventions

Pyridostigmine Bromide; microcrystalline cellulose

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Encephalomyelitis; Neuroinflammatory Diseases; Nervous System Diseases; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Orthostatic Intolerance; Primary Dysautonomias; Hypotension; Vascular Diseases; Cardiovascular Diseases; Rheumatic Diseases

Intervention Hierarchy (Ancestors)

Pyridinium Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Of the 45 subjects, 39 were female and 6 were male. Although this gender distribution is reflective of the gender differences seen in ME/CFS, our small sample size produced a randomization error where all 6 male participants were placed in the placebo group. We elected not to include males in the statistical analysis as their response to exercise was discordant compared to females who received placebo. In addition, reducing the sample size increases the likelihood of type II errors.

Results Point of Contact

• Title: Dr. David Systrom
• Organization: Brigham and Women's Hospital

dsystrom@bwh.harvard.edu

6175431554

Study Officials

• David Systrom, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator; Director, Dyspnea Center; Associate Professor of Medicine

Model Details: Subjects will be assigned randomly to receive either pyridostigmine or placebo, both study participants and investigators will be blinded.

Study Record Dates

• First Submitted: September 11, 2018
• First Posted: September 17, 2018
• Study Start: January 14, 2020
• Primary Completion: December 5, 2021
• Study Completion: December 20, 2021
• Last Updated: November 8, 2022
• Results First Posted: October 4, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 9 months and ending 36 months following article publication.
• Access Criteria: Proposals should be directed to jsquires1@bwh.harvard.edu. To gain access, data requestors will need to sign a data access agreement.

Locations

US (1)