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

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

Interventions

DRUG

Pyridostigmine Bromide

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

DRUG

Placebo

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

Sponsors & Collaborators

• Brigham and Women's Hospital

  lead OTHER

Principal Investigators

• David Systrom, MD · Brigham and Women's Hospital

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-01-14

Primary Completion

2021-12-05

Completion

2021-12-20

FDA Drug

Yes

Countries

• United States

Study Locations