The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
Condition: 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
MeSH terms: Encephalomyelitis; Fibromyalgia; Fatigue Syndrome, Chronic; Myalgia; Hypotension, Orthostatic; Primary Dysautonomias; Postural Orthostatic Tachycardia Syndrome; Hypotension; Tachycardia; Syndrome; Fatigue
Intervention: Pyridostigmine Bromide; Placebo
Intervention description: Pyridostigmine Bromide 60 mg capsule by mouth as a one time dose; Placebo (Cellulose microcrystalline) capsule by mouth as a one time dose
Intervention MeSH terms: Bromides; Pyridostigmine Bromide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will be assigned randomly to receive either pyridostigmine or placebo, both study participants and investigators will be blinded.
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 45.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Myalgic encephalomyelitis/Chronic fatigue syndrome; Myalgic encephalomyelitis; Chronic fatigue syndrome; Pyridostigmine; Exercise Intolerance; Invasive Cardiopulmonary Exercise Test

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Meets the Institute of Medicine (IOM) criteria for ME/CFS

          -  Completing the clinically indicated invasive cardiopulmonary exercise test (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.