Clinical trial NCT03674541: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2018-09-17
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be assigned randomly to receive either pyridostigmine or placebo, both study participants and investigators will be blinded.
Primary purpose: TREATMENT

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.

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 invasive cardiopulmonary exercise test (iCPET). 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 carbon dioxide(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 iCPET, 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 iCPET. Recovery cycling will be performed after a rest period of 50 minutes. This will be administered in a randomized, double-blind, placebo-controlled trial.

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.

Primary outcomes:
measure: Change in Peak Oxygen Uptake (Peak VO2) Between the First and Second iCPET
timeFrame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Secondary outcomes:
measure: Peak-Rest Oxygen Uptake (VO2)
timeFrame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
measure: Peak Cardiac Output (Qc)
timeFrame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
measure: Peak-Rest Cardiac Output (Qc)
timeFrame: First iCPET up to 30 min, 50 minutes rest, second iCPET up to 30 minutes
measure: Peak Right Atrial Pressure (RAP)
timeFrame: First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
measure: Peak-Rest Right Atrial Pressure (RAP)
timeFrame: First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
measure: Peak Pulmonary Arterial Wedge Pressure (PAWP)
timeFrame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
measure: Peak Stroke Volume (SV)
timeFrame: First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
measure: Peak (Ca-vO2)/[Hgb]
timeFrame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
measure: Ventilatory Efficiency (VE/VCO2)
timeFrame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
measure: Borg Fatigue Scale
timeFrame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
measure: Borg Dyspnea Scale
timeFrame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: David Systrom, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.