A Phase 2 interventional study of Pyridostigmine Bromide and Placebo in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Chronic Fatigue Syndrome and Myalgic Encephalomyelitis, sponsored by Brigham and Women's Hospital. Completed at 1 site in United States. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2022-11-08.
Sponsored by Brigham and Women's Hospital · Phase 2, Interventional, and Treatment
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Among 86 studies in Fatigue Syndrome, Chronic with a site in United States — 21 open to participants now, 24 under way, none of them phase 3. Fatigue Syndrome, Chronic · United States.
Among the 86 studies in Fatigue Syndrome, Chronic with a site in United States, this one is the 32nd largest by enrollment of the 58 interventional ones that give a count, is one of 5 that started in 2020, is one of 12 in phase 2, and was the 41st registered.
264 studies on the registry are indexed under Fatigue Syndrome, Chronic; 62 are open to participants now.
Browse Fatigue Syndrome, Chronic studies →21 of the 86 studies in Fatigue Syndrome, Chronic with a site in United States are open now. Recruiting first, the newest first:
Fred Friedberg · Sites in United States
Ages 18–65
University of Alabama at Birmingham · Sites in United States
Ages 18+
Mayo Clinic · Sites in United States
Ages 18+
University of California, San Francisco · Sites in United States
Ages 18+ · Healthy volunteers
IMMUNOe Research Centers · Sites in United States
Ages 18–90
A study can be open while its sites in United States have not opened yet or have stopped. Only those recruiting at a site in United States →
Of the 44 Fatigue Syndrome, Chronic studies recruiting now, 18 (41%) set no upper age limit and 20 (45%) stop at 75 or younger; 5 take children under 18; 10 take healthy volunteers.
This study: 18 Years to 80 Years · all sexes · no healthy volunteers.
The full table on the hub →This tab as a report to print or save as PDF → With an account.
86 studies; the count open now beside each. This study's row is marked.
A study in two phases is counted once above. Listed by phase, each with its combined phases: Phase 1 11 · Phase 2 17 · Phase 3 1 · Phase 4 5
First in 1994; this study’s year is marked. 5 started in 2020.
By drug class, each counting the studies that test any of its medicines:
This study's enrollment of 45 is below the median of 60 across 178 interventional studies indexed under Fatigue Syndrome, Chronic.
Median enrollment 50 across the 58 interventional studies, 152 across the 26 observational. Of the 47 that completed or were terminated, 15 (32%) have results posted.
This tab as a report to print or save as PDF → With an account.
10 of 86 have an industry lead sponsor. The 10 most frequent:
Brigham and Women's Hospital is the lead sponsor of 1,268 studies on the registry; 229 are open to participants now.
Of its 116 completed or terminated interventional studies of FDA-regulated products, 65 (56%) have results posted.
Brigham and Women's Hospital has 2 studies filed under Fatigue Syndrome, Chronic — fewer than ten, so there is no comparison to draw.
10 of the studies in Fatigue Syndrome, Chronic with a site in United States that are under way reach primary completion within a year, 0 of them phase 3. Phase 3 first, then by date:
| Study | Primary completion |
|---|---|
| NCT06511050Icahn School of Medicine at Mount SinaiLumbrokinase for Adults With Long Covid, Post-treatment Lyme Disease Syndrome, and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | 2026-12 |
| NCT06585254Icahn School of Medicine at Mount SinaitVNS in Long COVID-19 | 2026-12-31 |
| NCT04049331Seattle Institute for Biomedical and Clinical ResearchTestosterone Replacement in Male Cancer Survivors With Fatigue and Low Testosterone | 2027-01-30 |
| NCT04542161Weill Medical College of Cornell UniversityAssessment of N-Acetylcysteine as Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | 2027-04-30 |
| NCT07600320Icahn School of Medicine at Mount SinaiFareon Open Label Device Clinical Trial | 2027-04-30 |
Add all 10 to your calendar (.ics) → With an account.
Among the 86 studies in Fatigue Syndrome, Chronic with a site in United States, from their registry updates:
This tab as a report to print or save as PDF → With an account.
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.
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.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
COPD
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Relapsed and refractory
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Pyridostigmine 60 mg by mouth as a one time dose
Drug: Pyridostigmine Bromide
Placebo by mouth as a one time dose
Drug: Placebo
Pyridostigmine Bromide 60 mg capsule by mouth as a one time dose
Also known as: Mestinon
Placebo (Cellulose microcrystalline) capsule by mouth as a one time dose
Also known as: Cellulose microcrystalline
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).
Time frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak-Rest Oxygen Uptake (VO2)
Peak versus rest changes in oxygen uptake between first and second CPETs expressed as mL/min.
Time frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak Cardiac Output (Qc)
Arterial and mixed-venous blood gases and pH are measured at peak exercise and Qc is calculated using the direct Fick principle Qc=VO2/(Ca-Cv). Change in peak Qc between first and second iCPETs is measured in L/min.
Time frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak-Rest Cardiac Output (Qc)
Peak versus rest change in cardiac output expressed in L/min between first and second iCPETs. Cardiac output is determined using the direct Fick principle.
Time frame: First iCPET up to 30 min, 50 minutes rest, second iCPET up to 30 minutes
Peak Right Atrial Pressure (RAP)
Difference in peak RAP between first and second iCPETs measured in mmHg.
Time frame: First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak-Rest Right Atrial Pressure (RAP)
Peak versus rest changes in RAP between first and second iCPETs measured in mmHg
Time frame: First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak Pulmonary Arterial Wedge Pressure (PAWP)
Difference in peak PAWP between first and second iCPETs measured in mmHg
Time frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak Stroke Volume (SV)
Difference in peak SV between first and second iCPETs measured in mL
Time frame: First iCPEt up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Peak (Ca-vO2)/[Hgb]
Difference in peak arterial-venous oxygen content difference normalized to hemoglobin (Ca-vO2)/\[Hgb\] between first and second iCPETs
Time frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Ventilatory Efficiency (VE/VCO2)
Difference in ventilatory efficiency between first and second iCPETs
Time frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Borg Fatigue Scale
Difference in perception of fatigue at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).
Time frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Borg Dyspnea Scale
Difference in perceived dyspnea at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).
Time frame: First iCPET up to 30 minutes, 50 minutes rest, second iCPET up to 30 minutes.
Recruited from PI's clinic
| Milestone | Study Drug - Pyridostigmine | Placebo |
|---|---|---|
| Started | 23 | 22 |
| Completed | 23 | 22 |
| Not completed | 0 | 0 |
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).
| mL/min | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Change in Peak Oxygen Uptake (Peak VO2) Between the First and Second iCPET | 13.3 ± 13.4 | -40.3 ± 21.3 | 111.8 ± 65.0 |
Peak versus rest changes in oxygen uptake between first and second CPETs expressed as mL/min.
| mL/min | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Peak-Rest Oxygen Uptake (VO2) | 25.9 ± 15.3 | -60.8 ± 25.6 | 121.8 ± 80.0 |
Arterial and mixed-venous blood gases and pH are measured at peak exercise and Qc is calculated using the direct Fick principle Qc=VO2/(Ca-Cv). Change in peak Qc between first and second iCPETs is measured in L/min.
| L/min | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Peak Cardiac Output (Qc) | 0.2 ± 0.2 | -0.2 ± 0.3 | 1.1 ± 0.4 |
Peak versus rest change in cardiac output expressed in L/min between first and second iCPETs. Cardiac output is determined using the direct Fick principle.
| L/min | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Peak-Rest Cardiac Output (Qc) | -0.2 ± 0.6 | -1.9 ± 0.6 | 0.9 ± 0.8 |
Difference in peak RAP between first and second iCPETs measured in mmHg.
| mm Hg | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Peak Right Atrial Pressure (RAP) | 1.2 ± 0.3 | 0.1 ± 0.5 | 1.7 ± 0.7 |
Peak versus rest changes in RAP between first and second iCPETs measured in mmHg
| mm Hg | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Peak-Rest Right Atrial Pressure (RAP) | 1.0 ± 0.5 | -0.6 ± 0.5 | 0.0 ± 1.0 |
Difference in peak PAWP between first and second iCPETs measured in mmHg
| mm Hg | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Peak Pulmonary Arterial Wedge Pressure (PAWP) | 1.0 ± 0.8 | 1.0 ± 0.5 | 1.5 ± 1.4 |
Difference in peak SV between first and second iCPETs measured in mL
| mL | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Peak Stroke Volume (SV) | 3.0 ± 1.4 | -1.1 ± 1.9 | -12.7 ± 12.9 |
Difference in peak arterial-venous oxygen content difference normalized to hemoglobin (Ca-vO2)/\[Hgb\] between first and second iCPETs
| Ratio | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Peak (Ca-vO2)/[Hgb] | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.0 ± 0.1 |
Difference in ventilatory efficiency between first and second iCPETs
| Ratio | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Ventilatory Efficiency (VE/VCO2) | -0.2 ± 0.8 | 1.0 ± 0.6 | 1.7 ± 0.6 |
Difference in perception of fatigue at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).
| units on a scale | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Borg Fatigue Scale | 0.1 ± 0.2 | -0.6 ± 0.3 | 0.4 ± 0.4 |
Difference in perceived dyspnea at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).
| units on a scale | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) |
|---|---|---|---|
| Borg Dyspnea Scale | -0.1 ± 0.2 | -1.0 ± 0.5 | 0.3 ± 0.5 |
Collected over Adverse events were monitored during the two iCPETs and for the duration of the 50 minutes rest between the two iCPETs. After the second iCPET, the subjects were monitored for an hour in the recovery room. The subjects received a follow up phone call or email up to one week following the day of the procedure to assess if they experienced any adverse events from the study. This was documented for every patient.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Study Drug - Pyridostigmine | 0/23 (0%) | 0/23 (0%) | 15/23 (65.2%) |
| Placebo | 0/22 (0%) | 0/22 (0%) | 15/22 (68.2%) |
| Event | Study Drug - Pyridostigmine | Placebo |
|---|---|---|
| Post-Exertional Malaise (PEM)Immune system disorders | 13/23 | 11/22 |
| Wrist PainSkin and subcutaneous tissue disorders | 2/23 | 4/22 |
Data was collected for all 45 patient, 23 females on study drug, 22 on placebo (16 females, 6 males).
| Age, Continuous(Years) | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) | Total |
|---|---|---|---|---|
| Mean | 40 ± 16 | 40 ± 11 | 50 ± 20 | 42 ± 15 |
| Sex: Female, Male(Participants) | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) | Total |
|---|---|---|---|---|
| Female | 23 | 16 | 0 | 39 |
| Male | 0 | 0 | 6 | 6 |
| Race/Ethnicity, Customized(Participants) | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) | Total |
|---|---|---|---|---|
| White | 21 | 12 | 4 | 37 |
| Other | 2 | 4 | 2 | 8 |
| Body Mass Index (BMI)(kg/m^2) | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) | Total |
|---|---|---|---|---|
| Mean | 23.8 ± 2.7 | 23.0 ± 4.1 | 23.8 ± 2.7 | 23.5 ± 3.3 |
| Hemoglobin(g/dL) | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) | Total |
|---|---|---|---|---|
| Mean | 13.9 ± 1.3 | 14.0 ± 1.1 | 15.7 ± 1.4 | 14.2 ± 1.3 |
| Hypertension(Participants) | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) | Total |
|---|---|---|---|---|
| Count of participants | 3 | 1 | 1 | 5 |
| Dyslipidemia(Participants) | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) | Total |
|---|---|---|---|---|
| Count of participants | 1 | 1 | 2 | 4 |
| Obesity(Participants) | Study Drug - Pyridostigmine | Placebo (Female) | Placebo (Male) | Total |
|---|---|---|---|---|
| Count of participants | 0 | 0 | 0 | 0 |
19 further baseline measures are reported on the registry.
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: Yes — Individual participant data that underlie the results reported in this article, after de-identification(text, tables, figures, and appendices) will be available for researchers who provide a methodologically sound proposal to achieve aims in the approved proposal.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form
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.
Ran from Jan 2020 to primary completion in Dec 2021, 22 months.
Results were first posted in Oct 2022, 9 months after primary completion.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in Oct 2022. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Pyridostigmine
Brigham and Women's Hospital →