Clinical trial NCT02669212: Myalgic Encephalomyelitis Chronic Fatigue at the National Institutes of Health
Official title: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Fatigue Syndrome
Keywords: Chronic Fatigue Syndrome
Lyme Disease
Healthy Volunteers
Movement Disorder
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2016-02-01
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: SCREENING

Brief summary: Background:

Post-Infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (PI-ME/CFS) refers to long-lasting and disabling fatigue or malaise, inability to recover after exercise, and physical and emotional discomfort that may occur after a person has an infection. Researchers want to learn more about its causes.

Objective:

To learn more about PI-ME/CFS.

Eligibility:

Adults ages 18-60 years who have finished at least 7th grade education and either:

have ME/CFS that started after an infection

OR had Lyme disease, were treated, and returned to normal health

OR are healthy volunteers

Design:

Participants will initially have a 2-5 day inpatient visit at the National Institutes of Health Clinical Center in Bethesda. During the visit, participants will have:

Medical history

Physical exam

Intravenous (IV) line. A thin plastic tube is inserted into a vein.

Blood and urine collected

Magnetic resonance imaging (MRI). Participants will lie in a machine that takes pictures of their brain. They may get a dye through their IV.

Grip strength tested

Saliva, cheek swab, and stool collected

Tilt table test with measures of body functions such as sweating and breathing, blood pressure, and heart rate and blood and urine sample collection

Collection of blood cells. Participants can choose to have the blood drawn through the IV or through a machine that filters blood cells and returns the liquid blood back into the participant s vein.

Lumbar puncture. Fluid will be removed by placement of a needle between the back bones.

Heart monitoring

Sleep study for participants with PI ME/CFS

Questions about the participant s life and how they are feeling

Questions from a neuropsychologist

Questions from an occupational therapist for participants with PI ME/CFS

Questinos from a nutritionist

After the initial visit participants will return home. Participants evaluated for PI-ME/CFS during the first visit will have their information reviewed by an adjudication panel of experts in the diagnosis and care of ME/CFS to determine if they are eligible to participate in the second study visit.

Eligible participants will be invited back for a second study visit. If a participant was taking certain medications during the first visit, they may be asked to taper off of them prior to the second visit and report any problems. They will also receive an activity monitor, fatigue diary, and nutrition log to use for at least one week prior to their second visit.

Participants who are eligible will return for a 5-10 day inpatient hospital visit at the National Institutes of Health Clinical Center. During the visit, participants will undergo measurements before and up to 96 hours after performing a stationary bike exercise test. The purpose of the exercise test is to provoke ME/CFS symptoms (post-exertional malaise). Tests will be performed before and after exercise testing. These include:

Sleeping in a room that measures how the body uses energy with EEG monitoring

Eating a controlled diet

Performing vigorous exercise for 10-15 minutes

Questions about how participants are feeling

Questions about what participants usually eat

Samples of saliva, blood, urine and stool

Wearing an activity monitor

Having an Xray that measures body composition

Thinking and memory tests

Heart monitoring

Transcranial magnetic stimulation. A brief electrical current to the scalp creates a magnetic pulse that affects brain activity.

Magnetic resonance imaging (MRI). Participants will lie in a machine that takes pictures of their brain. They will do thinking and exercise tasks during the MRI.

Lumbar puncture. Fluid will be removed by placement of a needle between the back bones.

Detailed description: Objective:

The primary objective is to explore the clinical and biological phenotypes of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS). The secondary objective is to explore the pathophysiology of fatigue and post-exertional malaise (PEM).

Study population:

Up to 206 persons will be enrolled as part of this protocol. Up to 150 persons aged 18-60 will be part of 3 study groups: 50 ME/CFS patients whose fatigue began after an infection, 50 non-fatigued participants with a documented history of a full recovery from COVID-19 infection, and 50 healthy volunteers. The study has a target of completing all study procedures on 20 enrolled participants in each group. Up to an additional 36 persons reporting a community diagnosis of ME/CFS will be enrolled into focus groups to discuss the experience of post-exertional malaise. Up to an additional 10 healthy volunteers and 10 ME/CFS patients may be enrolled to refine the protocol's electrophysiological and neuroimaging techniques.

Design:

This is a single-center, exploratory, cross-sectional study of PI-ME/CFS. Participants will have a phenotyping visit, which will encompass a 2-5 day long inpatient admission at the NIH Clinical Center. Case status for ME/CFS participants will be determined after the phenotyping visit by a case adjudication process utilizing an expert physician committee and published guidelines. Adjudicated participants meeting inclusion criteria will be invited back to participate in an exercise stress visit, which will encompass a 5-10 day long inpatient admission. Detailed subjective and objective measurements and biological specimens will be serially collected before and up to 96 hours after a peak exercise test capable of inducing post-exertional malaise during this visit. All procedures will be completed on all three study groups to allow for optimal inter-group comparisons.

Outcome measures:

The primary purpose of this protocol is to perform exploratory analysis of collected samples for the generation of new hypotheses regarding ME/CFS. The types of analyses to be performed will be wide ranging. Planned areas of focus include:

1. Characterization of the immune system and inflammation at baseline
2. Characterization of the pattern of microbiome in collected samples at baseline
3. Characterization of bioenergetics, autonomic, and metabolic function in collected samples at baseline
4. Characterization of neurocognition at baseline
5. Characterization of autonomic function at baseline

Eligibility criteria: * INCLUSION CRITERIA:
* Inclusion criteria for all participants

  1. Adult participants aged 18-60 years at the time of enrollment.
  2. Self-reported completion of at least the 7th grade of school.
  3. Ability to speak, read, and understand English.
  4. Willing and able to complete all study procedures
  5. Participant has a primary care physician at the time of enrollment.
  6. Able to provide informed consent.
* Additional inclusion criteria for participants with PI-ME/CFS for the phenotyping visit:

  1. A self-reported illness narrative of the development of persistent fatigue and post-exertional malaise as the consequence of an acute infection. The persistent fatigue may have an acute onset or become progressively worse over 6 months.
  2. Licensed Independent Practitioner documentation of ME/CFS onset:

     * Medical documentation of absence of symptoms within one year of ME/CFS onset. This may include medical records, letters, or information gathered from telephone calls with study personnel.
     * Documentation of a medical evaluation for symptoms of an acute infection or documentation of a medical evaluation of persistent symptoms within 2 months following an assumed infection.
  3. Persistent fatigue and PEM onset less than 5 years prior to enrollment.
* Additional inclusion criteria for participants with PI-ME/CFS for the exercise stress visit:

  1. Be unanimously considered to be a case of PI-ME/CFS by the protocol s adjudication committee.
  2. Meet the 1994 Fukuda Criteria or the 2003 Canadian Consensus Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or the Institute of Medicine Diagnostic Criteria..
  3. Have moderate to severe clinical symptom severity:

     * Severe fatigue as determined using the Multidimensional Fatigue Inventory (MFI): score of greater than or equal to 13 on the general fatigue subscale or greater than or equal to 10 on the reduced activity subscale.
     * Functional impairment as determined using the Short-Form 36 (SF-36): score of less than or equal to 70 physical function subscale, or less than or equal to 50 on role physical subscale, or less than or equal to 75 on social function subscale
* Additional inclusion criteria for healthy volunteer group:

None

* Additional inclusion criteria for COVID-19 Healthy Volunteers: documented prior COVID19 infection as evidenced by:

  1. A history of clinical manifestations compatible with COVID-19
  2. Laboratory evidence of Covid-19 infection:

     * Detectionof SARS-CoV-2RNA or antigen in nasopharyngeal swab, sputum, other sample source with Emergency Use Authorization/approval from the FDA; OR
     * A positive antibody test using an assay that has received Emergency Use Authorization/approval from the FDA
  3. Has been recovered from the COVID-19 infection for at least six months and no more than five years.

     EXCLUSION CRITERIA:
* Exclusion criteria for all participants:

  1. Current or past psychotic disorder including depression with psychosis, bipolar disorder, and schizophrenia
  2. Current DSM-5-defined major depression disorder, generalized anxiety disorder, post-traumatic stress disorder, panic disorder, or obsessive-compulsive disorder unless managed for more than six months with a stable treatment regimen
  3. Current or prior substance use disorder as diagnosed on the Structured Clinical Interview for DSM-5 (SCID-5).
  4. Current suicidal ideation
  5. History of head injury with loss of consciousness or amnesia lasting greater than a few seconds within lasta five years or lasting greater than 5 minutes at any point during their lifetime. Persons with medical record evidence of post-concussive symptoms lasting more than six months are also excluded.

     Persons with medical record evidence of post-concussive symptoms lasting more than six months are also excluded.
  6. Women who are pregnant, actively seeking to become pregnant, or have been pregnant in the year prior to study enrollment.
  7. Current or previous malignancy. Certain dermatologic malignancies (e.g. basal cell carcinoma) will be allowed. A history of malignancy that have fully resolved with surgical resection only (i.e. no chemotherapy, radiation therapy, or immunotherapy) will be allowed.
  8. Current systemic immunologic disorder (e.g. Type 1 diabetes, rheumatoid arthritis) will be excluded. Allergies requiring anti-histamines may not be an exclusion, but allergies requiring immunosuppressants may be an exclusion.
  9. Current or previous long term immune suppressive or immunomodulatory therapy. Systemic steroid use, even short-term, must not have been used within the month prior to enrollment
  10. Any medical condition (eg, congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, severe osteoarthritis, poorly controlled asthma) that would make the study procedures risky for the participant (e.g. exercise-induced angina and asthma) or that may confound the study results (e.g. untreated obstructive sleep apnea, severe osteoarthritis).
  11. Participation in a clinical protocol (e.g. anti-inflammatory drug intervention study) which includes an intervention that may affect the results of the current study.
  12. Inability to perform the bicycling exercise task.
  13. Clinically significant claustrophobia
  14. Not willing to allow for research samples to be shared with other researchers.
  15. Employees or staff at NIH that are directly supervised by the primary investigator or associate investigators.
* Additional exclusion criteria for participants with PI-ME/CFS for phenotyping visit:

  1. Significant neurological disorder (e.g. neurodegenerative disorder, stroke, epilepsy).
  2. PI-ME/CFS disease severity that makes it impossible for the volunteer to leave the home or requires inpatient treatment.
  3. Suspected, probable, or confirmed Lyme disease per 2011 CDC Lyme Disease National Surveillance Case Definitions.
  4. Underlying illness that may cause fatigue such as thyroid dysfunction, hepatitis, or other systemic diseases.
* Additional exclusion criteria for participants with PI-ME/CFS for exercise stress visit:

  1. Current (within 1 week) use of prescription or over-the-counter medications, herbal supplements, or nutraceuticals that may influence brain excitability that the potential participant is either unwilling or clinically unable to safely wean off for the duration of the period of the exercise stress visit. The possibility for a potential participant to be weaned off medication will be cooperatively determined by both the clinical investigative team and personal physicians. Examples of medications that influence brain excitability include tricyclic antidepressants, hypnotic, antiepileptic, antipsychotic medication, stimulants, antihistamines, muscle relaxants, dopaminergic medications, and sleep medications.
* Additional exclusion criteria for healthy volunteer group:

  1. Substantial daily fatigue as determined using PROMIS-SF Fatigue: score of \> 17.
  2. Significant neurological disorder (e.g. neurodegenerative disorder, stroke, epilepsy).
  3. Current (within 1 week) use of prescription or over-the-counter medications, herbal supplements, or nutraceuticals that may influence brain excitability
* Additional exclusion criteria for COVID-19 healthy volunteer group:

  1. Substantial daily fatigue as determined using PROMIS-SF Fatigue: score of \>17.
  2. Significant neurological disorder (e.g. neurodegenerative disorder, stroke, epilepsy).
  3. Current (within 1 week) use of prescription or over-the-counter medications, herbal supplements, or nutraceuticals that may influence brain excitability

Primary outcomes:
measure: Cardiopulmonary Exercise Test (CPET) - ATVO2rel
timeFrame: At time of AT during CPET
measure: Cardiopulmonary Exercise Test (CPET) - RER
timeFrame: At time of AT during CPET
Secondary outcomes:
Other outcomes:
measure: Characterization of Total Body Energy Use (Bioenergetics/Metabolic)
timeFrame: 12 hours
measure: Characterization of the Immune System and Inflammation - WBC
timeFrame: Baseline
measure: Characterization of the Immune System and Inflammation - ESR
timeFrame: Baseline
measure: Characterization of the Immune System and Inflammation - CRP
timeFrame: Baseline
measure: Characterization of the Immune System and Inflammation - WBC in CFS
timeFrame: Baseline
measure: Mitochondrial Extracellular Flux Assay
timeFrame: Baseline
measure: Effect of Maximal Exertion on Autonomic Function as Measured by SDNNi in Healthy and ME/CFS Participants.
timeFrame: Baseline
measure: Clinical Response Effect of Tilt Table Testing
timeFrame: Baseline
measure: Characterization of the Pattern of Microbiome in Stool
timeFrame: Baseline
measure: Test of Variables of Attention (TOVA)
timeFrame: Baseline
measure: Paced Auditory Serial Addition Test (PASAT)
timeFrame: Baseline
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Neurological Disorders and Stroke (NINDS)
name: Avindra Nath, M.D.
role: PRINCIPAL_INVESTIGATOR
References: