Fecal Microbiota Transplantation in Chronic Fatigue Syndrome - an RCT
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Enrollment
- 80
- Locations
- 2
- Primary Endpoint
- Proportion with treatment success in FSS score in donor versus placebo FMT group. Treatment success is defined as an improvement of more than 1.2 points on the Fatigue Severity Scale (FSS)
Study Overview
Brief Summary
This is a single-center stratified (on gender and donor), block randomized, placebo-controlled, parallel group trial with 12-months follow-up of 80 chronic fatigue syndrome/encephalomyelitis (CFS/ME) participants. Participants will be randomized to treatment by preprocessed thawed donor fecal microbiota transplant or preprocessed thawed autologous fecal microbiota transplant. Primary endpoint is the efficacy of FMT at three months by the Fatigue Severity Scale. The investigators will use patient reported outcomes for primary and secondary outcome measures.
Previous studies suggest that a dysbiosis of the gut microbiota may be a key feature in CFS/ME. We hypothesize that
A: CFS/ME is caused by a dysbiosis in the gut flora causing barrier leakage of bacterial products, a low grade systemic immune activation and disturbances in the host energy metabolism.
B: Recovery of a normal gut flora by fecal microbiota transplantation (FMT) alleviates symptoms and may even induce remission of CFS/ME.
This project aims to determine if there is a true cause and effect relationship between a dysbiotic gut flora and CFS/ME by testing if treatment of the observed dysbiosis by FMT also can resolve CFS/ME symptoms. In this process, collection of blood, fecal, and urine samples before and after FMT will open the possibility to explore the relationship between the gut flora, immune response, host energy metabolism and CFS/ME using technologies of microbiomics, metabolomics and immunological characterizations for a better understanding of the pathobiology of CFS/ME.
Detailed Description
CFS/ME participants:
General practitioners recruit participants from the local area, by posters at the doctors' offices. In addition the study has a facebook site, named "the COMEBACK study", where interested CFS/ME subjects can submit their interest to be assessed for participation. After a telephone screening of potential participants by the International Consensus Criteria for CFS/ME and CFS/ME severity rating, eligible subjects will be referred to department of physical medicine and rehabilitation UNN Harstad (FYSMED) and re-assessed. During this screening process the investigators will keep a track record of screening failures noting reason for failure. Participants will have a physical exam and necessary workup including blood, fecal and urine tests to exclude differential diagnosis according to the Norwegian National Guidelines for Assessment of CFS/ME. Participants receive information about the study and give their written consent. Subjects earlier diagnosed with CFS/ME at FYSMED will undertake the same re-assessment.
During the work up, participants will do the Fatigue Severity Scale, Hospital Anxiety and Depression scale, SF 36, Modified DePaul Questionnaire, the Rome IV criteria for irritable bowel syndrome, and the "Repeatable Battery for the Assessment of Neuropsychological Status" test (RBANS). Heart rate variability is implemented as an additional measure when approximately 40 out of 80 participants are assigned treatment.
Donors are recruited informally from the local high schools. Donors are included and screened according to the European Consensus Guidelines from 2017. The full screening will be undertaken before the first feces donation and every 4th week. The inclusion and screening will be performed at the department of physical medicine and rehabilitation UNN Harstad. The investigators will keep a track record of screening failures noting reason for failure.
Participants receive FMT at the gastroenterology outpatient clinic at University Hospital of North Norway Harstad, Norway. No antibiotics are given prior to the intervention. The participants must do a bowel lavage using Sodiumpicosulphate/Magnesiumcitrate (Picoprep, Ferring) before intervention. The treatment will be administered by enema. Active treatment will be pre-processed frozen donor feces. Placebo will be the participant's own feces processed and frozen during the study inclusion. After the intervention, the participants have no restrictions on activity level and are asked to keep an unchanged diet without introduction of any new food supplements or probiotics in the follow up period. To keep track of change in diet investigators ask participants to do a food frequency questionnaire before the FMT and at 3 and 12 months after the intervention. Use of antibiotics, food supplement and use of medications will also be recorded.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •FMT PARTICIPANTS
- •Inclusion Criteria:
- •International Consensus Criteria for CFS/ME
- •18-65 years
- •Mild-severe CFS/ME
- •Fatigue Severity Scale score of 5,0-7,0
- •Symptom duration for 2-15 years
Exclusion Criteria
- •Kidney failure
- •Congestive heart failure
- •Immuno-deficiency or use of immune-suppresive drugs
- •Other disease that may explain ME/CFS symptoms discovered during diagnostic work up
- •Use of antibiotics the last three months,
- •Use of low dose naltrexone or Isoprinosin
- •Pregnancy or breastfeeding
- •Serious endogenous depression
- •Chronic infectious disease (HIV, hepatitis B or C etc.)
- •Introduction of new food supplements, change in diet or introduction of new medications the last three months
- •Assessed not be able to follow the instructions for data and sample collection
- •Very severe ME/CFS (WHO class IV)
- •Symptom duration of less than 24 months or more than 15 years
- •History of abdominal surgery, with the exception of appendectomy, cholecystectomy, caesarean section and hysterectomy
- •Previous treatment with FMT
- •Inclusion criteria:
- •Age 16-30 years
- •Type 3 or 4 stool by the Bristol Stool Scale
- •Exclusion criteria:
- •Use of peroral antibiotics past 3 months
- •Use of topical antibiotics past 2 months
- •Tattoo or piercing past 6 months
- •Former imprisonment
- •History of: -chronic diarrhea
- •constipation
- •inflammatory bowel disease
- •colorectal polyps
- •colorectal cancer
- •immuno-suppression
- •Metabolic syndrome
- •Atopic skin disease
- •Psychiatric disorders
- •Other serious autoimmune disease
- •Close relatives with serious autoimmune disease
- •High risk sexual behavior
- •Bowel movements that does not correspond to a Bristol Stool Scale type 3 or 4
- •Journeys abroad the last six months to countries high in antibiotic resistance
- •Use of food supplements, pre-, -pro, -or symbiotics past one month
- •Dysbiosis grade 3 or more by the GA dysbiosis test
Outcomes
Primary Outcomes
Proportion with treatment success in FSS score in donor versus placebo FMT group. Treatment success is defined as an improvement of more than 1.2 points on the Fatigue Severity Scale (FSS)
Time Frame: Three months after treatment
Fatigue Severity Scale (FSS) is a self-reported, 9-item fatigue scale. Participants rate all 9 items on a 7-point Likert scale (1-2-3-4-5-6-7) depending on how appropriate they felt the statement applied to them over the preceding week. The total score is calculated by adding up the answer from each item and divide by 9. Lower scores indicate better outcomes. Maximum score is 7. In an intention to treat analysis we will categorize participants as responders/non-responders, defining responders as decrease of more than 1,2 to the total baseline score in the FSS at 3 months post FMT by Chi Square. Baseline score will be the average of the two scores from the screening period. Missing values will be regarded as non responders
Secondary Outcomes
- Change in donor versus placebo FMT group in quality of life by the SF36 score(Change in SF36 score by repeated measures from baseline and until 3 and 12 months after treamtent)
- Change in donor versus placebo FMT group in gastrointestinal related complaints by the sum score of selected items in the DePaul Questionnaire (DPQ) (29, 30, 46 and 47)(Change in DPQ score by repeated measures from baseline and until 6 and 12 months after treatment)
- Change in donor versus placebo FMT group in anxiety and depression by the Hospital Anxiety Depression Scale (HADS) score(Change in HADS score by repeated measures from baseline and until 3 and 12 months after treatment)
- Change in HRV in donor FMT vs placebo FMT group derived from the R-R intervals in the resting continuous ECG recordings. The secondary vagal function outcome will be differences in changes from pre-post treatment between groups in RMSSD (RMSSD; in ms2)(3 months after treatment)
- Change in donor versus placebo FMT group in fatigue by the Fatigue Severity Scale score(Change in Fatigue severity scale by repeated measures from baseline and until 1, 3, 6, 9 and 12 months after treatment)
- Change in donor versus placebo FMT group in neurocognitive function by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score from baseline and until 3 months after treatment.(Change from baseline and until three months after treatment)
- Difference in mean baseline HRV (HF-HRV and RMSSD) between responders vs non-responders to donor FMT.(3 months after treatment)
- Number of Participants with Adverse Events as a Measure of Safety and Tolerability(Baseline to end of follow up at 12 months after FMT)
- Change in HRV in donor FMT vs placebo FMT group derived from the R-R intervals in continuous ECG recordings. The primary vagal function outcome will be differences in changes from pre-post treatment between groups in High Frequency HRV (HF-HRV; in ms2(3 months after treatment)