The Comeback Study

• ClinicalTrials.gov Identifier: NCT03691987
• Recruitment Status: Active, not recruiting
• First Posted: October 2, 2018
• Last Update Posted: March 3, 2023
• Sponsor: University Hospital of North Norway
• Collaborators: The Research Council of Norway; Quadram Institute Bioscience; Umeå University; Cornell University
• Information provided by (Responsible Party): University Hospital of North Norway

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Chronic Fatigue Syndrome; Myalgic Encephalomyelitis	Biological: Preprocessed thawed donor FMT; Biological: Preprocessed thawed autologous FMT	Phase 2

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.

The treatment will take place in blocks of four consecutive participants per day. A data engineer at the Department of Clinical Research at the University Hospital of North Norway, Tromsø (UNN,Tromsø) creates the allocation sequence using the REDCap software. The treatment is randomized on donor and placebo in fixed blocks of 4 with 2 active (1 donor A and 1 donor B) and 2 placebo. Block allocation will be stratified on gender.

A stratification on donor and gender will be performed by assigning full blocks of male and female participants. In the two active slots in each block of four, one active slot will be used for donor A and one for donor B. The stratification of gender reflects the higher incidence of CFS/ME in women. Donor fecal microbiota transplants stored for more than two years will be disposed and replaced with transplants from a new donor. If this happens, donor fecal microbiota transplants from the new donor will be assigned in remaining slots from the donor with the expired transplants.

Allocation is done in solitude in a closed room with no transparency, only containing a freezer with the active transplants (tagged by donor batch ID) and the placebo transplants (tagged by screening number). Before allocation of treatment, an investigator places the FMT-placebos on a table in the room. The allocator can then enter the room as the researcher placing all the placebos leaves the room. The allocator will access the randomization sequence when entering participants screening number on the REDCap software using a computer in the same room. The allocator will be the only person involved in the study that can access the randomization program at the REDCap software. If a screening number is randomized to active treatment, the allocator removes the tag from the placebo and places it on a donor FMT treatment instead. All unused placebo transplants will be disposed immediately. When finished, the allocator places the allocated treatment in a box in a designated freezer. The allocator will build a key file matching the active treatment to the donor batch id by updating a key file on paper and store it in a safe not accessible to any others. In addition the allocator will write the corresponding patient screeningnumber on tags from the used donor batch and keep them as backup in the same safe. This will allow for tracking of each individual donor batch to a corresponding participant at the end of trial when all follow up is complete.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Fecal Microbiota Transplantation in Chronic Fatigue Syndrome - an RCT
• Actual Study Start Date: February 15, 2019
• Estimated Primary Completion Date: March 1, 2023
• Estimated Study Completion Date: December 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Preprocessed thawed donor FMT; The active transplants are processed in a 2-3 weeks period before treatment of the first participant. Fifty to eighty grams of freshly delivered feces from donors is mixed with 100 mL isotonic saline and 25 mL 85% glycerol, homogenized and poured through a 0.5 mm mesh steel strainer, and transferred to 60 ml luerlock syringes and stored at -40°C. Frozen transplants are slowly thawed 2 hours prior to administration by transferring the FMT-syringes to a waterbath (+30°C). The transplant is then mixed with 125 mL 12°C isotonic saline in an enema bag prior to installation.	Biological: Preprocessed thawed donor FMT; Delivered as an enema using the same equipment and technique as X-ray of the colon
Placebo Comparator: Preprocessed thawed autologous FMT; The placebo transplant from each participant is prepared during the inclusion process four to six weeks before intervention and stored at -40°C. Fifty to eighty grams of freshly delivered feces from participants is mixed with 100 mL isotonic saline and 25 mL 85% glycerol is homogenized and poured through a 0.5 mm mesh steel strainer, and transferred to 60ml Luerlock syringes. Frozen transplants are slowly thawed 2 hours prior to administration by transferring the Luerlock syringes to a waterbath (+30°C). The transplant is then mixed with 125 mL 12°C isotonic saline in the enema bag prior to installation.	Biological: Preprocessed thawed autologous FMT; Delivered as an enema using the same equipment and technique as X-ray of the colon

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. Change in donor versus placebo FMT group in fatigue by the Fatigue Severity Scale score [ Time Frame: Change in Fatigue severity scale by repeated measures from baseline and until 1, 3, 6, 9 and 12 months after treatment ]
2. Change in donor versus placebo FMT group in quality of life by the SF36 score [ Time Frame: Change in SF36 score by repeated measures from baseline and until 3 and 12 months after treamtent ]
   The SF-36 consists of eight scaled scores (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health), which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability.
3. 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. [ Time Frame: Change from baseline and until three months after treatment ]
   RBANS is a neuropsychological assessment that consists of ten subtests which give scores to five domains: Immediate memory, visuospatial/constructional ability, language, attention and delayed memory.
4. Change in donor versus placebo FMT group in anxiety and depression by the Hospital Anxiety Depression Scale (HADS) score [ Time Frame: Change in HADS score by repeated measures from baseline and until 3 and 12 months after treatment ]
   HADS is an instrument with 14-items for detection of depression and anxiety in hospitalized patients. Scores range from 1-21 interpreted as: normal (0-7), mild (8-10), moderate (11-14), severe (15-21). Subscales for anxiety (HADS-A) and depression (HADS-D) is also defined. We will explore the FMT effects on HADS by an independent sample T-test (or, if necessary, non-parametric Mann-Whitney) comparing change in global score. We will apply last value forward for missing values.
5. 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) [ Time Frame: Change in DPQ score by repeated measures from baseline and until 6 and 12 months after treatment ]
   The DPQ assesses key symptoms of ME/CFS such as fatigue, gastrointestinal complaints, post-exertional malaise, sleep, pain, neurological/cognitive impairments and autonomic, neuroendocrine and immune symptoms. At each item, participants have to rate the frequency and severity of the symptom on a scale from 0 to 4. We wil use the sum score from the questions that assess gastrointestinal complaints in the DPQ in this endpoint. This endpoint was implemented after 19 out of 80 participants had completed the three months follow up
6. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Baseline to end of follow up at 12 months after FMT ]
   Participants will be screened for adverse events from the time of informed consent through the end of the trial. In case of an identified adverse event, this will be recorded and described in the CRF
7. 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 [ Time Frame: 3 months after treatment ]
   Firstbeat Bodyguard will record R-R interval and the Firstbeat life style assessment software will analyze the R-R interval recording and provide the outcome measure
8. 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) [ Time Frame: 3 months after treatment ]
9. Difference in mean baseline HRV (HF-HRV and RMSSD) between responders vs non-responders to donor FMT. [ Time Frame: 3 months after treatment ]
   As defined by the primary endpoint in the clinical study, a responder will be defined as an improvement of more than 1.2 points on the Fatigue Severity Scale (FSS) from baseline and until 3 months after treatment. To determine HRV in each group we will use High Frequency Power analysis denominating HRV in ms2.

Other Outcome Measures:

1. Engraftment of donor microbiota [ Time Frame: 3 months after FMT ]
   Comparison between baseline profile, post FMT and donor profile will show if engraftment of donor mikrobiota parallels clinical response to active FMT. To assess fecal gut microbiota composition, morning stool samples will be obtained at baseline and three and twelve months after FMT. Participants will collect their first morning bowel movement in a 120ml container for storing in their home freezer (-20C). Two-four weeks after, samples will be collected from participants home and stored on dry ice during transport until freezing at -80°C at the University Hospital of North Norway Harstad. Fecal analysis will be done by NextSeq500 allowing for enhanced metagenomics (prokaryote and viral) sequencing.
2. Engraftment of donor microbiota [ Time Frame: 12 months after FMT ]
   Comparison between baseline profile, post FMT and donor profile will show if engraftment of donor microbiota parallels clinical response to active FMT. To assess fecal gut microbiota composition, morning stool samples will be obtained at baseline and three and twelve months after FMT. Participants will collect their first morning bowel movement in a 120ml container for storing in their home freezer (-20C). Two-four weeks after, samples will be collected from participants home and stored on dry ice during transport until freezing at -80°C at the University Hospital of North Norway Harstad. Fecal analysis will be done by NextSeq500 allowing for enhanced metagenomics (prokaryote and viral) sequencing.
3. Difference in metagenomic profile between responders and non responder to FMT [ Time Frame: Baseline samples before FMT ]
   To assess fecal gut microbiota composition, morning stool samples will be obtained at baseline and three and twelve months after FMT. Participants will collect their first morning bowel movement in a 120ml container for storing in their home freezer (-20C). Two-four weeks after, samples will be collected from participants home and stored on dry ice during transport until freezing at -80°C at the University Hospital of North Norway Harstad. Fecal analysis will be done by NextSeq500 allowing for enhanced metagenomics (prokaryote and viral) sequencing.
4. Change in the nature of host immune and antibody response [ Time Frame: Change from baseline to 3 months and difference between responders and non-responders to treatment at 3 months ]
   Analysis (multipex technology) of mediators in the innate and adaptive immune response
5. Change in the nature of host immune and antibody response [ Time Frame: Change from baseline to 12 months and difference between responders and non-responders to treatment at 12 months ]
   Analysis (multipex technology) of mediators in the innate and adaptive immune response
6. Difference in the nature of host immune and antibody response between responders and non responders to FMT [ Time Frame: Baseline samples before FMT ]
   Analysis (multipex technology) of mediators in the innate and adaptive immune response
7. Change in the metabolome in feces, blood and urine [ Time Frame: Change from baseline to 3 months and difference between responders and non-responders to treatment at 3 months ]
   Analysis (mass spectrometry) on fecal extracts, urine and serum in order to assess the functional output of the microbiota
8. Change in biomarkers for breach in gut epithelium (sLPS-binding protein and sCD14) before and after transplantation [ Time Frame: Change from baseline to 3 months and difference between responders and non-responders to treatment at 3 months ]
   Analysis (ELISA) of immunological markers associated with gut barrier leak (sCD14 and sLPS-BP)
9. Change in biomarkers for breach in gut epithelium (sLPS-binding protein and sCD14) before and after transplantation [ Time Frame: Change from baseline to 12 months and difference between responders and non-responders to treatment at 12 months ]
   Analysis (ELISA) of immunological markers associated with gut barrier leak (sCD14 and sLPS-BP)
10. Difference in biomarkers for breach in gut epithelium (sLPS-binding protein and sCD14) in responders and non responders to FMT [ Time Frame: Baseline samples before FMT ]
    Analysis (ELISA) of immunological markers associated with gut barrier leak (sCD14 and sLPS-BP)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

FMT DONORS

Inclusion criteria:

• Healthy
• 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
• Obesity
• Metabolic syndrome
• Atopic skin disease
• CFS/ME
• 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

Contacts and Locations

Locations

Norway

University Hospital of North Norway, Harstad

Harstad, Troms, Norway, 9406

Sponsors and Collaborators

University Hospital of North Norway

The Research Council of Norway

Quadram Institute Bioscience

Umeå University

Cornell University

Investigators

• Principal Investigator: Rasmus Goll, MD. PhD.; University Hospital of North Norway

More Information

• Responsible Party: University Hospital of North Norway
• ClinicalTrials.gov Identifier: NCT03691987
• Other Study ID Numbers: 2018/180
• First Posted: October 2, 2018
• Last Update Posted: March 3, 2023
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made available
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Available when findings from primary and secondary endpoints are published. Study protocol will be available upon request when we initiate the inclusion.
• Access Criteria: Data access requests will be reviewed by study investigators. Requestors will be required to sign a Data Access Agreement

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital of North Norway:

fecal transplantation; bacterio therapy; fatigue; fecal microbiota transplantation

Additional relevant MeSH terms:

Encephalomyelitis; Fatigue Syndrome, Chronic; Syndrome; Fatigue; Disease; Pathologic Processes; Muscular Diseases; Musculoskeletal Diseases; Neuroinflammatory Diseases; Nervous System Diseases; Neuromuscular Diseases; Central Nervous System Infections; Infections; Central Nervous System Diseases