Clinical trial NCT03691987: The Comeback Study
Official title: Fecal Microbiota Transplantation in Chronic Fatigue Syndrome - an RCT
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Fatigue Syndrome
Myalgic Encephalomyelitis
Keywords: fecal transplantation
bacterio therapy
fatigue
fecal microbiota transplantation
Lead sponsor: University Hospital of North Norway
Sponsor class: OTHER
Collaborators: name: The Research Council of Norway
name: Quadram Institute Bioscience
name: Umeå University
name: Cornell University
First posted: 2018-10-02
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: 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)
timeFrame: Three months after treatment
Secondary outcomes:
measure: Change in donor versus placebo FMT group in fatigue by the Fatigue Severity Scale score
timeFrame: Change in Fatigue severity scale by repeated measures from baseline and until 1, 3, 6, 9 and 12 months after treatment
measure: Change in donor versus placebo FMT group in quality of life by the SF36 score
timeFrame: Change in SF36 score by repeated measures from baseline and until 3 and 12 months after treamtent
measure: 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.
timeFrame: Change from baseline and until three months after treatment
measure: Change in donor versus placebo FMT group in anxiety and depression by the Hospital Anxiety Depression Scale (HADS) score
timeFrame: Change in HADS score by repeated measures from baseline and until 3 and 12 months after treatment
measure: 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)
timeFrame: Change in DPQ score by repeated measures from baseline and until 6 and 12 months after treatment
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: Baseline to end of follow up at 12 months after FMT
measure: 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
timeFrame: 3 months after treatment
measure: 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)
timeFrame: 3 months after treatment
measure: Difference in mean baseline HRV (HF-HRV and RMSSD) between responders vs non-responders to donor FMT.
timeFrame: 3 months after treatment
Other outcomes:
measure: Engraftment of donor microbiota
timeFrame: 3 months after FMT
measure: Engraftment of donor microbiota
timeFrame: 12 months after FMT
measure: Difference in metagenomic profile between responders and non responder to FMT
timeFrame: Baseline samples before FMT
measure: Change in the nature of host immune and antibody response
timeFrame: Change from baseline to 3 months and difference between responders and non-responders to treatment at 3 months
measure: Change in the nature of host immune and antibody response
timeFrame: Change from baseline to 12 months and difference between responders and non-responders to treatment at 12 months
measure: Difference in the nature of host immune and antibody response between responders and non responders to FMT
timeFrame: Baseline samples before FMT
measure: Change in the metabolome in feces, blood and urine
timeFrame: Change from baseline to 3 months and difference between responders and non-responders to treatment at 3 months
measure: Change in biomarkers for breach in gut epithelium (sLPS-binding protein and sCD14) before and after transplantation
timeFrame: Change from baseline to 3 months and difference between responders and non-responders to treatment at 3 months
measure: Change in biomarkers for breach in gut epithelium (sLPS-binding protein and sCD14) before and after transplantation
timeFrame: Change from baseline to 12 months and difference between responders and non-responders to treatment at 12 months
measure: Difference in biomarkers for breach in gut epithelium (sLPS-binding protein and sCD14) in responders and non responders to FMT
timeFrame: Baseline samples before FMT
Locations:
city: Harstad
country: Norway
facility: University Hospital of North Norway, Harstad
state: Troms
Study officials:
affiliation: University Hospital of North Norway
name: Rasmus Goll, MD. PhD.
role: PRINCIPAL_INVESTIGATOR
References: