The Comeback Study

Sponsor:

Collaborators:

Information provided by (Responsible Party):

，

Tracking Information

First Submitted Date ^ICMJE

September 10, 2018

First Posted Date ^ICMJE

October 2, 2018

Last Update Posted Date

October 2, 2018

Actual Study Start Date ^ICMJE

November 1, 2018

Estimated Primary Completion Date

August 15, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Change in individual global Chalder Fatigue Scale (CFS) score.[ Time Frame: Proportion of participants with change from baseline in global Chalder Fatigue Score at 3 months after FMT ]

CFS is a self-reported, 11-item fatigue scale. Participants rate all 11 items on a 4-point Likert scale (0-1-2-3) with a maximum total score of 33. Lower scores indicate better outcomes. In an intention to treat analysis we will categorize participants as responders/non-responders, defining responders as decrease of 25% to the total baseline score in the Chalder Fatigue Scale at 3 months post FMT by Chi Square. Baseline score will be the average of the two scores from the screening period. We will apply last value forward if missing time points

Original Primary Outcome Measures ^ICMJE

Same as current

Current Secondary Outcome Measures ^ICMJE

Change in global score by the Chalder Fatigue Scale[ Time Frame: Change from baseline in global Chalder Fatigue Score at 1, 3, 6, 9 and 12 months after FMT ]
We will explore the FMT effects on Chalder Fatigue Scale by repeated measures ANOVA using treatment group (donor FMT and placebo), sex and donor with interactions as predictors. Non-significant terms will be removed. Then, susceptibility to infections, concurrent functional GI disorder, CFS/ME severity rating and use of antibiotics during study period, age, change in diet, use of food supplements, and probiotics will be tested for confounding effects.
Change in subscale score (physical and mental fatigue) by the Chalder Fatigue Scale[ Time Frame: Change from baseline in global Chalder Fatigue Score at 1, 3, 6, 9 and 12 months after FMT ]
We will explore the FMT effects on Chalder Fatigue Scale by repeated measures ANOVA using treatment group (donor FMT and placebo), sex and donor with interactions as predictors. Non-significant terms will be removed. Then, susceptibility to infections, concurrent functional GI disorder, CFS/ME severity rating and use of antibiotics during study period, age, change in diet, use of food supplements, and probiotics will be tested for confounding effects.
Change in global score by the SF36.[ Time Frame: Change from baseline global SF36 Score at 3 months after FMT ]
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. By an independent sample T-test (or, if necessary, non-parametric Mann-Whitney) we will compare change in global score
Change in subscale score by the SF36.[ Time Frame: Change from baseline in subscale SF36 Score at 3 months after FMT ]
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. By an independent sample T-test (or, if necessary, non-parametric Mann-Whitney) we will compare change in subscale score
Change in global score by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)[ Time Frame: Change from baseline in global RBANS score at 3 months after FMT ]
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. We will explore the FMT effects on RBANS by an independent sample T-test (or, if necessary, non-parametric Mann-Whitney) comparing change in global scores
Change in subscale score by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)[ Time Frame: Change from baseline in subscale RBANS score at 3 months after FMT ]
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. We will explore the FMT effects on RBANS by an independent sample T-test (or, if necessary, non-parametric Mann-Whitney) comparing change in subscale scores
Change in global score by the Hospital Anxiety Depression Scale (HADS)[ Time Frame: Change from baseline in global HADS score at 3 months after FMT ]
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
Change in subscale score by the Hospital Anxiety Depression Scale (HADS)[ Time Frame: Change from baseline in subscale HADS score at 12 months after FMT ]
We will explore the FMT effects on HADS by an independent sample T-test (or, if necessary, non-parametric Mann-Whitney) comparing change in subscale scores
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

Descriptive Information

Brief Title ^ICMJE

The Comeback Study

Official Title ^ICMJE

Fecal Microbiota Transplantation in Chronic Fatigue Syndrome - an RCT

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 Chalder Fatigue Scale. The investigators will use patient reported outcomes for primary and secondary outcome mesures. 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 Canada Criteria 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 Chalder Fatigue 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). 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 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 and donor. 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. 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. A minimum of four participants is allocated to treatment each time. 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 Type ^ICMJE

Interventional

Study Phase

Phase 2

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Masking: Interventional
Masking Description:
Primary Purpose: Treatment

Condition ^ICMJE

Intervention ^ICMJE

Biological: Preprocessed thawed donor FMT
Delivered as an enema using the same equipment and technique as X-ray of the colon
Biological: Preprocessed thawed autologous FMT
Delivered as an enema using the same equipment and technique as X-ray of the colon

Study Arms

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 with a blender for 30 seconds, 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.
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 with a blender for 30 seconds, 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.

Recruitment Information

Recruitment Status ^ICMJE

Not yet recruiting

Estimated Enrollment ^ICMJE

Original Estimated Enrollment ^ICMJE

Same as current

Estimated Study Completion Date

December 31, 2023

Estimated Primary Completion Date

August 15, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

FMT PARTICIPANTS Inclusion Criteria: - Canada Criteria (2011) - 18-65 years - Mild-severe CFS/ME - Chalder Fatigue Scale minimum 18 - 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, 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 FMT DONORS Inclusion criteria: - Healthy - Age 16-30 years Exclusion criteria: - Use of peroral antibiotics past 6 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 - Dysbiosis grade 2 or more by the GA dysbiosis test

Sex/Gender

Sexes Eligible for Study:

All

Ages

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Listed Location Countries ^ICMJE

Removed Location Countries

Administrative Information

Has Data Monitoring Committee

Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

Plan to Share IPD:

Yes

Responsible Party

，

Study Sponsor ^ICMJE

University Hospital of North Norway

Collaborators ^ICMJE

Investigators ^ICMJE

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

PRS Account

Verification Date

July 2018

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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