The Comeback Study

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Brief Title

The Comeback Study

Official Title

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 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 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 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).

      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.

      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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Change in individual global Fatigue Severity Scale score.

Secondary Outcome

 Change in individual global Fatigue Severity Scale score.

Condition

Chronic Fatigue Syndrome

Intervention

Preprocessed thawed donor FMT

Study Arms / Comparison Groups

 Preprocessed thawed donor FMT
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

80

Start Date

February 15, 2019

Completion Date

December 31, 2023

Primary Completion Date

February 2020

Eligibility Criteria

        FMT PARTICIPANTS

        Inclusion Criteria:

          -  Canada Criteria (2011)

          -  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, 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

          -  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
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Rasmus Goll, MD. PhD., +47 97673939, [email protected]

Location Countries

Norway

Location Countries

Norway

Administrative Informations


NCT ID

NCT03691987

Organization ID

2018/180


Responsible Party

Sponsor

Study Sponsor

University Hospital of North Norway

Collaborators

 The Research Council of Norway

Study Sponsor

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


Verification Date

February 2019