The Comeback Study

• 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

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.

• 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

• 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.