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Trial record 8 of 1046 for:    scale | Norway

The Comeback Study

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ClinicalTrials.gov Identifier: NCT03691987
Recruitment Status : Recruiting
First Posted : October 2, 2018
Last Update Posted : February 19, 2019
Sponsor:
Collaborators:
The Research Council of Norway
Quadram Institute Bioscience
Umeå University
Cornell University
Information provided by (Responsible Party):
University Hospital of North Norway

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

  Show Detailed Description

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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 : February 2020
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Change in individual global Fatigue Severity Scale score. [ Time Frame: Proportion of participants with change from baseline in global Fatigue Severity Scale score at 3 months after FMT ]

    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 individual global Fatigue Severity Scale score. [ Time Frame: Proportion of participants with change from baseline in global Fatigue Severity Scale score at 12 months after FMT ]
    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

  2. Change in individual global Fatigue Severity Scale score by repeated measures [ Time Frame: Change in Fatigue severity scale by repeated measures from baseline, 1, 3, 6, 9 and 12 months ]
    In a repeated measure ANOVA we will assess change in Fatigue Severity Scale 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, use of antibiotics during study period, age, change in diet, use of food supplements and probiotics will be tested for confounding effects. We will apply last value forward for missing values.

  3. 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. We will apply last value forward for missing values.

  4. 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 scor. We will apply last value forward for missing values.

  5. 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. We will apply last value forward for missing values.

  6. 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. We will apply last value forward for missing values.

  7. 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. We will apply last value forward for missing values.

  8. 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. We will apply last value forward for missing values.

  9. 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


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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03691987


Contacts
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Contact: Linn K Skjevling, MD +47 97673939 linn.christin.kallbekken.skjevling@unn.no
Contact: Peter H Johnsen, PhD +47 77015278 peter.holger.johnsen@unn.no

Locations
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Norway
University Hospital of North Norway, Harstad Recruiting
Harstad, Troms, Norway, 9406
Contact: Linn Kallbekken Skjevling, MD    +4797673939    Linn.Christin.Kallbekken.Skjevling@unn.no   
Sponsors and Collaborators
University Hospital of North Norway
The Research Council of Norway
Quadram Institute Bioscience
Umeå University
Cornell University
Investigators
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Principal Investigator: Rasmus Goll, MD. PhD. University Hospital of North Norway

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Responsible Party: University Hospital of North Norway
ClinicalTrials.gov Identifier: NCT03691987     History of Changes
Other Study ID Numbers: 2018/180
First Posted: October 2, 2018    Key Record Dates
Last Update Posted: February 19, 2019
Last Verified: February 2019
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

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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:
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Fatigue Syndrome, Chronic
Encephalomyelitis
Syndrome
Fatigue
Disease
Pathologic Processes
Signs and Symptoms
Virus Diseases
Muscular Diseases
Musculoskeletal Diseases
Central Nervous System Diseases
Nervous System Diseases
Neuromuscular Diseases
Central Nervous System Infections