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| Name | Class |
|---|---|
| Oslo University Hospital | OTHER |
| Sorlandet Hospital HF | OTHER_GOV |
| Haukeland University Hospital | OTHER |
| Alesund Hospital |
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Many patients with irritable bowel syndrome (IBS) do not experience adequate symptom relief with current treatments. The pathophysiology of IBS is diverse, controversial and not completely understood. The next disruptive frontier would be to find a cure where the effect is predictable and lasting. The study groups phase 2 pilot trial was the first indication of a possible benefit from treating IBS with fecal microbiota transplantation (FMT) (Number needed to treat only five) (Fecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomized, placebo-controlled, parallel-group, single-centre trial he Lancet Gastroenterology and Hepatology 2018). Additional results from the same trial show that the treatment response may be predicted (unpublished data), and that the pathophysiologic mechanisms behind the treatment response also can be identified (Effects of fecal microbiota transplantation in subjects with irritable bowel syndrome are mirrored by changes in gut microbiome, Gut Microbes 2020). This study is the first phase 3 trial of FMT for IBS worldwide.
The hypothesis of the trial is that donor FMT is more effective than placebo FMT in treating IBS, with little adverse events or complications. Patients ≥18 years with IBS are enrolled at five Norwegian Hospitals in this double blind randomized, placebo controlled, parallell-group multi center trial. Participants are randomized to FMT from a healthy donor (intervention group), or their own feces (placebo group). The primary outcome is the proportion of patients with ≥75 points decrease in the Irritable bowel Symptom Severity score 90 days after treatment.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fecal microbiota transplant from donor A | Active Comparator | One FMT delivered by enema |
|
| Fecal microbiota transplant from donor B | Active Comparator | One FMT delivered by enema |
|
| Fecal microbiota transplant from donor C | Active Comparator | One FMT delivered by enema |
|
| Fecal microbiota transplant from autologous feces | Placebo Comparator | One FMT delivered by enema |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fecal microbiota transplantation (FMT) | Biological | Delivered by enema |
|
| Measure | Description | Time Frame |
|---|---|---|
| Proportion in the donorFMT (dFMT) versus autologousFMT (aFMT) group with ≥75 points decrease in the Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS) day 90 after treatment when compared to the score 8 days before treatment | Scores on the IBS-SSS can range from 0 to 500 with higher scores indicating more severe symptoms. The IBS-SSS has five items. Subjects can be categorized as having mild (75-175), moderate (175-300), or severe (>300) IBS. A decrease of 50 points is associated with a clinically meaningful improvement. | Day 90 after treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion in dFMT versus aFMT group with ≥75 points decrease in the Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS) day 365 after treatment when compared to the score 8 days before treatment | Day 365 after treatment | |
| Proportion of patients in dFMT versus aFMT group with a ≥14 points increase in the IBS-Qualiy of Life (IBS-QoL) day 90 after treatment when compared to the score 8 days before treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in taxonomy and function of the microbiome, the immune system, metabolome and gut epithelial barrier in participants with vs without treatment success to dFMT and aFMT from before and until after treatment. | This exploratory endpoint will be further specified when all participants has completed their 12 months follow up after treatment. To explore the changes described above stool, serum, plasma and urine is obtained from participants before and at 90 and 365 days after treatment. The biobanking at 365 will only be performed on a subset of participants. Stool from each donor feces donation will also be biobanked. |
Inclusion
Exclusion
Planned evaluations or examinations for bowel related complaints
Known presence of:
Morbidly obesity (BMI ≥35)
Severe autoimmune disease
Severe immune deficiency (acquired, congenital or due to medication)
Previous treatment with FMT
History of:
"Red flags'' indicating severe undiagnosed disease including:
Family history of GI cancer defined as two or more first- or second-degree relatives, with:
Use of the following the previous 4 weeks:
Use of proton pump inhibitors or other antacids ≥3 days week
Introduction of antidepressants or anxiolytics the last 12 weeks. Patients on a stable dose >12 weeks are eligible.
Treatment with antibiotics 12 weeks prior to study entry.
Use of kolestyramin for bile acid malabsorption
Pregnant, lactating or planning pregnancy.
Physical exam indicating undiagnosed malignant, autoimmune, or infectious disease
Laboratory work up indicating undiagnosed digestive, malignant, autoimmune, infectious disease or alternative diagnosis to the IBS related signs and symptoms. The work up includes:
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| Name | Affiliation | Role |
|---|---|---|
| Peter H Johnsen, MD PhD | Univeristy Hospital of North Norway | Principal Investigator |
| Rasmus Goll, MD PhD | University Hospital of North Norway | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ålesund Hospital | Ålesund | Norway |
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| ID | Term |
|---|---|
| D043183 | Irritable Bowel Syndrome |
| ID | Term |
|---|---|
| D003109 | Colonic Diseases, Functional |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D005767 | Gastrointestinal Diseases |
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| ID | Term |
|---|---|
| D000069467 | Fecal Microbiota Transplantation |
| ID | Term |
|---|---|
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
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| OTHER |
Triple blind randomized, placebo controlled, parallell-group multi center trial
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The IBS-QoL is a validated self-report questionnaire specific to IBS to evaluate quality of life over the past 30 days. It consists of 34 items, each with a five-point Likert scale. The individual response to the 34 items are summed and averaged for a total score and then transformed to a 0-100 scale for ease of interpretation with higher scores indicating better IBS specific quality of life. The cut-off for meaningful clinical improvement is set at ≥14 points. There are also eight subscale scores for the IBS-QOL (Dysphoria, Interference with Activity, Body Image, Health Worry, Food Avoidance, Social Reaction, Sexual, Relationships) |
| Day 90 after treatment |
| Proportion in the dFMT vs aFMT group with 2 or more weeks with treatment success in Adequate relief by the Global Improvement Scale and Abdominal pain day 69, 76, 83 and 90 after treatment. For treatment success criteria A. and B. have to be fulfilled |
| Day 69, 76, 83 and 90 after treatment |
| Proportion of adverse events and serious adverse events in the dFMT versus aFMT group from treatment and until day 90 after treatment | Day 90 after treatment |
| Proportion of adverse events and serious adverse events in the dFMT versus aFMT group from treatment and until day 90 after treatment | Day 365 after treatment |
| Change in the dFMT vs aFMT group in mean stool consistency score in the period 8-2 days before treatment, compared to mean stool consistency score in the period 84-90 and 359-365 days after treatment. | This endpoint only apply to participants subtyped with IBS-diarrhea before treatment. Mean stool consistency score is measured by Bristol Stool Scale ("How would you rate the stool consistency overall the last 24 hours?"). Mean stool consistency score will be derived from: (Sum of each rating by the Bristol Stool Form Scale in a period )/(Number of ratings in a period). | 2-8 days before treatment and day 84 to 90 and day 259 to 365 after treatment |
| Change in the dFMT vs aFMT group in mean number of complete spontaneous bowel movements (CSBM) in the period 8-2 days before treatment, compared to CSBM in the period 84-90 and 359-365 days after treatment | This endpoint only apply to participants subtyped with with IBS-constipation before treatment. CSBM is measured by the question. "How many CSBM have you passed the last 24 hours?" reported by the participant every second day for eight days?'' Mean number of complete spontaneous bowel movements will be derived from: (Sum of number of CSBM in each period)/number of assessments of CSBM in a period) | 2-8 days before treatment and day 84 to 90 and day 259 to 365 after treatment |
| Change in the dFMT vs aFMT group in bowel-related complaints by the item specific and global Irritable Bowel Syndrome Symptom Severity Score score from before and until after treatment. | 8 days before treatment and until 30, 90, 180 and 365 days after treatment |
| Change in the dFMT vs aFMT group in quality of life by the global and subdomain specific score in the Irritable Bowel Syndrome-Qualiy of Life from before and until after treatment. | 8 days before treatment and until 90, 180 and 365 days after treatment |
| Change in the dFMT vs aFMT group in fatigue by the global and subdomain specific score in the Modified Fatigue Impact Scale from before and until after treatment. | Items on the MFIS can be aggregated into three subscales (physical (range 0 to 36), cognitive (range 0 to 40), and psychosocial (range 0 to 8)), as well as into a total MFIS score (range 0 to 84). All items are scaled so that higher scores indicate a greater impact of fatigue on a person's activities. | 8 days before treatment and until 90, 180 and 365 days after treatment |
| Change in the dFMT vs aFMT group in anxiety and depression (HADS) by the global and subdomain specific score on the Hospital Anxiety and Depression Scale from before and until after treatment. | The HADS is a fourteen item scale where seven of the items relate to anxiety and seven to depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. Higher scores indicates higher levels of anxiety or depression | 8 days before treatment and until 90, 180 and 365 days after treatment |
| Proportion of participants identified as treatment success (as defined by the primary endpoint) by a ten species profile generated from a metagenomic dataset from the pilot REFIT trial (unpublished data) | Day 90 |
| 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). | Firstbeat Bodyguard will record R-R interval and the Firstbeat life style assessment software will analyze the R-R interval recording and provide the outcome measure | 90 days after treatment |
| Change in HRV in donor FMT vs placebo FMT group derived from the R-R intervals in continuous ECG recordings. The secondary vagal function outcome will be differences in changes from pre-post treatment between groups in RMSSD (RMSSD; in ms2). | 90 days after treatment |
| Difference in mean baseline HRV (HF-HRV and RMSSD) between responders' vs non-responders to donor FMT. | As defined by the primary endpoint in the clinical phase III study, a responder will be defined by a decrease of 75 points from baseline in the irritable bowel symptom severity score 90 days after the intervention with FMT. To determine HRV in each group we will use High Frequency Power analysis denominating HRV in ms2. | 90 days after treatment |
| 8 days before treatment and until 90 and 365 days after treatment |
| Differences in taxonomy and function of the microbiome, the immune system, metabolome and gut epithelial barrier before treatment in FMT donors vs participants with vs without treatment success to dFMT and aFMT from before and until after treatment. | This exploratory endpoint will be further specified when all participants has completed their 12 months follow up after treatment. To explore the changes described above stool, serum, plasma and urine is obtained from participants before and at 90 and 365 days after treatment. The biobanking at 365 will only be performed on a subset of participants. Stool from each donor feces donation will also be biobanked. | 8 days before treatment and until 90 and 365 days after treatment |
| D004066 | Digestive System Diseases |