Inflammatory Bowel Diseases, Ulcerative Colitis
Conditions
Keywords
fecal transplantation, multidonor fecal transplantation
Brief summary
FRESCO is a randomized, longitudinal, prospective, three arm, multicentre, double blind study to determine safety and efficacy of repeated faecal microbiota transplantation (FMT) or faecal microbiota filtrate transplantation (FMFT) compared to placebo using oral, frozen capsules in 174 randomized patients with mild to moderate active Ulcerative Colitis.
Detailed description
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with significant morbidity and mortality. Although the precise cause remains unknown, disturbances in the intestinal microbial community and changes in the crosstalk between the microbiota and the mucosal immune system have been linked to its pathogenesis. As current therapies are limited, there is a medical need for new therapies. Faecal microbiota transplantation (FMT) has been proven to be effective in managing relapsing Clostridium difficile infection (CDI) and preliminary results indicated that also the transfer of filtrates of donor stool (FMFT) drives gastrointestinal microbiota changes and eliminate symptoms in CDI patients. FRESCO is a randomized, longitudinal, prospective, three arm, multicentre, double blind study to determine safety and efficacy of repeated FMT or FMFT compared to placebo using oral, frozen capsules in 174 randomized patients with mild to moderate active UC. The primary outcome will be clinical and endoscopic remission at week 12. This proposal aims to examine: (a) the efficacy of FMT / FMFT as a therapy for active UC, (b) the safety of FMT / FMFT in patients with UC and (c) the microbial and inflammable changes that occur after FMT / FMFT, to help understand how and why it works in this group of patients. All analyses will be conducted in both intention-to-treat (primary) and per-protocol (sensitivity analyses) populations, and the differences in remission rates and relapse rates between the groups will be statistically analysed to determine the efficiency of FMT versus FMFT.
Interventions
DRUGencapsulated faecal microbiota filtrate
Multidonor stool mixed with sterile normal saline, homogenized, filtered, centrifuged, air pressure filtered, encapsulated in hypromellose capsules and frozen.
DRUGencapsulated faecal microbiota
Multidonor stool mixed with sterile normal saline, homogenized, filtered, encapsulated in hypromellose capsules and frozen.
DRUGPlacebo
Sterile saline encapsulated in hypromellose capsules and frozen.
Sponsors
Andreas Stallmach
German Federal Ministry of Education and Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
To address "concealment of allocation", the randomization will be done centrally and each patient who is randomized and who received one of the compared treatments is part of the full analysis set (ITT analysis set).
Intervention model description
Patients will be randomized to receive intensive dosing multi-donor FMFT or FMT as therapeutic strategies or saline as a placebo comparator. To achieve balanced distributions for pretreatment factors, we propose to apply stratified (stratum 1: "biologicals yes/no"; stratum 2: "participating centre") block randomization.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age between 18 and 75 years * Prior endoscopic confirmation of UC of at least 6 months AND with a minimum disease extent of 15 cm from the anal verge. * Having active disease, defined with a Mayo Score between 4-10 and Mayo endoscopic subscore \>1 * Failure of conventional therapy or treatment with biologicals and / or small molecules. * previous medical therapy: * oral 5-ASA compounds (5-ASA); stable dosing for 4 weeks before randomization; * Azathioprine, 6-Mercaptopurine (6-MP) or Methotrexate (MTX); stable dosing for 8 weeks before randomization; * Oral corticosteroid therapy (prednisone ≤ 20 mg/day or budesonide ≤ 9 mg/day); stable dosing for 2 weeks before randomization; * Topical therapy (foams, clysms) with mesalazine or budesonide: stable dosing for 2 weeks before randomization. * previous vaccination against SARS-CoV-2 or previous SARS-CoV-2 infection or positive serology * Ability to understand and willingness to sign informed consent document in patients whom the investigator believes can and will comply with the requirements of the protocol. * Potentially childbearing patient: negative pregnancy test and use of a highly effective contraceptive method
Exclusion criteria
* Crohn's disease or indeterminate colitis or proctitis ulcerosa alone * Acute abdomen or other clinical emergencies (e.g. toxic megacolon, fulminant gastrointestinal hemorrhage, ileus, perforation, etc.) * Previous operations on the colon: colectomy, partial colon resections * current gastrointestinal infections * Congenital or acquired immunodeficiency * severe comorbidity (e.g. insulin-dependent diabetes mellitus, decompensated liver cirrhosis, primary sclerosing cholangitis, renal impairment \> grade 2) * diagnosis of a malignoma in the last 3 years * refusal of endoscopies with video documentation * No specific therapy for ulcerative colitis to date * Lack of immunity to SARS-CoV-2 * Previous treatment with TNF-, IL12/IL23-, IL23- or integrin-antibodies within the last 8 weeks before randomisation * Treatment with calcineurin inhibitors within the last 4 weeks before randomization * Treatment with JAK inhibitors (e.g., tofacitinib, filgotinib, or upadacitinib) within the last 4 weeks prior to randomization * Treatment with S1P receptor modulators (e.g. ozanimod, etrasimod) within the last 4 weeks before randomization * Systemic antibiotic treatment within the last 8 weeks prior to randomization. * Known intolerance of metronidazole or vancomycin * Previous FMT or FMFT, previous participation in this study (screening allowed) * Participation in a clinical trial within the last 3 months * Use of probiotics in tablet, capsule, or powder form, or appropriate drinking yogurts (or similar) within 2 weeks prior to randomization * Failure to ensure frozen storage of investigational products * Addictive or other medical conditions or circumstances that do not allow the subject to appreciate the nature, significance, scope, and possible consequences of the clinical trial * Indications that the patient would be unlikely to comply with the protocol (e.g., unwillingness to cooperate - compliance questionable)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| clinical remission | 12 weeks | The primary outcome will be clinical remission at week 12 post first transfer of FMFT or FMT, defined by Mayo score ≤ 2, all subscores ≤ 1; additionally patients unavailable at the week 12 follow-up will be included as non-responders (i.e. counted no remission). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| steroid-free clinical remission | 12 weeks | steroid-free clinical remission at week 12 post first transfer of FMFT or FMT, with a minimum of steroid free time of 4 weeks (week 8 to 12) |
| clinical response | 12 weeks | clinical response is defined by decrease in partial Mayo score by more than 3 points and a minimum decrease of 30% from output value and additional bleeding subscore by more than 1 point or absolute sub-score of 0-1 |
| change in quality of life | 52 weeks | quality of life is assessed at week 0,4,8,12 for short-term efficacy and for long-term efficacy at week 24,36 and 52 post first transfer by Inflammatory Bowel Disease Quality of Life Questionnaire (IBDQ). The IBDQ is a 32-item self-rated questionnaire with 4 domains (bowel symptoms, emotional function, social function, systemic symptoms). Each item is rated on a seven-point Likert Scale. The total score ranges from 32 to 224 points with higher scores reflecting better well-being. |
| endoscopic remission | 12 weeks | endoscopic remission at week 12 post first transfer of FMFT or FMT, with a score between 0 and 3, (0 = Normal or inactive disease, 1 = mild inflammatory activity, 2 = moderate disease, 3 = severe disease) |
| mucosal inflammation - measured through fecal calprotectin | 52 weeks | mucosal inflammation in stool samples at week 0, 4, 8, 12, 24, 36, 52 post first transfer of FMFT or FMT |
| microbiome analysis | 52 weeks | analysis of stool samples at week 0, 4, 8, 12, 24, 36, 52 post first transfer of FMFT or FMT regarding microbiome diversity and composition |
| virome analysis | 52 weeks | analysis of stool samples at week 0, 4, 8, 12, 24, 36, 52 post first transfer of FMFT or FMT regarding virome composition |
| MAYO Total Score | 52 weeks | Comparison of the MAYO total Score between the 3 Arms (FMFT, FMT and Placebo) |
| Histological mucosal inflammation - Nancy index | 12 weeks | Analysis of obtained mucosa biopsies at week 0 and 12, regarding disease activity graded with the Nancy index |
| Safety - adverse events and severe adverse events | 52 weeks | adverse events and severe adverse events in the different treatment arms will be recorded |
Countries
Germany
Contacts
STUDY_DIRECTORAndreas Stallmach, Prof.
Jena University Hospital
Outcome results
None listed