Clinical trial NCT03843385: Transfer of FRozen Encapsulated Multidonor Stool Filtrate for Active Ulcerative COlitis
Official title: Longterm Transfer of FRozen Encapsulated Multidonor Stool Filtrate or Encapsulated Multidonor Microbiome for Chronic Active Ulcerative COlitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Ulcerative Colitis
Inflammatory Bowel Diseases
Keywords: fecal transplantation
multidonor fecal transplantation
Lead sponsor: Jena University Hospital
Sponsor class: OTHER
Collaborators: name: German Federal Ministry of Education and Research
First posted: 2019-02-18
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: clinical remission
timeFrame: 12 weeks
Secondary outcomes:
measure: steroid-free clinical remission
timeFrame: 12 weeks
measure: clinical response
timeFrame: 12 weeks
measure: change in quality of life
timeFrame: 52 weeks
measure: endoscopic remission
timeFrame: 12 weeks
measure: mucosal inflammation - measured through fecal calprotectin
timeFrame: 52 weeks
measure: microbiome analysis
timeFrame: 52 weeks
measure: virome analysis
timeFrame: 52 weeks
measure: MAYO Total Score
timeFrame: 52 weeks
measure: Histological mucosal inflammation - Nancy index
timeFrame: 12 weeks
measure: Safety - adverse events and severe adverse events
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Jena
country: Germany
facility: Jena University Hospital
state: Thuringia
city: Bamberg
country: Germany
facility: Sozialstiftung Bamberg
city: Berlin
country: Germany
facility: Charité Berlin
city: Berlin
country: Germany
facility: DRK Kliniken Berlin Westend
city: Berlin
country: Germany
facility: Krankenhaus Waldfriede
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Erlangen
country: Germany
facility: FAU Universität Erlangen-Nürnberg
city: Frankfurt
country: Germany
facility: Agaplesion Markus Krankenhaus
city: Freiburg
country: Germany
facility: Universitätsklinik Freiburg
city: Fulda
country: Germany
facility: Klinikum Fulda
city: Halle
country: Germany
facility: Universitätsklinikum Halle (Saale)
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig Holstein
city: Leipzig
country: Germany
facility: Gesellschaft Klinische Studien Leipzig
city: Lueneburg
country: Germany
facility: Städtisches Klinikum Lüneburg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
Study officials:
affiliation: Jena University Hospital
name: Andreas Stallmach, Prof.
role: STUDY_DIRECTOR
References:
citation: Stallmach A, Grunert P, Stallhofer J, Loffler B, Baier M, Rodel J, Kiehntopf M, Neugebauer S, Pieper DH, Junca H, Tannapfel A, Merkel U, Schumacher U, Breternitz-Gruhne M, Heller T, Schauer A, Hartmann M, Steube A. Transfer of FRozen Encapsulated multi-donor Stool filtrate for active ulcerative Colitis (FRESCO): study protocol for a prospective, multicenter, double-blind, randomized, controlled trial. Trials. 2022 Feb 22;23(1):173. doi: 10.1186/s13063-022-06095-1.