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

Overview

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

• Drug encapsulated faecal microbiota filtrate
  Multidonor stool mixed with sterile normal saline, homogenized, filtered, centrifuged, air pressure filtered, encapsulated in hypromellose capsules and frozen.
• Drug encapsulated faecal microbiota
  Multidonor stool mixed with sterile normal saline, homogenized, filtered, encapsulated in hypromellose capsules and frozen.
• Drug Placebo
  Sterile saline encapsulated in hypromellose capsules and frozen.

Primary outcome measures

• clinical remission [Time frame: 12 weeks]

Secondary outcome measures (10)

• steroid-free clinical remission [Time frame: 12 weeks]
• clinical response [Time frame: 12 weeks]
• change in quality of life [Time frame: 52 weeks]
• endoscopic remission [Time frame: 12 weeks]
• mucosal inflammation - measured through fecal calprotectin [Time frame: 52 weeks]
• microbiome analysis [Time frame: 52 weeks]
• virome analysis [Time frame: 52 weeks]
• MAYO Total Score [Time frame: 52 weeks]
• Histological mucosal inflammation - Nancy index [Time frame: 12 weeks]
• Safety - adverse events and severe adverse events [Time frame: 52 weeks]

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Germany · 20 centers

• Jena University Hospital — Jena
• Sozialstiftung Bamberg — Bamberg
• Charité Berlin — Berlin
• DRK Kliniken Berlin Westend — Berlin
• Havelhöhe — Berlin
• Krankenhaus Waldfriede — Berlin
• Universitätsklinikum Carl Gustav Carus Dresden — Dresden
• FAU Universität Erlangen-Nürnberg — Erlangen
• … and 12 more centers

Publications

• 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 tr PMID 35193638

Identifiers

NCT: NCT03843385 · KS2017-114

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗