Transfer of FRozen Encapsulated Multidonor Stool Filtrate for Active Ulcerative COlitis

Ulcerative Colitis Clinical Trial

— FRESCO  

Official title:

Longterm Transfer of FRozen Encapsulated Multidonor Stool Filtrate or Encapsulated Multidonor Microbiome for Chronic Active Ulcerative COlitis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03843385
• Other study ID #: KS2017-114
• Status: Recruiting
• Phase: Phase 3
• Start date: January 31, 2023
• Est. completion date: July 2026

Study information

• Verified date: November 2023
• Source: Jena University Hospital
• Contact: Andreas Stallmach, Prof.
• Phone: +49-3641-9
• Email: andreas.stallmach[@]med.uni-jena.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 174
• Est. completion date: July 2026
• Est. primary completion date: January 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

• Complete vaccination against SARS-CoV-2 according to the recommendation of the "Ständige Impfkommission" (STIKO)

• 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

• Previous treatment with TNF-, IL12/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

• 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)

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Inflammatory Bowel Diseases
• Ulcer
• Ulcerative Colitis

Intervention

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

Locations

Country	Name	City	State
Germany	Sozialstiftung Bamberg	Bamberg
Germany	Charité Berlin	Berlin
Germany	DRK Kliniken Berlin Westend	Berlin
Germany	Krankenhaus Waldfriede	Berlin
Germany	Städtisches Klinikum Braunschweig	Braunschweig
Germany	Universitätsklinikum Carl Gustav Carus Dresden	Dresden
Germany	FAU Universität Erlangen-Nürnberg	Erlangen
Germany	Agaplesion Markus Krankenhaus	Frankfurt
Germany	Universitätsklinik Freiburg	Freiburg
Germany	Klinikum Fulda	Fulda
Germany	Jena University Hospital	Jena	Thuringia
Germany	Gesellschaft Klinische Studien Leipzig	Leipzig
Germany	Universitätsklinikum Ulm	Ulm

Sponsors (2)

Lead Sponsor	Collaborator
Tabitha Heller	German Federal Ministry of Education and Research

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	clinical remission	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).	12 weeks
Secondary	steroid-free clinical remission	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)	12 weeks
Secondary	clinical response	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	12 weeks
Secondary	change in quality of life	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.	52 weeks
Secondary	endoscopic remission	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)	12 weeks
Secondary	mucosal inflammation - measured through fecal calprotectin	mucosal inflammation in stool samples at week 0, 4, 8, 12, 24, 36, 52 post first transfer of FMFT or FMT	52 weeks
Secondary	microbiome analysis	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	52 weeks
Secondary	virome analysis	analysis of stool samples at week 0, 4, 8, 12, 24, 36, 52 post first transfer of FMFT or FMT regarding virome composition	52 weeks
Secondary	MAYO Total Score	Comparison of the MAYO total Score between the 3 Arms (FMFT, FMT and Placebo)	52 weeks
Secondary	Histological mucosal inflammation - Nancy index	Analysis of obtained mucosa biopsies at week 0 and 12, regarding disease activity graded with the Nancy index	12 weeks
Secondary	Safety - adverse events and severe adverse events	adverse events and severe adverse events in the different treatment arms will be recorded	52 weeks