Transfer of FRozen Encapsulated Multidonor Stool Filtrate for Active Ulcerative COlitis (FRESCO)

• ClinicalTrials.gov Identifier: NCT03843385
• Recruitment Status: Recruiting
• First Posted: February 18, 2019
• Last Update Posted: November 24, 2023
• Sponsor: Tabitha Heller
• Collaborator: German Federal Ministry of Education and Research
• Information provided by (Responsible Party): Tabitha Heller, Jena University Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Ulcerative Colitis; Inflammatory Bowel Diseases	Drug: encapsulated faecal microbiota filtrate; Drug: encapsulated faecal microbiota; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 174 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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.
• Masking: Quadruple (Participant, Care Provider, 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).
• Primary Purpose: Treatment
• Official Title: Longterm Transfer of FRozen Encapsulated Multidonor Stool Filtrate or Encapsulated Multidonor Microbiome for Chronic Active Ulcerative COlitis
• Actual Study Start Date: January 31, 2023
• Estimated Primary Completion Date: January 2025
• Estimated Study Completion Date: July 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: faecal microbiota filtrate; Encapsulated faecal microbiota filtrate . 2×5 frozen capsules by mouth on 5 consecutive days per week (5 days on and 2 days off; week 1 - week 12) with water or cool drink.	Drug: encapsulated faecal microbiota filtrate; Multidonor stool mixed with sterile normal saline, homogenized, filtered, centrifuged, air pressure filtered, encapsulated in hypromellose capsules and frozen.; Other Name: FMFT
Active Comparator: faecal microbiota; Encapsulated faecal microbiota. 2×5 frozen capsules by mouth on 5 consecutive days per week (5 days on and 2 days off; week 1 - week 12) with water or cool drink.	Drug: encapsulated faecal microbiota; Multidonor stool mixed with sterile normal saline, homogenized, filtered, encapsulated in hypromellose capsules and frozen.; Other Name: FMT
Sham Comparator: Placebo; Placebo: Encapsulated sterile saline. 2×5 frozen capsules by mouth on 5 consecutive days per week (5 days on and 2 days off; week 1 - week 12) with water or cool drink.	Drug: Placebo; Sterile saline encapsulated in hypromellose capsules and frozen.; Other Name: Encapsulated sterile saline

Outcome Measures

Primary Outcome Measures :

1. clinical remission [ Time Frame: 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 Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.
• 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)

Contacts and Locations

Contacts

Contact: Andreas Stallmach, Prof.; +49-3641-9 ext 324401; andreas.stallmach@med.uni-jena.de

Contact: Johannes Stallhofer, MD; +49-3641-9 ext 322303; johannes.stallhofer@med.uni-jena.de

Locations

Germany

Jena University Hospital; Recruiting

Jena, Thuringia, Germany

Contact: Andreas Stallmach, Prof. +49 3641 32 44 01 andreas.stallmach@med.uni-jena.de

Sozialstiftung Bamberg; Recruiting

Bamberg, Germany

Contact: Jost Langhorst, Prof.

Charité Berlin; Recruiting

Berlin, Germany

Contact: Britta Siegmund, Prof.

DRK Kliniken Berlin Westend; Recruiting

Berlin, Germany

Contact: Andreas Sturm, Prof.

Krankenhaus Waldfriede; Recruiting

Berlin, Germany

Contact: Carsten Büning, Prof.

Städtisches Klinikum Braunschweig; Recruiting

Braunschweig, Germany

Contact: Max Reinshagen, Prof.

Universitätsklinikum Carl Gustav Carus Dresden; Recruiting

Dresden, Germany

Contact: Renate Schmelz, Dr. med.

FAU Universität Erlangen-Nürnberg; Recruiting

Erlangen, Germany

Contact: Raja Atreya, Prof.

Agaplesion Markus Krankenhaus; Recruiting

Frankfurt, Germany

Contact: Axel Dignaß, Prof.

Universitätsklinik Freiburg; Recruiting

Freiburg, Germany

Contact: Peter Hasselblatt, Prof.

Klinikum Fulda; Recruiting

Fulda, Germany

Contact: Carsten Schmidt, Prof.

Gesellschaft Klinische Studien Leipzig; Recruiting

Leipzig, Germany

Contact: Nils Teich, Prof.

Universitätsklinikum Ulm; Recruiting

Ulm, Germany

Contact: Jochen Klaus, Prof.

Sponsors and Collaborators

Tabitha Heller

German Federal Ministry of Education and Research

Investigators

• Study Director: Andreas Stallmach, Prof.; Jena University Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Tabitha Heller, Project manager, Jena University Hospital
• ClinicalTrials.gov Identifier: NCT03843385
• Other Study ID Numbers: KS2017-114
• First Posted: February 18, 2019
• Last Update Posted: November 24, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tabitha Heller, Jena University Hospital:

fecal transplantation; multidonor fecal transplantation

Additional relevant MeSH terms:

Colitis; Colitis, Ulcerative; Inflammatory Bowel Diseases; Ulcer; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases; Pathologic Processes