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

Tracking Information

• First Submitted Date: February 14, 2019
• First Posted Date: February 18, 2019
• Last Update Posted Date: November 24, 2023
• Actual Study Start Date: January 31, 2023
• Estimated Primary Completion Date: January 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 21, 2023)

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).

Original Primary Outcome Measures (submitted: February 14, 2019)

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 without any subscore >1 and a Mayo endoscopic subscore 0-1; additionally patients unavailable at the week 12 follow-up will be included as non-responders (i.e. counted no remission).

Current Secondary Outcome Measures (submitted: November 21, 2023)

• 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)
• 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
• 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.
• 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)
• 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
• 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
• 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
• MAYO Total Score [ Time Frame: 52 weeks ]
  Comparison of the MAYO total Score between the 3 Arms (FMFT, FMT and Placebo)
• 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
• 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

Original Secondary Outcome Measures (submitted: February 14, 2019)

• steroid-free clinical remission [ Time Frame: 12 weeks ]
  steroid-free clinical remission at week 12 post first transfer of FMFT or FMT, defined by Mayo score ≤ 2 without any subscore >1 and a Mayo endoscopic subscore 0-1; additionally patients unavailable at the week 12 follow-up will be included as non-responders (i.e. counted no remission).
• clinical response [ Time Frame: 12 weeks ]
  clinical response is defined by decrease in Mayo score by 3 points, decrease in bleeding subscore by 1 as an important patient-related outcome parameter, or absolute sub-score of 0-1
• change in quality of life [ Time Frame: 12 weeks ]
  assessed by Inflammatory Bowel Disease Quality of Life Questionnaire (IBDQ)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

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

Condition

• Ulcerative Colitis
• Inflammatory Bowel Diseases

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.
  Other Name: FMFT
• Drug: encapsulated faecal microbiota
  Multidonor stool mixed with sterile normal saline, homogenized, filtered, encapsulated in hypromellose capsules and frozen.
  Other Name: FMT
• Drug: Placebo
  Sterile saline encapsulated in hypromellose capsules and frozen.
  Other Name: Encapsulated sterile saline

Study Arms

• 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.
  Intervention: Drug: encapsulated faecal microbiota filtrate
• 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.
  Intervention: Drug: encapsulated faecal microbiota
• 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.
  Intervention: Drug: Placebo

• 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 trial. Trials. 2022 Feb 22;23(1):173. doi: 10.1186/s13063-022-06095-1.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 14, 2019): 174
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 2026
• Estimated Primary Completion Date: January 2025 (Final data collection date for primary outcome measure)

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.
• 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

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

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT03843385
• Other Study ID Numbers: KS2017-114
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Tabitha Heller, Jena University Hospital
• Original Responsible Party: Jena University Hospital
• Current Study Sponsor: Tabitha Heller
• Original Study Sponsor: Jena University Hospital
• Collaborators: German Federal Ministry of Education and Research

Investigators

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

• PRS Account: Jena University Hospital
• Verification Date: November 2023