Transfer of FRozen Encapsulated Multidonor Stool Filtrate for Active Ulcerative COlitis

Phase 3

Recruiting

• Conditions: Ulcerative Colitis; Inflammatory Bowel Diseases
• Interventions: Drug: encapsulated faecal microbiota; Drug: encapsulated faecal microbiota filtrate; Drug: Placebo

• Registration Number: NCT03843385
• Lead Sponsor: Tabitha Heller

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 Timeline

• Study First Submitted: 2019-02-14
• Study First Submitted QC: 2019-02-14
• Study First Posted: 2019-02-18
• Study Start: 2023-01-31
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-21
• Last Update Posted: 2023-11-24
• Primary Completion: 2025-01
• Study Completion: 2026-07

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 174

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
faecal microbiota	encapsulated 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.
faecal microbiota filtrate	encapsulated 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.
Placebo	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.

Primary Outcome Measures

Name	Time	Method
clinical remission	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

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

Trial Locations

Locations (15)

Universitätsklinikum Halle (Saale); 🇩🇪 Halle, Germany

Universitätsklinikum Schleswig Holstein; 🇩🇪 Kiel, Germany

Städtisches Klinikum Lüneburg; 🇩🇪 Lueneburg, Germany

Jena University Hospital; 🇩🇪 Jena, Thuringia, Germany

Sozialstiftung Bamberg; 🇩🇪 Bamberg, Germany

Charité Berlin; 🇩🇪 Berlin, Germany

DRK Kliniken Berlin Westend; 🇩🇪 Berlin, Germany

Krankenhaus Waldfriede; 🇩🇪 Berlin, Germany

Universitätsklinikum Carl Gustav Carus Dresden; 🇩🇪 Dresden, Germany

FAU Universität Erlangen-Nürnberg; 🇩🇪 Erlangen, Germany

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