Combined Microbiota and Metabolic Signature in Ulcerative Colitis Predicts Anti-Inflammatory Therapy Success (COMMIT)

An Early Combined Microbiota and Metabolic Signature in Ulcerative Colitis Patients Predict the Clinical Success of Anti-inflammatory Therapy

The primary goal of the study is to develop an early (within 4 weeks) combined microbiota/metabolic signature predicting clinical response upon anti-inflammatory treatment in UC patients.

Study Overview

• Status: Recruiting
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: Ozanimod; Drug: TNF Inhibitor; Drug: Steroids; Drug: Vedolizumab; Drug: Ustekinumab

Detailed Description

The investigators perform a longitudinal prospective multi-center study for ulcerative colitis (UC) patients with a flare at/and after the time of starting a new treatment and healthy household controls. They will perform intense longitudinal bio-sampling and deep clinical characterization.

With this information the aim is to develop a predictive signature regarding the success of a new ly started anti-inflammatory therapy after an UC flare.

• Study Type: Observational
• Enrollment (Estimated): 240

Contacts and Locations

• Study Contact: Name: Benjamin Misselwitz, Prof.; Phone Number: +41 31 664 0430; Email: benjamin.misselwitz@dbmr.unibe.ch
• Study Contact Backup: Name: Jacqueline Wyss, Dr.; Phone Number: +41 764411617; Email: jacqueline.wyss@dbmr.unibe.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3013
    • Recruiting
    • University Hospital Bern Inselspital
    • Contact: Benjamin Misselwitz, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients/ participants fulfilling inclusion criteria to one of the following groups will be included:

1. Patients with a flare of ulcerative colitis who meet the inclusion criteria (see above). Inclusion of 120 patients is planned.
2. Healthy controls. For each patient, a healthy control individual who shares the same living conditions (e.g., spouse or roommate) is attempted. Enrolment of controls will not be enforced but enrolment of ≥100 controls for 120 patients is expected.

Description

Inclusion criteria ulcerative colitis:

1. Signed informed consent
2. Age 18-80 years
3. General ability to understand and follow study procedures, fluency in German, French, or English
4. Diagnosis of ulcerative colitis since ≥3 months
5. Confirmed flare of ulcerative colitis with partial SCCAI score ≥5 points and at least one biomarker supporting intestinal inflammation
6. Planned start with ozanimod, steroids (prednisone ≥20mg/d or equivalent), or a biological (vedolizumab, infliximab, adalimumab, golimumab, ustekinumab)

Exclusion criteria ulcerative colitis

1. Confirmed cytomegalovirus (CMV) reactivation within the previous 2 weeks (tested as part of standard medical practice at the discretion of the responsible physician)
2. C. difficile related diarrhea, or other confirmed infectious diarrhea in the last 4 weeks (tested as part of standard medical practice at the discretion of the responsible physician)
3. Diagnosis of Crohn's disease
4. Current pouch or ileostomy/ colostomy
5. Severe medical, surgical, or psychiatric comorbidities interfering with study procedures

Inclusion criteria controls

1. Signed informed consent
2. Age 18-80 years
3. General ability to understand and follow study procedures, fluency in German, French, or English
4. No current or past diagnosis of inflammatory bowel disease (IBD)

5. No current medical complaints typic for IBD e.g.

   • Diarrhea, severe constipation, abdominal pain, blood in stool, weight loss
   • Slight symptoms (without impact onto daily activities) are permitted
6. No other current relevant gastrointestinal disease or condition plausibly interfering with microbiota assessment according to the discretion of the study physician

Exclusion criteria controls

1. Confirmed cytomegalovirus (CMV) reactivation within the previous 2 weeks
2. C. difficile related diarrhea, or other confirmed infectious diarrhea in the last 4 weeks
3. Diagnosis of Crohn's disease, ulcerative colitis
4. Current pouch or ileostomy/ colostomy
5. Severe medical, surgical, or psychiatric comorbidities interfering with study procedures

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Ulcerative colitis patients; Patients with a flare of ulcerative colitis who meet the inclusion criteria. 120 patients will be included.	Drug: Ozanimod; Start of standard therapy; Drug: TNF Inhibitor; Start of standard therapy; Other Names: infliximab, adalimumab, etanercept, golimumab, and certolizumab.; Drug: Steroids; Start of standard therapy; Other Names: Prednisolon; Drug: Vedolizumab; Start of standard therapy; Drug: Ustekinumab; Start of standard therapy
Controls; For each patient, enrollment of a healthy control individual who shares the same living conditions (e.g., spouse or roommate) is attempted

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of a predictive score regarding success of anti-inflammatory therapy after start of a new treatment in ulcerative colitis	The predictive microbiota signature will be developed using machine learning, considering clinical data, microbiota descriptors, and metabolic changes from day 0 to week 4 (see analysis). Clinical response will be defined as a decrease in the simple clinical colitis activity index (SCCAI) score by ≥3 points 25or to a level of ≤2.5 points 26 at 8 weeks after the start of anti-inflammatory treatment.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predicting clinical remission	Assessment of the microbiota/metabolic signature predicting clinical remission (SSCAI <2.5)	8 weeks
Predicting clinical remission	Assessment of the microbiota/metabolic signature predicting clinical remission (SSCAI <2.5)	12 weeks
Predicting clinical remission	Assessment of the microbiota/metabolic signature predicting clinical remission (SSCAI <2.5)	6 months
Predicting clinical remission	Assessment of the microbiota/metabolic signature predicting clinical remission (SSCAI <2.5)	12 months
Predicting calprotectin reduction	Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels	2 weeks
Predicting calprotectin reduction	Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels	8 weeks
Predicting calprotectin reduction	Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels	12 weeks
Predicting calprotectin reduction	Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels	6 months
Predicting calprotectin reduction	Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels	12 months
Differential microbiota response to therapy: Ozanimod	Sensitivity analysis in the subgroup treated with Ozanimod in regards to differential signatures in the prediction signature	12 months
Differential microbiota response to therapy: TNF-inhibitors	Sensitivity analysis in the subgroup treated with TNF-inhibitors in regards to differential signatures in the prediction signature	12 months
Differential microbiota response to therapy: Vedolizumab	Sensitivity analysis in the subgroup treated with Vedolizumab in regards to differential signatures in the prediction signature	12 months
Differential microbiota response to therapy: Ustekinumab	Sensitivity analysis in the subgroup treated with Ustekinumab in regards to differential signatures in the prediction signature	12 months
Differential microbiota response to therapy: Steroids	Sensitivity analysis in the subgroup treated with Steroids in regards to differential signatures in the prediction signature	12 months
Signature differences between ulcerative colitis and healthy controls	Comparison of microbiota/metabolic signatures between ulcerative colitis patients and controls using clustering and differential abundance analysis	12 months
Metagenomic substrain assessment	Identification of substrains in patient samples using metagenomic sequencing and follow up their persistence/loss over time	12 months
Fatigue assessment	Fatigue severity measured by the fatigue severity scale over time and assessed for reduction after therapy start	12 months
Adverse effects	Assessment regarding potential adverse effects in relation medical therapy by screening questionnaires	12 months

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Benjamin Misselwitz, Prof., Insel Gruppe AG, University Hospital Bern

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2023
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): January 31, 2025

Study Registration Dates

• First Submitted: January 18, 2023
• First Submitted That Met QC Criteria: January 26, 2023
• First Posted (Actual): January 27, 2023

Study Record Updates

• Last Update Posted (Estimated): December 6, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Sphingosine 1 Phosphate Receptor Modulators; Prednisolone; Etanercept; Adalimumab; Vedolizumab; Infliximab; Golimumab; Tumor Necrosis Factor Inhibitors; Ozanimod; Ustekinumab
• Other Study ID Numbers: 2022-02008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Analytic code for generation of the predictive signature will be made available to other researchers
• IPD Sharing Time Frame: With publication of results
• IPD Sharing Access Criteria: Acess to analytic code will be detailed in the final publication
• IPD Sharing Supporting Information Type: ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No