The Efficacy and Safety of Combining Probiotic VSL#3 With Vedolizumab for the Treatment of Moderate Ulcerative Colitis

Official title

A Multicenter Randomized, Double-blind, Placebo-controlled Study on the Efficacy and Safety of Combining Probiotic VSL#3 With Vedolizumab for the Treatment of Moderate Ulcerative Colitis

Overview

An imbalance in the gut microbiota and mucosal immune dysfunction leading to intestinal inflammation are central to the pathogenesis of ulcerative colitis (UC). Both international and domestic inflammatory bowel disease (IBD) guidelines consistently recommend the use of the probiotic VSL#3 for inducing or maintaining remission in cases of mild-to-moderate UC. While the development of biologic therapies in recent years has provided new directions for IBD treatment, classic biologics such as infliximab may increase the risk of opportunistic infections and malignancies. Vedolizumab, when used for the induction therapy of UC, has a response rate of less than 80%, a slightly slower onset of action, and a slight increase in Clostridioides difficile infection (CDI) incidence. Currently, there is a lack of clinical data on the adjunctive use of VSL#3 with biologic agents in the treatment of UC globally. Therefore, this project aims to design a multi-center, randomized, placebo-controlled, double-blind study. The primary objective is to compare the changes in clinical response in patients with moderately active UC treated with either VSL#3 or placebo in combination with vedolizumab (VDZ) for six weeks.

Detailed description

This study enrolled patients aged 18-85 years with moderate ulcerative colitis and randomly assigned them in a 1:1 ratio to an experimental group and a control group. Patients in the experimental group received two packets of VSL#3 (450 billion CFU/packet) daily for 14 weeks, along with Vedolizumab (300 mg once weekly at weeks 0, 2, 6, and 14). The control group received placebo packets and Vedolizumab on the same schedule. The primary outcome was the proportion of patients with a decrease of ≥3 points in the SCCAI score at week 6, along with improvement in fecal calprotectin (FC) levels (decrease of ≥50% from baseline) at weeks 6 and 14. Secondary outcomes included clinical response, clinical remission, corticosteroid-free clinical remission, and changes in quality of life scores at week 14.

Interventions

• Dietary supplement VSL#3
  VSL#3 450 billion CFU/sachet
• Dietary supplement Placebo
  Placebo sachets with maltose, cornstarch and dioxide
• Drug Vedolizumab
  Patients will start combined therapy with vedolizumab and VSL#3 or placebo at the same time. Vedolizumab will be administered according to clinical practice with the following schedule: 300 mg intravenously on Baseline (Day 1 / Week 0) and Weeks 2, 6, and 14, with a flexibility of ±3 days relative to the start of VSL#3 administration.

Primary outcome measures

• Clinical Response rate at week 6 [Time frame: At week 6]

Secondary outcome measures (7)

• Clinical Response rate at week 14 [Time frame: At Week 14]
• Clinical Remission rate at week 14 [Time frame: At Week 14]
• Steroid-free Clinical Remission rate at week 14 [Time frame: At Week 14]
• At week 2 on PRO2 and Urgency NRS through dairy daily [Time frame: At Week 2]
• Inflammatory Bowel Disease Questionnaire (IBDQ) variation [Time frame: At the end of treatment weeks 6 and 14]
• The proportion of patients with a ≥50% decrease in fecal calprotectin (FC) and the changes in the Urgency Numeric Rating Scale (UNRS) [Time frame: At the end of treatment weeks 6 and 14]
• Adverse Events [Time frame: Through Week 14]

Eligibility criteria

Inclusion criteria

• Subject must be a man or woman aged 18-85 years, inclusive.
• Diagnosed with ulcerative colitis (UC) at least 90 days prior to baseline, supported by comprehensive colonoscopy findings and histopathological evidence obtained within the past year. Participants must provide full colonoscopy or sigmoidoscopy reports along with pathology results conducted within the last 3 months, as well as blood indicators (within 1 week) at baseline screening. Individuals currently experiencing infection, dysplasia, or malignancy will be excluded from participation.
• Subject has moderate active UC and had a Mayo score of 6-10 at screening.
• Planned treatment with Vedolizumab as initial therapy or reinduction, with reinduction defined as no vedolizumab treatment within 1 year.
• Confirmed by the investigator that despite receiving at least one of the following treatments, the subject has shown an inadequate response, loss of response, or intolerance:

• Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide), where the subject exhibits ongoing signs and symptoms of active disease during at least 4 weeks of treatment with mesalamine 2.4 g/day, sulfasalazine 4 g/day, olsalazine 1 g/day, or balsalazide 6.75 g/day.
• Immunosuppressants: failure to respond after receiving at least 42 consecutive days of treatment with azathioprine, 6-mercaptopurine, or methotrexate (MTX) injections prior to baseline (Week 0), with minimum doses of azathioprine ≥ 0.75 mg/kg/day or 6-MP ≥ 0.5 mg/kg/day (rounded to the nearest tablet dose) or MTX ≥ 15 mg/week (SC/IM), or the highest tolerated dose due to adverse effects such as leukopenia, elevated liver enzymes, or nausea.
• No increase in dose of oral 5-ASA and Immunosuppressants could be allowed if it is maintained stable at least 2 weeks before screening.
• Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
• Willing and able to complete the required Subject Diary.
• Willing and able to meet all study requirements, including attending all assessment visits and phone calls.

Exclusion criteria

• Diagnosis of Crohn's disease, undetermined IBD or other colitis.
• UC disease limited to the rectum (<15 cm from the anal verge)
• Steroid therapy initiation within 2 weeks before screening visit.
• Used antibiotics for intestinal or other infections within 2 weeks of the screening
• Use of other probiotics preparations within the last 2 weeks before study entry (screening)
• Used rectal 5-ASA within the past week before study entry (screening)
• Adjustment of oral 5-ASA and immunosuppressant dosages due to disease progression after colonoscopy screening until enrollment.
• Within 1 week prior to screening, the participant has taken nonsteroidal anti-inflammatory drugs (NSAIDs) or anti-diarrheal medications for 5 consecutive days.
• Positive Clostridioides difficile detection toxin results within the past month prior to screening.
• Pregnancy and breastfeeding women
• Other biologics/advanced therapies are used as concomitant therapy and Previous use of other biologics
• History of allergy to maltose and/or cornstarch and/or silica
• Subjects with severe primary heart, liver, lung, kidney, hematologic, or serious diseases that affect their survival, such as cancer, AIDS, asthma, kidney stones, renal dysfunction; urine protein >+, microscopic hematuria, ALT >2N (N is the upper limit of normal), Cr > normal upper limit, platelet count <50x10\^9/L, white blood cell count <3.0x10\^9/L.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

China · 12 centers

• The Seventh Medical Center, PLA General Hospital — Beijing
• Chongqing General Hospital — Chongqing
• The Sixth Affiliated Hospital, Sun Yat-sen University — Guangzhou
• Renmin Hospital of Wuhan University — Wuhan
• The Second Affiliated Hospital of Xi&#39;an Jiaotong University — Xi’an
• West China Hospital of Sichuan University — Chengdu
• Zhejiang Provincial Hospital of Traditional Chinese Medicine — Hangzhou
• 2nd Affiliated Hospital, Zhejiang University School of Medicine — Hangzhou
• … and 4 more centers

Identifiers

NCT: NCT06609447 · 2024-0602

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗