Vedolizumab Intravenous (IV) Dose Optimization in Ulcerative Colitis (ENTERPRET)

A Phase 4 Open-Label Study to Evaluate Vedolizumab IV Dose Optimization on Treatment Outcomes In Nonresponders With Moderately to Severely Active Ulcerative Colitis (ENTERPRET)

The purpose of this study is to investigate the efficacy and safety of vedolizumab intravenous (IV) dose optimization on mucosal healing compared with the standard vedolizumab IV dosing regimen over a 30 week treatment period in participants with moderately to severely active ulcerative colitis (UC) and high vedolizumab clearance, based on a Week 5 predefined serum vedolizumab concentration threshold less than (<) 50 microgram per milliliter (microg/mL) and who are Week 6 non-responders based on partial Mayo score.

Study Overview

• Status: Completed
• Conditions: Colitis, Ulcerative
• Intervention / Treatment: Drug: Vedolizumab IV

Detailed Description

The drug being tested in this study is called Vedolizumab. Vedolizumab will be administered as an IV infusion. It is being tested in this study with new doses. This study will investigate the efficacy and safety of dose optimization of vedolizumab IV, compared with standard dosing of vedolizumab IV, over a 30-week treatment period.

The study will enroll approximately 250 moderately to severely active subjects with UC in order to randomize approximately 100 non-responder subjects with high vedolizumab drug clearance. Subjects will receive induction therapy of vedolizumab IV 300 mg on Day 1 and Week 2 (Lead-in Period). At Week 5, serum vedolizumab concentration will be measured. At Week 6, subjects will be assessed for clinical response based on partial Mayo score.

Results of both Week 5 vedolizumab concentration and Week 6 clinical response will determine the treatment pathway. Those who are non-responders based on partial Mayo score at Week 6 and who are assessed as having high vedolizumab clearance, based on a predefined Week 5 serum vedolizumab concentration threshold (<50 microg/mL) will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

• Vedolizumab IV Standard Treatment
• Vedolizumab IV Dose Optimized

All randomized subjects will receive vedolizumab IV either 300 mg or 600 mg every 4 or 8 weeks.

This multi-center trial will be conducted in United States of America and Canada. The overall time to participate in this study is 56 weeks. Subjects will make multiple visits to the clinic, and will be contacted by telephone, 6 months after last dose of study drug for a long term follow-up safety survey.

• Study Type: Interventional
• Enrollment (Actual): 278
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • British Colombia
    • Victoria, British Colombia, Canada, V8V 3M9
      • PerCuro Clinical Research Ltd.
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • LHSC - University Hospital
    • London, Ontario, Canada, N6A 5W9
      • LHSC - Victoria Hospital
    • Oshawa, Ontario, Canada, L1H 7K4
      • Taunton Surgical Centre
    • Vaughan, Ontario, Canada, L4L4Y7
      • Toronto Digestive Disease Associates, Inc.
• United States
  • Arizona
    • Tucson, Arizona, United States, 85712
      • Advanced Clinical Therapeutics, LLC
  • Arkansas
    • Little Rock, Arkansas, United States, 72204
      • Arkansas Primary Care Clinic, PA
  • California
    • San Pablo, California, United States, 94806
      • Care Access Research, San Pablo
    • San Pablo, California, United States, 94806
      • Care Access Research LLC
  • Connecticut
    • Bridgeport, Connecticut, United States, 06066
      • Gastroenterology Associates of Fairfield County
  • Florida
    • Clearwater, Florida, United States, 33756
      • Gastro Florida
    • Gainesville, Florida, United States, 32605
      • Florida Research Network, LLC
    • Hialeah, Florida, United States, 33016
      • Wellness Clinical Research, LLC
    • Maitland, Florida, United States, 32751
      • Center for Advanced Gastro
    • Orlando, Florida, United States, 32803
      • Center for Interventional Endo
    • Pembroke Pines, Florida, United States, 33028
      • BRCR Medical Center, Inc.
    • Tampa, Florida, United States, 33626
      • Gastro Florida
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Atlanta Gastroenterology Specialists, PC
    • Decatur, Georgia, United States, 30033
      • Atlanta Center For Gastroenterology
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Grand Teton Research Group, PLLC
  • Illinois
    • Evanston, Illinois, United States, 60201
      • Northshore University Healthsystem
  • Indiana
    • New Albany, Indiana, United States, 47150
      • Aquiant Research
  • Iowa
    • Clive, Iowa, United States, 50325
      • Iowa Digestive Disease Center
  • Kansas
    • Topeka, Kansas, United States, 66604
      • Cotton O'Neil Clinical Research Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Gastroenterology Associates LLC
    • Shreveport, Louisiana, United States, 71105
      • Louisiana Research Center, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • 4940 Eastern Ave A building
    • Columbia, Maryland, United States, 20721
      • Gastro Center of Maryland
    • Glen Burnie, Maryland, United States, 21061
      • Woodholme Gastroenterology Associates
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Nevada
    • Las Vegas, Nevada, United States, 89113
      • Las Vegas Medical Research
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Charlotte Gastroenterology and Hepatology
  • Ohio
    • Dayton, Ohio, United States, 45415
      • Dayton Gastroenterology, Inc
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Health System
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Gastroenterology Associates PA
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Midwest Medical Care
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt Medical Center
  • Texas
    • Dallas, Texas, United States, 75231
      • Texas Digestive Disease Consultants - Dallas
    • Decatur, Texas, United States, 76234
      • Ygenics
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Keller, Texas, United States, 76248
      • Texas Digestive Disease Consultants
    • Richardson, Texas, United States, 75082
      • DHAT Research Institute
    • Southlake, Texas, United States, 76092
      • Texas Digestive Disease Consultants - Southlake
    • Temple, Texas, United States, 76508
      • BaylorScott&White Research Institute
    • Webster, Texas, United States, 77598
      • GI Liver Research LLC
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Gastroenterology Associates of Northern Virginia, Ltd.
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53266
      • Medical College of Wisconsin, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Has a diagnosis of UC established at least 1 month prior to Screening by clinical and endoscopic evidence and corroborated by a histopathology report.
2. Has moderately to severely active UC as determined by a complete Mayo score of 6 to 12 with an endoscopic subscore ≥2 within 28 days prior to enrollment.
3. Has evidence of UC proximal to the rectum (≥15 cm of involved colon) prior to start of vedolizumab IV dosing.
4. Has been determined to be suitable for vedolizumab IV for routine management of UC by their physician.
5. Has a family history of colorectal cancer, personal history of increased colorectal cancer risk, age >50 years, or other known risk factor must be up-to-date on colorectal cancer surveillance (may be performed during screening).

6. Has demonstrated an inadequate response with, lost response to, or intolerance of at least 1 of the following agents: immunomodulators, corticosteroids, or tumor necrosis factor-alpha (TNF-α) antagonists. Subject who are naive to TNF-α antagonist therapy or who have previously failed TNF-α antagonist therapy (including primary and secondary non-responders or intolerant) may be included.

   Week 6 Randomized Treatment Period Inclusion Criteria

7. Following Lead-in Period, the subject is assessed as having high vedolizumab drug clearance based on a predefined Week 5 serum vedolizumab concentration threshold (<50 microg/mL).
8. Following Lead-in Period, the subject is a non-responder based on partial Mayo score at Week 6.

Exclusion Criteria:

1. Has clinical evidence of abdominal abscess or toxic megacolon at the Screening Visit.
2. Has had an extensive colonic resection, subtotal or total colectomy.
3. Has had ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
4. Has a diagnosis of Crohn's colitis or indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis.

5. Has received any of the following for the treatment of underlying disease within 30 days of screening:

   1. Non-biologic therapies (eg. cyclosporine, tacrolimus, thalidomide)
   2. An approved non-biologic therapy in an investigational protocol.
6. Has received any investigational or approved biologic or biosimilar agent within 60 days or 5 half-lives prior to screening (whichever is longer).
7. Has previously had prior exposure to approved or investigational anti-integrin antibodies (e.g. natalizumab, efalizumab, etrolizumab, AMG-181, anti-MAdCAM-1 antibodies or rituximab).
8. Has previously received approved or investigational vedolizumab.
9. The subject currently requires or is anticipated to require surgical intervention for UC during the study.
10. Has history or evidence of adenomatous colonic polyps that have not been removed, or colonic mucosal dysplasia.
11. Has any evidence of an active infection during Screening (eg, sepsis, cytomegalovirus, or listeriosis).
12. Has a clinically significant infection (eg, pneumonia, pyelonephritis) within 30 days prior to screening, or ongoing chronic infection.
13. Has evidence of active C. difficile as evidenced by positive C. difficile toxin or is having treatment for C. difficile infection or other intestinal pathogens during Screening.
14. Has a known history of infection with human immunodeficiency virus (HIV), hepatitis B (HBV), or chronic HBV (HBV immune subjects (ie, being hepatitis B surface antigen [HBsAg] negative and hepatitis B antibody positive) may, however, be included), or hepatitis C virus (HCV) infection. Subjects with documented successful treatment of HCV with sustained virological response (SVR) at 26 weeks can be enrolled.

15. Has active or latent tuberculosis (TB), as evidenced by the following:

    a. A diagnostic TB test performed within 30 days of screening or during the Screening Period that is positive, defined as: i. Positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, OR ii. A TB skin test reaction ≥ 5 mm OR, b. Chest X-ray within 3 months of screening that is suspicious for pulmonary TB, and a positive or 2 successive indeterminate QuantiFERON tests within 30 days prior to Screening or during the Screening Period.

16. Has any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, HIV infection, organ transplantation).
17. Has any live vaccination within 30 days prior to Screening or is planning to receive any live vaccination during participation in the study.
18. Has used a topical (rectal) treatment with (5-ASA) or corticosteroid enemas/suppositories within 2 weeks prior to Screening.
19. Has a history of hypersensitivity or allergies to vedolizumab IV or its components.
20. Has received total parenteral nutrition (TPN) or albumin in the last 30 days prior to screening.
21. Has any unstable or uncontrolled cardiovascular disorder, heart failure moderate to severe (New York Class Association III or IV), any pulmonary, hepatic, renal, GI, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, would confound the study results or compromise subject safety.
22. Has had a surgical procedure requiring general anesthesia within 30 days prior to screening or is planning to undergo major surgery during the study period.
23. Has a history of malignancy, except for the following: adequately-treated non-metastatic basal cell skin cancer; squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to Screening; and history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to screening. Subjects with remote history of malignancy (eg, >10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy received and must be discussed with the sponsor on a case by-case basis prior to Screening.
24. Has a history of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, demyelinating, or neurodegenerative disease.
25. Has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist during Screening or prior to the administration of the first dose of study drug on Day 1.
26. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the Screening Visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lead-in Period: Vedolizumab 300 mg; Vedolizumab 300 mg intravenous (IV) infusion once at Day 1 and at Week 2. Participants who were non-responders based on partial Mayo score at Week 6 and who had high vedolizumab clearance (>0.14 L/day) at Week 5 were eligible for Randomized Treatment Period (RTP). Participants who were responders (Lead-In Failures) entered the 18-week follow-up period and discontinued the study.	Drug: Vedolizumab IV; Vedolizumab intravenous infusion.; Other Names: Entyvio; MLN0002
Experimental: Randomized Treatment Period (RTP): Standard Treatment Arm; Following Lead-in Period, participants received vedolizumab 300 mg, IV infusion, once every 8 weeks (Q8W) at Weeks 6, 14 and 22 as standard treatment plus 18 weeks follow-up.	Drug: Vedolizumab IV; Vedolizumab intravenous infusion.; Other Names: Entyvio; MLN0002
Experimental: RTP: Dose Optimized Arm; Following Lead-in Period, participants received vedolizumab 600 mg, IV infusion at Week 6, followed by Regimen A: vedolizumab 300 mg once in every 4 weeks (Q4W) thereafter (Weeks 10, 14, 18, 22 and 26) plus 18 weeks follow-up, or Regimen B: vedolizumab 600 mg, IV infusion Q4W (Weeks 10, 14, 18, 22 and 26) plus 18 weeks follow-up based on drug clearance.	Drug: Vedolizumab IV; Vedolizumab intravenous infusion.; Other Names: Entyvio; MLN0002

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Mucosal Healing at Week 30	Mucosal healing is defined as Mayo endoscopic subscore <=1 point. Mayo score was used in clinical trials to assess UC disease activity. It consisted of 4 disease activity variables (stool frequency, rectal bleeding, findings on sigmoidoscopy and physician's global assessment), each scored on a scale of 0 to 3, where 0 normal condition and 3 = severe disease condition. The total Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.	Week 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Clinical Remission at Week 30	Clinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point at Week 30. Mayo score was used in clinical trials to assess UC disease activity. It consisted of 4 disease activity variables (stool frequency, rectal bleeding, findings on sigmoidoscopy and physician's global assessment), each scored on a scale of 0 to 3, where 0 = normal condition and 3 = severe disease condition. The total Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.	Week 30
Percentage of Participants Achieving Clinical Response at Week 30	Clinical response is defined as a reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (Day 1) with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point, at Week 30. Mayo score was used in clinical trials to assess UC disease activity. It consisted of 4 disease activity variables (stool frequency, rectal bleeding, findings on sigmoidoscopy and physician's global assessment), each scored on a scale of 0 to 3, where 0 = normal condition and 3 = severe disease condition. The total Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.	Week 30
Percentage of Participants Achieving Clinical Response at Week 14	Clinical response is defined as A reduction in partial Mayo score of ≥2 points and ≥25% from Baseline (Day 1) with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. Mayo score was used in clinical trials to assess UC disease activity. A composite index of 3 disease activity variables (stool frequency, rectal bleeding, and physician's global assessment), each scored on a scale from 0 to 3 with total partial Mayo score ranging from 0 to 9 (higher scores indicate greater disease activity). Partial Mayo score is calculated analogously to the complete Mayo score but excludes the sigmoidoscopy subscore.	Week 14
Percentage of Participants Achieving Corticosteroid-Free Remission	Participants using oral corticosteroids at Baseline who have discontinued corticosteroids and are in clinical remission. Mayo score was used in clinical trials to assess UC disease activity. Clinical Remission is defined as a complete Mayo score of <=2 points and no individual subscore >1 point at Week 30. It consisted of 4 disease activity variables (stool frequency, rectal bleeding, findings on sigmoidoscopy and physician's global assessment), each scored on a scale of 0 to 3, where 0 = normal condition and 3 = severe disease condition. The total Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.	Week 30
Percentage of Participants Achieving Durable Clinical Response	A clinical response (based on partial Mayo score), which is defined as a reduction in partial Mayo score of ≥2 points and ≥25% from Baseline with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point at Weeks 14 and 30. Mayo score was used in clinical trials to assess UC disease activity. A composite index of 3 disease activity variables (stool frequency, rectal bleeding, and physician's global assessment), each scored on a scale from 0 to 3 with total partial Mayo score ranging from 0 to 9 (higher scores indicate greater disease activity). Partial Mayo score is calculated analogously to the complete Mayo score but excludes the sigmoidoscopy subscore. Percentage of participants with durable clinical response, clinical response achieved at both Weeks 14 and 30 are reported.	Weeks 14 and 30

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Medical Director Clinical Science, Takeda

Publications and helpful links

Helpful Links

• To obtain more information on the study, click on this link

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2017
• Primary Completion (Actual): October 16, 2020
• Study Completion (Actual): October 16, 2020

Study Registration Dates

• First Submitted: January 20, 2017
• First Submitted That Met QC Criteria: January 20, 2017
• First Posted (Estimated): January 24, 2017

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 20, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Gastrointestinal Agents; Vedolizumab
• Other Study ID Numbers: Vedolizumab-4014; U1111-1183-0451 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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