Vedolizumab Intravenous (IV) Dose Optimization in Ulcerative Colitis

NCT ID: NCT03029143

Last Updated: 2023-07-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 278 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-29
• Study Completion Date: 2020-10-16

Brief Summary

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.

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.

Conditions

Colitis, Ulcerative

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Vedolizumab IV

Intervention Type: DRUG

Vedolizumab intravenous infusion.

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.

Group Type: EXPERIMENTAL

Vedolizumab IV

Intervention Type: DRUG

Vedolizumab intravenous infusion.

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.

Group Type: EXPERIMENTAL

Vedolizumab IV

Intervention Type: DRUG

Vedolizumab intravenous infusion.

Interventions

Vedolizumab IV

Vedolizumab intravenous infusion.

Intervention Type: DRUG

Other Intervention Names

Entyvio; MLN0002

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director Clinical Science

Role: STUDY_DIRECTOR

Takeda

Locations

Advanced Clinical Therapeutics, LLC

Tucson, Arizona, United States

Arkansas Primary Care Clinic, PA

Little Rock, Arkansas, United States

Care Access Research LLC

San Pablo, California, United States

Care Access Research, San Pablo

San Pablo, California, United States

Gastroenterology Associates of Fairfield County

Bridgeport, Connecticut, United States

Gastro Florida

Clearwater, Florida, United States

Florida Research Network, LLC

Gainesville, Florida, United States

Wellness Clinical Research, LLC

Hialeah, Florida, United States

Center for Advanced Gastro

Maitland, Florida, United States

Center for Interventional Endo

Orlando, Florida, United States

BRCR Medical Center, Inc.

Pembroke Pines, Florida, United States

Gastro Florida

Tampa, Florida, United States

Atlanta Gastroenterology Specialists, PC

Atlanta, Georgia, United States

Atlanta Center for Gastroenterology

Decatur, Georgia, United States

Grand Teton Research Group, PLLC

Idaho Falls, Idaho, United States

NorthShore University HealthSystem

Evanston, Illinois, United States

Aquiant Research

New Albany, Indiana, United States

Iowa Digestive disease center

Clive, Iowa, United States

Cotton O'Neil Clinical Research Center

Topeka, Kansas, United States

Gastroenterology Associates LLC

Baton Rouge, Louisiana, United States

Louisiana Research Center, LLC

Shreveport, Louisiana, United States

4940 Eastern Ave A building

Baltimore, Maryland, United States

Gastro Center of Maryland

Columbia, Maryland, United States

Woodholme Gastroenterology Associates

Glen Burnie, Maryland, United States

University of Minnesota

Minneapolis, Minnesota, United States

Las Vegas Medical Research

Las Vegas, Nevada, United States

Weill Cornell Medical College

New York, New York, United States

Charlotte Gastroenterology and Hepatology

Charlotte, North Carolina, United States

Dayton Gastroenterology, Inc

Dayton, Ohio, United States

University of Pennsylvania Health System

Philadelphia, Pennsylvania, United States

Gastroenterology Associates PA

Greenville, South Carolina, United States

Midwest Medical Care

Sioux Falls, South Dakota, United States

Vanderbilt Medical Center

Nashville, Tennessee, United States

Texas Digestive Disease Consultants - Dallas

Dallas, Texas, United States

Ygenics

Decatur, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

Texas Digestive Disease Consultants

Keller, Texas, United States

DHAT Research Institute

Richardson, Texas, United States

Texas Digestive Disease Consultants - Southlake

Southlake, Texas, United States

BaylorScott&White Research Institute

Temple, Texas, United States

GI Liver Research LLC

Webster, Texas, United States

Gastroenterology Associates of Northern Virginia, Ltd.

Fairfax, Virginia, United States

Swedish Medical Center

Seattle, Washington, United States

Medical College of Wisconsin, Inc.

Milwaukee, Wisconsin, United States

PerCuro Clinical Research Ltd.

Victoria, British Colombia, Canada

LHSC - University Hospital

London, Ontario, Canada

LHSC - Victoria Hospital

London, Ontario, Canada

Taunton Surgical Centre

Oshawa, Ontario, Canada

Toronto Digestive Disease Associates, Inc.

Vaughan, Ontario, Canada

Countries

United States; Canada

References

Jairath V, Yarur A, Osterman MT, James A, Balma D, Mehrotra S, Yang L, Yajnik V, Qasim Khan RM. ENTERPRET: A Randomized Controlled Trial of Vedolizumab Dose Optimization in Patients With Ulcerative Colitis Who Have Early Nonresponse. Clin Gastroenterol Hepatol. 2024 May;22(5):1077-1086.e13. doi: 10.1016/j.cgh.2023.10.029. Epub 2023 Nov 10.

Reference Type: DERIVED

PMID: 37951560 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.takeda.com/study-detail/5f6b60394db2bf003ab4a241?idFilter=%5B%22Vedolizumab-4014%22%5D

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

Other Identifiers

U1111-1183-0451

Identifier Type: OTHER

Identifier Source: secondary_id

Vedolizumab-4014

Identifier Type: -

Identifier Source: org_study_id