Clinical trial NCT03029143: Vedolizumab Intravenous (IV) Dose Optimization in Ulcerative Colitis
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Colitis, Ulcerative
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2017-01-24
Enrollment: 278
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

   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.

Primary outcomes:
measure: Percentage of Participants Achieving Mucosal Healing at Week 30
timeFrame: Week 30
Secondary outcomes:
measure: Percentage of Participants Achieving Clinical Remission at Week 30
timeFrame: Week 30
measure: Percentage of Participants Achieving Clinical Response at Week 30
timeFrame: Week 30
measure: Percentage of Participants Achieving Clinical Response at Week 14
timeFrame: Week 14
measure: Percentage of Participants Achieving Corticosteroid-Free Remission
timeFrame: Week 30
measure: Percentage of Participants Achieving Durable Clinical Response
timeFrame: Weeks 14 and 30
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Advanced Clinical Therapeutics, LLC
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Primary Care Clinic, PA
state: Arkansas
city: San Pablo
country: United States
facility: Care Access Research LLC
state: California
city: San Pablo
country: United States
facility: Care Access Research, San Pablo
state: California
city: Bridgeport
country: United States
facility: Gastroenterology Associates of Fairfield County
state: Connecticut
city: Clearwater
country: United States
facility: Gastro Florida
state: Florida
city: Gainesville
country: United States
facility: Florida Research Network, LLC
state: Florida
city: Hialeah
country: United States
facility: Wellness Clinical Research, LLC
state: Florida
city: Maitland
country: United States
facility: Center for Advanced Gastro
state: Florida
city: Orlando
country: United States
facility: Center for Interventional Endo
state: Florida
city: Pembroke Pines
country: United States
facility: BRCR Medical Center, Inc.
state: Florida
city: Tampa
country: United States
facility: Gastro Florida
state: Florida
city: Atlanta
country: United States
facility: Atlanta Gastroenterology Specialists, PC
state: Georgia
city: Decatur
country: United States
facility: Atlanta Center for Gastroenterology
state: Georgia
city: Idaho Falls
country: United States
facility: Grand Teton Research Group, PLLC
state: Idaho
city: Evanston
country: United States
facility: NorthShore University HealthSystem
state: Illinois
city: New Albany
country: United States
facility: Aquiant Research
state: Indiana
city: Clive
country: United States
facility: Iowa Digestive disease center
state: Iowa
city: Topeka
country: United States
facility: Cotton O'Neil Clinical Research Center
state: Kansas
city: Baton Rouge
country: United States
facility: Gastroenterology Associates LLC
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana Research Center, LLC
state: Louisiana
city: Baltimore
country: United States
facility: 4940 Eastern Ave A building
state: Maryland
city: Columbia
country: United States
facility: Gastro Center of Maryland
state: Maryland
city: Glen Burnie
country: United States
facility: Woodholme Gastroenterology Associates
state: Maryland
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Las Vegas
country: United States
facility: Las Vegas Medical Research
state: Nevada
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Charlotte
country: United States
facility: Charlotte Gastroenterology and Hepatology
state: North Carolina
city: Dayton
country: United States
facility: Dayton Gastroenterology, Inc
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Greenville
country: United States
facility: Gastroenterology Associates PA
state: South Carolina
city: Sioux Falls
country: United States
facility: Midwest Medical Care
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Texas Digestive Disease Consultants - Dallas
state: Texas
city: Decatur
country: United States
facility: Ygenics
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Keller
country: United States
facility: Texas Digestive Disease Consultants
state: Texas
city: Richardson
country: United States
facility: DHAT Research Institute
state: Texas
city: Southlake
country: United States
facility: Texas Digestive Disease Consultants - Southlake
state: Texas
city: Temple
country: United States
facility: BaylorScott&White Research Institute
state: Texas
city: Webster
country: United States
facility: GI Liver Research LLC
state: Texas
city: Fairfax
country: United States
facility: Gastroenterology Associates of Northern Virginia, Ltd.
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin, Inc.
state: Wisconsin
city: Victoria
country: Canada
facility: PerCuro Clinical Research Ltd.
state: British Colombia
city: London
country: Canada
facility: LHSC - University Hospital
state: Ontario
city: London
country: Canada
facility: LHSC - Victoria Hospital
state: Ontario
city: Oshawa
country: Canada
facility: Taunton Surgical Centre
state: Ontario
city: Vaughan
country: Canada
facility: Toronto Digestive Disease Associates, Inc.
state: Ontario
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References: