Vedolizumab Intravenous (IV) Dose Optimization in Ulcerative Colitis

Colitis, Ulcerative Clinical Trial

— ENTERPRET  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03029143
• Other study ID #: Vedolizumab-4014
• Secondary ID: U1111-1183-0451
• Status: Completed
• Phase: Phase 4
• Start date: March 29, 2017
• Est. completion date: October 16, 2020

Study information

• Verified date: July 2023
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 278
• Est. completion date: October 16, 2020
• Est. primary completion date: October 16, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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-a) antagonists. Subject who are naive to TNF-a antagonist therapy or who have previously failed TNF-a 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.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer

Intervention

Drug:
• Vedolizumab IV
Vedolizumab intravenous infusion.

Locations

Country	Name	City	State
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	PerCuro Clinical Research Ltd.	Victoria	British Colombia
United States	Atlanta Gastroenterology Specialists, PC	Atlanta	Georgia
United States	4940 Eastern Ave A building	Baltimore	Maryland
United States	Gastroenterology Associates LLC	Baton Rouge	Louisiana
United States	Gastroenterology Associates of Fairfield County	Bridgeport	Connecticut
United States	Charlotte Gastroenterology and Hepatology	Charlotte	North Carolina
United States	Gastro Florida	Clearwater	Florida
United States	Iowa Digestive disease center	Clive	Iowa
United States	Gastro Center of Maryland	Columbia	Maryland
United States	Texas Digestive Disease Consultants - Dallas	Dallas	Texas
United States	Dayton Gastroenterology, Inc	Dayton	Ohio
United States	Atlanta Center for Gastroenterology	Decatur	Georgia
United States	Ygenics	Decatur	Texas
United States	NorthShore University HealthSystem	Evanston	Illinois
United States	Gastroenterology Associates of Northern Virginia, Ltd.	Fairfax	Virginia
United States	Florida Research Network, LLC	Gainesville	Florida
United States	Woodholme Gastroenterology Associates	Glen Burnie	Maryland
United States	Gastroenterology Associates PA	Greenville	South Carolina
United States	Wellness Clinical Research, LLC	Hialeah	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	Grand Teton Research Group, PLLC	Idaho Falls	Idaho
United States	Texas Digestive Disease Consultants	Keller	Texas
United States	Las Vegas Medical Research	Las Vegas	Nevada
United States	Arkansas Primary Care Clinic, PA	Little Rock	Arkansas
United States	Center for Advanced Gastro	Maitland	Florida
United States	Medical College of Wisconsin, Inc.	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt Medical Center	Nashville	Tennessee
United States	Aquiant Research	New Albany	Indiana
United States	Weill Cornell Medical College	New York	New York
United States	Center for Interventional Endo	Orlando	Florida
United States	BRCR Medical Center, Inc.	Pembroke Pines	Florida
United States	University of Pennsylvania Health System	Philadelphia	Pennsylvania
United States	DHAT Research Institute	Richardson	Texas
United States	Care Access Research LLC	San Pablo	California
United States	Care Access Research, San Pablo	San Pablo	California
United States	Swedish Medical Center	Seattle	Washington
United States	Louisiana Research Center, LLC	Shreveport	Louisiana
United States	Midwest Medical Care	Sioux Falls	South Dakota
United States	Texas Digestive Disease Consultants - Southlake	Southlake	Texas
United States	Gastro Florida	Tampa	Florida
United States	BaylorScott&White Research Institute	Temple	Texas
United States	Cotton O'Neil Clinical Research Center	Topeka	Kansas
United States	Advanced Clinical Therapeutics, LLC	Tucson	Arizona
United States	GI Liver Research LLC	Webster	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

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