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

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ClinicalTrials.gov Identifier: NCT03029143
Recruitment Status : Recruiting
First Posted : January 24, 2017
Last Update Posted : May 6, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda

Tracking Information
First Submitted Date  ICMJE January 20, 2017
First Posted Date  ICMJE January 24, 2017
Last Update Posted Date May 6, 2019
Actual Study Start Date  ICMJE March 29, 2017
Estimated Primary Completion Date January 26, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 4, 2018)
Proportion of Subjects Achieving Mucosal Healing [ Time Frame: Week 30 ]
Mucosal healing is defined as Mayo endoscopic subscore less than or equal to (less than or equal to [<=] 1) point. Mayo score is used in clinical trials to assess UC disease activity. It consists 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 is equal to (=) normal condition and 3 = severe disease condition. The total Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.
Original Primary Outcome Measures  ICMJE
 (submitted: January 20, 2017)
Percentage of Participants Achieving Mucosal Healing [ Time Frame: Week 30 ]
Mucosal healing is defined as Mayo endoscopic subscore ≤1 point. Mayo score is used in clinical trials to assess Ulcerative Colitis disease activity. It consists of 4 subscales: stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscale is 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.
Change History Complete list of historical versions of study NCT03029143 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2018)
  • Proportion of Subjects Achieving Clinical Remission [ Time Frame: Week 30 ]
    Clinical remission is defined as a complete Mayo score of <=2 points and no individual subscore greater than (>) 1 point. Mayo score is used in clinical trials to assess UC disease activity. It consists 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.
  • Proportion of Subjects Achieving Clinical Response [ Time Frame: Week 30 ]
    Clinical response is defined as a reduction in complete Mayo score of greater than or equal to (>=) 3 points and >=30 percentage (%) from Baseline with an accompanying decrease in rectal bleeding subscore of >=1 point or absolute rectal bleeding subscore of <=1 point. Mayo score is used in clinical trials to assess UC disease activity. It consists 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.
  • Proportion of Subjects Achieving Clinical Response Based on Partial Mayo Score [ Time Frame: Week 14 ]
    Clinical response based on partial Mayo score 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. The partial Mayo score is a composite index of 3 disease activity variables (stool frequency, rectal bleeding, and physician's gobal assessment), each scored on a scale from 0 = normal to 3 = severe disease. Partial Mayo score is calculated analogously to the complete Mayo score but excludes the sigmoidoscopy subscore. The total partial Mayo score ranges from 0 to 9, with higher scores indicating more severe disease.
  • Proportion of Subjects With Corticosteroid-Free Remission [ Time Frame: Week 30 ]
    Subjects using oral corticosteroids at Baseline who have discontinued corticosteroids and are in clinical remission at Week 30 will be reported.
  • Proportion of Subjects Achieving Durable Clinical Response [ Time Frame: Weeks 14 and 30 ]
    Durable clinical response 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 20, 2017)
  • Percentage of Participants Achieving Clinical Remission [ Time Frame: Week 30 ]
    Clinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point. Mayo score used in clinical trials to assess Ulcerative Colitis disease activity. It consists of 4 subscales: stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscale is 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.
  • Percentage of Participants Achieving Clinical Response [ Time Frame: 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. Mayo score used in clinical trials to assess Ulcerative Colitis disease activity. It consists of 4 subscales: stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscale is 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.
  • Percentage of Participants Achieving Clinical Response Based on Partial Mayo Score [ Time Frame: Week 14 ]
    Clinical response based on partial Mayo score 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. The partial Mayo score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 9 (severe disease) and is a composite of 3 subscores: stool frequency subscore, rectal bleeding subscore, and physician's gobal assessment subscore, each of which ranges from 0 = normal to 3 = severe disease. The total partial Mayo score ranges from 0 to 9, with higher scores indicating more severe disease.
  • Percentage of Participants With Corticosteroid-Free Remission [ Time Frame: Week 30 ]
    Participants using oral corticosteroids at Baseline (Day 1) who have discontinued corticosteroids and are in clinical remission at Week 30 will be reported.
  • Percentage of Participants Achieving Durable Clinical Response [ Time Frame: Weeks 14 and 30 ]
    Durable clinical response based on partial Mayo score is defined as 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vedolizumab Intravenous (IV) Dose Optimization in Ulcerative Colitis
Official Title  ICMJE 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)
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 subjects 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Colitis, Ulcerative
Intervention  ICMJE Drug: Vedolizumab IV
Vedolizumab intravenous infusion
Other Names:
  • Entyvio
  • MLN0002
Study Arms  ICMJE
  • Experimental: Vedolizumab IV Standard Treatment Arm
    Vedolizumab 300 milligram (mg), IV infusion on Day 1 and Week 2 as induction therapy in Lead-in Period followed by vedolizumab 300 mg, IV infusion, once in every 8 weeks (Q8W) (Weeks 6, 14, and 22) as standard treatment.
    Intervention: Drug: Vedolizumab IV
  • Experimental: Vedolizumab IV Dose Optimized Arm
    Vedolizumab 300 mg, IV infusion on Day 1 and Week 2 as induction therapy in Lead-in Period followed by Regimen A: vedolizumab 600 mg, IV infusion at Week 6 and 300 mg once in every 4 weeks (Q4W) thereafter (Weeks 10, 14, 18, 22 and 26), or Regimen B: vedolizumab 600 mg, IV infusion Q4W (Weeks 6, 10, 14, 18, 22 and 26). At Week 14 and beyond, dosing in the dose optimized arm will continue as previously assigned unless the subjects most recent preceding serum vedolizumab concentration is >90 microg/mL. In the event that steady-state Ctrough levels exceed safety exposure limits of 90 microg/mL, the next dose will be withheld and another Pharmacokinetics (PK) sample will be taken 1 week prior to the next scheduled dose. If at the next scheduled visit the Ctrough is still >90 microg/mL, the next dose will be similarly held and the PK repeated 1 week prior to the next scheduled dose. Once Ctrough is <90 microg/mL, the subject will move to the next lowest dose.
    Intervention: Drug: Vedolizumab IV
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 4, 2018)
250
Original Estimated Enrollment  ICMJE
 (submitted: January 20, 2017)
200
Estimated Study Completion Date  ICMJE June 30, 2020
Estimated Primary Completion Date January 26, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Takeda Study Registration Call Center +1-877-825-3327 medicalinformation@tpna.com
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03029143
Other Study ID Numbers  ICMJE Vedolizumab-4014
U1111-1183-0451 ( Other Identifier: WHO )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Responsible Party Takeda
Study Sponsor  ICMJE Takeda
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Clinical Science Takeda
PRS Account Takeda
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP