Triple Combination Therapy in High Risk Crohn's Disease (CD)

An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Triple Combination Therapy With Vedolizumab IV, Adalimumab SC, and Oral Methotrexate in Early Treatment of Subjects With Crohn's Disease Stratified at Higher Risk for Developing Complications

The purpose of this study is to determine the effect of triple combination therapy with an anti-integrin (vedolizumab intravenous [IV]), a tumor necrosis factor (TNF) antagonist (adalimumab subcutaneously [SC]), and an immunomodulator (oral methotrexate) on endoscopic remission in participants with newly-diagnosed CD stratified at higher risk for complications.

Study Overview

• Status: Completed
• Conditions: Crohn Disease
• Intervention / Treatment: Drug: Vedolizumab; Drug: Adalimumab; Drug: Methotrexate

Detailed Description

The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who have CD. This study will look at the endoscopic remission and mucosal healing of gastrointestinal tract of people who take vedolizumab as triple combination therapy with adalimumab and methotrexate.

The study will enroll approximately 60 participants. Participants will receive triple combination therapy which includes:

• Vedolizumab 300 mg (intravenous)
• Adalimumab 160/80/40 mg (subcutaneous)
• Methotrexate 15 mg (oral)

All participants will receive vedolizumab intravenous infusion on Weeks 0, 2, 6, 14 and 22 along with adalimumab 160 mg, subcutaneous injection at Week 0, 80 mg at Week 2, then 40 mg once at Week 4 and every 2 weeks thereafter until Week 26 along with methotrexate tablets orally, once weekly from Weeks 0 up to Week 34. In monotherapy phase, all participants will receive vedolizumab intravenous infusion once at Weeks 30, 38, 46, 54, 62, 70, 78, 86, 94 and 102.

This multi-center trial will be conducted in the United States and Canada. The overall time to participate in this study is 128 weeks. Participants will make multiple visits to the clinic, plus a final visit 18 weeks after last dose of study drug for a safety follow-up assessment. Participants will also participate in a long-term safety questionnaire, by phone, at 26 weeks (6 months) from the last dose of study drug.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6L 6K3
      • Covenant Health
  • British Columbia
    • Victoria, British Columbia, Canada, V8V 3M9
      • Percuro Clinical Research Ltd
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • LHSC - Victoria Hospital
    • Vaughan, Ontario, Canada, L4L 4Y7
      • Toronto Digestive Disease Associates Inc
  • Quebec
    • Sherbrooke, Quebec, Canada, J1G 2E8
      • CIUSSS de I'Estrie-CHUS
• United States
  • Alabama
    • Dothan, Alabama, United States, 36305
      • Digestive Health Specialists of the Southeast
  • Florida
    • Clearwater, Florida, United States, 33761
      • Gastro Florida
  • Georgia
    • Atlanta, Georgia, United States, 30342-5000
      • Atlanta Gastroenterology Associates
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Grand Teton Research Group, PLLC
  • Illinois
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
    • Topeka, Kansas, United States, 66606
      • Cotton O'Neil Clinical Research
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Texas Digestive Disease Consultants Baton Rouge
    • Shreveport, Louisiana, United States, 71105
      • Louisana Research Center, LLC
  • Michigan
    • Troy, Michigan, United States, 48098
      • Center for Digestive Health
    • Ypsilanti, Michigan, United States, 48197
      • Huron Gastroenterology Associates
  • Minnesota
    • Plymouth, Minnesota, United States, 55446
      • Minnesota Gastroenterology, PA - Plymouth
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89113
      • Las Vegas Medical Research
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mt. Sinai
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Digestive Health Partners, PS
    • Charlotte, North Carolina, United States, 28204
      • Carolinas HealthCare System Digestive Health
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Digestive Disease Specialists, Inc.
    • Tulsa, Oklahoma, United States, 74104
      • Options Health Research, LLC
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78229
      • Pinnacle Clinical Research
    • Southlake, Texas, United States, 76092
      • Texas Digestive Disease Consultants Southlake
    • Tyler, Texas, United States, 75701
      • Tyler Research Institute, LLC
    • Webster, Texas, United States, 77598
      • Texas Digestive Disease Consultants, Webster
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Sciences Center
  • Washington
    • Tacoma, Washington, United States, 98405
      • Digestive Health Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Has an initial diagnosis of CD established within 24 months prior to screening with involvement of the ileum and/or colon that can be assessed by ileocolonoscopy.
2. Has moderate to severely active CD during Screening defined by a centrally assessed simple endoscopic score for Crohn disease (SES-CD) score >=7 (or >=4 if isolated ileal disease).

Exclusion Criteria:

Gastrointestinal (GI) Exclusion Criteria

1. Has a diagnosis of ulcerative colitis (UC) or indeterminate colitis.
2. Has clinical evidence of a current abdominal abscess or a history of prior abdominal abscess.
3. Has a known perianal fistula with abscess. (The participant may have a perianal fistula without abscess.)
4. Has a known fistula (other than perianal fistula).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Vedolizumab 300 mg (IV) + Adalimumab 160-80-40 mg (SC) + Methotrexate 15 mg (Oral); In Triple Combination Therapy Phase, vedolizumab 300 mg, intravenous (IV) infusion, once at Weeks 0, 2, 6, 14 and 22, with adalimumab 160 mg subcutaneously (SC), once at Week 0, then 80 mg once at Week 2, then 40 mg once at Week 4 and every 2 weeks thereafter until Week 26 along with oral methotrexate 15 mg tablets orally once weekly from Weeks 0 up to Week 34. In Monotherapy Phase, vedolizumab 300 mg IV infusion once at Weeks 30, 38, 46, 54, 62, 70, 78, 86, 94 and 102.

Drug: Vedolizumab; Vedolizumab intravenous infusion.; Other Names: Entyvio; MLN0002 IV; Drug: Adalimumab; Adalimumab injection for subcutaneous use.; Other Names: Humira; Drug: Methotrexate; Methotrexate oral tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Endoscopic Remission at Week 26	Endoscopic remission was defined as simple endoscopic score for Crohn's Disease (SES-CD) scale score from 0-2. The SES-CD evaluated 4 endoscopic variables: ulcer size, proportion of the surface area that was ulcerated, proportion of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable was the sum of values obtained for each segment. The SES-CD total was the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.	Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Endoscopic Healing at Week 26	Endoscopic healing was defined as SES-CD score ≤4 and reduction from Baseline in SES-CD score of at least 2 points and no individual SES-CD subscore >1. The SES-CD evaluated 4 endoscopic variables: ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable was the sum of values obtained for each segment. The SES-CD total was the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease. Percentages are rounded off to single decimal.	Week 26
Percentage of Participants Achieving Endoscopic Response at Week 26	Endoscopic response was defined as 50% reduction in SES-CD score from Baseline. The SES-CD evaluated 4 endoscopic variables: ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable was sum of values obtained for each segment. The SES-CD total was the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease. Percentages are rounded off to single decimal.	Week 26
Change From Baseline in SES-CD Score at Week 26	The SES-CD evaluated 4 endoscopic variables: ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable was the sum of values obtained for each segment. The SES-CD total was the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease. Negative change indicates improvement.	Baseline and Week 26
Percentage of Participants Achieving Deep Remission at Week 26	Deep remission was defined as Crohn's disease activity index (CDAI) score <150 and SES-CD score from 0-2. CDAI was scoring system for the assessment of CD activity, index values of 150 and below were associated with quiescent disease; values above that indicated active disease and values above 450 were seen with extremely severe disease. The SES-CD evaluated 4 endoscopic variables: ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable was sum of values obtained for each segment. The SES-CD total was sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease. Percentages are rounded off to single decimal.	Week 26
Percentage of Participants Achieving Clinical Remission and Endoscopic Response as a Measure of Mucosal Healing at Week 26	Clinical remission was defined as CDAI score <150. Endoscopic response was defined as 50% reduction in SES-CD score from Baseline, as mucosal healing. CDAI was scoring system for assessment of CD activity, index values of 150 and below are associated with quiescent disease; values above that indicated active disease and values above 450 were seen with extremely severe disease. The SES-CD evaluated 4 endoscopic variables: ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The SES-CD total was sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease. Percentages are rounded off to single decimal.	Week 26
Percentage of Participants Achieving Clinical Remission at Weeks 10 and 26	Clinical remission was defined as CDAI score <150. CDAI was scoring system for the assessment of CD activity, index values of 150 and below were associated with quiescent disease; values above that indicated active disease and values above 450 were seen with extremely severe disease. Percentages are rounded off to single decimal.	Weeks 10 and 26
Percentage of Participants Achieving Clinical Response at Weeks 10 and 26	Clinical response was defined as ≥100-point decrease in CDAI score. CDAI was scoring system for the assessment of CD activity, index values of 150 and below were associated with quiescent disease; values above that indicated active disease and values above 450 were seen with extremely severe disease. Percentages are rounded off to single decimal.	Weeks 10 and 26
Change From Baseline in C-reactive Protein (CRP) Levels at Weeks 10 and 26	The change between the CRP levels were collected at Weeks 10 and 26 relative to Baseline. Negative change indicates improvement.	Baseline, Weeks 10 and 26
Change From Baseline in Fecal Calprotectin Concentrations at Weeks 10, 14, 26, 52, 78, and 102	The change between the fecal calprotectin concentrations collected at Weeks 10, 14, 26, 52, 78, and 102 relative to Baseline were reported. Baseline is defined as the last observation prior to the first dose of the study drug.	Baseline, Weeks 10, 14, 26, 52, 78 and 102
Percentage of Participants Achieving Clinical Remission and CRP <5 Milligram Per Liter (mg/L) at Weeks 26, 52, 78, and 102	Clinical remission was defined as CDAI score <150 and CRP level <5 mg/L in participants with elevated CRP level at Baseline. CDAI was scoring system for the assessment of CD activity, index values of 150 and below were associated with quiescent disease; values above that indicate active disease and values above 450 were seen with extremely severe disease. Percentages are rounded off to single decimal.	Weeks 26, 52, 78 and 102
Percentage of Participants Using Oral Corticosteroids at Baseline Who Have Discontinued Corticosteroids and Are in Clinical Remission at Weeks 10, 26, and 102	Percentage of participants using oral corticosteroids at Baseline who had discontinued corticosteroids and were in clinical remission at weeks 10, 26, and 102 were reported. Clinical remission was defined as CDAI score <150. CDAI was scoring system for the assessment of CD activity, index values of 150 and below are associated with quiescent disease; values above that indicate active disease and values above 450 were seen with extremely severe disease. Percentages are rounded off to single decimal.	Weeks 10, 26 and 102
Percentage of Participants Maintaining Clinical Remission at Weeks 52, 78, and 102	Clinical remission was defined as CDAI score <150. Clinical remission was defined as CDAI score <150. CDAI was scoring system for the assessment of CD activity, index values of 150 and below are associated with quiescent disease; values above that indicated active disease and values above 450 were seen with extremely severe disease. Percentages are rounded off to single decimal.	Weeks 52, 78 and 102
Percentage of Participants Maintaining Clinical Response at Weeks 52, 78, and 102	Clinical response was defined as ≥100-point decrease in CDAI score. CDAI was scoring system for the assessment of CD activity, index values of 150 and below were associated with quiescent disease; values above that indicated active disease and values above 450 were seen with extremely severe disease. Percentages are rounded off to single decimal.	Weeks 52, 78 and 102
Percentage of Participants Maintaining Endoscopic Remission at Week 102	Endoscopic remission was defined as SES-CD score 0-2. The SES-CD evaluated 4 endoscopic variables: ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable was sum of values obtained for each segment. The SES-CD total was the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicated more severe disease. Percentages are rounded off to single decimal.	Week 102
Percentage of Participants Maintaining Deep Remission at Week 102	Deep remission was defined as CDAI score <150 and SES-CD score 0-2. Clinical remission was defined as CDAI score <150. CDAI was scoring system for the assessment of CD activity, index values of 150 and below are associated with quiescent disease; values above that indicated active disease and values above 450 were seen with extremely severe disease. The SES-CD evaluated 4 endoscopic variables: ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The SES-CD total was the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease. Percentages are rounded off to single decimal.	Week 102
Percentage of Participants Maintaining Endoscopic Healing at Week 102	Endoscopic healing was defined as SES-CD score <=4 and reduction from Baseline in SES-CD score of at least 2 points and no individual SES-CD subscore >1. The SES-CD evaluated 4 endoscopic variables: ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable was sum of values obtained for each segment. The SES-CD total was the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease. Percentages are rounded off to single decimal.	Week 102
Percentage of Participants Maintaining Endoscopic Response at Week 102	Endoscopic response was defined as 50% reduction in SES-CD score from Baseline. The SES-CD evaluated 4 endoscopic variables: ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable was sum of values obtained for each segment. The SES-CD total was the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.	Week 102
Percentage of Participants Maintaining Clinical Remission and Endoscopic Response as a Measure of Mucosal Healing at Week 102	Clinical remission is defined as CDAI score <150. Endoscopic response defined as 50% reduction in SES-CD score from Baseline, as mucosal healing. CDAI is scoring system for assessment of CD activity, index values of 150 and below are associated with quiescent disease; values above that indicate active disease and values above 450 are seen with extremely severe disease. The SES-CD evaluates 4 endoscopic variables (ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and stenosis in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The SES-CD total is sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease. Percentages are rounded off to the nearest decimal value.	Week 102
Percentage of Participants With First Exacerbation of CD	First exacerbation of CD after 26 weeks was defined as either: 1) a CDAI increase of >70 from the prior visit on 2 occasions separated by a 2-week interval, objective evidence of disease activity by colonoscopy or CRP above normal OR 2) fecal calprotectin >250 microgram per gram (mcg/g) alone. CDAI was scoring system for the assessment of CD activity, index values of 150 and below were associated with quiescent disease; values above that indicated active disease and values above 450 are seen with extremely severe disease. Percentages are rounded off to the nearest decimal value.	After 26 Weeks up to Week 120

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2017
• Primary Completion (Actual): September 22, 2020
• Study Completion (Actual): July 5, 2022

Study Registration Dates

• First Submitted: May 5, 2016
• First Submitted That Met QC Criteria: May 5, 2016
• First Posted (Estimated): May 6, 2016

Study Record Updates

• Last Update Posted (Actual): July 14, 2023
• Last Update Submitted That Met QC Criteria: June 27, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Tumor Necrosis Factor Inhibitors; Adalimumab; Vedolizumab; Methotrexate
• Other Study ID Numbers: Vedolizumab-4006; U1111-1175-9094 (Registry 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.: Yes