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

• ClinicalTrials.gov Identifier: NCT02764762
• Recruitment Status: Completed
• First Posted: May 6, 2016
• Results First Posted: October 21, 2021
• Last Update Posted: July 20, 2022
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Crohn Disease	Drug: Vedolizumab; Drug: Adalimumab; Drug: Methotrexate	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 12, 2017
• Actual Primary Completion Date: September 22, 2020
• Actual Study Completion Date: July 5, 2022

Arms and Interventions

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 infusion, once at Weeks 0, 2, 6, 14 and 22, with adalimumab 160 mg subcutaneously, 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.

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

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Achieving Endoscopic Remission at Week 26 [ Time Frame: 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.

Secondary Outcome Measures :

1. Percentage of Participants Achieving Endoscopic Healing at Week 26 [ Time Frame: Week 26 ]
   Endoscopic healing is defined as SES-CD score less than or equal to (≤) 4 and reduction from Baseline in SES-CD score of at least 2 points and no individual SES-CD subscore greater than (>) 1. The SES-CD evaluates 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 is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
2. Percentage of Participants Achieving Endoscopic Response at Week 26 [ Time Frame: Week 26 ]
   Endoscopic response is defined as 50% reduction in SES-CD score from Baseline. 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 score for each endoscopic variable is sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
3. Change From Baseline in SES-CD Score at Week 26 [ Time Frame: Baseline and Week 26 ]
   The SES-CD evaluates 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 is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
4. Percentage of Participants Achieving Deep Remission at Week 26 [ Time Frame: Week 26 ]
   Deep remission is defined as Crohn's disease activity index (CDAI) score less than (<) 150 and SES-CD score from 0-2. CDAI is 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 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 score for each endoscopic variable is sum of values obtained for each segment. The SES-CD total is sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
5. Percentage of Participants Achieving Clinical Remission and Endoscopic Response as a Measure of Mucosal Healing at Week 26 [ Time Frame: Week 26 ]
   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.
6. Percentage of Participants Achieving Clinical Remission at Weeks 10 and 26 [ Time Frame: Weeks 10 and 26 ]
   Clinical remission is defined as CDAI score <150. CDAI is 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 are seen with extremely severe disease.
7. Percentage of Participants Achieving Clinical Response at Weeks 10 and 26 [ Time Frame: Weeks 10 and 26 ]
   Clinical response is defined as greater than or equal to (≥) 100-point decrease in CDAI score. CDAI is 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 are seen with extremely severe disease.
8. Change From Baseline in C-reactive Protein (CRP) Levels at Weeks 10 and 26 [ Time Frame: Baseline, Weeks 10 and 26 ]
   The change between the CRP levels collected at Weeks 10 and 26 relative to Baseline.
9. Change From Baseline in Fecal Calprotectin Concentrations at Weeks 10, 14, 26, 52, 78, and 102 [ Time Frame: Baseline, 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.
10. Percentage of Participants Achieving Clinical Remission and CRP <5 Milligram Per Liter (mg/L) at Weeks 26, 52, 78, and 102 [ Time Frame: Weeks 26, 52, 78 and 102 ]
    Clinical remission is defined as CDAI score <150 and CRP level <5 mg/L in participants with elevated CRP level at Baseline. CDAI is 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 are seen with extremely severe disease.
11. Percentage of Participants Using Oral Corticosteroids at Baseline Who Have Discontinued Corticosteroids and Are in Clinical Remission at Weeks 10, 26, and 102 [ Time Frame: Weeks 10, 26 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 will be reported. Clinical remission is defined as CDAI score <150. CDAI is 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 are seen with extremely severe disease.
12. Percentage of Participants Maintaining Clinical Remission at Weeks 52, 78, and 102 [ Time Frame: Weeks 52, 78 and 102 ]
    Clinical remission is defined as CDAI score <150. Clinical remission is defined as CDAI score <150. CDAI is 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 are seen with extremely severe disease.
13. Percentage of Participants Maintaining Endoscopic Remission at Week 102 [ Time Frame: Week 102 ]
    Endoscopic remission is defined as SES-CD score 0-2. 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 score for each endoscopic variable is sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
14. Percentage of Participants Maintaining Deep Remission at Week 102 [ Time Frame: Week 102 ]
    Deep remission is defined as CDAI score <150 and SES-CD score 0-2. Clinical remission is defined as CDAI score <150. CDAI is 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 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 the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
15. Percentage of Participants Maintaining Endoscopic Healing at Week 102 [ Time Frame: Week 102 ]
    Endoscopic healing is 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 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 score for each endoscopic variable is sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
16. Percentage of Participants Maintaining Endoscopic Response at Week 102 [ Time Frame: Week 102 ]
    Endoscopic response is defined as 50% reduction in SES-CD score from Baseline. 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 score for each endoscopic variable is sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
17. Percentage of Participants Maintaining Clinical Remission and Endoscopic Response as a Measure of Mucosal Healing at Week 102 [ Time Frame: 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.
18. Percentage of Participants With First Exacerbation of CD [ Time Frame: After 26 Weeks up to Week 128 ]
    First exacerbation of CD after 26 weeks is 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. Clinical remission is defined as CDAI score <150. CDAI is 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 are seen with extremely severe disease.

Eligibility Criteria

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

Criteria

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).

Contacts and Locations

Locations

United States, Alabama

Digestive Health Specialists of the Southeast

Dothan, Alabama, United States, 36305

United States, Florida

Gastro Florida

Clearwater, Florida, United States, 33761

United States, Georgia

Atlanta Gastroenterology Associates

Atlanta, Georgia, United States, 30342-5000

United States, Idaho

Grand Teton Research Group, PLLC

Idaho Falls, Idaho, United States, 83404

United States, Illinois

Northshore University HealthSystem

Evanston, Illinois, United States, 60201

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

Cotton O'Neil Clinical Research

Topeka, Kansas, United States, 66606

United States, Louisiana

Texas Digestive Disease Consultants Baton Rouge

Baton Rouge, Louisiana, United States, 70809

Louisana Research Center, LLC

Shreveport, Louisiana, United States, 71105

United States, Michigan

Center for Digestive Health

Troy, Michigan, United States, 48098

Huron Gastroenterology Associates

Ypsilanti, Michigan, United States, 48197

United States, Minnesota

Minnesota Gastroenterology, PA - Plymouth

Plymouth, Minnesota, United States, 55446

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, Nevada

Las Vegas Medical Research

Las Vegas, Nevada, United States, 89113

United States, New York

Icahn School of Medicine at Mt. Sinai

New York, New York, United States, 10029

United States, North Carolina

Digestive Health Partners, PS

Asheville, North Carolina, United States, 28801

Carolinas HealthCare System Digestive Health

Charlotte, North Carolina, United States, 28204

United States, Ohio

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Oklahoma

Digestive Disease Specialists, Inc.

Oklahoma City, Oklahoma, United States, 73112

Options Health Research, LLC

Tulsa, Oklahoma, United States, 74104

United States, Texas

Baylor College of Medicine

Houston, Texas, United States, 77030

Pinnacle Clinical Research

San Antonio, Texas, United States, 78229

Texas Digestive Disease Consultants Southlake

Southlake, Texas, United States, 76092

Tyler Research Institute, LLC

Tyler, Texas, United States, 75701

Texas Digestive Disease Consultants, Webster

Webster, Texas, United States, 77598

United States, Utah

University of Utah Health Sciences Center

Salt Lake City, Utah, United States, 84132

United States, Washington

Digestive Health Specialists

Tacoma, Washington, United States, 98405

Canada, Alberta

Covenant Health

Edmonton, Alberta, Canada, T6L 6K3

Canada, British Columbia

PerCuro Clinical Research Ltd

Victoria, British Columbia, Canada, V8V 3M9

Canada, Ontario

LHSC - Victoria Hospital

London, Ontario, Canada, N6A 5W9

Toronto Digestive Disease Associates Inc

Vaughan, Ontario, Canada, L4L 4Y7

Canada, Quebec

CIUSSS de I'Estrie-CHUS

Sherbrooke, Quebec, Canada, J1G 2E8

Sponsors and Collaborators

Takeda

Investigators

• Study Director: Medical Director; Takeda

  Study Documents (Full-Text)

Documents provided by Takeda:

Study Protocol  [PDF] June 30, 2020

Statistical Analysis Plan  [PDF] July 19, 2021

More Information

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02764762
• Other Study ID Numbers: Vedolizumab-4006; U1111-1175-9094 ( Registry Identifier: WHO )
• First Posted: May 6, 2016
• Results First Posted: October 21, 2021
• Last Update Posted: July 20, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• 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.
• URL: https://vivli.org/ourmember/takeda/

• 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

Keywords provided by Takeda:

Drug Therapy

Additional relevant MeSH terms:

Crohn Disease; Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Adalimumab; Methotrexate; Vedolizumab; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors; Anti-Inflammatory Agents; Gastrointestinal Agents