A Study of Vedolizumab Intravenous (IV) and Adalimumab or Vedolizumab and Ustekinumab in Adults With Crohn's Disease

Study Overview
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Brief Summary
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The main aim of this study is to learn about the effect of treatment with vedolizumab IV (vedolizumab) together with adalimumab or vedolizumab together with ustekinumab in adults with moderate to severe Crohn's Disease, and the effect of treatment with vedolizumab alone, after the dual targeted treatment. The study is conducted in two parts. In Part A, participants will receive the dual targeted treatment (vedolizumab together with either adalimumab or ustekinumab). In part B, participants will receive vedolizumab only. Part B will include participants who responded to the treatment in Part A. Each participant will be followed up for at least 26 weeks after the last dose of treatment.

Detailed Description
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The drug being tested in this study is vedolizumab. Vedolizumab is being tested to treat people with moderate to severe Crohn's disease who have experienced inadequate response, loss of response or intolerance to either one prior interleukin [IL] antagonist (Cohort 1) or one prior tumor necrosis factor inhibitor [TNFi] (Cohort 2). The study will look at the efficacy and safety of dual targeted therapy. The study will enroll approximately 150 patients. Participants will be assigned to one of the two treatment groups in Part A: Part A, Cohort 1: Vedolizumab + Adalimumab Part A, Cohort 2: Vedolizumab + Ustekinumab All participants who achieve clinical remission in Part A will receive vedolizumab IV 300 mg monotherapy from Week 30 until Week 46 in Part B. Participants will be followed for a further 20-week safety follow-up period to Week 72 (or 26 weeks post-last dose of study drug). This multi-center trial will be conducted in the United States and Canada. The overall time to participate in this study is approximately 76 weeks.

Official Title
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An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Dual Targeted Therapy With Vedolizumab Intravenous (IV) and Adalimumab Subcutaneous (SC) or Vedolizumab IV and Ustekinumab IV/SC in Moderate to Severe Crohn's Disease (CD)

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: Vedolizumab
* Drug: Adalimumab
* Drug: Ustekinumab
* Drug: Ustekinumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A: Has a confirmed diagnosis of CD at least 3 months before baseline, based on endoscopy results. Has moderately to severely active CD at Screening, defined as a CDAI score ≥220 and a SES-CD ≥6 (≥4 if isolated ileal disease). Has demonstrated at least 1 of the following (a, b, or c) to at least 1 IL antagonist or at least 1 tumor necrosis factor (TNF) antagonist, at doses approved for the treatment of CD: Inadequate response after completing the full induction regimen; Loss of response (recurrence of symptoms during scheduled maintenance dosing after prior clinical benefit); or Intolerance (a significant adverse event that precluded further use, including but not limited to serious infection including opportunistic infections, malignancy, infusion-related and hypersensitivity reactions including anaphylaxis, and liver injury). Note: Participants with primary nonresponse to ≥2 agents are not eligible. Participants with intolerance to 2 agents may be eligible at the investigator's discretion. Part B: Participant is in clinical remission at Week 26. Note: Participants exhibiting a clinical response (defined as a ≥ 100-point decrease in CDAI) at Week 26 may enter Part B at the investigator's discretion. Exclusion Criteria: A current diagnosis of ulcerative colitis or indeterminate colitis. Clinical evidence of a current abdominal abscess or a history of prior abdominal abscess. Known fistula (other than perianal fistula) or phlegmon. Known perianal fistula with abscess. Ileostomy, colostomy, or severe, or symptomatic stenosis of the intestine. Previous extensive colon resection with ≥2 colonic segments remaining, performed ≥ 6 months prior to screening. Short bowel syndrome. Any planned surgical intervention for CD, except for seton placement for perianal fistula without abscess. History or evidence of adenomatous colonic polyps that have not been removed. History or evidence of colonic mucosal dysplasia. Intolerance or contraindication to ileocolonoscopy. Any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection). Active or latent tuberculosis (TB), regardless of treatment history. A positive test for hepatitis B virus (HBV) as defined by the presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) test. A positive test for hepatitis C virus (HCV), as defined by a positive hepatitis C virus antibody (HCVAb) test and detectable HCV ribonucleic acid (RNA). Primary nonresponse to ≥2 IL antagonists (Cohort 1) or ≥2 TNF antagonists (Cohort 2) for the treatment of CD. Received approved or investigational anti-integrin antibodies (i.e., vedolizumab, natalizumab, efalizumab, etrolizumab, abrilumab [AMG 181], anti- mucosal addressin cell adhesion molecule-1 [MAdCAM-1] antibodies, or rituximab). History of or symptoms of progressive multifocal leukoencephalopathy (PML) in the investigator's opinion. If a participant has symptoms consistent with PML, a PML checklist must be completed and submitted to the PML independent adjudication committee (IAC). If the PML IAC deems the participant to have PML, the participant is ineligible.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Cohort 1: Vedolizumab + Adalimumab<br>Participants will receive vedolizumab IV 300 mg, at Weeks 0, 2, and 6, then every 8 weeks (Q8W) until Week 22 and adalimumab SC 160, 80, and 40 mg at Weeks 0, 2, and 4, respectively, then 40 mg every 2 weeks (Q2W) until Week 26. | Drug: Vedolizumab<br>* Vedolizumab intravenous infusion.<br>* Other names: Entyvio;Drug: Adalimumab<br>* Adalimumab subcutaneous injection.<br>* Other names: Humira;|
| Experimental: Part A, Cohort 2: Vedolizumab + Ustekinumab<br>Participants will receive vedolizumab IV 300 mg, at Weeks 0, 2, and 6, then Q8W until Week 22 and ustekinumab IV 520, 390, or 260 mg (weight-based), then SC 90 mg 8 weeks after initial IV dose, then Q8W until Week 24. | Drug: Vedolizumab<br>* Vedolizumab intravenous infusion.<br>* Other names: Entyvio;Drug: Ustekinumab<br>* Ustekinumab intravenous infusion.<br>* Other names: Stelara;Drug: Ustekinumab<br>* Ustekinumab subcutaneous injection.<br>* Other names: Stelara;|
| Experimental: Part B: Vedolizumab Monotherapy<br>Participants who achieve clinical remission in Part A will receive vedolizumab IV 300 mg monotherapy, Q8W from Week 30 until Week 46. | Drug: Vedolizumab<br>* Vedolizumab intravenous infusion.<br>* Other names: Entyvio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Percentage of Participants Achieving Clinical Remission Based on the Crohn's Disease Activity Index (CDAI) at Week 26 | Clinical remission is defined as a CDAI score of ≤150 points. CDAI assesses CD based on clinical signs such as number of liquid or very soft stools, abdominal pain, general wellbeing, extra-intestinal manifestations of CD, antidiarrheal use, presence of abdominal mass, hematocrit and body weight. CDAI consists of eight factors, each summed after adjustment with a weighting factor. Total score ranges from 0 to 600 points. Higher scores indicate more severity. | Week 26 | 
| Part B: Percentage of Participants in Clinical Remission Based on the CDAI at Week 52 | Clinical remission is defined as a CDAI score of ≤150 points. CDAI assesses CD based on clinical signs such as number of liquid or very soft stools, abdominal pain, general wellbeing, extra-intestinal manifestations of CD, antidiarrheal use, presence of abdominal mass, hematocrit and body weight. CDAI consists of eight factors, each summed after adjustment with a weighting factor. Total score ranges from 0 to 600 points. Higher scores indicate more severity. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Remission Based on the CDAI at Week 12 | Clinical remission is defined as a CDAI score of ≤150 points. CDAI assesses CD based on clinical signs such as number of liquid or very soft stools, abdominal pain, general wellbeing, extra-intestinal manifestations of CD, antidiarrheal use, presence of abdominal mass, hematocrit and body weight. CDAI consists of eight factors, each summed after adjustment with a weighting factor. Total score ranges from 0 to 600 points. Higher scores indicate more severity. | Week 12 | 
| Percentage of Participants Achieving 2-item Patient-reported Outcome Measure (PRO2) Remission at Weeks 12, 26, and 52 | Clinical remission based on PRO2 is defined as PRO2 score ≤8 from baseline. The PRO2 is comprised of the stool frequency and abdominal pain components of the CDAI. The PRO-2 score is the sum of the abdominal pain and stool frequency subscores of the CDAI score. The average daily number of liquid or very soft stools and abdominal pain score (with 0 indicating no pain and 3 indicating severe pain) are weighted according to the CDAI multiplication factors (2 for stool frequency and 5 for abdominal pain). A higher score indicates more frequent stools and more severe abdominal pain. | Weeks 12, 26 and 52 | 
| Change in PRO2 Score from Week 26 to 52 | The PRO2 is comprised of the stool frequency and abdominal pain components of the CDAI. The PRO-2 score is the sum of the abdominal pain and stool frequency subscores of the CDAI score. The average daily number of liquid or very soft stools and abdominal pain score (with 0 indicating no pain and 3 indicating severe pain) are weighted according to the CDAI multiplication factors (2 for stool frequency and 5 for abdominal pain). A higher score indicates more frequent stools and more severe abdominal pain. | Weeks 26 and 52 | 
| Percentage of Participants with Stool Frequency Remission at Weeks 12, 26, and 52 | Stool frequency remission is defined as average daily number of liquid or very soft stools ≤3 and not worse than baseline assessed as per the stool frequency subscore of the CDAI score. The average daily number is weighted according to the CDAI multiplication factor of 2 for stool frequency. A higher score indicates more frequent stools. | Weeks 12, 26, and 52 | 
| Percentage of Participants with Abdominal Pain Remission at Weeks 12, 26, and 52 | Abdominal pain remission is defined as abdominal pain score ≤1, and not worse than baseline assessed as per the abdominal pain subscore of the CDAI score. The abdominal pain score (with 0 indicating no pain and 3 indicating severe pain) is weighted according to the CDAI multiplication factor of 5. A higher score indicates more severe abdominal pain. | Weeks 12, 26, and 52 | 
| Percentage of Participants Achieving Endoscopic Remission Based on Simple Endoscopic Score for Crohn's Disease (SES-CD) at Weeks 26 and 52 | Endoscopic remission as per SES-CD is defined as SES-CD score from 0-2. SES-CD evaluates 4 endoscopic variables (ulcer size, percentage of surface area (SA) that is ulcerated, percentage of SA affected, and presence and type of narrowings in 5 colonic segments evaluated during ileocolonoscopy. Each variable is coded from 0 to 3 based on severity, where 0 is none or not severe and 3 is most severe case, with sum of scores for each variable ranging from 0 to 15, except for presence of narrowing. Presence of narrowing ranges from 0 to 11 since a severity of 3 represents a narrowing which a colonoscope cannot be passed and, thus, can only be observed once among the bowel segments. The overall SES-CD score ranges from 0 to 56 and is sum of 4 variables across 5 bowel segments. Higher scores indicate more severe disease. Percentage of participants achieving endoscopic remission based on SES-CD at either Week 26 or Week 52 will be reported in this outcome measure. | Weeks 26 and 52 | 
| Percentage of Participants Achieving Endoscopic Remission Based on SES-CD at Both Weeks 26 and 52 | Endoscopic remission as per SES-CD is defined as SES-CD score from 0-2. SES-CD evaluates 4 endoscopic variables (ulcer size, percentage of surface area (SA) that is ulcerated, percentage of SA affected, and presence and type of narrowings in 5 colonic segments evaluated during ileocolonoscopy. Each variable is coded from 0 to 3 based on severity, where 0 is none or not severe and 3 is most severe case, with sum of scores for each variable ranging from 0 to 15, except for presence of narrowing. Presence of narrowing ranges from 0 to 11 since a severity of 3 represents a narrowing which a colonoscope cannot be passed and, thus, can only be observed once among the bowel segments. The overall SES-CD score ranges from 0 to 56 and is sum of 4 variables across 5 bowel segments. Higher scores indicate more severe disease. Percentage of participants achieving endoscopic remission based on SES-CD at both Weeks 26 and 52 will be reported in this outcome measure. | Weeks 26 and 52 | 
| Percentage of Participants Exhibiting an Endoscopic Response Based on SES-CD at Weeks 26 and 52 | Endoscopic response is defined as SES-CD reduction by ≥50% from Baseline. SES-CD evaluates 4 endoscopic variables (ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and presence and type of narrowings in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). Each variable is coded from 0 to 3 based on severity, where 0 is none or not severe and 3 is the most severe case, with the sum of the scores for each variable ranging from 0 to 15, except for presence of narrowing. Presence of narrowing ranges from 0 to 11 since a severity of 3 represents a narrowing which a colonoscope cannot be passed and, thus, can only be observed once among the bowel segments. The overall SES-CD score ranges from 0 to 56 and is the sum of 4 variables across 5 bowel segments. Higher scores indicate more severe disease. | Weeks 26 and 52 | 
| Percentage of Participants in Deep Remission Based on the CDAI and SES-CD at Weeks 26 and 52 | Deep remission:CDAI <150 points and SES-CD 0-2. CDAI assesses CD per clinical signs such as number of liquid/soft stools,abdominal pain,general wellbeing,extra-intestinal manifestations of CD, antidiarrheal use,presence of abdominal mass, hematocrit and body weight. It has 8 factors each summed after adjustment with weighting factor; total score:0 to 600 points, higher scores=more severity. SES-CD evaluates 4 endoscopic variables(ulcer size, percentage of ulcerated surface area, percentage of affected surface area, and presence and type of narrowings in 5 colonic segments evaluated during ileocolonoscopy. Each variable is coded from 0=none or not severe to 3=most severe case; sum of the scores range from 0 to 15, except for narrowing. Presence of narrowing ranges from 0 to 11. Overall SES-CD score ranges from 0 to 56 and is the sum of 4 variables. Higher scores=more severe disease. Participants achieving deep remission at either Week 26 or 52 will be assessed in this outcome measure. | Weeks 26 and 52 | 
| Percentage of Participants in Deep Remission Based on the CDAI and SES-CD at Both Weeks 26 and 52 | Deep remission:CDAI <150 points and SES-CD 0-2. CDAI assesses CD per clinical signs such as number of liquid/soft stools,abdominal pain,general wellbeing,extra-intestinal manifestations of CD, antidiarrheal use,presence of abdominal mass, hematocrit and body weight. It has 8 factors each summed after adjustment with weighting factor; total score:0 to 600 points, higher scores=more severity. SES-CD evaluates 4 endoscopic variables(ulcer size, percentage of ulcerated surface area, percentage of affected surface area, and presence and type of narrowings in 5 colonic segments evaluated during ileocolonoscopy. Each variable is coded from 0=none or not severe to 3=most severe case; sum of the scores range from 0 to 15, except for narrowing. Presence of narrowing ranges from 0 to 11. Overall SES-CD score ranges from 0 to 56 and is the sum of 4 variables. Higher scores=more severe disease. Participants achieving deep remission at both Weeks 26 and 52 will be assessed in this outcome measure. | Weeks 26 and 52 | 
| Percentage of Participants Exhibiting a Clinical Response Based on the CDAI at Weeks 12, 26, and 52 | Clinical response is defined as ≥100-point decrease from Baseline in CDAI score. CDAI assesses CD based on clinical signs such as number of liquid or very soft stools, abdominal pain, general wellbeing, extra-intestinal manifestations of CD, antidiarrheal use, presence of abdominal mass, hematocrit and body weight. CDAI consist of eight factors, each summed after adjustment with a weighting factor. Total score ranges from 0 to 600 points. Higher scores indicate more severity. | Weeks 12, 26, and 52 | 
| Percentage of Participants Using Oral Corticosteroids at Baseline who have Discontinued Corticosteroids and are in Clinical Remission Based on the CDAI | Percentage of participants using oral corticosteroids at Baseline who have discontinued corticosteroids and are in clinical remission per CDAI will be reported. Clinical remission is defined as a CDAI score of ≤150 points. CDAI assesses CD based on clinical signs such as number of liquid or very soft stools, abdominal pain, general wellbeing, extra-intestinal manifestations of CD, antidiarrheal use, presence of abdominal mass, hematocrit and body weight. CDAI consist of eight factors, each summed after adjustment with a weighting factor. Total score ranges from 0 to 600 points. Higher scores indicate more severity. | Week 30 through Week 64 | 
| Percentage of Participants Achieving Complete Endoscopic Healing Based on SES-CD at Weeks 26 and 52 | Complete endoscopic healing is defined as SES-CD score ≤4 with a ≥2-point decrease from baseline and no individual subscore >1. SES-CD evaluates 4 endoscopic variables (ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and presence and type of narrowings in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). Each variable is coded from 0 to 3 based on severity, where 0 is none or not severe and 3 is the most severe case, with the sum of the scores for each variable ranging from 0 to 15, except for presence of narrowing. Presence of narrowing ranges from 0 to 11 since a severity of 3 represents a narrowing which a colonoscope cannot be passed and, thus, can only be observed once among the bowel segments. The overall SES-CD score ranges from 0 to 56 and is the sum of 4 variables across 5 bowel segments. Higher scores indicate more severe disease. | Weeks 26 and 52 | 
| Change in SES-CD from Baseline to Weeks 26 and 52 | SES-CD evaluates 4 endoscopic variables (ulcer size, percentage of the surface area that is ulcerated, percentage of the surface area affected, and presence and type of narrowings in 5 colonic segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). Each variable is coded from 0 to 3 based on severity, where 0 is none or not severe and 3 is the most severe case, with the sum of the scores for each variable ranging from 0 to 15, except for presence of narrowing. Presence of narrowing ranges from 0 to 11 since a severity of 3 represents a narrowing which a colonoscope cannot be passed and, thus, can only be observed once among the bowel segments. The overall SES-CD score ranges from 0 to 56 and is the sum of 4 variables across 5 bowel segments. Higher scores indicate more severe disease. | Baseline, Weeks 26 and 52 | 
| Percentage of Participants with First CD Exacerbation After 26 Weeks | CD exacerbation is defined as a >70-point increase in CDAI from the prior visit on 2 occasions separated by a 2-week interval, and either CRP above normal or fecal calprotectin [FCP] >250 micrograms per gram (μg/g). CDAI assesses CD based on clinical signs such as number of liquid or very soft stools, abdominal pain, general wellbeing, extra-intestinal manifestations of CD, antidiarrheal use, presence of abdominal mass, hematocrit and body weight. CDAI consist of eight factors, each summed after adjustment with a weighting factor. Total score ranges from 0 to 600 points. Higher scores indicate more severity. | Week 26 through Week 52 | 
| Change in FCP Concentrations from Baseline to Weeks 12, 26, 42, and 52 |  | Baseline, Weeks 12, 26, 42, and 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy