A Study of Vedolizumab With Tofacitinib in Adults With Ulcerative Colitis (UC)

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 tofacitinib in adults with moderate and severe ulcerative colitis (UC). Another aim is to learn about treatment with Vedolizumab alone after the double treatment. All participants will receive vedolizumab together with tofacitinib for 8 weeks and will be checked for response. Participants who show a response to the treatment after 8 weeks will be treated with vedolizumab alone for an additional 44 weeks. Each participant will be followed up for at least 26 weeks after the last dose of vedolizumab.

Detailed Description
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The drugs being tested in this study are called Vedolizumab and Tofacitinib. Vedolizumab and Tofacitinib dual targeted therapy is being tested to treat people with moderate to severe ulcerative colitis (UC) who have experienced inadequate response, loss of response or intolerance to no more than 2 prior tumor necrosis factor (TNF) antagonists. This study will look at the clinical remission in people who take Vedolizumab and Tofacitinib dual targeted therapy. The study will enroll approximately 65 patients. All the participants will be enrolled in a single treatment group to receive dual targeted treatment with Vedolizumab and Tofacitinib for the first 8 weeks: Vedolizumab 300 mg + Tofacitinib 10 mg Only those participants who show a clinical response at Week 8 will transition to Vedolizumab monotherapy for 44 weeks. This multi-center trial will be conducted in the United States and Canada. The overall duration of the study is up to 76 weeks. Participants will be followed up for 26 weeks after the last dose of the study drug for safety.

Official Title
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An Open-Label, Phase 4, Single-Arm, Multicenter Study to Evaluate the Induction of Response and Remission of Vedolizumab Dual Targeted Therapy With Tofacitinib in Adult Patients With Moderately to Severely Active Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Vedolizumab
* Drug: Tofacitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a confirmed diagnosis of UC established at least 3 months prior to screening, by clinical and endoscopic evidence and corroborated by a histopathology report. Has moderately to severely active UC as determined by a complete Mayo score [including physician's global assessment (PGA)] of 6 to 12 with a rectal bleeding subscore ≥>1 and a centrally assessed endoscopic subscore ≥2 at screening. Has evidence of UC extending proximally to the rectum [≥15 centimeter (cm) of involved colon]. Participants with extensive colitis or pancolitis of >8 years duration or left sided colitis >12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit. Participants with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age >50 years, or other known risk factors must be up to date on colorectal cancer surveillance. Has demonstrated an inadequate response to, loss of response to, or intolerance to no more than 2 TNF antagonists. If using corticosteroids must be on a stable dose of oral corticosteroids up to a maximum of 20 milligrams per day (mg/day) of prednisone or equivalent for at least 4 weeks prior to screening endoscopy and must be willing to follow a mandatory taper of corticosteroids from enrollment. Exclusion Criteria: Gastrointestinal Exclusion criteria: Has any of the following UC-related complications: Acute severe UC. The participant has had extensive colonic resection, subtotal or total colectomy. The participant has clinical evidence of abdominal abscess or toxic megacolon. The participant has had ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine. Short bowel syndrome. Has Crohn's colitis, indeterminate colitis, ischemic colitis, nonsteroidal anti-inflammatory drug (NSAID) induced colitis, idiopathic colitis (i.e, colitis not consistent with UC), radiation colitis, microscopic colitis, colonic mucosal dysplasia, or untreated bile acid malabsorption. Has uncontrolled primary sclerosing cholangitis. Infectious Disease Exclusion Criteria: Has any evidence of an active infection during screening. Has active or latent tuberculosis (TB), regardless of treatment history, as evidenced by any of the following: a. History of TB. b. A diagnostic TB test performed during screening that is positive, as defined by: i. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests or ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in subjects receiving the equivalent of >15 mg/day prednisone). A positive test for hepatitis B virus (HBV). A positive test for hepatitis C virus (HCV). Evidence of, or treatment for, Clostridium difficile infection or other intestinal pathogen within 28 days prior to first dose of study treatment. 7. Evidence of active Cytomegalovirus (CMV) infection at screening. Medication exclusion criteria: Has received immunomodulators (eg, 6-mercaptopurine, azathioprine, and methotrexate) within 4 weeks prior to first dose or immunosuppressants (eg, cyclosporine, tacrolimus) within 8 weeks prior to first dose. Any medicinal product, herbal medication, or natural health product which might interfere with cytochrome P450 genotype 3A4 (CYP3A4) within 2 weeks prior to enrollment. Has received any of the following medical therapies for UC: IV antibiotics within 8 weeks prior to enrollment. Any rectal therapy for treatment of UC within 2 weeks prior to screening endoscopy. NSAIDs as long-term treatment, defined as use for at least 4 days a week each month (>100 milligrams (mg) daily or acetaminophen and aspirin >325 mg daily.) Has received a live virus or live bacterial vaccine within 4 weeks prior to enrollment, or planned vaccination during the study and for 12 weeks after last dose. General Exclusion Criteria: Has any of the following cardiovascular or thrombotic conditions: Recent (within past 6 months) cerebrovascular accident, myocardial infarction, or coronary stenting. Recent (within past 6 months) moderate to severe congestive heart failure (New York Heart Association class III or IV). Prior history of thrombotic events, including deep vein thrombosis and pulmonary embolism. Known inherited conditions that predispose to hypercoagulability. History of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly. A surgical procedure requiring general anesthesia within 3 months prior to screening or is planning to undergo major surgery during the study period. Any investigational procedure ≤4 weeks prior to screening.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vedolizumab 300 mg + Tofacitinib 10 mg<br>Participants will receive Vedolizumab 300 mg , intravenous (IV) infusion, at Week 0, Week 2 and Week 6 along with Tofacitinib 10 mg, tablets, orally, twice daily from Week 0 to Week 8. Participants with clinical response at Week 8 will transition to receive vedolizumab 300 mg IV infusion every 8 weeks (Q8W) through Week 46. | Drug: Vedolizumab<br>* Vedolizumab IV infusions<br>* Other names: MLN0002;Drug: Tofacitinib<br>* Tofacitinib Tablets<br>* Other names: CP-550;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Remission at Week 8 Based on Complete Mayo Score | Clinical remission based on complete Mayo Score is where a participant achieves complete Mayo Score ≤2 points with no individual subscore >1 at Week 8. The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a Physician's Global Index (PGA) and Mayo endoscopic findings (MES). Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity. | At Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Remission at Week 52 Based on Complete Mayo Score | Clinical remission based on complete Mayo Score is where a participant achieves complete Mayo Score ≤2 points with no individual subscore >1 at Week 8. The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a Physician's Global Index (PGA) and Mayo endoscopic findings (MES). Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity | At Week 52 | 
| Percentage of Participants Achieving Clinical Remission at Weeks 8, 14, and 26 Based on Partial Mayo Score | Clinical remission based on complete Mayo Score is where a participant achieves complete Mayo Score ≤2 points with no individual subscore >1. Partial Mayo Score consists of 3 variables of the Mayo Clinic Score: stool frequency, rectal bleeding and PGA. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease. These scores are summed to give a total score range of 0 to 9 where higher scores indicate maximum disease activity.. | At Weeks 8, 14 and 26 | 
| Percentage of Participants Achieving Clinical Response at Weeks 2, 6, 8, 14, 26 and 52 Based on Complete or Partial Mayo Score | Clinical response based on complete Mayo Score is where a participant achieves a reduction in complete Mayo score of ≥3 points and ≥30% from Baseline or a partial Mayo score of ≥2 points and ≥25% from baseline, if the complete Mayo score was not performed at the visit with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a PGA and MES. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity. | At Weeks 2, 6, 8, 14, 26, and 52 | 
| Percentage of Participants Achieving Clinical Remission at Week 8 and Week 52 Based on Modified Mayo Score | Clinical remission based on modified Mayo Score is where a participant achieves component modified Mayo score of ≤2 with modified MES ≤1, rectal bleeding = 0, and stool frequency ≤1. Modified Mayo Score consists of 3 variables: stool frequency, rectal bleeding and MES. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease. These scores are summed to give a total score range of 0 to 9 where higher scores indicate maximum disease activity. | At Weeks 8 and 52 | 
| Percentage of Participants With Durable Clinical Remission at Week 8 and Week 52 | Durable clinical remission is defined as the clinical remission at Week 8 and Week 52. Clinical remission is defined as complete Mayo Score of ≤2 points and no individual subscore >1 point at Weeks 8 and 52. The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a PGA and MES. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity. | At Week 8 and Week 52 | 
| Percentage of Participants Using Oral Corticosteroids at Baseline Achieving Clinical Remission at Week 8 | Clinical remission is defined as complete Mayo Score of ≤2 points and no individual subscore >1 point at Week 8. The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a PGA and MES. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity. | At Week 8 | 
| Percentage of Participants With Corticosteroid-Free Clinical Remission at Week 8 | Corticosteroid-free clinical remission is where a participant achieves corticosteroid-free clinical remission at Week 8. Clinical remission is defined as complete Mayo Score of ≤2 points and no individual subscore >1 point at Week 8. The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a PGA and MES. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity. | At Week 8 | 
| Percentage of Participants Using Oral Corticosteroids at Baseline Achieving Clinical Remission at Week 52 | Clinical remission is defined as complete Mayo Score of ≤2 points and no individual subscore >1 point at Week 52. The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a PGA and MES. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity. | At Week 52 | 
| Percentage of Participants With Corticosteroid-Free Clinical Remission at Week 52 | Corticosteroid-free clinical remission is where a participant achieves corticosteroid-free clinical remission at Week 52, and was off corticosteroids at least 3 months prior to Week 52. Clinical remission is defined as complete Mayo Score of ≤2 points and no individual subscore >1 point at Week 8. The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a PGA and MES. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity. | At Week 52 | 
| Percentage of Participants Achieving Clinical Response at Week 8 | Clinical response based on complete Mayo Score is where a participant achieves a reduction in complete Mayo score of ≥3 points and ≥30% from Baseline with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a PGA and MES. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity. | At Week 8 | 
| Percentage of Participants With Mucosal Healing Based on MES at Week 52 | Mucosal healing is defined as MES ≤1 point at Week 52. MES is a subscale of the Mayo score, an instrument designed to measure disease activity of UC. The subscale is graded from 0 to 3 based on the findings on endoscopy were 0= Normal appearance of mucosa, 1=mild disease (erythema, decreased vascular pattern), 2=moderate disease (marked erythema, lack of vascular pattern, friability, erosions), 3=severe disease (spontaneous bleeding, ulceration). Higher scores indicate more severe disease. | At Week 52 | 
| Percentage of Participants With Histological Remission Based on Geboes Score at Week 52 | Histological remission is defined as Geboes score <2 at Week 52. The Geboes score is a histological grading system for assessing histological disease activity in UC. The Geboes score evaluates 7 histological features. It consists of 6 grades (0-6). Each of the grades is divided into subgrades, based on the severity of tissue abnormalities or the extent of inflammatory cell infiltration. The Geboes score ranges from 0.0 to 5.4, and higher grades are indicative of more severe disease activity. | At Week 52 | 
| Change in C-Reactive Protein Levels (CRP) From Baseline | CRP is a useful marker of inflammation in participants with inflammatory bowel disease (IBD). In participants with UC, elevated CRP has been associated with severe clinical activity | Baseline to Weeks 2, 6, 8, 14, 26, 42 and 52 | 
| Change in Fecal Calprotectin Concentrations From Baseline | Fecal calprotectin is a biomarker for intestinal inflammatory activity. | Baseline to Weeks 2, 6, 8, 14, 26, 42 and 52 | 
| Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Score From Baseline | The IBDQ is an instrument used to assess quality of life in adult participants with inflammatory bowel disease (IBD). It includes 32 questions on 4 domains of Health-Related Quality-of-Life (HRQOL): Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic Function (5 items). Participants are asked to recall symptoms and quality of life from the last 2 weeks and rate each item on a 7-point Likert scale (1=worst to 7=best). A total IBDQ score is calculated by summing the scores from each domain; the total IBDQ score ranges from 32 to 224, with lower scores reflecting worse HRQOL. A positive change from Baseline indicates improvement. | At Weeks 8, 26 and 52 | 
| Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline | The FACIT-F is a validated, 13-item questionnaire to assess fatigue in participants with a variety of chronic illnesses, including participants with IBD. Items are rated on a 5-point Likert scale and the total score ranges from 0 to 52 with lower scores representing greater fatigue. | At Weeks 8, 26 and 52 | 
| Number of Participants With Adverse Events (AEs), Adverse Events of Special Interest (AESIs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of the study intervention, whether or not the occurrence is considered related to the study intervention. | Up to 76 Weeks | 
| Number of Participants With Clinically Significant Change in Vital Signs From Baseline | Vital signs will include body temperature, respiratory rate, blood pressure (resting more than 5 minutes), and pulse (resting more than 5 minutes). | Up to 76 Weeks | 
| Number of Participants With Clinically Significant Physical Examination Findings | A baseline physical examination (defined as the assessment before first dose of study medication) will consist of the following body systems: general appearance; HEENT (head, eyes, ears, nose, and throat); cardiovascular system; respiratory system; gastrointestinal system; dermatologic system; extremities; musculoskeletal system; nervous system; lymph nodes; and other. All subsequent physical examinations will assess clinically significant changes from the assessment prior to first dose examination. | At Baseline and From Week 14 to Week 72 | 
| Number of Participants With Markedly Abnormal Laboratory Values | Standard laboratory tests will include clinical chemistry, hematology, coagulation and urinalysis. | Up to Week 76 | 

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