Colitis, Ulcerative
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to evaluate the efficacy and safety of vedolizumab intravenous (IV) treatment compared to adalimumab subcutaneous (SC) treatment over a 52-week treatment period.
Detailed description
The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who have ulcerative colitis. This study will look at the stool frequency, rectal bleeding and findings on endoscopy of people who take vedolizumab compared to those who take adalimumab. The study will enroll approximately 658 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): * Vedolizumab 300 mg IV * Adalimumab 160 mg on Day 1 followed by 80 mg on Week 2 then 40 mg every 2 weeks SC All participants will receive 1 intravenous infusion on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. All participants will also receive 4 SC injections on Day 1 or 2 SC injections each on Days 1 and 2, followed by 2 SC injections in 1 day on Week 2 and then 1 SC injection every 2 weeks for up to Week 50. All participants will be asked to record the symptoms of ulcerative colitis in a daily diary. This multi-center trial will be conducted worldwide. The overall time to participate in this study is 79 weeks. Participants will make approximately 11 visits to the clinic, and will be contacted by telephone 6 months after last dose of study drug for a follow-up assessment.
Interventions
DRUGVedolizumab
Vedolizumab infusion
Adalimumab placebo-matching injection
DRUGAdalimumab
Adalimumab injection
Vedolizumab placebo-matching infusion
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Has a diagnosis of ulcerative colitis established at least 3 months prior to screening by clinical and endoscopic evidence and corroborated by a histopathology report. 2. Has moderately to severely active ulcerative colitis as determined by a Mayo score of 6 to 12 with an endoscopic subscore greater than or equal to \>=2 within 14 days prior to the randomization. 3. Has evidence of ulcerative colitis proximal to the rectum (\>=15 centimeter \[cm\] of involved colon). 4. With extensive colitis (up to the hepatic flexure) or pancolitis of \>8 years duration or left-sided colitis of \>12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit (may be performed during the Screening Period). 5. The participant: 1. Has had previous treatment with tumor necrosis factor- alpha (TNF-alpha) antagonists without documented clinical response to treatment (example, due to lack of response \[primary nonresponders\], loss of response, or intolerance \[secondary nonresponders\]), or 2. Has previously used a TNF-alpha antagonists (except adalimumab), and discontinued its use due to reasons other than safety, or 3. Is naïve to TNF-alpha antagonist therapy but is failing current treatment (example, corticosteroids, 5-aminosalicylate \[5-ASA\], or immunomodulators).
Exclusion criteria
1. Clinical evidence of abdominal abscess or toxic megacolon at Screening. 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 randomization: 1. Non-biologic therapies (example, cyclosporine, tacrolimus, thalidomide) other than those specifically listed in Section Permitted Medications For Treatment of UC. 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 the screening (whichever is longer). 7. Has previously received natalizumab, efalizumab, adalimumab, AMG-181, anti-mucosal addressin cell adhesion molecule-1 antibodies, or rituximab. 8. Has previously received vedolizumab. 9. Has history or evidence of adenomatous colonic polyps that have not been removed, or colonic mucosal dysplasia. 10. Evidence of an active infection during Screening. 11. Evidence of, or treatment for, Clostridium difficile (C. difficile) or other intestinal pathogen within 28 days prior to the 1st dose of study drug. 12. Has chronic hepatitis B virus (HBV) infection\* or chronic hepatitis C virus (HCV) infection (\* HBV immune participants, ie, being hepatitis B surface antigen \[HBsAg\], may participate). 13. Has active or latent TB, regardless of treatment history. 14. Has used a topical (rectal) treatment with (5-ASA) or corticosteroid enemas/suppositories within 2 weeks of the administration of the 1st dose of study drug. 15. Has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist prior to the administration of the first dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Clinical Remission | Week 52 | Clinical remission was defined as a complete Mayo score of ≤2 points and no individual subscore \>1 point. The Mayo score was a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consisted of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore was scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Mucosal Healing | Week 52 | Mucosal healing was defined as a Mayo score endoscopic subscore of \<= 1 point. The Mayo score was a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consisted of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore was scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). |
| Percentage of Participants Who Used Oral Corticosteroids at Baseline Who Discontinued Corticosteroids and Were in Clinical Remission | Week 52 | Corticosteroid-free remission was defined as participants using oral corticosteroids at Baseline (Week 0) who had discontinued oral corticosteroids and were in clinical remission at Week 52. Clinical remission was defined as a complete Mayo score of ≤ 2 points and no individual subscore \> 1 point. The Mayo score was a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consisted of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore was scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). |
Countries
Argentina, Australia, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Colombia, Croatia, Czechia, Denmark, Estonia, France, Germany, Hong Kong, Hungary, Israel, Italy, Latvia, Lithuania, Mexico, Netherlands, Poland, Portugal, Romania, Russia, Serbia, Slovakia, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 205 investigative sites worldwide from 29 June 2015 up to 18 January 2019.
Pre-assignment details
Participants with a diagnosis of moderately to severely active ulcerative colitis (UC) were enrolled in a 1:1 ratio to receive vedolizumab or adalimumab and matching placebo.
Participants by arm
| Arm | Count |
|---|---|
| Adalimumab SC, 160/80/40 mg Adalimumab 160 mg, injection, subcutaneously on Day 1, adalimumab 80 mg, injection, subcutaneously at Week 2, then adalimumab 40 mg, injection, subcutaneously every 2 weeks thereafter up to Week 50. Vedolizumab placebo-matching infusion, intravenously on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. | 386 |
| Vedolizumab IV 300 mg Vedolizumab 300 mg, infusion, intravenously over 30 minutes on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. Adalimumab placebo-matching injection, subcutaneously on Day 1, Week 2, and every 2 weeks thereafter up to Week 50. | 385 |
| Total | 771 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 86 | 40 |
| Overall Study | Leukopenia or Lymphopenia | 1 | 0 |
| Overall Study | Lost to Follow-up | 14 | 4 |
| Overall Study | Pregnancy | 1 | 1 |
| Overall Study | Pretreatment Event/Adverse Event | 18 | 16 |
| Overall Study | Randomized but not Treated | 0 | 2 |
| Overall Study | Reason not Specified | 6 | 6 |
| Overall Study | Significant Protocol Deviation | 4 | 5 |
| Overall Study | Voluntary Withdrawal | 39 | 41 |
Baseline characteristics
| Characteristic | Vedolizumab IV 300 mg | Adalimumab SC, 160/80/40 mg | Total |
|---|---|---|---|
| Age, Continuous | 40.8 years STANDARD_DEVIATION 13.74 | 40.5 years STANDARD_DEVIATION 13.44 | 40.7 years STANDARD_DEVIATION 13.59 |
| Body Mass Index (BMI) | 24.46 kg/m^2 STANDARD_DEVIATION 4.786 | 25.17 kg/m^2 STANDARD_DEVIATION 5.646 | 24.82 kg/m^2 STANDARD_DEVIATION 5.244 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 6 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 39 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 354 Participants | 341 Participants | 695 Participants |
| Female Reproductive Status Female of Childbearing Potential | 102 Participants | 123 Participants | 225 Participants |
| Female Reproductive Status Postmenopausal | 32 Participants | 29 Participants | 61 Participants |
| Female Reproductive Status Surgically Sterile | 17 Participants | 18 Participants | 35 Participants |
| Height | 172.0 cm STANDARD_DEVIATION 9.9 | 170.5 cm STANDARD_DEVIATION 9.65 | 171.3 cm STANDARD_DEVIATION 9.79 |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 11 Participants | 15 Participants |
| Race (NIH/OMB) Asian | 32 Participants | 30 Participants | 62 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 345 Participants | 341 Participants | 686 Participants |
| Region of Enrollment Argentina | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Australia | 5 Participants | 3 Participants | 8 Participants |
| Region of Enrollment Belgium | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Bosnia | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Bulgaria | 6 Participants | 10 Participants | 16 Participants |
| Region of Enrollment Canada | 20 Participants | 18 Participants | 38 Participants |
| Region of Enrollment Colombia | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Croatia | 5 Participants | 11 Participants | 16 Participants |
| Region of Enrollment Czech Republic | 8 Participants | 13 Participants | 21 Participants |
| Region of Enrollment Denmark | 3 Participants | 8 Participants | 11 Participants |
| Region of Enrollment France | 6 Participants | 4 Participants | 10 Participants |
| Region of Enrollment Germany | 6 Participants | 3 Participants | 9 Participants |
| Region of Enrollment Hong Kong | 4 Participants | 1 Participants | 5 Participants |
| Region of Enrollment Hungary | 16 Participants | 16 Participants | 32 Participants |
| Region of Enrollment Israel | 13 Participants | 9 Participants | 22 Participants |
| Region of Enrollment Italy | 11 Participants | 9 Participants | 20 Participants |
| Region of Enrollment Korea, Republic Of | 16 Participants | 19 Participants | 35 Participants |
| Region of Enrollment Latvia | 7 Participants | 6 Participants | 13 Participants |
| Region of Enrollment Lithuania | 7 Participants | 7 Participants | 14 Participants |
| Region of Enrollment Mexico | 3 Participants | 9 Participants | 12 Participants |
| Region of Enrollment Netherlands | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Poland | 85 Participants | 78 Participants | 163 Participants |
| Region of Enrollment Portugal | 4 Participants | 9 Participants | 13 Participants |
| Region of Enrollment Romania | 6 Participants | 6 Participants | 12 Participants |
| Region of Enrollment Russia | 44 Participants | 41 Participants | 85 Participants |
| Region of Enrollment Serbia | 18 Participants | 11 Participants | 29 Participants |
| Region of Enrollment Slovakia | 8 Participants | 5 Participants | 13 Participants |
| Region of Enrollment Spain | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Taiwan, Province Of China | 1 Participants | 4 Participants | 5 Participants |
| Region of Enrollment Turkey | 5 Participants | 9 Participants | 14 Participants |
| Region of Enrollment Ukraine | 39 Participants | 26 Participants | 65 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment United States | 29 Participants | 42 Participants | 71 Participants |
| Sex: Female, Male Female | 151 Participants | 170 Participants | 321 Participants |
| Sex: Female, Male Male | 234 Participants | 216 Participants | 450 Participants |
| Smoking Classification Has Never Smoked | 280 Participants | 259 Participants | 539 Participants |
| Smoking Classification Is a Current Smoker | 19 Participants | 23 Participants | 42 Participants |
| Smoking Classification Is an Ex-smoker | 84 Participants | 104 Participants | 188 Participants |
| Smoking Classification Missing | 2 Participants | 0 Participants | 2 Participants |
| Weight | 72.67 kg STANDARD_DEVIATION 16.952 | 73.43 kg STANDARD_DEVIATION 18.374 | 73.05 kg STANDARD_DEVIATION 17.673 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 386 | 1 / 383 |
| other Total, other adverse events | 114 / 386 | 103 / 383 |
| serious Total, serious adverse events | 53 / 386 | 42 / 383 |
Outcome results
Primary
Percentage of Participants Who Achieved Clinical Remission
Clinical remission was defined as a complete Mayo score of ≤2 points and no individual subscore \>1 point. The Mayo score was a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consisted of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore was scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity).
Time frame: Week 52
Population: Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adalimumab SC, 160/80/40 mg | Percentage of Participants Who Achieved Clinical Remission | 22.5 percentage of participants |
| Vedolizumab IV 300 mg | Percentage of Participants Who Achieved Clinical Remission | 31.3 percentage of participants |
p-value: 0.006195% CI: [2.5, 15]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieved Mucosal Healing
Mucosal healing was defined as a Mayo score endoscopic subscore of \<= 1 point. The Mayo score was a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consisted of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore was scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity).
Time frame: Week 52
Population: FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adalimumab SC, 160/80/40 mg | Percentage of Participants Who Achieved Mucosal Healing | 27.7 percentage of participants |
| Vedolizumab IV 300 mg | Percentage of Participants Who Achieved Mucosal Healing | 39.7 percentage of participants |
p-value: 0.000595% CI: [5.3, 18.5]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Used Oral Corticosteroids at Baseline Who Discontinued Corticosteroids and Were in Clinical Remission
Corticosteroid-free remission was defined as participants using oral corticosteroids at Baseline (Week 0) who had discontinued oral corticosteroids and were in clinical remission at Week 52. Clinical remission was defined as a complete Mayo score of ≤ 2 points and no individual subscore \> 1 point. The Mayo score was a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consisted of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore was scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity).
Time frame: Week 52
Population: Particiopants from, FAS, included all randomized participants who received at least 1 dose of study drug who used who used oral corticosteroids at Baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adalimumab SC, 160/80/40 mg | Percentage of Participants Who Used Oral Corticosteroids at Baseline Who Discontinued Corticosteroids and Were in Clinical Remission | 21.8 percentage of participants |
| Vedolizumab IV 300 mg | Percentage of Participants Who Used Oral Corticosteroids at Baseline Who Discontinued Corticosteroids and Were in Clinical Remission | 12.6 percentage of participants |
p-value: 0.064195% CI: [-18.9, 0.4]Cochran-Mantel-Haenszel