Ulcerative Colitis
Conditions
Brief summary
The primary purpose of this study was to determine the effect of vedolizumab induction treatment on clinical response at 6 weeks and to determine the effect of vedolizumab maintenance treatment on clinical remission at 52 weeks.
Detailed description
This multicenter, phase 3, randomized, blinded, placebo-controlled study in patients with moderately to severely active ulcerative colitis comprises two phases: * The Induction Phase, designed to establish the efficacy and safety of vedolizumab for the induction of clinical response and remission. * The Maintenance Phase, designed to establish the efficacy and safety of vedolizumab for the maintenance of clinical response and remission. The 6-week Induction Phase contained 2 cohorts of participants: Cohort 1 participants were randomized and treated with double-blind study drug, and Cohort 2 participants were treated with open-label vedolizumab. The second cohort was enrolled to ensure that the sample size of Induction Phase responders randomized into the Maintenance Study provided sufficient power for the Maintenance Study primary efficacy analysis. These participants did not contribute to the efficacy analyses performed for the Induction Study. Participants in both cohorts were assessed for treatment response at Week 6. In the Maintenance Phase vedolizumab-treated participants from both Cohort 1 and Cohort 2 who demonstrated a clinical response were randomized in a 1:1:1 ratio to double-blind treatment with vedolizumab administered every 4 weeks (Q4W), vedolizumab administered every 8 weeks (Q8W), or placebo. Vedolizumab-treated participants who did not demonstrate response at Week 6 continued treatment with open-label vedolizumab, administered Q4W. Participants treated with double-blind placebo in the Induction Phase continued on double-blind placebo during the Maintenance Phase, regardless of treatment response during induction. The Maintenance Phase began at Week 6 and concluded with Week 52 assessments. After the Week 52 assessments, participants meeting protocol-defined criteria were eligible to enroll in Study C13008 (NCT00790933; Long-term Safety) to receive open-label vedolizumab treatment. Participants who withdrew early (prior to Week 52) due to sustained nonresponse, disease worsening, or the need for rescue medications may also have been eligible for Study C13008. Participants who did not enroll into Study C13008 were to complete a final on-study safety assessment at Week 66 (or final safety visit 16 weeks after the last dose) in the Maintenance Phase of Study C13006.
Interventions
DRUGvedolizumab
Vedolizumab for intravenous infusion
OTHERPlacebo
Placebo intravenous infusion
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 1. Diagnosis of moderately to severely active ulcerative colitis 2. Demonstrated, over the previous 5 year period, an inadequate response to, loss of response to, or intolerance at least 1 of the following agents: 1. Immunomodulators 2. Tumor necrosis factor-alpha (TNFα) antagonists 3. Corticosteroids 3. May be receiving a therapeutic dose of conventional therapies for inflammatory bowel disease (IBD) as defined by the protocol
Exclusion criteria
1. Evidence of abdominal abscess at the initial screening visit 2. Extensive colonic resection, subtotal or total colectomy 3. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine 4. Have received non permitted IBD therapies within either 30 or 60 days, depending on the medication, as stated in the protocol 5. Chronic hepatitis B or C infection 6. Active or latent tuberculosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Induction Phase: Percentage of Participants With a Clinical Response at Week 6 | Baseline and Week 6 | Clinical response is defined as 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 Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving clinical response. |
| Maintenance Phase: Percentage of Participants in Clinical Remission at Week 52 | Week 52 | Clinical Remission is defined as a complete Mayo score of ≤ 2 points and no individual subscore \> 1 point. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving clinical remission. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maintenance Phase: Percentage of Participants With Durable Clinical Response | Baseline, Week 6 and Week 52 | Durable clinical response is defined as reduction in complete Mayo score of ≥ 3 points and ≥ 30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 1 point at both Weeks 6 and 52. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving durable clinical response. |
| Maintenance Phase: Percentage of Participants With Mucosal Healing at Week 52 | Week 52 | Mucosal healing is defined as a Mayo endoscopic subscore of ≤ 1 point. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Endoscopic findings were scored on a scale from 0 to 3 as follows: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern, mild friability); 2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). All participants who prematurely discontinued for any reason were considered as not achieving mucosal healing. |
| Induction Phase: Percentage of Participants in Clinical Remission at Week 6 | Week 6 | Clinical Remission is defined as a complete Mayo score of ≤ 2 points and no individual subscore \> 1 point. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving clinical remission. |
| Maintenance Phase: Percentage of Participants With Corticosteroid-free Remission at Week 52 | Week 52 | Clinical Remission is defined as a complete Mayo score of ≤ 2 points and no individual subscore \> 1 point. Corticosteroid-free clinical remission is defined as participants using oral corticosteroids at baseline (Week 0) who discontinued corticosteroids and were in clinical remission at Week 52. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving corticosteroid-free remission. |
| Maintenance Phase: Percentage of Participants With Durable Clinical Remission | Week 6 and Week 52 | Durable clinical remission is defined as complete Mayo score of ≤ 2 points and no individual subscore \> 1 point at both Weeks 6 and 52. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving durable clinical remission. |
| Induction Phase: Percentage of Participants With Mucosal Healing at Week 6 | Week 6 | Mucosal healing is defined as a Mayo endoscopic subscore of ≤ 1 point. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Endoscopic findings were scored on a scale from 0 to 3 as follows: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern, mild friability); 2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). All participants who prematurely discontinued for any reason were considered as not achieving mucosal healing. |
Countries
Canada, Puerto Rico, United States
Participant flow
Recruitment details
Participants took part in the study at 211 investigative sites worldwide. The Induction Phase contained 2 cohorts. The eligibility criteria for both cohorts were identical. The purpose of Cohort 2 was to provide enough responders to power the Maintenance Phase primary efficacy analysis.
Pre-assignment details
In Cohort 1, eligible patients who met entry criteria were randomized to treatment with double-blind vedolizumab 300 mg or placebo in a 3:2 ratio. All Cohort 2 patients were treated with open-label vedolizumab. In the Maintenance Phase participants were assigned to treatment groups based on their Induction Phase treatment and response to therapy.
Participants by arm
| Arm | Count |
|---|---|
| Placebo In the Induction Phase participants in Cohort 1 were randomized to receive double-blind placebo intravenous infusions at Week 0 and Week 2. Participants continued to receive placebo every 4 weeks from Week 6 through Week 50 during the Maintenance Phase, regardless of treatment response during induction. | 149 |
| Induction Phase: DB Vedolizumab In the Induction Phase participants in Cohort 1 were randomized to receive double-blind vedolizumab 300 mg, administered by intravenous infusion at Week 0 and Week 2. | 225 |
| Induction Phase: OL Vedolizumab In the Induction Phase participants in Cohort 2 received open-label vedolizumab 300 mg, administered by intravenous infusion at Week 0 and Week 2. | 521 |
| Total | 895 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Induction Phase | Adverse Event | 4 | 0 | 7 | 0 | 0 | 0 | 0 |
| Induction Phase | Lack of Efficacy | 5 | 2 | 14 | 0 | 0 | 0 | 0 |
| Induction Phase | Lost to Follow-up | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Induction Phase | Protocol Violation | 1 | 1 | 6 | 0 | 0 | 0 | 0 |
| Induction Phase | Withdrawal by Subject | 3 | 4 | 8 | 0 | 0 | 0 | 0 |
| Maintenance Phase | Adverse Event | 12 | 0 | 0 | 15 | 7 | 6 | 16 |
| Maintenance Phase | Lack of Efficacy | 83 | 0 | 0 | 61 | 31 | 33 | 155 |
| Maintenance Phase | Lost to Follow-up | 3 | 0 | 0 | 0 | 2 | 0 | 2 |
| Maintenance Phase | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 | 2 |
| Maintenance Phase | Withdrawal by Subject | 6 | 0 | 0 | 2 | 5 | 2 | 20 |
Baseline characteristics
| Characteristic | Placebo | Total | Induction Phase: OL Vedolizumab | Induction Phase: DB Vedolizumab |
|---|---|---|---|---|
| Age, Continuous | 41.2 years STANDARD_DEVIATION 12.5 | 40.3 years STANDARD_DEVIATION 13.09 | 40.1 years STANDARD_DEVIATION 13.27 | 40.1 years STANDARD_DEVIATION 13.11 |
| Age, Customized < 35 | 53 participants | 353 participants | 214 participants | 86 participants |
| Age, Customized ≥ 35 | 96 participants | 542 participants | 307 participants | 139 participants |
| Age, Customized < 65 | 142 participants | 862 participants | 503 participants | 217 participants |
| Age, Customized ≥ 65 | 7 participants | 33 participants | 18 participants | 8 participants |
| Baseline Disease Activity Complete Mayo score < 6 | 5 participants | 25 participants | 14 participants | 6 participants |
| Baseline Disease Activity Complete Mayo score of 6 to 8 (inclusive) | 70 participants | 424 participants | 249 participants | 105 participants |
| Baseline Disease Activity Complete Mayo score of 9 to 12 (inclusive) | 74 participants | 446 participants | 258 participants | 114 participants |
| Baseline Fecal Calprotectin | 2369.9 μg/g STANDARD_DEVIATION 3258.82 | 1868.8 μg/g STANDARD_DEVIATION 2753.28 | 1442.7 μg/g STANDARD_DEVIATION 1855.61 | 2552.2 μg/g STANDARD_DEVIATION 3800.36 |
| Baseline Mayo Score | 8.6 units on a scale STANDARD_DEVIATION 1.68 | 8.6 units on a scale STANDARD_DEVIATION 1.75 | 8.6 units on a scale STANDARD_DEVIATION 1.76 | 8.5 units on a scale STANDARD_DEVIATION 1.78 |
| Body Mass Index (BMI) | 24.6 kg/m^2 STANDARD_DEVIATION 5.11 | 25.1 kg/m^2 STANDARD_DEVIATION 5.62 | 25.3 kg/m^2 STANDARD_DEVIATION 6.05 | 24.9 kg/m^2 STANDARD_DEVIATION 4.85 |
| Body Weight | 72.4 kg STANDARD_DEVIATION 17.65 | 73.4 kg STANDARD_DEVIATION 18.51 | 74.2 kg STANDARD_DEVIATION 19.32 | 72.4 kg STANDARD_DEVIATION 17.11 |
| Categorical Baseline Fecal Calprotectin > 250 to ≤ 500 μg/g | 20 participants | 122 participants | 82 participants | 20 participants |
| Categorical Baseline Fecal Calprotectin ≤ 250 μg/g | 27 participants | 158 participants | 94 participants | 37 participants |
| Categorical Baseline Fecal Calprotectin > 500 μg/g | 92 participants | 577 participants | 329 participants | 156 participants |
| Categorical Baseline Fecal Calprotectin Missing | 10 participants | 38 participants | 16 participants | 12 participants |
| Categorical Duration of Ulcerative Colitis ≥1 - < 3 years | 44 participants | 228 participants | 121 participants | 63 participants |
| Categorical Duration of Ulcerative Colitis < 1 year | 13 participants | 64 participants | 38 participants | 13 participants |
| Categorical Duration of Ulcerative Colitis ≥ 3 - < 7 years | 39 participants | 279 participants | 163 participants | 77 participants |
| Categorical Duration of Ulcerative Colitis ≥ 7 years | 53 participants | 322 participants | 197 participants | 72 participants |
| Categorical Duration of Ulcerative Colitis Missing | 0 participants | 2 participants | 2 participants | 0 participants |
| Disease Localization Extensive colitis | 18 participants | 109 participants | 66 participants | 25 participants |
| Disease Localization Left-sided colitis | 59 participants | 339 participants | 188 participants | 92 participants |
| Disease Localization Pancolitis | 50 participants | 331 participants | 198 participants | 83 participants |
| Disease Localization Proctosigmoiditis | 22 participants | 116 participants | 69 participants | 25 participants |
| Duration of Ulcerative Colitis | 7.1 years STANDARD_DEVIATION 7.25 | 6.9 years STANDARD_DEVIATION 6.39 | 7.2 years STANDARD_DEVIATION 6.61 | 6.1 years STANDARD_DEVIATION 5.08 |
| History of Extraintestinal Manifestations No | 105 participants | 597 participants | 341 participants | 151 participants |
| History of Extraintestinal Manifestations Yes | 44 participants | 298 participants | 180 participants | 74 participants |
| Race/Ethnicity, Customized Asian | 32 participants | 135 participants | 67 participants | 36 participants |
| Race/Ethnicity, Customized Black | 2 participants | 12 participants | 5 participants | 5 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 participants | 46 participants | 31 participants | 10 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 140 participants | 832 participants | 481 participants | 211 participants |
| Race/Ethnicity, Customized Not reported | 4 participants | 17 participants | 9 participants | 4 participants |
| Race/Ethnicity, Customized Other | 0 participants | 14 participants | 13 participants | 1 participants |
| Race/Ethnicity, Customized White | 115 participants | 734 participants | 436 participants | 183 participants |
| Region of Enrollment Australia | 7 participants | 53 participants | 29 participants | 17 participants |
| Region of Enrollment Austria | 4 participants | 19 participants | 12 participants | 3 participants |
| Region of Enrollment Belgium | 7 participants | 56 participants | 35 participants | 14 participants |
| Region of Enrollment Bulgaria | 2 participants | 6 participants | 3 participants | 1 participants |
| Region of Enrollment Canada | 16 participants | 92 participants | 62 participants | 14 participants |
| Region of Enrollment Czech Republic | 7 participants | 38 participants | 19 participants | 12 participants |
| Region of Enrollment Denmark | 2 participants | 14 participants | 5 participants | 7 participants |
| Region of Enrollment Estonia | 1 participants | 10 participants | 5 participants | 4 participants |
| Region of Enrollment France | 1 participants | 17 participants | 13 participants | 3 participants |
| Region of Enrollment Germany | 0 participants | 17 participants | 16 participants | 1 participants |
| Region of Enrollment Greece | 0 participants | 5 participants | 4 participants | 1 participants |
| Region of Enrollment Hong Kong | 0 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Hungary | 2 participants | 16 participants | 8 participants | 6 participants |
| Region of Enrollment Iceland | 0 participants | 3 participants | 2 participants | 1 participants |
| Region of Enrollment India | 18 participants | 58 participants | 24 participants | 16 participants |
| Region of Enrollment Ireland | 0 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Israel | 0 participants | 2 participants | 1 participants | 1 participants |
| Region of Enrollment Italy | 1 participants | 21 participants | 11 participants | 9 participants |
| Region of Enrollment Korea, Republic of | 5 participants | 41 participants | 26 participants | 10 participants |
| Region of Enrollment Latvia | 1 participants | 3 participants | 0 participants | 2 participants |
| Region of Enrollment Malaysia | 5 participants | 9 participants | 2 participants | 2 participants |
| Region of Enrollment Netherlands | 1 participants | 3 participants | 2 participants | 0 participants |
| Region of Enrollment New Zealand | 0 participants | 11 participants | 6 participants | 5 participants |
| Region of Enrollment Norway | 2 participants | 9 participants | 6 participants | 1 participants |
| Region of Enrollment Poland | 2 participants | 60 participants | 52 participants | 6 participants |
| Region of Enrollment Russian Federation | 9 participants | 49 participants | 25 participants | 15 participants |
| Region of Enrollment Singapore | 0 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment South Africa | 4 participants | 19 participants | 10 participants | 5 participants |
| Region of Enrollment Spain | 0 participants | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Switzerland | 2 participants | 6 participants | 3 participants | 1 participants |
| Region of Enrollment Turkey | 0 participants | 6 participants | 3 participants | 3 participants |
| Region of Enrollment United Kingdom | 2 participants | 6 participants | 4 participants | 0 participants |
| Region of Enrollment United States | 47 participants | 238 participants | 127 participants | 64 participants |
| Sex: Female, Male Female | 57 Participants | 370 Participants | 220 Participants | 93 Participants |
| Sex: Female, Male Male | 92 Participants | 525 Participants | 301 Participants | 132 Participants |
| Smoking Status Current smoker | 11 participants | 55 participants | 32 participants | 12 participants |
| Smoking Status Former smoker | 50 participants | 285 participants | 167 participants | 68 participants |
| Smoking Status Nonsmoker | 88 participants | 555 participants | 322 participants | 145 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 67 / 149 | 69 / 126 | 321 / 620 |
| serious Total, serious adverse events | 17 / 149 | 20 / 126 | 77 / 620 |
Outcome results
Primary
Induction Phase: Percentage of Participants With a Clinical Response at Week 6
Clinical response is defined as 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 Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving clinical response.
Time frame: Baseline and Week 6
Population: Induction Study Intent-to-treat (ITT) population which consisted of all randomized patients in Cohort 1 who received any amount of blinded study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Induction Phase: Percentage of Participants With a Clinical Response at Week 6 | 25.5 percentage of participants |
| DB Vedolizumab | Induction Phase: Percentage of Participants With a Clinical Response at Week 6 | 47.1 percentage of participants |
Comparison: The primary comparison of the Induction Phase was tested using the Cochran-Mantel-Haenszel (CMH) chi-square test at a 5% significance level, with stratification according to the stratification factors (concomitant use of oral corticosteroids and previous exposure to tumor necrosis factor alpha (TNFα) antagonists or concomitant immunomodulator \[6-mercaptopurine or azathioprine\] use).p-value: <0.000195% CI: [11.6, 31.7]Cochran-Mantel-Haenszel
Primary
Maintenance Phase: Percentage of Participants in Clinical Remission at Week 52
Clinical Remission is defined as a complete Mayo score of ≤ 2 points and no individual subscore \> 1 point. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving clinical remission.
Time frame: Week 52
Population: Maintenance Study ITT Population, defined as all randomized participants who received vedolizumab during the Induction Phase and met the protocol definition of clinical response at Week 6, as assessed by the investigator, were randomized, and received any amount of double-blind study drug in the Maintenance Phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Maintenance Phase: Percentage of Participants in Clinical Remission at Week 52 | 15.9 percentage of participants |
| DB Vedolizumab | Maintenance Phase: Percentage of Participants in Clinical Remission at Week 52 | 41.8 percentage of participants |
| Vedolizumab Q4W | Maintenance Phase: Percentage of Participants in Clinical Remission at Week 52 | 44.8 percentage of participants |
Comparison: The Hochberg method was applied to control the overall Type I error rate at a 5% significance level. If both P-values were ≤ 0.05, both dose regimens were to be declared significant. If 1 of the P-values for the 2 dose comparisons was \> 0.05, the other P-value was to be tested at the 0.025 level and declared significant only if the P-value was ≤ 0.025. If neither dose was declared significant for the primary endpoint, no further testing was to be conducted.p-value: <0.000195% CI: [14.9, 37.2]Cochran-Mantel-Haenszel
Comparison: The Hochberg method was applied to control the overall Type I error rate at a 5% significance level. If both P-values were ≤ 0.05, both dose regimens were to be declared significant. If 1 of the P-values for the 2 dose comparisons was \> 0.05, the other P-value was to be tested at the 0.025 level and declared significant only if the P-value was ≤ 0.025. If neither dose was declared significant for the primary endpoint, no further testing was to be conducted.p-value: <0.000195% CI: [17.9, 40.4]Cochran-Mantel-Haenszel
Secondary
Induction Phase: Percentage of Participants in Clinical Remission at Week 6
Clinical Remission is defined as a complete Mayo score of ≤ 2 points and no individual subscore \> 1 point. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving clinical remission.
Time frame: Week 6
Population: Induction Study ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Induction Phase: Percentage of Participants in Clinical Remission at Week 6 | 5.4 percentage of participants |
| DB Vedolizumab | Induction Phase: Percentage of Participants in Clinical Remission at Week 6 | 16.9 percentage of participants |
Comparison: To maintain the overall Type I error rate at 5%, the key secondary assessments were performed sequentially (closed sequential method). The first secondary endpoint was to be tested only if the primary comparison was significant and the second key secondary endpoint was to be tested only if the first secondary endpoint was significant for vedolizumab.p-value: 0.000995% CI: [4.7, 18.3]Cochran-Mantel-Haenszel
Secondary
Induction Phase: Percentage of Participants With Mucosal Healing at Week 6
Mucosal healing is defined as a Mayo endoscopic subscore of ≤ 1 point. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Endoscopic findings were scored on a scale from 0 to 3 as follows: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern, mild friability); 2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). All participants who prematurely discontinued for any reason were considered as not achieving mucosal healing.
Time frame: Week 6
Population: Induction Study ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Induction Phase: Percentage of Participants With Mucosal Healing at Week 6 | 24.8 percentage of participants |
| DB Vedolizumab | Induction Phase: Percentage of Participants With Mucosal Healing at Week 6 | 40.9 percentage of participants |
Comparison: To maintain the overall Type I error rate at 5%, the key secondary assessments were performed sequentially (closed sequential method). The first secondary endpoint was to be tested only if the primary comparison was significant and the second key secondary endpoint was to be tested only if the first secondary endpoint was significant for vedolizumab.p-value: 0.001295% CI: [6.4, 25.9]Cochran-Mantel-Haenszel
Secondary
Maintenance Phase: Percentage of Participants With Corticosteroid-free Remission at Week 52
Clinical Remission is defined as a complete Mayo score of ≤ 2 points and no individual subscore \> 1 point. Corticosteroid-free clinical remission is defined as participants using oral corticosteroids at baseline (Week 0) who discontinued corticosteroids and were in clinical remission at Week 52. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving corticosteroid-free remission.
Time frame: Week 52
Population: Maintenance Study ITT Population, participants who were on corticosteroids at Baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Maintenance Phase: Percentage of Participants With Corticosteroid-free Remission at Week 52 | 13.9 percentage of participants |
| DB Vedolizumab | Maintenance Phase: Percentage of Participants With Corticosteroid-free Remission at Week 52 | 31.4 percentage of participants |
| Vedolizumab Q4W | Maintenance Phase: Percentage of Participants With Corticosteroid-free Remission at Week 52 | 45.2 percentage of participants |
Comparison: To maintain the overall Type I error rate at 5% for the 2 dose regimen comparisons for each key secondary endpoint, the Hochberg method was used as described for the primary outcome measure. To further maintain the overall Type I error rate at 5%, the key secondary endpoints were also performed sequentially. The first was tested only if 1 or both of the primary comparisons were significant and the next endpoint was tested only if the previous endpoint was significant for at least 1 dose.p-value: 0.01295% CI: [3.9, 31.3]Cochran-Mantel-Haenszel
Comparison: To maintain the overall Type I error rate at 5% for the 2 dose regimen comparisons for each key secondary endpoint, the Hochberg method was used as described for the primary outcome measure. To further maintain the overall Type I error rate at 5%, the key secondary endpoints were also performed sequentially. The first was tested only if 1 or both of the primary comparisons were significant and the next endpoint was tested only if the previous endpoint was significant for at least 1 dose.p-value: <0.000195% CI: [16.6, 46.2]Cochran-Mantel-Haenszel
Secondary
Maintenance Phase: Percentage of Participants With Durable Clinical Remission
Durable clinical remission is defined as complete Mayo score of ≤ 2 points and no individual subscore \> 1 point at both Weeks 6 and 52. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving durable clinical remission.
Time frame: Week 6 and Week 52
Population: Maintenance Study ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Maintenance Phase: Percentage of Participants With Durable Clinical Remission | 8.7 percentage of participants |
| DB Vedolizumab | Maintenance Phase: Percentage of Participants With Durable Clinical Remission | 20.5 percentage of participants |
| Vedolizumab Q4W | Maintenance Phase: Percentage of Participants With Durable Clinical Remission | 24.0 percentage of participants |
Comparison: To maintain the overall Type I error rate at 5% for the 2 dose regimen comparisons for each key secondary endpoint, the Hochberg method was used as described for the primary outcome measure. To further maintain the overall Type I error rate at 5%, the key secondary endpoints were also performed sequentially. The first was tested only if 1 or both of the primary comparisons were significant and the next endpoint was tested only if the previous endpoint was significant for at least 1 dose.p-value: 0.007995% CI: [3.1, 20.5]Cochran-Mantel-Haenszel
Comparison: To maintain the overall Type I error rate at 5% for the 2 dose regimen comparisons for each key secondary endpoint, the Hochberg method was used as described for the primary outcome measure. To further maintain the overall Type I error rate at 5%, the key secondary endpoints were also performed sequentially. The first was tested only if 1 or both of the primary comparisons were significant and the next endpoint was tested only if the previous endpoint was significant for at least 1 dose.p-value: 0.000995% CI: [6.2, 24.4]Cochran-Mantel-Haenszel
Secondary
Maintenance Phase: Percentage of Participants With Durable Clinical Response
Durable clinical response is defined as reduction in complete Mayo score of ≥ 3 points and ≥ 30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 1 point at both Weeks 6 and 52. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity). All participants who prematurely discontinued for any reason were considered as not achieving durable clinical response.
Time frame: Baseline, Week 6 and Week 52
Population: Maintenance Study ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Maintenance Phase: Percentage of Participants With Durable Clinical Response | 23.8 percentage of participants |
| DB Vedolizumab | Maintenance Phase: Percentage of Participants With Durable Clinical Response | 56.6 percentage of participants |
| Vedolizumab Q4W | Maintenance Phase: Percentage of Participants With Durable Clinical Response | 52.0 percentage of participants |
Comparison: To maintain the overall Type I error rate at 5% for the 2 dose regimen comparisons for each key secondary endpoint, the Hochberg method was used as described for the primary outcome measure. To further maintain the overall Type I error rate at 5%, the key secondary endpoints were also performed sequentially. The first was tested only if 1 or both of the primary comparisons were significant and the next endpoint was tested only if the previous endpoint was significant for at least 1 dose.p-value: <0.000195% CI: [20.8, 44.7]Cochran-Mantel-Haenszel
Comparison: To maintain the overall Type I error rate at 5% for the 2 dose regimen comparisons for each key secondary endpoint, the Hochberg method was used as described for the primary outcome measure. To further maintain the overall Type I error rate at 5%, the key secondary endpoints were also performed sequentially. The first was tested only if 1 or both of the primary comparisons were significant and the next endpoint was tested only if the previous endpoint was significant for at least 1 dose.p-value: <0.000195% CI: [16.7, 40.3]Cochran-Mantel-Haenszel
Secondary
Maintenance Phase: Percentage of Participants With Mucosal Healing at Week 52
Mucosal healing is defined as a Mayo endoscopic subscore of ≤ 1 point. The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Endoscopic findings were scored on a scale from 0 to 3 as follows: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern, mild friability); 2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). All participants who prematurely discontinued for any reason were considered as not achieving mucosal healing.
Time frame: Week 52
Population: Maintenance Study ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Maintenance Phase: Percentage of Participants With Mucosal Healing at Week 52 | 19.8 percentage of participants |
| DB Vedolizumab | Maintenance Phase: Percentage of Participants With Mucosal Healing at Week 52 | 51.6 percentage of participants |
| Vedolizumab Q4W | Maintenance Phase: Percentage of Participants With Mucosal Healing at Week 52 | 56.0 percentage of participants |
Comparison: To maintain the overall Type I error rate at 5% for the 2 dose regimen comparisons for each key secondary endpoint, the Hochberg method was used as described for the primary outcome measure. To further maintain the overall Type I error rate at 5%, the key secondary endpoints were also performed sequentially. The first was tested only if 1 or both of the primary comparisons were significant and the next endpoint was tested only if the previous endpoint was significant for at least 1 dose.p-value: <0.000195% CI: [20.3, 43.8]Cochran-Mantel-Haenszel
Comparison: To maintain the overall Type I error rate at 5% for the 2 dose regimen comparisons for each key secondary endpoint, the Hochberg method was used as described for the primary outcome measure. To further maintain the overall Type I error rate at 5%, the key secondary endpoints were also performed sequentially. The first was tested only if 1 or both of the primary comparisons were significant and the next endpoint was tested only if the previous endpoint was significant for at least 1 dose.p-value: <0.000195% CI: [24.4, 48.3]Cochran-Mantel-Haenszel