Crohn's Disease
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to assess the effect of vedolizumab subcutaneous (vedolizumab SC) as maintenance treatment in participants with moderately to severely active CD who achieved clinical response following administration of vedolizumab intravenous (vedolizumab IV) induction therapy.
Detailed description
The drug being tested in this study is called vedolizumab SC. Vedolizumab SC is being tested to treat people who have moderate to severely active CD. This study will look at clinical remission, as well as enhanced clinical response and corticosteroid-free remission in participants with CD who receive vedolizumab SC maintenance therapy after having achieved a clinical response to vedolizumab IV induction therapy. The study will enroll approximately 824 participants. All participants will enter a 6 week Induction Phase where they will be administered open-label vedolizumab IV 300 mg via IV infusion at Week 0 (Day 1) and Week 2 (Day 15), and will then be assessed for a clinical response at Week 6. Participants who achieve a clinical response at Week 6 will be randomly assigned to one of the two treatment groups: * Vedolizumab SC 108 mg Maintenance Arm * Placebo SC Maintenance Arm Participants who do not achieve a clinical response will not be randomized into the Maintenance Period, and instead will receive a third infusion of vedolizumab IV 300 mg at Week 6. This multi-center trial will be conducted worldwide. The overall time to participate in this study is up to 71 weeks. Participants will make multiple visits to the clinic, plus a final visit 18 weeks after last dose of study drug for a follow-up assessment. Participants will also participate in a long-term safety follow-up, by phone, at 6 months after the last dose of study drug.
Interventions
DRUGVedolizumab SC 108 mg
Vedolizumab SC Injection.
DRUGPlacebo
Vedolizumab placebo-matching SC injection.
DRUGVedolizumab IV 300 mg
Vedolizumab IV Injection.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of CD established at least 3 months prior to screening by clinical and endoscopic evidence corroborated by a histopathology report. 2. Moderately to severely active CD as determined by a CDAI score of 220 to 450 and 1 of the following: * C-reactive protein (CRP) level greater than (\>) 2.87 milligram per liter (mg/L) OR * Ileocolonoscopy with photographic documentation of a minimum of 3 nonanastomotic ulcerations (each \>0.5 centimeter \[cm\] in diameter) or 10 aphthous ulcerations (involving a minimum of 10 contiguous cm of intestine) consistent with CD OR * Fecal calprotectin \>250 microgram per gram (mcg/g) stool during the screening period in conjunction with computed tomography enterography (CTE), magnetic resonance enterography (MRE), contrast-enhanced small bowel radiography, or wireless capsule endoscopy revealing CD ulcerations (aphthae not sufficient). 3. CD involvement of the ileum and/or colon, at a minimum. 4. Inadequate response with, loss of response to, or intolerance to corticosteroids, immunomodulators, or Tumor necrosis factor-alpha (TNF-α) antagonists.
Exclusion criteria
1. Evidence of abdominal abscess at Screening. 2. Extensive colonic resection, subtotal or total colectomy. 3. History of \>3 small bowel resections or diagnosis of short bowel syndrome. 4. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine. 5. Prior exposure to investigational or approved non-biologic therapies (example, cyclosporine, tacrolimus, thalidomide, or tofacitinib) for the treatment of underlying disease within 30 days or 5 half-lives of screening (whichever is longer). 6. Prior exposure to any investigational or approved biologic or biosimilar agent within 60 days or 5 half-lives of screening (whichever is longer). 7. Prior exposure to vedolizumab. 8. Surgical intervention for CD required at any time during the study. 9. History or evidence of adenomatous colonic polyps that have not been removed, or of colonic mucosal dysplasia. 10. Suspected or confirmed diagnosis of ulcerative colitis, indeterminate colitis, ischaemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis. 11. Active infections. 12. Chronic hepatitis B virus (HBV) or C (HCV) infection, tuberculosis (TB) (active or latent), or congenital or acquired immunodeficiency. HBV immune participants (that is, being hepatitis B surface antigen \[HBsAg\] negative and hepatitis B antibody positive) may, however, be included. 13. History of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Clinical Remission at Week 52 | Week 52 | Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) score less than or equal to (\<=) 150 at Week 52. A CDAI is a multi-item instrument which measures severity of active Crohn's Disease monitored over 7 days includes participant reported symptoms, physician-assessed signs, and laboratory markers. CDAI score is equal to (=) sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Enhanced Clinical Response at Week 52 | Week 52 | Enhanced clinical response is defined as a decrease from Baseline of greater than or equal to (\>=) 100 points in the CDAI score at Week 52. A CDAI is a multi-item instrument which measures severity of active CD monitored over 7 days includes participant reported symptoms, physician-assessed signs, and laboratory markers. CDAI score = Sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity. |
| Percentage of Participants Achieving Corticosteroid-free Remission at Week 52 | Week 52 | Corticosteroid-free remission is defined as participants using oral corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in clinical remission at Week 52. Clinical remission is defined as a CDAI score \<=150 at Week 52. CDAI score = Sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity. |
| Percentage of TNF-alpha Antagonist Naive Participants Achieving Clinical Remission at Week 52 | Week 52 | Clinical remission is defined as CDAI score \<=150 at Week 52. CDAI score = Sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity. |
Countries
Australia, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Czechia, Denmark, Estonia, Germany, Hungary, Israel, Italy, Japan, Lithuania, Mexico, Netherlands, Poland, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants with moderate to severe Crohn's disease (CD) took part in the study at 169 investigative sites in North America, South America, Western/Northern Europe, Central Europe, Eastern Europe, East Asia, and Africa/Australia from 04 Jan 2016 to 06 Aug 2019.
Pre-assignment details
Participants were enrolled in open-label (OL) induction phase to receive vedolizumab (VDZ) intravenous (IV). Participants with clinical response (CR) at Week 6 were randomized into double-blind maintenance phase to receive VDZ subcutaneous/placebo, and who did not achieve CR at Week 6 received 3rd infusion of OL VDZ IV and completed Week 14 visit.
Participants by arm
| Arm | Count |
|---|---|
| Induction Phase Only: Vedolizumab 300 mg IV Vedolizumab 300 mg, infusion, intravenously, once at Weeks 0, 2 in the open-label induction phase Participants who did not achieve clinical response at Week 6 received third infusion of vedolizumab 300 mg IV on Week 6. | 235 |
| Maintenance Phase: Induction IV + Placebo Vedolizumab placebo-matching injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Participants who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive placebo in maintenance phase. | 134 |
| Maintenance Phase: Induction IV + Vedolizumab 108 mg SC Vedolizumab 108 mg, injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Participants who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab injection subcutaneously in maintenance phase. | 275 |
| Total | 644 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Maintenance Phase | Adverse Event | 0 | 12 | 11 |
| Double-blind Maintenance Phase | Lack of Efficacy | 0 | 43 | 78 |
| Double-blind Maintenance Phase | Lost to Follow-up | 0 | 0 | 1 |
| Double-blind Maintenance Phase | Pregnancy | 0 | 0 | 1 |
| Double-blind Maintenance Phase | Randomized but not Treated | 0 | 1 | 0 |
| Double-blind Maintenance Phase | Reason not Specified | 0 | 1 | 2 |
| Double-blind Maintenance Phase | Withdrawal by Subject | 0 | 5 | 14 |
| Open-label Induction Phase | Adverse Event | 16 | 0 | 0 |
| Open-label Induction Phase | Lack of Efficacy | 8 | 0 | 0 |
| Open-label Induction Phase | Lost to Follow-up | 2 | 0 | 0 |
| Open-label Induction Phase | Pregnancy | 1 | 0 | 0 |
| Open-label Induction Phase | Protocol Violation | 5 | 0 | 0 |
| Open-label Induction Phase | Reason not Specified | 9 | 0 | 0 |
| Open-label Induction Phase | Withdrawal by Subject | 9 | 0 | 0 |
Baseline characteristics
| Characteristic | Induction Phase Only: Vedolizumab 300 mg IV | Total | Maintenance Phase: Induction IV + Vedolizumab 108 mg SC | Maintenance Phase: Induction IV + Placebo |
|---|---|---|---|---|
| Age, Continuous | 37.4 years STANDARD_DEVIATION 12.79 | 37.5 years STANDARD_DEVIATION 13.29 | 38.2 years STANDARD_DEVIATION 13.85 | 36.1 years STANDARD_DEVIATION 12.93 |
| Body Mass Index | 24.20 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.073 | 24.51 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.909 | 25.06 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.915 | 23.93 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.541 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 130 Participants | 60 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 185 Participants | 511 Participants | 213 Participants | 113 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 23 Participants | 46 Participants | 17 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 11 Participants | 7 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 207 Participants | 581 Participants | 250 Participants | 124 Participants |
| Sex: Female, Male Female | 119 Participants | 305 Participants | 118 Participants | 68 Participants |
| Sex: Female, Male Male | 116 Participants | 339 Participants | 157 Participants | 66 Participants |
| Smoking Classification Current smoker | 49 Participants | 129 Participants | 54 Participants | 26 Participants |
| Smoking Classification Ex-smoker | 46 Participants | 142 Participants | 73 Participants | 23 Participants |
| Smoking Classification Never smoked | 140 Participants | 373 Participants | 148 Participants | 85 Participants |
| Weight | 69.94 kilogram (kg) STANDARD_DEVIATION 18.403 | 71.68 kilogram (kg) STANDARD_DEVIATION 18.684 | 74.08 kilogram (kg) STANDARD_DEVIATION 18.994 | 69.79 kilogram (kg) STANDARD_DEVIATION 18.103 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 235 | 0 / 134 | 0 / 275 |
| other Total, other adverse events | 40 / 235 | 54 / 134 | 102 / 275 |
| serious Total, serious adverse events | 39 / 235 | 14 / 134 | 23 / 275 |
Outcome results
Primary
Percentage of Participants Achieving Clinical Remission at Week 52
Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) score less than or equal to (\<=) 150 at Week 52. A CDAI is a multi-item instrument which measures severity of active Crohn's Disease monitored over 7 days includes participant reported symptoms, physician-assessed signs, and laboratory markers. CDAI score is equal to (=) sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity.
Time frame: Week 52
Population: The full analysis set (FAS): All randomized participants who received at least 1 dose of study SC drug (placebo or VDZ). Participants who only received induction IV therapy and were not randomized into the maintenance phase were not included in FAS. Participants in this set were analyzed according to the treatment they were randomized to receive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maintenance Phase: Induction IV + Placebo | Percentage of Participants Achieving Clinical Remission at Week 52 | 34.3 percentage of participants |
| Maintenance Phase: Induction IV + Vedolizumab 108 mg SC | Percentage of Participants Achieving Clinical Remission at Week 52 | 48.0 percentage of participants |
Comparison: P-value was calculated by Cochran-Mantel-Haenszel (CMH) test stratified by electronic data capture (EDC) stratum according to concomitant use of corticosteroids, clinical remission status at Week 6, and previous TNF-alpha antagonist failure/exposed or concomitant immunomodulator use.p-value: 0.00895% CI: [3.8, 23.7]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving Corticosteroid-free Remission at Week 52
Corticosteroid-free remission is defined as participants using oral corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in clinical remission at Week 52. Clinical remission is defined as a CDAI score \<=150 at Week 52. CDAI score = Sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity.
Time frame: Week 52
Population: Participants from FAS, who used concomitant oral corticosteroid at Baseline. FAS had all participants who received at least 1 dose of SC drug. Participants who only received induction IV therapy and were not randomized into maintenance phase were not included in FAS. Participants were analyzed according to randomized treatment assignment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maintenance Phase: Induction IV + Placebo | Percentage of Participants Achieving Corticosteroid-free Remission at Week 52 | 18.2 percentage of participants |
| Maintenance Phase: Induction IV + Vedolizumab 108 mg SC | Percentage of Participants Achieving Corticosteroid-free Remission at Week 52 | 45.3 percentage of participants |
Comparison: P-value was calculated by CMH test stratified by EDC stratum according to concomitant use of corticosteroids, clinical remission status at Week 6, and previous TNF-alpha antagonist failure/exposed or concomitant immunomodulator use.p-value: 0.00295% CI: [11.9, 42.3]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving Enhanced Clinical Response at Week 52
Enhanced clinical response is defined as a decrease from Baseline of greater than or equal to (\>=) 100 points in the CDAI score at Week 52. A CDAI is a multi-item instrument which measures severity of active CD monitored over 7 days includes participant reported symptoms, physician-assessed signs, and laboratory markers. CDAI score = Sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity.
Time frame: Week 52
Population: The FAS included all randomized participants who received at least 1 dose of study SC drug (placebo or VDZ). Participants who only received induction IV therapy and were not randomized into the maintenance phase were not included in FAS. Participants in this set were analyzed according to the treatment they were randomized to receive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maintenance Phase: Induction IV + Placebo | Percentage of Participants Achieving Enhanced Clinical Response at Week 52 | 44.8 percentage of participants |
| Maintenance Phase: Induction IV + Vedolizumab 108 mg SC | Percentage of Participants Achieving Enhanced Clinical Response at Week 52 | 52.0 percentage of participants |
Comparison: P-value was calculated by CMH test stratified by EDC stratum according to concomitant use of corticosteroids, clinical remission status at Week 6, and previous TNF-alpha antagonist failure/exposed or concomitant immunomodulator use.p-value: 0.16795% CI: [-3, 17.5]Cochran-Mantel-Haenszel
Secondary
Percentage of TNF-alpha Antagonist Naive Participants Achieving Clinical Remission at Week 52
Clinical remission is defined as CDAI score \<=150 at Week 52. CDAI score = Sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity.
Time frame: Week 52
Population: Participants from FAS, who were TNF-alpha antagonist naïve and had clinical remission. FAS had all participants who received at least 1 dose of SC drug. Participants who only received induction IV therapy and were not randomized in maintenance phase were not included in FAS. Participants were analyzed according to randomized treatment assignment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maintenance Phase: Induction IV + Placebo | Percentage of TNF-alpha Antagonist Naive Participants Achieving Clinical Remission at Week 52 | 42.9 percentage of participants |
| Maintenance Phase: Induction IV + Vedolizumab 108 mg SC | Percentage of TNF-alpha Antagonist Naive Participants Achieving Clinical Remission at Week 52 | 48.6 percentage of participants |
Comparison: P-value was calculated by CMH test stratified by EDC stratum according to concomitant use of corticosteroids, clinical remission status at Week 6, and previous TNF-alpha antagonist failure/exposed or concomitant immunomodulator use.p-value: 0.59195% CI: [-11.6, 20.3]Cochran-Mantel-Haenszel