Ulcerative Colitis
Conditions
Keywords
Ulcerative Colitis, adalimumab
Brief summary
The purpose of the study is to demonstrate the efficacy and safety, and to assess the pharmacokinetics of adalimumab administered subcutaneously (SC) in pediatric subjects with moderate to severe ulcerative colitis (UC).
Interventions
BIOLOGICALAdalimumab
Subcutaneous (SC) injection
BIOLOGICALPlacebo
Subcutaneous (SC) injection
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of UC for at least 12 weeks prior to screening, confirmed by endoscopy with biopsy. * Active ulcerative colitis with a Mayo Score of 6 - 12 points and endoscopy subscore of 2 - 3 despite concurrent treatment with oral corticosteroids or immunosuppressants or both.
Exclusion criteria
* Subject with Crohn's disease (CD) or indeterminate colitis (IC). * Current diagnosis of fulminant colitis and/or toxic megacolon. * Subjects with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy. * Chronic recurring infections or active tuberculosis (TB).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period | Week 8 | The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 sub scores (stool frequency, rectal bleeding and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). A negative change in PMS indicates improvement. Clinical remission was defined as a PMS ≤ 2 and no individual subscore \> 1. |
| Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period | Week 52 | The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore \> 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | Week 52 | The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Clinical response per FMS is defined as a decrease in FMS ≥ 3 points and ≥ 30% from Baseline. |
| Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period | Week 52 | The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those participants with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Mucosal healing per Mayo endoscopy subscore is defined as a subscore of ≤ 1. |
| Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period | Week 52 | The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS remitters are defined as those participants with a PMS ≤ 2 and no individual subscore \> 1. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore \> 1. |
| Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | Week 52 | The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from baseline. Among participants receiving systemic corticosteroids at Baseline, corticosteroid-free clinical remission per FMS at Week 52 is defined as having discontinued systemic corticosteroids prior to Week 52 and being in FMS clinical remission at Week 52 (defined as Mayo Score ≤ 2 and no individual subscore \> 1). |
Countries
Australia, Austria, Belgium, Canada, Czechia, Hungary, Israel, Japan, New Zealand, Poland, Slovakia, Spain, United Kingdom, United States
Participant flow
Recruitment details
Prior to Protocol Amendment 4, participants were randomized 3:2 at baseline to adalimumab induction high dose or adalimumab induction standard dose. At Week 8, those demonstrating a clinical response per Partial Mayo Score (PMS) were randomized 2:2:1 to adalimumab maintenance standard dose, adalimumab maintenance high dose, or maintenance placebo.
Pre-assignment details
After Protocol Amendment 4, participants received adalimumab induction high dose open-label. At Week 8, those demonstrating a clinical response per PMS were randomized in a 1:1 ratio to adalimumab maintenance standard dose or adalimumab maintenance high dose. Integrated Study data includes data from both the Main Study and the Japan Sub-Study.
Participants by arm
| Arm | Count |
|---|---|
| Integrated Study (Main + Japan Sub- Study): I-SD Participants randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and matching placebo at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. | 32 |
| Integrated Study (Main + Japan Sub- Study): I-HD Participants randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. | 51 |
| Integrated Study (Main + Japan Sub- Study): I-HD-OL (After Amendment 4) participants assigned to open-label adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. | 18 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Induction Period | Adverse Event | 1 | 1 | 0 | 0 | 0 | 0 |
| Induction Period | Lack of Efficacy | 2 | 1 | 1 | 0 | 0 | 0 |
| Induction Period | Non-Responder at Week 8 | 4 | 4 | 0 | 0 | 0 | 0 |
| Induction Period | Requires Alternative/Prohibited Therapy | 1 | 1 | 1 | 0 | 0 | 0 |
| Induction Period | Withdrawal by Subject | 2 | 1 | 0 | 0 | 0 | 0 |
| Maintenance Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 5 | 2 |
| Maintenance Period | Requires Alternative/Prohibited Therapy | 0 | 0 | 0 | 1 | 1 | 0 |
| Maintenance Period | Subject Non-Compliance | 0 | 0 | 0 | 0 | 0 | 1 |
| Maintenance Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Integrated Study (Main + Japan Sub- Study): I-SD | Integrated Study (Main + Japan Sub- Study): I-HD | Integrated Study (Main + Japan Sub- Study): I-HD-OL |
|---|---|---|---|---|
| Age, Continuous | 14.1 years STANDARD_DEVIATION 2.9 | 14.7 years STANDARD_DEVIATION 2.66 | 13.8 years STANDARD_DEVIATION 3.06 | 13.8 years STANDARD_DEVIATION 2.82 |
| Endoscopy Subscore | 2.2 score on a scale STANDARD_DEVIATION 0.38 | 2.1 score on a scale STANDARD_DEVIATION 0.34 | 2.2 score on a scale STANDARD_DEVIATION 0.4 | 2.2 score on a scale STANDARD_DEVIATION 0.43 |
| Full Mayo Score (FMS) | 7.8 score on a scale STANDARD_DEVIATION 1.2 | 7.8 score on a scale STANDARD_DEVIATION 1.22 | 7.7 score on a scale STANDARD_DEVIATION 1.25 | 7.7 score on a scale STANDARD_DEVIATION 1.09 |
| Partial Mayo Score (PMS) | 5.6 score on a scale STANDARD_DEVIATION 1.17 | 5.7 score on a scale STANDARD_DEVIATION 1.14 | 5.5 score on a scale STANDARD_DEVIATION 1.24 | 5.5 score on a scale STANDARD_DEVIATION 1.06 |
| Physicians Global Assessment Subscore | 2.2 score on a scale STANDARD_DEVIATION 0.41 | 2.2 score on a scale STANDARD_DEVIATION 0.4 | 2.2 score on a scale STANDARD_DEVIATION 0.43 | 2.2 score on a scale STANDARD_DEVIATION 0.38 |
| Race/Ethnicity, Customized Asian | 9 Participants | 3 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Japanese | 8 Participants | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized No Ethnicity | 89 Participants | 29 Participants | 45 Participants | 15 Participants |
| Race/Ethnicity, Customized White | 88 Participants | 28 Participants | 45 Participants | 15 Participants |
| Rectal Bleeding Subscore | 1.5 score on a scale STANDARD_DEVIATION 0.91 | 1.4 score on a scale STANDARD_DEVIATION 0.93 | 1.5 score on a scale STANDARD_DEVIATION 0.88 | 1.4 score on a scale STANDARD_DEVIATION 0.97 |
| Sex: Female, Male Female | 51 Participants | 15 Participants | 23 Participants | 13 Participants |
| Sex: Female, Male Male | 50 Participants | 17 Participants | 28 Participants | 5 Participants |
| Stool Frequency Subscore | 1.9 score on a scale STANDARD_DEVIATION 0.83 | 2.1 score on a scale STANDARD_DEVIATION 0.78 | 1.8 score on a scale STANDARD_DEVIATION 0.88 | 1.9 score on a scale STANDARD_DEVIATION 0.73 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 51 | 0 / 18 | 0 / 33 | 0 / 36 | 0 / 12 | 0 / 101 |
| other Total, other adverse events | 13 / 32 | 16 / 51 | 14 / 18 | 15 / 33 | 20 / 36 | 10 / 12 | 65 / 101 |
| serious Total, serious adverse events | 5 / 32 | 4 / 51 | 1 / 18 | 5 / 33 | 5 / 36 | 1 / 12 | 22 / 101 |
Outcome results
Primary
Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period
The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 sub scores (stool frequency, rectal bleeding and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). A negative change in PMS indicates improvement. Clinical remission was defined as a PMS ≤ 2 and no individual subscore \> 1.
Time frame: Week 8
Population: Intent-to-Treat (ITT): all participants who received at least 1 dose of study drug during the Induction period; analyzed as enrolled/randomized. Non-responder imputation (NRI): missing data is imputed as not having met the endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Study: I-SD | Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period | 43.3 percentage of participants |
| Main Study: I-HD | Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period | 59.6 percentage of participants |
| Main Study: I-SD + I-HD | Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period | 53.2 percentage of participants |
| Main Study: I-HD-OL | Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period | 68.8 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD | Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period | 40.6 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD | Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period | 58.8 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD + I-HD | Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period | 51.8 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD-OL | Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period | 66.7 percentage of participants |
Comparison: Efficacy analysis was based on the Intent-To-Treat-Efficacy (ITT-E) population for the induction period. The ITT-E population was a subpopulation of the ITT population, which consisted of all participants who received at least one SC injection of the study medication during the induction period. Participants who received open-label high induction dose, because they enrolled after Protocol Amendment 4 was released, were excluded from the ITT-E population.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the Intent-To-Treat-Efficacy (ITT-E) population for the induction period. The ITT-E population was a subpopulation of the ITT population, which consisted of all participants who received at least one SC injection of the study medication during the induction period. Participants who received open-label high induction dose, because they enrolled after Protocol Amendment 4 was released, were excluded from the ITT-E population.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the Intent-To-Treat-Efficacy (ITT-E) population for the induction period. The ITT-E population was a subpopulation of the ITT population, which consisted of all participants who received at least one SC injection of the study medication during the induction period. Participants who received open-label high induction dose, because they enrolled after Protocol Amendment 4 was released, were excluded from the ITT-E population.p-value: 0.382rejective multiple test procedure
Comparison: Efficacy analysis was based on the Intent-To-Treat-Efficacy (ITT-E) population for the induction period. The ITT-E population was a subpopulation of the ITT population, which consisted of all participants who received at least one SC injection of the study medication during the induction period. Participants who received open-label high induction dose, because they enrolled after Protocol Amendment 4 was released, were excluded from the ITT-E population.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the Intent-To-Treat-Efficacy (ITT-E) population for the induction period. The ITT-E population was a subpopulation of the ITT population, which consisted of all participants who received at least one SC injection of the study medication during the induction period. Participants who received open-label high induction dose, because they enrolled after Protocol Amendment 4 was released, were excluded from the ITT-E population.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the Intent-To-Treat-Efficacy (ITT-E) population for the induction period. The ITT-E population was a subpopulation of the ITT population, which consisted of all participants who received at least one SC injection of the study medication during the induction period. Participants who received open-label high induction dose, because they enrolled after Protocol Amendment 4 was released, were excluded from the ITT-E population.p-value: 0.344rejective multiple test procedure
Primary
Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period
The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore \> 1.
Time frame: Week 52
Population: Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized at the beginning of the Maintenance phase. NRI: missing data is imputed as not having met the endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Study: I-SD | Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 33.3 percentage of participants |
| Main Study: I-HD | Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 29.0 percentage of participants |
| Main Study: I-SD + I-HD | Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 45.2 percentage of participants |
| Main Study: I-HD-OL | Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 37.1 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD | Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 33.3 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD | Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 27.3 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD + I-HD | Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 42.9 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD-OL | Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 35.3 percentage of participants |
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.382rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.344rejective multiple test procedure
Secondary
Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period
The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Clinical response per FMS is defined as a decrease in FMS ≥ 3 points and ≥ 30% from Baseline.
Time frame: Week 52
Population: Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized at the beginning of the Maintenance phase. NRI: missing data is imputed as not having met the endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Study: I-SD | Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 33.3 percentage of participants |
| Main Study: I-HD | Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 61.3 percentage of participants |
| Main Study: I-SD + I-HD | Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 67.7 percentage of participants |
| Main Study: I-HD-OL | Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 64.5 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD | Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 33.3 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD | Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 57.6 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD + I-HD | Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 65.7 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD-OL | Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 61.8 percentage of participants |
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001Chi-squared
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.008Chi-squared
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.038rejective multiple test procedure
Secondary
Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period
The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those participants with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Mucosal healing per Mayo endoscopy subscore is defined as a subscore of ≤ 1.
Time frame: Week 52
Population: Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized at the beginning of the Maintenance phase. NRI: missing data is imputed as not having met the endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Study: I-SD | Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 33.3 percentage of participants |
| Main Study: I-HD | Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 38.7 percentage of participants |
| Main Study: I-SD + I-HD | Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 51.6 percentage of participants |
| Main Study: I-HD-OL | Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 45.2 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD | Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 33.3 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD | Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 36.4 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD + I-HD | Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 48.6 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD-OL | Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 42.6 percentage of participants |
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.382rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.344rejective multiple test procedure
Secondary
Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period
The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS remitters are defined as those participants with a PMS ≤ 2 and no individual subscore \> 1. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore \> 1.
Time frame: Week 52
Population: Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized at the beginning of the Maintenance phase. Participants who were also Week 8 remitters. NRI: missing data is imputed as not having met the endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Study: I-SD | Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period | 37.5 percentage of participants |
| Main Study: I-HD | Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period | 42.9 percentage of participants |
| Main Study: I-SD + I-HD | Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period | 45.5 percentage of participants |
| Main Study: I-HD-OL | Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period | 44.2 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD | Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period | 37.5 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD | Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period | 42.9 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD + I-HD | Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period | 44.0 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD-OL | Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period | 43.5 percentage of participants |
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.292rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: <0.001rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.292rejective multiple test procedure
Secondary
Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period
The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from baseline. Among participants receiving systemic corticosteroids at Baseline, corticosteroid-free clinical remission per FMS at Week 52 is defined as having discontinued systemic corticosteroids prior to Week 52 and being in FMS clinical remission at Week 52 (defined as Mayo Score ≤ 2 and no individual subscore \> 1).
Time frame: Week 52
Population: mITT: all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized at the beginning of the Maintenance phase. Participants receiving systemic corticosteroids at baseline. NRI: missing data is imputed as not having met the endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main Study: I-SD | Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 40.0 percentage of participants |
| Main Study: I-HD | Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 30.8 percentage of participants |
| Main Study: I-SD + I-HD | Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 31.3 percentage of participants |
| Main Study: I-HD-OL | Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 31.0 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD | Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 40.0 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD | Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 26.7 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-SD + I-HD | Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 35.3 percentage of participants |
| Integrated Study (Main + Japan Sub-Study): I-HD-OL | Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period | 31.3 percentage of participants |
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.382rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 1rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 1rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.344rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.559rejective multiple test procedure
Comparison: Efficacy analysis was based on the modified Intent-To-Treat-Efficacy (mITT-E) population for the maintenance period. The mITT-E population was a subpopulation of the mITT population, where participants in M-PL arm were excluded.p-value: 0.815rejective multiple test procedure