HIBISCUS II: A Study Comparing the Efficacy and Safety of Etrolizumab With Adalimumab and Placebo in Participants With Moderate to Severe Ulcerative Colitis (UC) in Participants Naive to Tumor Necrosis Factor (TNF) Inhibitors
Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT02171429
Collaborator
(none)
358
90
3
66.3
4
0.1
Study Details
Study Description
Brief Summary
This Phase III, double-blind, placebo and active-comparator controlled, multicenter study will investigate the efficacy and safety of etrolizumab in induction of remission in participants with moderately to severely active ulcerative colitis (UC) who are naIve to tumor necrosis factor (TNF) inhibitors and refractory to or intolerant of prior immunosuppressant and/or corticosteroid treatment. In addition to this study, a second Phase III trial with identical study design (GA28948; NCT02163759) was independently conducted.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
358 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
Phase III, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy (Induction of Remission) and Safety of Etrolizumab Compared With Adalimumab and Placebo in Patients With Moderate to Severe Ulcerative Colitis Who Are Naive to TNF Inhibitors
Actual Study Start Date
:
Nov 14, 2014
Actual Primary Completion Date
:
Mar 2, 2020
Actual Study Completion Date
:
May 25, 2020
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo Participants will receive placebo matching to etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8. |
Other: Adalimumab Placebo
Placebo matching to adalimumab will be administered SC at Weeks 0, 2, 4, 6, and 8.
Other: Etrolizumab Placebo
Placebo matching to etrolizumab will be administered SC once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).
|
| Active Comparator: Adalimumab Participants will receive adalimumab up to Week 8 and placebo matching to etrolizumab up to Week 12. |
Drug: Adalimumab
Adalimumab 160 milligrams (mg) will be administered subcutaneously (SC) at Week 0; 80 mg SC at Week 2; 40 mg SC at Weeks 4, 6 and 8.
Other Names:
Other: Etrolizumab Placebo
Placebo matching to etrolizumab will be administered SC once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).
|
| Experimental: Etrolizumab Participants will receive etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8. |
Other: Adalimumab Placebo
Placebo matching to adalimumab will be administered SC at Weeks 0, 2, 4, 6, and 8.
Drug: Etrolizumab
Etrolizumab 105 mg will be administered SC every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants in Remission at Week 10 With Etrolizumab Compared With Placebo, as Determined by the Mayo Clinic Score (MCS), GA28949 Population [Week 10]
The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the Cochran-Mantel-Haenszel test adjusted the difference in remission rates and associated 95% confidence interval for the stratification factors.
Secondary Outcome Measures
- Percentage of Participants in Remission at Week 10 With Etrolizumab Compared With Adalimumab, as Determined by the MCS, GA28949 Population [Week 10]
The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and associated 95% confidence interval for the stratification factors.
- Percentage of Participants in Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population [Week 10]
The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and associated 95% confidence interval for the stratification factors.
- Percentage of Participants With Clinical Response at Week 10, as Determined by the MCS, GA28949 Population [Week 10]
The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Clinical Response was defined as: MCS ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9 or ≥10); the CMH test adjusted the differences in response rates and associated 95% CIs for the stratification factors.
- Percentage of Participants With Clinical Response at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population [Week 10]
The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Clinical Response was defined as: MCS ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9 or ≥10); the CMH test adjusted the differences in response rates and associated 95% CIs for the stratification factors.
- Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10, as Determined by the Mayo Endoscopy Subscore, GA28949 Population [Week 10]
Improvement in endoscopic appearance of the mucosa was defined as a Mayo Clinic Score (MCS) endoscopy subscore ≤1. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment.
- Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS Endoscopy Subscore, GA28948 & GA28949 Pooled Population [Week 10]
Improvement in endoscopic appearance of the mucosa was defined as a Mayo Clinic Score (MCS) endoscopy subscore ≤1. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment.
- Percentage of Participants in Endoscopic Remission at Week 10, as Determined by the MCS Endoscopy Subscore, GA28949 Population [Week 10]
Endoscopic remission was defined as a Mayo Clinic Score (MCS) endoscopy subscore of 0. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment.
- Percentage of Participants in Endoscopic Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS Endoscopy Subscore, GA28948 & GA28949 Pooled Population [Week 10]
Endoscopic remission was defined as a Mayo Clinic Score (MCS) endoscopy subscore of 0. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment.
- Percentage of Participants With Histologic Remission at Week 10, as Determined by the Nancy Histological Index, GA28949 Population [Week 10]
Histologic remission is defined by the resolution of neutrophilic inflammation (e.g., absence of neutrophils in the crypts and lamina propria), defined by a Nancy Histological Index (NHI) score of ≤1. The NHI score ranges from 0 to 4, with the following definitions for each grade: 0 is no histologically significant disease; 1 is chronic inflammatory infiltrate with no acute inflammatory infiltrate; and 2, 3, and 4 are mildly, moderately, and severely active disease, respectively. A small pool of central readers who were blinded to both treatment arm and timepoint performed the histologic scoring. The same reader scored all slides for a given participant based on biopsies from the most inflamed region of the sigmoid colon. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received rescue therapy prior to assessment. The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and 95% CI for the stratification factors.
- Percentage of Participants With Histologic Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the Nancy Histological Index, GA28948 & GA28949 Pooled Population [Week 10]
Histologic remission is defined by the resolution of neutrophilic inflammation (e.g., absence of neutrophils in the crypts and lamina propria), defined by a Nancy Histological Index (NHI) score of ≤1. The NHI score ranges from 0 to 4, with the following definitions for each grade: 0 is no histologically significant disease; 1 is chronic inflammatory infiltrate with no acute inflammatory infiltrate; and 2, 3, and 4 are mildly, moderately, and severely active disease, respectively. A small pool of central readers who were blinded to both treatment arm and timepoint performed the histologic scoring. The same reader scored all slides for a given participant based on biopsies from the most inflamed region of the sigmoid colon. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received rescue therapy prior to assessment. The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and 95% CI for the stratification factors.
- Change From Baseline in the MCS Rectal Bleeding Subscore at Week 6, GA28949 Population [Baseline, Week 6]
Rectal bleeding data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = no blood in the stool; 1 = streaks of blood with stool less than half the time; 2 = obvious blood with stool most of the time; 3 = blood alone passed. The Mayo Clinic Score (MCS) rectal bleeding subscore was calculated as the worst value of three days of daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline rectal bleeding (RB) subscore.
- Change From Baseline in the MCS Rectal Bleeding Subscore at Week 6 With Etrolizumab as Compared With Adalimumab, GA28948 & GA28949 Pooled Population [Baseline, Week 6]
Rectal bleeding data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = no blood in the stool; 1 = streaks of blood with stool less than half the time; 2 = obvious blood with stool most of the time; 3 = blood alone passed. The Mayo Clinic Score (MCS) rectal bleeding subscore was calculated as the worst value of three days of daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline rectal bleeding (RB) subscore.
- Change From Baseline in the MCS Stool Frequency Subscore at Week 6, GA28949 Population [Baseline, Week 6]
Stool frequency data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = normal number of stools; 1 = 1 to 2 more stools than normal; 2 = 3 to 4 more stools than normal; 3 = 5 or more stools than normal. The Mayo Clinic Score (MCS) stool frequency subscore was calculated as the average of three days daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline stool frequency (SF) subscore.
- Change From Baseline in the MCS Stool Frequency Subscore at Week 6 With Etrolizumab as Compared With Adalimumab, GA28948 & GA28949 Pooled Population [Baseline, Week 6]
Stool frequency data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = normal number of stools; 1 = 1 to 2 more stools than normal; 2 = 3 to 4 more stools than normal; 3 = 5 or more stools than normal. The Mayo Clinic Score (MCS) stool frequency subscore was calculated as the average of three days daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline stool frequency (SF) subscore.
- Change From Baseline in Ulcerative Colitis (UC) Bowel Movement Signs and Symptoms at Week 10, as Assessed by the UC Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS), GA28949 Population [Baseline, Week 10]
The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The bowel movement domain score ranges from 0 to 27, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors within the MMRM.
- Change From Baseline in Ulcerative Colitis Bowel Movement Signs and Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28948 & GA28949 Pooled Population [Baseline, Week 10]
The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The bowel movement domain score ranges from 0 to 27, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors within the MMRM.
- Change From Baseline in Ulcerative Colitis Functional Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28949 Population [Baseline, Week 10]
The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The functional symptoms domain score ranges from 0 to 12, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors in the MMRM.
- Change From Baseline in Ulcerative Colitis Functional Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28948 & GA28949 Pooled Population [Baseline, Week 10]
The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The functional symptoms domain score ranges from 0 to 12, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors in the MMRM.
- Percentage of Participants in Clinical Remission at Week 10, as Determined by the MCS, GA28949 Population [Week 10]
The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Clinical remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the differences in remission rates and associated 95% confidence intervals for the stratification factors.
- Percentage of Participants in Remission at Week 10 and Week 14, as Determined by the MCS, GA28949 Population [Weeks 10 and 14]
The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 or 14 assessments were missing or the participant received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the differences in remission rates and associated 95% confidence intervals for the stratification factors.
- Change From Baseline in Health-Related Quality of Life at Week 10, as Assessed by the Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score, GA28949 Population [Baseline, Week 10]
The IBDQ is a 32-item questionnaire containing four domains: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). An overall total IBDQ score was computed by summing the individual 32-item scores. The range for the IBDQ total score is 32 to 224, with higher scores denoting better health-related quality of life. The unadjusted mean and standard deviation for each study arm are reported. The change from baseline in the IBDQ score was analyzed using an ANCOVA model taking the stratification factors used at randomization into account (concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening [MCS ≤9/MCS ≥10]), and the baseline IBDQ score used as a covariate.
- Pharmacokinetics of Etrolizumab: Serum Concentration, GA28949 Population [Weeks 10 and 14]
Serum concentrations of etrolizumab were evaluated at the primary endpoint visit (Week 10) and the secondary endpoint visit (Week 14). Both time points were two weeks after the most recent dose.
- Number and Percentage of Participants With at Least One Adverse Event by Severity, According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0), GA28949 Population [From Baseline until the end of study (up to 26 weeks)]
An adverse event (AE) is any untoward medical occurrence in a clinical investigation in which a patient is administered a pharmaceutical product, regardless of causal attribution. The investigator independently assessed the severity and seriousness of each recorded AE. The AE severity grading scale for the NCI CTCAE v4.0 was used for assessing severity; any AE not specifically listed was rated according to the following grading scale from 1 to 5: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death. AEs of special interest included: elevated AST/ALT in combination with either elevated bilirubin or clinical jaundice; suspected transmission of infectious agent by the study drug; anaphylactic, anaphylactoid and systemic hypersensitivity reactions; and neurological signs, symptoms, and AEs that may suggest possible progressive multifocal leukoencephalopathy (PML).
- Number and Percentage of Participants by Marked Laboratory Abnormality Status for Hematology Parameters as a Shift Table From Baseline to Week 10, GA28949 Population [From Baseline up to Week 10]
Laboratory tests for hematology parameters were performed and values were compared with the Roche marked reference range. A marked abnormality was defined as a test result that was outside of the Roche marked reference range (labelled as 'High' or 'Low') and represented a clinically significant change from baseline. Not every laboratory abnormality qualified as an adverse event. A laboratory test result must have been reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment or a medical intervention; or was clinically significant in the investigator's judgment. The results are presented as a shift from the baseline status to the post-baseline (Week 10) status. Baseline was defined as the last available assessment prior to first receipt of study drug. The 'missing' status included participants with missing baseline or post-baseline values. Ery. = erythrocyte
- Number and Percentage of Participants by Marked Laboratory Abnormality Status for Chemistry Parameters as a Shift Table From Baseline to Week 10, GA28949 Population [From Baseline up to Week 10]
Laboratory tests for chemistry parameters were performed and values were compared with the Roche marked reference range. A marked abnormality was defined as a test result that was outside of the Roche marked reference range (labelled as 'High' or 'Low') and represented a clinically significant change from baseline. Not every laboratory abnormality qualified as an adverse event. A laboratory test result must have been reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment or a medical intervention; or was clinically significant in the investigator's judgment. The results are presented as a shift from the baseline status to the post-baseline (Week 10) status. Baseline was defined as the last available assessment prior to first receipt of study drug. The 'missing' status included participants with missing baseline or post-baseline values.
- Number and Percentage of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Anytime Post-Baseline, GA28949 Population [Pre-dose (0 hour) on Day 1 and Week 4, Week 10, Week 14, and early termination/end of safety follow-up (up to 26 weeks)]
Anti-drug antibody (ADA) serum samples were collected from participants and analyzed using validated assays. Participants were considered to be ADA positive post-baseline if they were ADA negative or had missing data at baseline, but developed an ADA response following etrolizumab drug exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be ADA negative if they were ADA negative or had missing data at baseline and all post-baseline samples were negative, or if they were ADA positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected).
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 80 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Diagnosis of ulcerative colitis (UC) established at least 3 months prior to randomization (Day 1)
-
Moderately to severely active UC as determined by the MCS
-
Naive to treatment with TNF inhibitor therapy
-
An inadequate response, loss of response, or intolerance to prior corticosteroid and/or immunosuppressant treatment
-
Background UC therapy may include oral 5-aminosalisylate (5-ASA), budesonide, oral corticosteroids, probiotics, azathioprine (AZA), 6-mercaptopurine (6MP), or methotrexate (MTX) if doses have been stable for:
-
AZA, 6-MP, MTX: 8 weeks immediately prior to randomization
-
5-ASA: 4 weeks immediately prior to randomization
-
Corticosteroids: 4 weeks immediately prior to randomization; if corticosteroids are being tapered, dose has to be stable for at least 2 weeks prior to randomization
-
Use of highly effective contraception method as defined by the protocol
-
Have received a colonoscopy within the past year or be willing to undergo a colonoscopy in lieu of a flexible sigmoidoscopy at screening
Exclusion Criteria:
Exclusion Criteria Related to Inflammatory Bowel Disease:
-
Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC
-
Past or present ileostomy or colostomy
-
Diagnosis of indeterminate colitis
-
Suspicion of ischemic colitis, radiation colitis, or microscopic colitis
-
Diagnosis of toxic megacolon within 12 months of initial screening visit
-
Any diagnosis of Crohn's disease
-
Past or present fistula or abdominal abscess
-
A history or current evidence of colonic mucosal dysplasia
-
Patients with any stricture (stenosis) of the colon
-
Patients with history or evidence of adenomatous colonic polyps that have not been removed
Exclusion Criteria Related to Prior or Concomitant Therapy:
-
Prior treatment with TNF-alpha antagonists
-
Any prior treatment with etrolizumab or other anti-integrin agents
-
Any prior treatment with rituximab
-
Any treatment with tofacitinib during screening
-
Any prior treatment with anti-adhesion molecules
-
Use of intravenous (IV) steroids within 30 days prior to screening with the exception of a single administration of IV steroid
-
Use of agents that deplete B or T cells
-
Use of anakinra, abatacept, cyclosporine, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks prior to randomization
-
Chronic nonsteroidal anti-inflammatory drug (NSAID) use
-
Patients who are currently using anticoagulants including, but not limited to, warfarin, heparin, enoxaparin, dabigatran, apixaban, rivaroxaban
-
Patients who have received treatment with corticosteroid enemas/suppositories and/or topical (rectal) 5-ASA preparations within 2 weeks prior to randomization
-
Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to randomization
-
Received any investigational treatment including investigational vaccines within 5 half lives of the investigational product or 28 days after the last dose, whichever is greater, prior to randomization
-
History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to etrolizumab (active drug substance) or any of the excipients (L histidine, L-arginine, succinic acid, polysorbate 20)
-
Patients administered tube feeding, defined formula diets, or parenteral alimentation/nutrition who have not discontinued these treatments within 3 weeks prior to randomization
Exclusion Criteria Related to General Safety:
-
Pregnant or lactating
-
Lack of peripheral venous access
-
Hospitalization (other than for elective reasons) during the screening period
-
Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure New York Heart Association Class III/IV), pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders
-
Neurological conditions or diseases that may interfere with monitoring for PML
-
History of demyelinating disease
-
Clinically significant abnormalities on screening neurologic examination (PML Objective Checklist)
-
Clinically significant abnormalities on the screening PML Subjective Checklist
-
History of alcohol, drug, or chemical abuse less than 6 months prior to screening
-
Conditions other than UC that could require treatment with >10 mg/day of prednisone (or equivalent) during the course of the study
-
History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, within 5 years before screening
Exclusion Criteria Related to Infection Risk
-
Congenital or acquired immune deficiency
-
Patients must undergo screening for HIV and test positive for preliminary and confirmatory tests
-
Positive hepatitis C virus (HCV) antibody test result
-
Positive hepatitis B virus (HBV) antibody test result
-
Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin testing) within 60 days prior to randomization or other intestinal pathogens (as assessed by stool culture and ova and parasite evaluation) within 30 days prior to randomization
-
Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on the investigator's judgment) within 60 days prior to randomization
-
History of active or latent TB
-
History of recurrent opportunistic infections and/or history of severe disseminated viral infections
-
Any serious opportunistic infection within the last 6 months prior to screening
-
Any current or recent signs or symptoms (within 4 weeks before screening and during screening) of infection
-
Any major episode of infection requiring treatment with IV antibiotics within 8 weeks prior to screening or oral antibiotics within 4 weeks prior to screening
-
Received a live attenuated vaccine within 4 weeks prior to randomization
-
History of organ transplant
Exclusion Criteria Related to Laboratory Abnormalities (at Screening)
-
Serum creatinine >2 x upper limit of normal (ULN)
-
ALT or AST >3 x ULN or alkaline phosphatase >3 x ULN or total bilirubin >2.5 x ULN
-
Platelet count <100,000/uL
-
Hemoglobin <8 g/dL
-
Absolute neutrophil count <1500/uL
-
Absolute lymphocyte count <500/uL
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Center For Digestive Health | Orlando | Florida | United States | 32803 |
| 2 | Internal Medicine Specialists | Orlando | Florida | United States | 32806 |
| 3 | Cotton-O'Neil Clinical Research Center, Digestive Health | Topeka | Kansas | United States | 66606 |
| 4 | Great Lakes Gastroenterology Research, LLC | Mentor | Ohio | United States | 44060 |
| 5 | Centro de Investigaciones Medicas Mar Del Plata | Mar del Plata | Argentina | B7600DHK | |
| 6 | Concord Repatriation General Hospital | Concord | New South Wales | Australia | 2139 |
| 7 | Royal Adelaide Hospital | Adelaide | South Australia | Australia | 5000 |
| 8 | Flinders Medical Centre | Bedford Park | South Australia | Australia | 5042 |
| 9 | St Vincent's Hospital Melbourne | Fitzroy | Victoria | Australia | 3065 |
| 10 | Footscray Hospital; Gastroenterology | Footscray | Victoria | Australia | 3011 |
| 11 | Hospital Universitario Prof Edgar Santos-Ufba; Ambulatorio Magalhaes Neto 3Andar- Dermatologia | Salvador | BA | Brazil | 41110-170 |
| 12 | Hospital Universitario Walter Cantidio - UFC | Fortaleza | CE | Brazil | 60430-370 |
| 13 | Centro Digestivo de Curitiba | Curitiba | PR | Brazil | 80430-160 |
| 14 | Hospital Ernesto Dornelles | Porto Alegre | RS | Brazil | 90160-092 |
| 15 | Pesquisare Saúde Sociedade Simples | Santo Andre | SP | Brazil | 09080-000 |
| 16 | Medical Centre "Asklepii", OOD | Dupnitsa | Bulgaria | 2600 | |
| 17 | DCC Sv. Pantaleymon OOD | Pleven | Bulgaria | 5800 | |
| 18 | Medical center Medconsult Pleven OOD | Pleven | Bulgaria | 5800 | |
| 19 | MHAT - Ruse, AD | Ruse | Bulgaria | 7002 | |
| 20 | MHAT "Hadzhi Dimitar", OOD | Sliven | Bulgaria | 8800 | |
| 21 | "City Clinic UMHAC" EOOD | Sofia | Bulgaria | 1407 | |
| 22 | Medical center CONVEX EOOD | Sofia | Bulgaria | 1680 | |
| 23 | Medical Center "Nov Rehabilitatsionen Tsentar", EOOD | Stara Zagora | Bulgaria | 6000 | |
| 24 | MHAT 'Sv. Marina', EAD | Varna | Bulgaria | 9010 | |
| 25 | RTS - Fundación Valle de Lili | Cali | Colombia | 0 | |
| 26 | Instituto de Coloproctologia ICO S.A.S. | Medellin | Colombia | 050025 | |
| 27 | Clinical Hospital Centre Osijek | Osijek | Croatia | 31000 | |
| 28 | Clinical Hospital Sveti Duh | Zagreb | Croatia | 10000 | |
| 29 | Fakultni nemocnice Hradec Kralove | Hradec Kralove | Czechia | 500 05 | |
| 30 | Hepato-Gastroenterologie HK, s.r.o. | Hradec Kralove | Czechia | 500 12 | |
| 31 | PreventaMed, s.r.o. | Olomouc | Czechia | 779 00 | |
| 32 | Pardubicka krajska nemocnice, a.s. | Pardubice | Czechia | 532 03 | |
| 33 | ISCARE a.s. | Praha 7 | Czechia | 170 04 | |
| 34 | Centre Hospitalier Lyon Sud | Pierre Benite | France | 69495 | |
| 35 | University General Hospital of Heraklion | Herakleion | Greece | 711 10 | |
| 36 | Petz Aladar Megyei Oktato Korhaz | Gyor | Hungary | 9024 | |
| 37 | Central Outpatient Clinic | Daugavpils | Latvia | LV-5401 | |
| 38 | Pauls Stradins Clinical University Hospital | Rīga | Latvia | LV-1002 | |
| 39 | Digestive Diseases Center "Gastro" | Rīga | Latvia | LV-1079 | |
| 40 | Hospital of Lithuanian University of Health. Sciences Kaunas Clinics | Kaunas | Lithuania | 50009 | |
| 41 | Klaipeda Seamen's Hospital, Public Institution | Klaipeda | Lithuania | 92288 | |
| 42 | Vilnius University Hospital Santariskiu Clinic, Public Institution; Cardiology | Vilnius | Lithuania | LT-08661 | |
| 43 | Hospital Raja Perempuan Zainab II; Department of Medicine | Kota Bahru | Malaysia | 15586 | |
| 44 | Pusat Perubatan Universiti Kebangsaan Malaysia | Kuala Lumpur | Malaysia | 56000 | |
| 45 | University Malaya Medical Centre | Kuala Lumpur | Malaysia | 59100 | |
| 46 | Hospital Tengku Ampuan Afzan | Pahang | Malaysia | 25100 | |
| 47 | North Shore Hospital | Auckland | New Zealand | 0620 | |
| 48 | Dunedin Hospital | Dunedin | New Zealand | ||
| 49 | Waikato Hospital | Hamilton | New Zealand | 3248 | |
| 50 | Shakespeare Specialist Group | Takapuna | New Zealand | 0620 | |
| 51 | Tauranga Hospital | Tauranga | New Zealand | 3143 | |
| 52 | Pro Familia Altera Sp z o.o. | Katowice | Poland | 40-645 | |
| 53 | Nzoz All-Medicus | Katowice | Poland | 40-660 | |
| 54 | Uniwersyteckie Centrum Kliniczne im. prof. K. Gibinskiego SUM | Katowice | Poland | 40-752 | |
| 55 | Centrum Opieki Zdrowotnej Orkan-Med | Ksawerow | Poland | 95-054 | |
| 56 | Allmedica Badania Kliniczne Sp z o.o. Sp K. | Nowy Targ | Poland | 34-400 | |
| 57 | Centrum Medyczne Medyk | Rzeszow | Poland | 35-055 | |
| 58 | Gabinet Lekarski, Bartosz Korczowski | Rzeszów | Poland | 35-302 | |
| 59 | Niepubliczny Zaklad Opieki Zdrowotnej SONOMED | Szczecin | Poland | 70-351 | |
| 60 | Endoterapia PFG Sp. z o.o. | Warszawa | Poland | 02-653 | |
| 61 | LexMedica Osrodek Badan Klinicznych | Wroclaw | Poland | 53-114 | |
| 62 | AppleTreeClinics Sp. z o.o. | Łódź | Poland | 90-349 | |
| 63 | SBIH City Clinical Hospital #31 | Sankt-peterburg | Sankt Petersburg | Russian Federation | 197110 |
| 64 | SBEI HPE Altai State Medical University of MoH and SD; Out-patient Department | Barnaul | Russian Federation | 656038 | |
| 65 | Irkutsk State Medical Academy of Continuing Education | Irkutsk | Russian Federation | ||
| 66 | FSBI "Scientific Research Institute of Physyology and Basic Medicine" under the SB of RAMS | Novosibirsk | Russian Federation | 630117 | |
| 67 | BHI of Omsk region Clinical Oncology Dispensary | Omsk | Russian Federation | 644013 | |
| 68 | Center of Emergency and Radiation Medicine; Pulmonology | St. Petersburg | Russian Federation | 194044 | |
| 69 | Pavlov First Saint Petersburg State Medical University | St. Petersburg | Russian Federation | 197022 | |
| 70 | SPb SHI "City Hospital #9" | St. Petersburg | Russian Federation | 197110 | |
| 71 | FSBEI HE "Stavropol State Medical University" of Ministry of Healthcare of Russian Federation | Stavropol | Russian Federation | 355018 | |
| 72 | Voronezh Regional Clinical Hospital #1 | Voronezh | Russian Federation | 394066 | |
| 73 | Ankara Diskapi Yildirim Beyazit Training and Research Hospital; Gastroenterology | Ankara | Turkey | 06110 | |
| 74 | Gaziantep University Medical Faculty Sahinbey Educational Research Hospital; Medical Oncology | Gaziantep | Turkey | 27310 | |
| 75 | Haydarpasa Numune Training and Research Hospital; Gastroenterology | Istanbul | Turkey | 34668 | |
| 76 | Kocaeli Universitesi Tip Fakultesi | Kocaeli | Turkey | 41380 | |
| 77 | CI of SRC Sumy RCH Dept of Gasroenterology Sumy SU MI | Sumy | Kharkiv Governorate | Ukraine | 40022 |
| 78 | CNE Kyiv CCH #18 | Kyiv | KIEV Governorate | Ukraine | 01030 |
| 79 | CI of Kyiv RC Kyiv Regional Clinical Hospital | Kyiv | KIEV Governorate | Ukraine | 04107 |
| 80 | Med Center of International Institute of Clinical Trials LLC; Medical Center "OK!Clinic+" | Kyiv | KIEV Governorate | Ukraine | 2091 |
| 81 | A.Novak Transcarpathian Regional Clinical Hospital | Uzhgorod | KIEV Governorate | Ukraine | 88018 |
| 82 | RCNECRCH Dept of Surgery, SHEI Ukr BSMU | Chernivtsi | Podolia Governorate | Ukraine | 58002 |
| 83 | SI inst. of Gastroenterology of NAMSU Dept of Stomach & Duodenum Diseases, D&ThN SI DMA of MoHU | Dnipropetrovsk | Ukraine | 49074 | |
| 84 | GI L.T.Malaya Therapy National Institute of the NAMS of Ukraine | Kharkiv | Ukraine | 61039 | |
| 85 | CI Kherson Afanasii and Olha Tropiny City Clinical Hospital | Kherson | Ukraine | 73000 | |
| 86 | M.V. Sklifosovskyi Poltava RCH Dept of Gastroenterology HSEIU UMSA | Poltava | Ukraine | 36011 | |
| 87 | Private Small Enterprise Medical Center Pulse | Vinnytsia | Ukraine | 21001 | |
| 88 | MCIC MC LLC Health Clinic | Vinnytsia | Ukraine | 21029 | |
| 89 | Zaporizhzhia SMU | Zaporizhzhia | Ukraine | 69104 | |
| 90 | LLC Diaservis | Zaporizhzhia | Ukraine | 69106 |
Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT02171429
Other Study ID Numbers:
- GA28949
- 2013-004277-27
First Posted:
Jun 24, 2014
Last Update Posted:
Jul 23, 2021
Last Verified:
Jul 1, 2021
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | Participants who were on concomitant background therapy were allowed to continue receiving stable baseline doses of the following non-investigational medicinal products during the study: oral 5-aminosalicylic acid; azathioprine; 6-mercaptopurine; methotrexate; corticosteroids up to 30 mg/day of prednisone (or equivalent); and/or budesonide up to 9 mg/day. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Period Title: Overall Study | |||
| STARTED | 72 | 143 | 143 |
| Completed Week 10 Visit | 70 | 141 | 141 |
| COMPLETED | 71 | 140 | 138 |
| NOT COMPLETED | 1 | 3 | 5 |
Baseline Characteristics
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab | Total |
|---|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | Total of all reporting groups |
| Overall Participants | 144 | 285 | 287 | 716 |
| Age (Years) [Mean (Standard Deviation) ] | ||||
| GA28949 Population |
40.3
(12.5)
|
39.7
(12.6)
|
41.1
(14.4)
|
40.4
(13.3)
|
| GA28948 & GA28949 Pooled Population |
39.4
(12.9)
|
40.8
(13.2)
|
40.6
(13.9)
|
40.4
(13.4)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
34
23.6%
|
62
21.8%
|
59
20.6%
|
155
21.6%
|
| Male |
38
26.4%
|
81
28.4%
|
84
29.3%
|
203
28.4%
|
| Female |
67
46.5%
|
122
42.8%
|
129
44.9%
|
318
44.4%
|
| Male |
77
53.5%
|
163
57.2%
|
158
55.1%
|
398
55.6%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
5
3.5%
|
11
3.9%
|
12
4.2%
|
28
3.9%
|
| Not Hispanic or Latino |
67
46.5%
|
130
45.6%
|
128
44.6%
|
325
45.4%
|
| Unknown or Not Reported |
0
0%
|
2
0.7%
|
3
1%
|
5
0.7%
|
| Hispanic or Latino |
13
9%
|
27
9.5%
|
26
9.1%
|
66
9.2%
|
| Not Hispanic or Latino |
130
90.3%
|
253
88.8%
|
256
89.2%
|
639
89.2%
|
| Unknown or Not Reported |
1
0.7%
|
5
1.8%
|
5
1.7%
|
11
1.5%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||
| Asian |
4
2.8%
|
4
1.4%
|
4
1.4%
|
12
1.7%
|
| Black or African American |
1
0.7%
|
4
1.4%
|
1
0.3%
|
6
0.8%
|
| White |
65
45.1%
|
131
46%
|
133
46.3%
|
329
45.9%
|
| Other |
2
1.4%
|
4
1.4%
|
5
1.7%
|
11
1.5%
|
| Asian |
4
2.8%
|
6
2.1%
|
4
1.4%
|
14
2%
|
| Black or African American |
3
2.1%
|
4
1.4%
|
2
0.7%
|
9
1.3%
|
| White |
133
92.4%
|
261
91.6%
|
271
94.4%
|
665
92.9%
|
| Other |
4
2.8%
|
14
4.9%
|
10
3.5%
|
28
3.9%
|
| Disease Location (Count of Participants) | ||||
| Left-Sided Colitis |
48
33.3%
|
86
30.2%
|
86
30%
|
220
30.7%
|
| Extensive Colitis |
7
4.9%
|
13
4.6%
|
11
3.8%
|
31
4.3%
|
| Pancolitis |
17
11.8%
|
44
15.4%
|
46
16%
|
107
14.9%
|
| Left-Sided Colitis |
92
63.9%
|
170
59.6%
|
175
61%
|
437
61%
|
| Extensive Colitis |
17
11.8%
|
36
12.6%
|
33
11.5%
|
86
12%
|
| Pancolitis |
35
24.3%
|
79
27.7%
|
79
27.5%
|
193
27%
|
| Mayo Clinic Score (MCS) ≤9 or ≥10 at Baseline (Count of Participants) | ||||
| MCS ≤9 |
46
31.9%
|
96
33.7%
|
96
33.4%
|
238
33.2%
|
| MCS ≥10 |
26
18.1%
|
47
16.5%
|
47
16.4%
|
120
16.8%
|
| MCS ≤9 |
93
64.6%
|
192
67.4%
|
196
68.3%
|
481
67.2%
|
| MCS ≥10 |
51
35.4%
|
93
32.6%
|
91
31.7%
|
235
32.8%
|
| Baseline Treatment: None, Corticosteroids (CS) or Immunosuppressants (IS) Alone, or Both CS and IS (Count of Participants) | ||||
| None |
27
18.8%
|
53
18.6%
|
55
19.2%
|
135
18.9%
|
| Corticosteroids (CS) Alone |
23
16%
|
42
14.7%
|
40
13.9%
|
105
14.7%
|
| Immunosuppressants (IS) Alone |
14
9.7%
|
28
9.8%
|
28
9.8%
|
70
9.8%
|
| Both CS and IS |
8
5.6%
|
20
7%
|
20
7%
|
48
6.7%
|
| None |
51
35.4%
|
104
36.5%
|
100
34.8%
|
255
35.6%
|
| Corticosteroids (CS) Alone |
48
33.3%
|
88
30.9%
|
90
31.4%
|
226
31.6%
|
| Immunosuppressants (IS) Alone |
29
20.1%
|
58
20.4%
|
60
20.9%
|
147
20.5%
|
| Both CS and IS |
16
11.1%
|
35
12.3%
|
37
12.9%
|
88
12.3%
|
| Nancy Histological Index (NHI) Score of ≤1 or >1, or Missing, at Baseline (Count of Participants) | ||||
| NHI Score ≤1 |
9
6.3%
|
23
8.1%
|
21
7.3%
|
53
7.4%
|
| NHI Score >1 |
62
43.1%
|
114
40%
|
108
37.6%
|
284
39.7%
|
| Missing |
1
0.7%
|
6
2.1%
|
14
4.9%
|
21
2.9%
|
| NHI Score ≤1 |
17
11.8%
|
38
13.3%
|
36
12.5%
|
91
12.7%
|
| NHI Score >1 |
124
86.1%
|
230
80.7%
|
228
79.4%
|
582
81.3%
|
| Missing |
3
2.1%
|
17
6%
|
23
8%
|
43
6%
|
Outcome Measures
| Title | Percentage of Participants in Remission at Week 10 With Etrolizumab Compared With Placebo, as Determined by the Mayo Clinic Score (MCS), GA28949 Population |
|---|---|
| Description | The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the Cochran-Mantel-Haenszel test adjusted the difference in remission rates and associated 95% confidence interval for the stratification factors. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Placebo | Etrolizumab |
|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 |
| Number (95% Confidence Interval) [Percentage of participants] |
11.1
7.7%
|
18.2
6.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | The null hypothesis (H0): the percentage of participants achieving remission at Week 10 was the same in both the placebo and etrolizumab arms. The alternative hypothesis (H1): the percentage of participants achieving remission at Week 10 was not the same in the placebo and etrolizumab arms. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1729 |
| Comments | The threshold for statistical significance was a p-value <0.05. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | 7.2 | |
| Confidence Interval |
(2-Sided) 95% -3.83 to 16.12 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the placebo arm. | |
| Title | Percentage of Participants in Remission at Week 10 With Etrolizumab Compared With Adalimumab, as Determined by the MCS, GA28949 Population |
|---|---|
| Description | The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and associated 95% confidence interval for the stratification factors. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Adalimumab | Etrolizumab |
|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 143 | 143 |
| Number (95% Confidence Interval) [Percentage of participants] |
24.5
17%
|
18.2
6.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1458 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | -6.8 | |
| Confidence Interval |
(2-Sided) 95% -16.26 to 2.73 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants in Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population |
|---|---|
| Description | The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and associated 95% confidence interval for the stratification factors. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28948 & GA28949 Pooled Population, Modified Intent-to-Treat: including all randomized participants in studies GA28948 & GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Adalimumab | Etrolizumab |
|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 285 | 287 |
| Number (95% Confidence Interval) [Percentage of participants] |
23.5
16.3%
|
18.8
6.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 3 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | -5.0 | |
| Confidence Interval |
(2-Sided) 95% -11.66 to 1.75 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants With Clinical Response at Week 10, as Determined by the MCS, GA28949 Population |
|---|---|
| Description | The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Clinical Response was defined as: MCS ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9 or ≥10); the CMH test adjusted the differences in response rates and associated 95% CIs for the stratification factors. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Number (95% Confidence Interval) [Percentage of participants] |
38.9
27%
|
54.5
19.1%
|
52.4
18.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 1 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1729 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Response Rates |
| Estimated Value | 14.0 | |
| Confidence Interval |
(2-Sided) 95% -0.12 to 27.19 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in response rates was calculated as the etrolizumab arm minus the placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.6726 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Response Rates |
| Estimated Value | -2.5 | |
| Confidence Interval |
(2-Sided) 95% -13.83 to 9.01 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in response rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants With Clinical Response at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population |
|---|---|
| Description | The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Clinical Response was defined as: MCS ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9 or ≥10); the CMH test adjusted the differences in response rates and associated 95% CIs for the stratification factors. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28948 & GA28949 Pooled Population, Modified Intent-to-Treat: including all randomized participants in studies GA28948 & GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Adalimumab | Etrolizumab |
|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 285 | 287 |
| Number (95% Confidence Interval) [Percentage of participants] |
53.3
37%
|
54.7
19.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 3 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Response Rates |
| Estimated Value | 1.2 | |
| Confidence Interval |
(2-Sided) 95% -6.98 to 9.26 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in response rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10, as Determined by the Mayo Endoscopy Subscore, GA28949 Population |
|---|---|
| Description | Improvement in endoscopic appearance of the mucosa was defined as a Mayo Clinic Score (MCS) endoscopy subscore ≤1. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Number (95% Confidence Interval) [Percentage of participants] |
30.6
21.3%
|
42.7
15%
|
39.9
13.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 1 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2372 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Response Rates |
| Estimated Value | 9.4 | |
| Confidence Interval |
(2-Sided) 95% -4.31 to 21.95 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in response rates was calculated as the etrolizumab arm minus the placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5341 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Response Rates |
| Estimated Value | -3.5 | |
| Confidence Interval |
(2-Sided) 95% -14.76 to 7.82 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in response rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS Endoscopy Subscore, GA28948 & GA28949 Pooled Population |
|---|---|
| Description | Improvement in endoscopic appearance of the mucosa was defined as a Mayo Clinic Score (MCS) endoscopy subscore ≤1. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28948 & GA28949 Pooled Population, Modified Intent-to-Treat: including all randomized participants in studies GA28948 & GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Adalimumab | Etrolizumab |
|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 285 | 287 |
| Number (95% Confidence Interval) [Percentage of participants] |
37.9
26.3%
|
40.1
14.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 3 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Response Rates |
| Estimated Value | 1.9 | |
| Confidence Interval |
(2-Sided) 95% -6.04 to 9.88 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in response rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants in Endoscopic Remission at Week 10, as Determined by the MCS Endoscopy Subscore, GA28949 Population |
|---|---|
| Description | Endoscopic remission was defined as a Mayo Clinic Score (MCS) endoscopy subscore of 0. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Number (95% Confidence Interval) [Percentage of participants] |
8.3
5.8%
|
26.6
9.3%
|
19.6
6.8%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 2 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2372 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | 11.2 | |
| Confidence Interval |
(2-Sided) 95% 0.59 to 19.76 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1192 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | -7.5 | |
| Confidence Interval |
(2-Sided) 95% -17.20 to 2.33 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants in Endoscopic Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS Endoscopy Subscore, GA28948 & GA28949 Pooled Population |
|---|---|
| Description | Endoscopic remission was defined as a Mayo Clinic Score (MCS) endoscopy subscore of 0. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28948 & GA28949 Pooled Population, Modified Intent-to-Treat: including all randomized participants in studies GA28948 & GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Adalimumab | Etrolizumab |
|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 285 | 287 |
| Number (95% Confidence Interval) [Percentage of participants] |
23.5
16.3%
|
20.2
7.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 5 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | -3.5 | |
| Confidence Interval |
(2-Sided) 95% -10.27 to 3.30 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants With Histologic Remission at Week 10, as Determined by the Nancy Histological Index, GA28949 Population |
|---|---|
| Description | Histologic remission is defined by the resolution of neutrophilic inflammation (e.g., absence of neutrophils in the crypts and lamina propria), defined by a Nancy Histological Index (NHI) score of ≤1. The NHI score ranges from 0 to 4, with the following definitions for each grade: 0 is no histologically significant disease; 1 is chronic inflammatory infiltrate with no acute inflammatory infiltrate; and 2, 3, and 4 are mildly, moderately, and severely active disease, respectively. A small pool of central readers who were blinded to both treatment arm and timepoint performed the histologic scoring. The same reader scored all slides for a given participant based on biopsies from the most inflamed region of the sigmoid colon. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received rescue therapy prior to assessment. The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and 95% CI for the stratification factors. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Histology-Evaluable Population: included all randomized participants in study GA28949 who received at least one dose of study drug and had documented neutrophilic inflammation (i.e., NHI >1) at baseline. This excludes participants who had no baseline histology assessment or had no indication of neutrophilic inflammation at baseline. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 62 | 114 | 108 |
| Number (95% Confidence Interval) [Percentage of participants] |
21.0
14.6%
|
43.9
15.4%
|
30.6
10.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 2 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2729 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | 9.6 | |
| Confidence Interval |
(2-Sided) 95% -4.71 to 22.02 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0215 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | -14.8 | |
| Confidence Interval |
(2-Sided) 95% -26.97 to -2.04 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants With Histologic Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the Nancy Histological Index, GA28948 & GA28949 Pooled Population |
|---|---|
| Description | Histologic remission is defined by the resolution of neutrophilic inflammation (e.g., absence of neutrophils in the crypts and lamina propria), defined by a Nancy Histological Index (NHI) score of ≤1. The NHI score ranges from 0 to 4, with the following definitions for each grade: 0 is no histologically significant disease; 1 is chronic inflammatory infiltrate with no acute inflammatory infiltrate; and 2, 3, and 4 are mildly, moderately, and severely active disease, respectively. A small pool of central readers who were blinded to both treatment arm and timepoint performed the histologic scoring. The same reader scored all slides for a given participant based on biopsies from the most inflamed region of the sigmoid colon. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received rescue therapy prior to assessment. The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and 95% CI for the stratification factors. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28948 & GA28949 Pooled, Histology-Evaluable Population: included all randomized participants in studies GA28948 & GA28949 who received at least one dose of study drug and had documented neutrophilic inflammation (i.e., NHI >1) at baseline. This excludes participants who had no baseline histology assessment or had no indication of neutrophilic inflammation at baseline. |
| Arm/Group Title | Adalimumab | Etrolizumab |
|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 230 | 228 |
| Number (95% Confidence Interval) [Percentage of participants] |
36.5
25.3%
|
36.8
12.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 5 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | -0.3 | |
| Confidence Interval |
(2-Sided) 95% -9.13 to 8.45 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Change From Baseline in the MCS Rectal Bleeding Subscore at Week 6, GA28949 Population |
|---|---|
| Description | Rectal bleeding data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = no blood in the stool; 1 = streaks of blood with stool less than half the time; 2 = obvious blood with stool most of the time; 3 = blood alone passed. The Mayo Clinic Score (MCS) rectal bleeding subscore was calculated as the worst value of three days of daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline rectal bleeding (RB) subscore. |
| Time Frame | Baseline, Week 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Median (Inter-Quartile Range) [Score on a scale] |
0.0
|
-1.0
|
-1.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 2 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1729 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Rank ANCOVA | |
| Comments | Model adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL), MCS (≤9 or ≥10) at BL, and RB score at BL. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2864 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Rank ANCOVA | |
| Comments | Model adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL), MCS (≤9 or ≥10) at BL, and RB score at BL. | |
| Title | Change From Baseline in the MCS Rectal Bleeding Subscore at Week 6 With Etrolizumab as Compared With Adalimumab, GA28948 & GA28949 Pooled Population |
|---|---|
| Description | Rectal bleeding data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = no blood in the stool; 1 = streaks of blood with stool less than half the time; 2 = obvious blood with stool most of the time; 3 = blood alone passed. The Mayo Clinic Score (MCS) rectal bleeding subscore was calculated as the worst value of three days of daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline rectal bleeding (RB) subscore. |
| Time Frame | Baseline, Week 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28948 & GA28949 Pooled Population, Modified Intent-to-Treat: including all randomized participants in studies GA28948 & GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Adalimumab | Etrolizumab |
|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 285 | 287 |
| Median (Inter-Quartile Range) [Score on a scale] |
-1.0
|
-1.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 5 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Rank ANCOVA | |
| Comments | Model adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL), MCS (≤9 or ≥10) at BL, and RB score at BL. | |
| Title | Change From Baseline in the MCS Stool Frequency Subscore at Week 6, GA28949 Population |
|---|---|
| Description | Stool frequency data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = normal number of stools; 1 = 1 to 2 more stools than normal; 2 = 3 to 4 more stools than normal; 3 = 5 or more stools than normal. The Mayo Clinic Score (MCS) stool frequency subscore was calculated as the average of three days daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline stool frequency (SF) subscore. |
| Time Frame | Baseline, Week 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Median (Inter-Quartile Range) [Score on a scale] |
0.0
|
-1.0
|
-1.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 2 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1729 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Rank ANCOVA | |
| Comments | Model adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL), MCS (≤9 or ≥10) at BL, and SF score at BL. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4174 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Rank ANCOVA | |
| Comments | Model adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL), MCS (≤9 or ≥10) at BL, and SF score at BL. | |
| Title | Change From Baseline in the MCS Stool Frequency Subscore at Week 6 With Etrolizumab as Compared With Adalimumab, GA28948 & GA28949 Pooled Population |
|---|---|
| Description | Stool frequency data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = normal number of stools; 1 = 1 to 2 more stools than normal; 2 = 3 to 4 more stools than normal; 3 = 5 or more stools than normal. The Mayo Clinic Score (MCS) stool frequency subscore was calculated as the average of three days daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline stool frequency (SF) subscore. |
| Time Frame | Baseline, Week 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28948 & GA28949 Pooled Population, Modified Intent-to-Treat: including all randomized participants in studies GA28948 & GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Adalimumab | Etrolizumab |
|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 285 | 287 |
| Median (Inter-Quartile Range) [Score on a scale] |
-1.0
|
-1.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 5 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Rank ANCOVA | |
| Comments | Model adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL), MCS (≤9 or ≥10) at BL, and SF score at BL. | |
| Title | Change From Baseline in Ulcerative Colitis (UC) Bowel Movement Signs and Symptoms at Week 10, as Assessed by the UC Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS), GA28949 Population |
|---|---|
| Description | The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The bowel movement domain score ranges from 0 to 27, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors within the MMRM. |
| Time Frame | Baseline, Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. The analysis only included participants with non-missing results at baseline and at least one post-baseline timepoint. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 59 | 111 | 108 |
| Least Squares Mean (Standard Error) [Score on a scale] |
-4.7
(0.7)
|
-5.9
(0.5)
|
-5.8
(0.5)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1659 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Mixed Model for Repeated Measures | |
| Comments | Model adjusted for treatment, visit, stratification factors, treatment-by-visit, baseline UC-PRO/SS domain, and baseline UC-PRO/SS domain-by-visit. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -1.1 | |
| Confidence Interval |
(2-Sided) 95% -2.8 to 0.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9182 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Mixed Model for Repeated Measures | |
| Comments | Model adjusted for treatment, visit, stratification factors, treatment-by-visit, baseline UC-PRO/SS domain, and baseline UC-PRO/SS domain-by-visit. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 0.1 | |
| Confidence Interval |
(2-Sided) 95% -1.3 to 1.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus adalimumab arm. | |
| Title | Change From Baseline in Ulcerative Colitis Bowel Movement Signs and Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28948 & GA28949 Pooled Population |
|---|---|
| Description | The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The bowel movement domain score ranges from 0 to 27, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors within the MMRM. |
| Time Frame | Baseline, Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28948 & GA28949 Pooled Population, Modified Intent-to-Treat: including all randomized participants in studies GA28948 & GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. The analysis only included participants with non-missing results at baseline and at least one post-baseline timepoint. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 109 | 217 | 225 |
| Least Squares Mean (Standard Error) [Score on a scale] |
-5.0
(0.5)
|
-5.8
(0.4)
|
-6.0
(0.3)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 4 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Mixed Model for Repeated Measures | |
| Comments | Model adjusted for treatment, visit, stratification factors, treatment-by-visit, baseline UC-PRO/SS domain, and baseline UC-PRO/SS domain-by-visit. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -1.0 | |
| Confidence Interval |
(2-Sided) 95% -2.1 to 0.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 6 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Mixed Model for Repeated Measures | |
| Comments | Model adjusted for treatment, visit, stratification factors, treatment-by-visit, baseline UC-PRO/SS domain, and baseline UC-PRO/SS domain-by-visit. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -0.3 | |
| Confidence Interval |
(2-Sided) 95% -1.2 to 0.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus adalimumab arm. | |
| Title | Change From Baseline in Ulcerative Colitis Functional Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28949 Population |
|---|---|
| Description | The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The functional symptoms domain score ranges from 0 to 12, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors in the MMRM. |
| Time Frame | Baseline, Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. The analysis only included participants with non-missing results at baseline and at least one post-baseline timepoint. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 59 | 111 | 108 |
| Least Squares Mean (Standard Error) [Score on a scale] |
-1.0
(0.3)
|
-1.8
(0.2)
|
-2.0
(0.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0116 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Mixed Model for Repeated Measures | |
| Comments | Model adjusted for treatment, visit, stratification factors, treatment-by-visit, baseline UC-PRO/SS domain, and baseline UC-PRO/SS domain-by-visit. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -1.0 | |
| Confidence Interval |
(2-Sided) 95% -1.7 to -0.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.6771 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Mixed Model for Repeated Measures | |
| Comments | Model adjusted for treatment, visit, stratification factors, treatment-by-visit, baseline UC-PRO/SS domain, and baseline UC-PRO/SS domain-by-visit. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -0.1 | |
| Confidence Interval |
(2-Sided) 95% -0.8 to 0.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus adalimumab arm. | |
| Title | Change From Baseline in Ulcerative Colitis Functional Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28948 & GA28949 Pooled Population |
|---|---|
| Description | The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The functional symptoms domain score ranges from 0 to 12, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors in the MMRM. |
| Time Frame | Baseline, Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28948 & GA28949 Pooled Population, Modified Intent-to-Treat: including all randomized participants in studies GA28948 & GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. The analysis only included participants with non-missing results at baseline and at least one post-baseline timepoint. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 109 | 217 | 225 |
| Least Squares Mean (Standard Error) [Score on a scale] |
-1.4
(0.2)
|
-1.6
(0.2)
|
-1.9
(0.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 4 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Mixed Model for Repeated Measures | |
| Comments | Model adjusted for treatment, visit, stratification factors, treatment-by-visit, baseline UC-PRO/SS domain, and baseline UC-PRO/SS domain-by-visit. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -0.5 | |
| Confidence Interval |
(2-Sided) 95% -1.0 to 0.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. This comparison was part of Family 6 of the testing procedure; please refer to the statistical analysis plan for details. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1 |
| Comments | p-value has been adjusted for multiplicity. | |
| Method | Mixed Model for Repeated Measures | |
| Comments | Model adjusted for treatment, visit, stratification factors, treatment-by-visit, baseline UC-PRO/SS domain, and baseline UC-PRO/SS domain-by-visit. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -0.3 | |
| Confidence Interval |
(2-Sided) 95% -0.7 to 0.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus adalimumab arm. | |
| Title | Percentage of Participants in Clinical Remission at Week 10, as Determined by the MCS, GA28949 Population |
|---|---|
| Description | The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Clinical remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the differences in remission rates and associated 95% confidence intervals for the stratification factors. |
| Time Frame | Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Number (95% Confidence Interval) [Percentage of participants] |
11.1
7.7%
|
25.9
9.1%
|
18.9
6.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1382 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | 7.9 | |
| Confidence Interval |
(2-Sided) 95% -3.19 to 16.87 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1163 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | -7.5 | |
| Confidence Interval |
(2-Sided) 95% -17.10 to 2.22 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Percentage of Participants in Remission at Week 10 and Week 14, as Determined by the MCS, GA28949 Population |
|---|---|
| Description | The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 or 14 assessments were missing or the participant received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the differences in remission rates and associated 95% confidence intervals for the stratification factors. |
| Time Frame | Weeks 10 and 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Number (95% Confidence Interval) [Percentage of participants] |
6.9
4.8%
|
14.7
5.2%
|
9.8
3.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4772 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | 2.9 | |
| Confidence Interval |
(2-Sided) 95% -6.47 to 10.14 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1801 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Difference and 95% CI adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL) and MCS (≤9 or ≥10) at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Remission Rates |
| Estimated Value | -5.2 | |
| Confidence Interval |
(2-Sided) 95% -12.95 to 2.63 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in remission rates was calculated as the etrolizumab arm minus the adalimumab arm. | |
| Title | Change From Baseline in Health-Related Quality of Life at Week 10, as Assessed by the Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score, GA28949 Population |
|---|---|
| Description | The IBDQ is a 32-item questionnaire containing four domains: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). An overall total IBDQ score was computed by summing the individual 32-item scores. The range for the IBDQ total score is 32 to 224, with higher scores denoting better health-related quality of life. The unadjusted mean and standard deviation for each study arm are reported. The change from baseline in the IBDQ score was analyzed using an ANCOVA model taking the stratification factors used at randomization into account (concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening [MCS ≤9/MCS ≥10]), and the baseline IBDQ score used as a covariate. |
| Time Frame | Baseline, Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Population, Modified Intent-to-Treat: including all randomized participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment assigned at randomization. The analysis only included participants with non-missing results at baseline and at least one post-baseline timepoint. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 62 | 125 | 125 |
| Mean (Standard Deviation) [Score on a scale] |
31.2
(39.5)
|
34.8
(36.5)
|
36.2
(43.4)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4833 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | ANCOVA | |
| Comments | Model adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL), MCS (≤9 or ≥10) at BL, and IBDQ score at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Adjusted Means |
| Estimated Value | 4.0 | |
| Confidence Interval |
(2-Sided) 95% -7.2 to 15.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus placebo arm. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Etrolizumab, Etrolizumab |
|---|---|---|
| Comments | Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. This comparison was not considered a key secondary outcome measure and was not part of the multiple testing procedure for statistical significance. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9931 |
| Comments | Nominal p-value; it has not been adjusted for multiplicity. | |
| Method | ANCOVA | |
| Comments | Model adjusted for concomitant treatment with corticosteroids or immunosuppressants at baseline (BL), MCS (≤9 or ≥10) at BL, and IBDQ score at BL. | |
| Method of Estimation | Estimation Parameter | Difference in Adjusted Means |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -9.2 to 9.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference was calculated as etrolizumab arm minus adalimumab arm. | |
| Title | Pharmacokinetics of Etrolizumab: Serum Concentration, GA28949 Population |
|---|---|
| Description | Serum concentrations of etrolizumab were evaluated at the primary endpoint visit (Week 10) and the secondary endpoint visit (Week 14). Both time points were two weeks after the most recent dose. |
| Time Frame | Weeks 10 and 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Pharmacokinetics Evaluable Population: includes participants in study GA28949 who had received at least one dose of study drug and had at least one quantifiable concentration measured post-baseline. Only participants who were treated with etrolizumab were included in this analysis. |
| Arm/Group Title | Etrolizumab |
|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 139 |
| Week 10 |
12.4
(5.51)
|
| Week 14 |
15.5
(6.49)
|
| Title | Number and Percentage of Participants With at Least One Adverse Event by Severity, According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0), GA28949 Population |
|---|---|
| Description | An adverse event (AE) is any untoward medical occurrence in a clinical investigation in which a patient is administered a pharmaceutical product, regardless of causal attribution. The investigator independently assessed the severity and seriousness of each recorded AE. The AE severity grading scale for the NCI CTCAE v4.0 was used for assessing severity; any AE not specifically listed was rated according to the following grading scale from 1 to 5: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death. AEs of special interest included: elevated AST/ALT in combination with either elevated bilirubin or clinical jaundice; suspected transmission of infectious agent by the study drug; anaphylactic, anaphylactoid and systemic hypersensitivity reactions; and neurological signs, symptoms, and AEs that may suggest possible progressive multifocal leukoencephalopathy (PML). |
| Time Frame | From Baseline until the end of study (up to 26 weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Safety Population: includes all participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment received. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Any Adverse Event (AE) |
33
22.9%
|
62
21.8%
|
63
22%
|
| AE with Fatal Outcome |
0
0%
|
0
0%
|
1
0.3%
|
| Serious AE |
5
3.5%
|
3
1.1%
|
7
2.4%
|
| AE Leading to Study Treatment Discontinuation |
1
0.7%
|
2
0.7%
|
4
1.4%
|
| AE Leading to Dose Interruption |
0
0%
|
2
0.7%
|
1
0.3%
|
| Related AE |
9
6.3%
|
15
5.3%
|
12
4.2%
|
| AE by Worst Severity, Grade 1 |
14
9.7%
|
29
10.2%
|
30
10.5%
|
| AE by Worst Severity, Grade 2 |
13
9%
|
25
8.8%
|
24
8.4%
|
| AE by Worst Severity, Grade 3 |
6
4.2%
|
8
2.8%
|
8
2.8%
|
| AE by Worst Severity, Grade 4 |
0
0%
|
0
0%
|
0
0%
|
| AE by Worst Severity, Grade 5 |
0
0%
|
0
0%
|
1
0.3%
|
| Any AEs of Special Interest (AESIs), Except for Hypersensitivity Reactions |
0
0%
|
0
0%
|
0
0%
|
| AESIs: Anaphylactic, Anaphylactoid, and Systemic Hypersensitivity Reactions |
0
0%
|
1
0.4%
|
0
0%
|
| Confirmed PML |
0
0%
|
0
0%
|
0
0%
|
| Infections |
13
9%
|
18
6.3%
|
23
8%
|
| Serious Infections |
0
0%
|
1
0.4%
|
2
0.7%
|
| Gastrointestinal Infections |
1
0.7%
|
0
0%
|
3
1%
|
| Opportunistic Infections |
0
0%
|
0
0%
|
0
0%
|
| Malignancies |
0
0%
|
2
0.7%
|
0
0%
|
| Injection Site Reactions |
2
1.4%
|
3
1.1%
|
2
0.7%
|
| Title | Number and Percentage of Participants by Marked Laboratory Abnormality Status for Hematology Parameters as a Shift Table From Baseline to Week 10, GA28949 Population |
|---|---|
| Description | Laboratory tests for hematology parameters were performed and values were compared with the Roche marked reference range. A marked abnormality was defined as a test result that was outside of the Roche marked reference range (labelled as 'High' or 'Low') and represented a clinically significant change from baseline. Not every laboratory abnormality qualified as an adverse event. A laboratory test result must have been reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment or a medical intervention; or was clinically significant in the investigator's judgment. The results are presented as a shift from the baseline status to the post-baseline (Week 10) status. Baseline was defined as the last available assessment prior to first receipt of study drug. The 'missing' status included participants with missing baseline or post-baseline values. Ery. = erythrocyte |
| Time Frame | From Baseline up to Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Safety Population: includes all participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment received. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Eosinophils Absolute Count (Abs) - Normal to Normal |
63
43.8%
|
133
46.7%
|
124
43.2%
|
| Eosinophils Abs - Normal to High |
0
0%
|
0
0%
|
2
0.7%
|
| Eosinophils Abs - Normal to Missing |
7
4.9%
|
9
3.2%
|
15
5.2%
|
| Eosinophils Abs - High to Normal |
2
1.4%
|
1
0.4%
|
0
0%
|
| Eosinophils Abs - High to High |
0
0%
|
0
0%
|
1
0.3%
|
| Eosinophils Abs - Missing to Normal |
0
0%
|
0
0%
|
1
0.3%
|
| Hematocrit - Low to Low |
0
0%
|
1
0.4%
|
1
0.3%
|
| Hematocrit - Low to Normal |
3
2.1%
|
2
0.7%
|
5
1.7%
|
| Hematocrit - Low to Missing |
0
0%
|
0
0%
|
1
0.3%
|
| Hematocrit - Normal to Low |
0
0%
|
1
0.4%
|
2
0.7%
|
| Hematocrit - Normal to Normal |
62
43.1%
|
128
44.9%
|
119
41.5%
|
| Hematocrit - Normal to Missing |
7
4.9%
|
10
3.5%
|
14
4.9%
|
| Hematocrit - Missing to Normal |
0
0%
|
1
0.4%
|
1
0.3%
|
| Hemoglobin - Low to Low |
3
2.1%
|
10
3.5%
|
13
4.5%
|
| Hemoglobin - Low to Normal |
2
1.4%
|
7
2.5%
|
9
3.1%
|
| Hemoglobin - Low to Missing |
2
1.4%
|
3
1.1%
|
4
1.4%
|
| Hemoglobin - Normal to Low |
4
2.8%
|
4
1.4%
|
7
2.4%
|
| Hemoglobin - Normal to Normal |
56
38.9%
|
113
39.6%
|
99
34.5%
|
| Hemoglobin - Normal to Missing |
5
3.5%
|
6
2.1%
|
10
3.5%
|
| Hemoglobin - Missing to Normal |
0
0%
|
0
0%
|
1
0.3%
|
| Lymphocytes Abs - Low to Low |
2
1.4%
|
2
0.7%
|
2
0.7%
|
| Lymphocytes Abs - Low to Normal |
2
1.4%
|
9
3.2%
|
4
1.4%
|
| Lymphocytes Abs - Low to Missing |
0
0%
|
0
0%
|
1
0.3%
|
| Lymphocytes Abs - Normal to Low |
1
0.7%
|
2
0.7%
|
2
0.7%
|
| Lymphocytes Abs - Normal to Normal |
60
41.7%
|
121
42.5%
|
119
41.5%
|
| Lymphocytes Abs - Normal to Missing |
7
4.9%
|
9
3.2%
|
14
4.9%
|
| Lymphocytes Abs - Missing to Normal |
0
0%
|
0
0%
|
1
0.3%
|
| Ery. Mean Corpuscular Volume - Normal to Low |
0
0%
|
1
0.4%
|
1
0.3%
|
| Ery. Mean Corpuscular Volume - Normal to Normal |
65
45.1%
|
130
45.6%
|
126
43.9%
|
| Ery. Mean Corpuscular Volume - Normal to Missing |
7
4.9%
|
9
3.2%
|
15
5.2%
|
| Ery. Mean Corpuscular Volume - High to High |
0
0%
|
1
0.4%
|
0
0%
|
| Ery. Mean Corpuscular Volume - High to Missing |
0
0%
|
1
0.4%
|
0
0%
|
| Ery. Mean Corpuscular Volume - Missing to Normal |
0
0%
|
1
0.4%
|
1
0.3%
|
| Neutrophils, Total, Abs - Low to Low |
1
0.7%
|
1
0.4%
|
0
0%
|
| Neutrophils, Total, Abs - Low to Normal |
0
0%
|
3
1.1%
|
4
1.4%
|
| Neutrophils, Total, Abs - Low to Missing |
0
0%
|
1
0.4%
|
0
0%
|
| Neutrophils, Total, Abs - Normal to Low |
0
0%
|
7
2.5%
|
4
1.4%
|
| Neutrophils, Total, Abs - Normal to Normal |
55
38.2%
|
105
36.8%
|
105
36.6%
|
| Neutrophils, Total, Abs - Normal to High |
1
0.7%
|
1
0.4%
|
2
0.7%
|
| Neutrophils, Total, Abs - Normal to Missing |
8
5.6%
|
7
2.5%
|
15
5.2%
|
| Neutrophils, Total, Abs - High to Normal |
3
2.1%
|
15
5.3%
|
7
2.4%
|
| Neutrophils, Total, Abs - High to High |
4
2.8%
|
1
0.4%
|
5
1.7%
|
| Neutrophils, Total, Abs - High to Missing |
0
0%
|
2
0.7%
|
0
0%
|
| Neutrophils, Total, Abs - Missing to Normal |
0
0%
|
0
0%
|
1
0.3%
|
| Platelets - Normal to Normal |
59
41%
|
128
44.9%
|
116
40.4%
|
| Platelets - Normal to High |
1
0.7%
|
0
0%
|
3
1%
|
| Platelets - Normal to Missing |
9
6.3%
|
9
3.2%
|
15
5.2%
|
| Platelets - High to Normal |
2
1.4%
|
2
0.7%
|
4
1.4%
|
| Platelets - High to High |
1
0.7%
|
2
0.7%
|
2
0.7%
|
| Platelets - High to Missing |
0
0%
|
1
0.4%
|
2
0.7%
|
| Platelets - Missing to Normal |
0
0%
|
1
0.4%
|
1
0.3%
|
| White Blood Cell Count - Low to Low |
1
0.7%
|
1
0.4%
|
0
0%
|
| White Blood Cell Count - Low to Normal |
0
0%
|
4
1.4%
|
2
0.7%
|
| White Blood Cell Count - Low to Missing |
0
0%
|
1
0.4%
|
0
0%
|
| White Blood Cell Count - Normal to Low |
0
0%
|
3
1.1%
|
2
0.7%
|
| White Blood Cell Count - Normal to Normal |
64
44.4%
|
123
43.2%
|
124
43.2%
|
| White Blood Cell Count - Normal to High |
0
0%
|
1
0.4%
|
0
0%
|
| White Blood Cell Count - Normal to Missing |
7
4.9%
|
8
2.8%
|
14
4.9%
|
| White Blood Cell Count - High to Normal |
0
0%
|
2
0.7%
|
0
0%
|
| White Blood Cell Count - Missing to Normal |
0
0%
|
0
0%
|
1
0.3%
|
| Title | Number and Percentage of Participants by Marked Laboratory Abnormality Status for Chemistry Parameters as a Shift Table From Baseline to Week 10, GA28949 Population |
|---|---|
| Description | Laboratory tests for chemistry parameters were performed and values were compared with the Roche marked reference range. A marked abnormality was defined as a test result that was outside of the Roche marked reference range (labelled as 'High' or 'Low') and represented a clinically significant change from baseline. Not every laboratory abnormality qualified as an adverse event. A laboratory test result must have been reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment or a medical intervention; or was clinically significant in the investigator's judgment. The results are presented as a shift from the baseline status to the post-baseline (Week 10) status. Baseline was defined as the last available assessment prior to first receipt of study drug. The 'missing' status included participants with missing baseline or post-baseline values. |
| Time Frame | From Baseline up to Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Safety Population: includes all participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment received. |
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab |
|---|---|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 72 | 143 | 143 |
| Albumin - Low to Normal |
2
1.4%
|
3
1.1%
|
2
0.7%
|
| Albumin - Low to Missing |
0
0%
|
0
0%
|
2
0.7%
|
| Albumin - Normal to Low |
0
0%
|
1
0.4%
|
0
0%
|
| Albumin - Normal to Normal |
65
45.1%
|
134
47%
|
137
47.7%
|
| Albumin - Normal to Missing |
5
3.5%
|
5
1.8%
|
2
0.7%
|
| Alkaline Phosphatase - Normal to Normal |
67
46.5%
|
138
48.4%
|
137
47.7%
|
| Alkaline Phosphatase - Normal to Missing |
5
3.5%
|
5
1.8%
|
5
1.7%
|
| Alkaline Phosphatase - High to Normal |
0
0%
|
0
0%
|
1
0.3%
|
| Alanine Aminotransferase - Normal to Normal |
65
45.1%
|
134
47%
|
134
46.7%
|
| Alanine Aminotransferase - Normal to High |
0
0%
|
1
0.4%
|
0
0%
|
| Alanine Aminotransferase - Normal to Missing |
6
4.2%
|
7
2.5%
|
5
1.7%
|
| Alanine Aminotransferase - High to Normal |
1
0.7%
|
1
0.4%
|
2
0.7%
|
| Alanine Aminotransferase - High to High |
0
0%
|
0
0%
|
2
0.7%
|
| Aspartate Aminotransferase - Normal to Normal |
65
45.1%
|
135
47.4%
|
135
47%
|
| Aspartate Aminotransferase - Normal to High |
0
0%
|
0
0%
|
2
0.7%
|
| Aspartate Aminotransferase - Normal to Missing |
6
4.2%
|
8
2.8%
|
5
1.7%
|
| Aspartate Aminotransferase - High to Normal |
1
0.7%
|
0
0%
|
1
0.3%
|
| Bicarbonate (CO2) - Low to Low |
1
0.7%
|
0
0%
|
0
0%
|
| Bicarbonate (CO2) - Low to Normal |
1
0.7%
|
3
1.1%
|
0
0%
|
| Bicarbonate (CO2) - Normal to Low |
6
4.2%
|
9
3.2%
|
10
3.5%
|
| Bicarbonate (CO2) - Normal to Normal |
55
38.2%
|
121
42.5%
|
116
40.4%
|
| Bicarbonate (CO2) - Normal to High |
0
0%
|
0
0%
|
1
0.3%
|
| Bicarbonate (CO2) - Normal to Missing |
5
3.5%
|
7
2.5%
|
3
1%
|
| Bicarbonate (CO2) - High to Normal |
4
2.8%
|
1
0.4%
|
10
3.5%
|
| Bicarbonate (CO2) - High to High |
0
0%
|
2
0.7%
|
1
0.3%
|
| Bicarbonate (CO2) - High to Missing |
0
0%
|
0
0%
|
2
0.7%
|
| Blood Urea Nitrogen - Normal to Normal |
67
46.5%
|
138
48.4%
|
139
48.4%
|
| Blood Urea Nitrogen - Normal to Missing |
5
3.5%
|
5
1.8%
|
4
1.4%
|
| Calcium - Normal to Normal |
67
46.5%
|
138
48.4%
|
139
48.4%
|
| Calcium - Normal to Missing |
5
3.5%
|
5
1.8%
|
4
1.4%
|
| Chloride - Low to Low |
0
0%
|
1
0.4%
|
0
0%
|
| Chloride - Low to Missing |
0
0%
|
1
0.4%
|
0
0%
|
| Chloride - Normal to Low |
1
0.7%
|
1
0.4%
|
3
1%
|
| Chloride - Normal to Normal |
66
45.8%
|
135
47.4%
|
136
47.4%
|
| Chloride - Normal to Missing |
5
3.5%
|
5
1.8%
|
4
1.4%
|
| Creatinine - Normal to Normal |
67
46.5%
|
138
48.4%
|
139
48.4%
|
| Creatinine - Normal to Missing |
5
3.5%
|
5
1.8%
|
4
1.4%
|
| Direct Bilirubin - Normal to Normal |
66
45.8%
|
132
46.3%
|
137
47.7%
|
| Direct Bilirubin - Normal to Missing |
6
4.2%
|
10
3.5%
|
6
2.1%
|
| Direct Bilirubin - Missing to Normal |
0
0%
|
1
0.4%
|
0
0%
|
| Potassium - Normal to Low |
0
0%
|
1
0.4%
|
0
0%
|
| Potassium - Normal to Normal |
66
45.8%
|
135
47.4%
|
137
47.7%
|
| Potassium - Normal to Missing |
6
4.2%
|
7
2.5%
|
6
2.1%
|
| Sodium - Normal to Normal |
67
46.5%
|
137
48.1%
|
139
48.4%
|
| Sodium - Normal to Missing |
5
3.5%
|
6
2.1%
|
4
1.4%
|
| Total Bilirubin - Normal to Normal |
66
45.8%
|
135
47.4%
|
136
47.4%
|
| Total Bilirubin - Normal to High |
1
0.7%
|
3
1.1%
|
3
1%
|
| Total Bilirubin - Normal to Missing |
5
3.5%
|
5
1.8%
|
4
1.4%
|
| Protein, Total - Low to Normal |
1
0.7%
|
0
0%
|
1
0.3%
|
| Protein, Total - Normal to Low |
0
0%
|
1
0.4%
|
0
0%
|
| Protein, Total - Normal to Normal |
64
44.4%
|
132
46.3%
|
135
47%
|
| Protein, Total - Normal to High |
1
0.7%
|
5
1.8%
|
0
0%
|
| Protein, Total - Normal to Missing |
5
3.5%
|
5
1.8%
|
5
1.7%
|
| Protein, Total - High to Normal |
1
0.7%
|
0
0%
|
1
0.3%
|
| Protein, Total - High to High |
0
0%
|
0
0%
|
1
0.3%
|
| Title | Number and Percentage of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Anytime Post-Baseline, GA28949 Population |
|---|---|
| Description | Anti-drug antibody (ADA) serum samples were collected from participants and analyzed using validated assays. Participants were considered to be ADA positive post-baseline if they were ADA negative or had missing data at baseline, but developed an ADA response following etrolizumab drug exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be ADA negative if they were ADA negative or had missing data at baseline and all post-baseline samples were negative, or if they were ADA positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected). |
| Time Frame | Pre-dose (0 hour) on Day 1 and Week 4, Week 10, Week 14, and early termination/end of safety follow-up (up to 26 weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| GA28949 Safety Population: includes all participants in study GA28949 who received at least one dose of study drug, with participants grouped according to the treatment received. The analysis of ADAs at baseline and post-baseline only included participants who received treatment with etrolizumab. |
| Arm/Group Title | Etrolizumab |
|---|---|
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). |
| Measure Participants | 141 |
| Positive for ADAs at Baseline (BL) |
7
4.9%
|
| Negative for ADAs at BL |
134
93.1%
|
| Post-BL: Positive for Treatment Emergent ADAs |
26
18.1%
|
| Post-BL ADA Positive: Treatment-Induced ADAs |
26
18.1%
|
| Post-BL ADA Positive: Treatment-Enhanced ADAs |
0
0%
|
| Post-BL: Negative for Treatment Emergent ADAs |
115
79.9%
|
| Post-BL ADA Negative: Treatment Unaffected |
7
4.9%
|
Adverse Events
| Time Frame | From Baseline until the end of study (up to 26 weeks) | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | The adverse events reported here are those that occurred only in participants enrolled in study GA28949 who received at least one dose of study drug. For the adverse events that occurred in participants enrolled in the identically designed study, GA28948, please refer to its study record, NCT02163759. | |||||
| Arm/Group Title | Placebo | Adalimumab | Etrolizumab | |||
| Arm/Group Description | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]). | The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). | |||
All Cause Mortality |
||||||
| Placebo | Adalimumab | Etrolizumab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/72 (0%) | 0/143 (0%) | 1/143 (0.7%) | |||
Serious Adverse Events |
||||||
| Placebo | Adalimumab | Etrolizumab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/72 (6.9%) | 3/143 (2.1%) | 7/143 (4.9%) | |||
| Eye disorders | ||||||
| Visual impairment | 0/72 (0%) | 0 | 0/143 (0%) | 0 | 1/143 (0.7%) | 1 |
| Gastrointestinal disorders | ||||||
| Colitis ulcerative | 2/72 (2.8%) | 2 | 1/143 (0.7%) | 1 | 1/143 (0.7%) | 1 |
| Colon dysplasia | 0/72 (0%) | 0 | 0/143 (0%) | 0 | 1/143 (0.7%) | 1 |
| Pancreatitis acute | 1/72 (1.4%) | 1 | 0/143 (0%) | 0 | 0/143 (0%) | 0 |
| Proctitis | 0/72 (0%) | 0 | 0/143 (0%) | 0 | 1/143 (0.7%) | 1 |
| Rectal haemorrhage | 0/72 (0%) | 0 | 0/143 (0%) | 0 | 1/143 (0.7%) | 1 |
| General disorders | ||||||
| Sudden cardiac death | 0/72 (0%) | 0 | 0/143 (0%) | 0 | 1/143 (0.7%) | 1 |
| Infections and infestations | ||||||
| Clostridium difficile infection | 0/72 (0%) | 0 | 0/143 (0%) | 0 | 1/143 (0.7%) | 1 |
| Pulpitis dental | 0/72 (0%) | 0 | 0/143 (0%) | 0 | 1/143 (0.7%) | 1 |
| Urinary tract infection | 0/72 (0%) | 0 | 1/143 (0.7%) | 1 | 0/143 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Costochondritis | 0/72 (0%) | 0 | 0/143 (0%) | 0 | 1/143 (0.7%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Anaplastic oligodendroglioma | 0/72 (0%) | 0 | 1/143 (0.7%) | 1 | 0/143 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Pulmonary embolism | 1/72 (1.4%) | 1 | 0/143 (0%) | 0 | 0/143 (0%) | 0 |
| Vascular disorders | ||||||
| Deep vein thrombosis | 2/72 (2.8%) | 2 | 0/143 (0%) | 0 | 0/143 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Placebo | Adalimumab | Etrolizumab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 14/72 (19.4%) | 23/143 (16.1%) | 20/143 (14%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 5/72 (6.9%) | 5 | 2/143 (1.4%) | 2 | 5/143 (3.5%) | 5 |
| Gastrointestinal disorders | ||||||
| Colitis ulcerative | 8/72 (11.1%) | 8 | 12/143 (8.4%) | 12 | 11/143 (7.7%) | 11 |
| Infections and infestations | ||||||
| Upper respiratory tract infection | 4/72 (5.6%) | 5 | 3/143 (2.1%) | 4 | 4/143 (2.8%) | 4 |
| Nervous system disorders | ||||||
| Headache | 0/72 (0%) | 0 | 9/143 (6.3%) | 10 | 3/143 (2.1%) | 3 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The study being conducted under this agreement is part of the overall study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the study, but only after the first publication or presentation that involves the overall study. The Sponsor may request that confidential information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
| Name/Title | Medical Communications |
|---|---|
| Organization | Hoffmann-La Roche |
| Phone | 800-821-8590 |
| genentech@druginfo.com |
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT02171429
Other Study ID Numbers:
- GA28949
- 2013-004277-27
First Posted:
Jun 24, 2014
Last Update Posted:
Jul 23, 2021
Last Verified:
Jul 1, 2021