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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02171429
Registration number
NCT02171429
Ethics application status
Date submitted
20/06/2014
Date registered
24/06/2014
Date last updated
23/07/2021
Titles & IDs
Public title
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
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Scientific 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
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Secondary ID [1]
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2013-004277-27
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Secondary ID [2]
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GA28949
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Universal Trial Number (UTN)
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Trial acronym
HIBISCUS II
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Ulcerative Colitis
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Condition category
Condition code
Oral and Gastrointestinal
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Inflammatory and Immune System
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Other inflammatory or immune system disorders
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Oral and Gastrointestinal
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Inflammatory bowel disease
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Adalimumab
Other interventions - Adalimumab Placebo
Treatment: Drugs - Etrolizumab
Other interventions - Etrolizumab Placebo
Placebo Comparator: Placebo - Participants will receive placebo matching to etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8.
Active Comparator: Adalimumab - Participants will receive adalimumab up to Week 8 and placebo matching to etrolizumab up to Week 12.
Experimental: Etrolizumab - Participants will receive etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8.
Treatment: Drugs: 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 interventions: Adalimumab Placebo
Placebo matching to adalimumab will be administered SC at Weeks 0, 2, 4, 6, and 8.
Treatment: Drugs: 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 interventions: 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]).
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage of Participants in Remission at Week 10 With Etrolizumab Compared With Placebo, as Determined by the Mayo Clinic Score (MCS), GA28949 Population
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Assessment method [1]
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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.
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Timepoint [1]
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Week 10
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Secondary outcome [1]
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Percentage of Participants in Remission at Week 10 With Etrolizumab Compared With Adalimumab, as Determined by the MCS, GA28949 Population
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Assessment method [1]
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0
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.
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Timepoint [1]
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Week 10
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Secondary outcome [2]
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Percentage of Participants in Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population
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Assessment method [2]
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0
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.
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Timepoint [2]
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Week 10
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Secondary outcome [3]
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Percentage of Participants With Clinical Response at Week 10, as Determined by the MCS, GA28949 Population
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Assessment method [3]
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0
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.
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Timepoint [3]
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Week 10
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Secondary outcome [4]
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Percentage of Participants With Clinical Response at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population
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Assessment method [4]
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0
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.
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Timepoint [4]
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Week 10
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Secondary outcome [5]
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Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10, as Determined by the Mayo Endoscopy Subscore, GA28949 Population
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Assessment method [5]
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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.
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Timepoint [5]
0
0
Week 10
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Secondary outcome [6]
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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
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Assessment method [6]
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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.
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Timepoint [6]
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Week 10
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Secondary outcome [7]
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Percentage of Participants in Endoscopic Remission at Week 10, as Determined by the MCS Endoscopy Subscore, GA28949 Population
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Assessment method [7]
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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.
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Timepoint [7]
0
0
Week 10
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Secondary outcome [8]
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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
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Assessment method [8]
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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.
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Timepoint [8]
0
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Week 10
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Secondary outcome [9]
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Percentage of Participants With Histologic Remission at Week 10, as Determined by the Nancy Histological Index, GA28949 Population
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Assessment method [9]
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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.
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Timepoint [9]
0
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Week 10
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Secondary outcome [10]
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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
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Assessment method [10]
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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.
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Timepoint [10]
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Week 10
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Secondary outcome [11]
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Change From Baseline in the MCS Rectal Bleeding Subscore at Week 6, GA28949 Population
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Assessment method [11]
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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.
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Timepoint [11]
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Baseline, Week 6
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Secondary outcome [12]
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Change From Baseline in the MCS Rectal Bleeding Subscore at Week 6 With Etrolizumab as Compared With Adalimumab, GA28948 & GA28949 Pooled Population
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Assessment method [12]
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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.
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Timepoint [12]
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Baseline, Week 6
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Secondary outcome [13]
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Change From Baseline in the MCS Stool Frequency Subscore at Week 6, GA28949 Population
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Assessment method [13]
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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.
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Timepoint [13]
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Baseline, Week 6
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Secondary outcome [14]
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Change From Baseline in the MCS Stool Frequency Subscore at Week 6 With Etrolizumab as Compared With Adalimumab, GA28948 & GA28949 Pooled Population
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Assessment method [14]
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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.
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Timepoint [14]
0
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Baseline, Week 6
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Secondary outcome [15]
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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
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Assessment method [15]
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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.
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Timepoint [15]
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Baseline, Week 10
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Secondary outcome [16]
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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
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Assessment method [16]
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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.
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Timepoint [16]
0
0
Baseline, Week 10
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Secondary outcome [17]
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Change From Baseline in Ulcerative Colitis Functional Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28949 Population
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Assessment method [17]
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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.
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Timepoint [17]
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Baseline, Week 10
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Secondary outcome [18]
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Change From Baseline in Ulcerative Colitis Functional Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28948 & GA28949 Pooled Population
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Assessment method [18]
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0
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.
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Timepoint [18]
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0
Baseline, Week 10
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Secondary outcome [19]
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Percentage of Participants in Clinical Remission at Week 10, as Determined by the MCS, GA28949 Population
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Assessment method [19]
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0
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.
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Timepoint [19]
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0
Week 10
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Secondary outcome [20]
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Percentage of Participants in Remission at Week 10 and Week 14, as Determined by the MCS, GA28949 Population
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Assessment method [20]
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0
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.
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Timepoint [20]
0
0
Weeks 10 and 14
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Secondary outcome [21]
0
0
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
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Assessment method [21]
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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.
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Timepoint [21]
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0
Baseline, Week 10
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Secondary outcome [22]
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Pharmacokinetics of Etrolizumab: Serum Concentration, GA28949 Population
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Assessment method [22]
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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.
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Timepoint [22]
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Weeks 10 and 14
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Secondary outcome [23]
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0
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
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Assessment method [23]
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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).
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Timepoint [23]
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0
From Baseline until the end of study (up to 26 weeks)
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Secondary outcome [24]
0
0
Number and Percentage of Participants by Marked Laboratory Abnormality Status for Hematology Parameters as a Shift Table From Baseline to Week 10, GA28949 Population
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Assessment method [24]
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0
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
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Timepoint [24]
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0
From Baseline up to Week 10
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Secondary outcome [25]
0
0
Number and Percentage of Participants by Marked Laboratory Abnormality Status for Chemistry Parameters as a Shift Table From Baseline to Week 10, GA28949 Population
Query!
Assessment method [25]
0
0
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.
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Timepoint [25]
0
0
From Baseline up to Week 10
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Secondary outcome [26]
0
0
Number and Percentage of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Anytime Post-Baseline, GA28949 Population
Query!
Assessment method [26]
0
0
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).
Query!
Timepoint [26]
0
0
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)
Query!
Eligibility
Key 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
Query!
Minimum age
18
Years
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Maximum age
80
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
Query!
Key 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
Query!
Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people analysing the results/data
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Query!
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
14/11/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
25/05/2020
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Sample size
Target
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Accrual to date
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Final
358
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Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
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Recruitment hospital [1]
0
0
Concord Repatriation General Hospital - Concord
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Recruitment hospital [2]
0
0
Royal Adelaide Hospital - Adelaide
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Recruitment hospital [3]
0
0
Flinders Medical Centre - Bedford Park
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Recruitment hospital [4]
0
0
St Vincent's Hospital Melbourne - Fitzroy
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Recruitment hospital [5]
0
0
Footscray Hospital; Gastroenterology - Footscray
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Recruitment postcode(s) [1]
0
0
2139 - Concord
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Recruitment postcode(s) [2]
0
0
5000 - Adelaide
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Recruitment postcode(s) [3]
0
0
5042 - Bedford Park
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Recruitment postcode(s) [4]
0
0
3065 - Fitzroy
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Recruitment postcode(s) [5]
0
0
3011 - Footscray
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Recruitment outside Australia
Country [1]
0
0
United States of America
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State/province [1]
0
0
Florida
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Country [2]
0
0
United States of America
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State/province [2]
0
0
Kansas
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0
0
United States of America
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State/province [3]
0
0
Ohio
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Country [4]
0
0
Argentina
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State/province [4]
0
0
Mar del Plata
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Country [5]
0
0
Brazil
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State/province [5]
0
0
BA
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Country [6]
0
0
Brazil
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State/province [6]
0
0
CE
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Country [7]
0
0
Brazil
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State/province [7]
0
0
PR
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Country [8]
0
0
Brazil
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State/province [8]
0
0
RS
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Country [9]
0
0
Brazil
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State/province [9]
0
0
SP
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Country [10]
0
0
Bulgaria
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State/province [10]
0
0
Dupnitsa
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Country [11]
0
0
Bulgaria
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State/province [11]
0
0
Pleven
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Country [12]
0
0
Bulgaria
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State/province [12]
0
0
Ruse
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Country [13]
0
0
Bulgaria
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State/province [13]
0
0
Sliven
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Country [14]
0
0
Bulgaria
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State/province [14]
0
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Sofia
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0
0
Bulgaria
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State/province [15]
0
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Stara Zagora
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0
Bulgaria
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State/province [16]
0
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Varna
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0
0
Colombia
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0
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Cali
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0
0
Colombia
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0
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Medellin
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0
0
Croatia
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0
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Osijek
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0
0
Croatia
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State/province [20]
0
0
Zagreb
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0
0
Czechia
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State/province [21]
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Hradec Kralove
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Country [22]
0
0
Czechia
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State/province [22]
0
0
Olomouc
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0
0
Czechia
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State/province [23]
0
0
Pardubice
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0
0
Czechia
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State/province [24]
0
0
Praha 7
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0
0
France
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State/province [25]
0
0
Pierre Benite
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0
0
Greece
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State/province [26]
0
0
Herakleion
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0
0
Hungary
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State/province [27]
0
0
Gyor
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Country [28]
0
0
Latvia
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State/province [28]
0
0
Daugavpils
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0
0
Latvia
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State/province [29]
0
0
Riga
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0
0
Lithuania
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State/province [30]
0
0
Kaunas
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0
0
Lithuania
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0
Klaipeda
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0
0
Lithuania
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0
Vilnius
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0
0
Malaysia
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0
Kota Bahru
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0
Malaysia
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Kuala Lumpur
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0
Malaysia
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0
Pahang
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0
0
New Zealand
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State/province [36]
0
0
Auckland
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Country [37]
0
0
New Zealand
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State/province [37]
0
0
Dunedin
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Country [38]
0
0
New Zealand
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State/province [38]
0
0
Hamilton
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Country [39]
0
0
New Zealand
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State/province [39]
0
0
Takapuna
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Country [40]
0
0
New Zealand
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State/province [40]
0
0
Tauranga
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Country [41]
0
0
Poland
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State/province [41]
0
0
Katowice
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0
0
Poland
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State/province [42]
0
0
Ksawerow
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0
0
Poland
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State/province [43]
0
0
Nowy Targ
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0
0
Poland
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State/province [44]
0
0
Rzeszow
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0
0
Poland
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State/province [45]
0
0
Rzeszów
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0
0
Poland
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State/province [46]
0
0
Szczecin
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0
0
Poland
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State/province [47]
0
0
Warszawa
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0
0
Poland
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State/province [48]
0
0
Wroclaw
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0
0
Poland
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State/province [49]
0
0
Lódz
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Country [50]
0
0
Russian Federation
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State/province [50]
0
0
Sankt Petersburg
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Country [51]
0
0
Russian Federation
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State/province [51]
0
0
Barnaul
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0
0
Russian Federation
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State/province [52]
0
0
Irkutsk
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Country [53]
0
0
Russian Federation
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State/province [53]
0
0
Novosibirsk
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Country [54]
0
0
Russian Federation
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State/province [54]
0
0
Omsk
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Country [55]
0
0
Russian Federation
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State/province [55]
0
0
St. Petersburg
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Country [56]
0
0
Russian Federation
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State/province [56]
0
0
Stavropol
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Country [57]
0
0
Russian Federation
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State/province [57]
0
0
Voronezh
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Country [58]
0
0
Turkey
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State/province [58]
0
0
Ankara
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Country [59]
0
0
Turkey
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State/province [59]
0
0
Gaziantep
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Country [60]
0
0
Turkey
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State/province [60]
0
0
Istanbul
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Country [61]
0
0
Turkey
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State/province [61]
0
0
Kocaeli
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Country [62]
0
0
Ukraine
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State/province [62]
0
0
Kharkiv Governorate
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Country [63]
0
0
Ukraine
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State/province [63]
0
0
KIEV Governorate
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Country [64]
0
0
Ukraine
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State/province [64]
0
0
Podolia Governorate
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Country [65]
0
0
Ukraine
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State/province [65]
0
0
Dnipropetrovsk
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Country [66]
0
0
Ukraine
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State/province [66]
0
0
Kharkiv
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Country [67]
0
0
Ukraine
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State/province [67]
0
0
Kherson
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Country [68]
0
0
Ukraine
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State/province [68]
0
0
Poltava
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Country [69]
0
0
Ukraine
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State/province [69]
0
0
Vinnytsia
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Country [70]
0
0
Ukraine
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State/province [70]
0
0
Zaporizhzhia
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Hoffmann-La Roche
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02171429
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
0
0
Clinical Trials
Query!
Address
0
0
Hoffmann-La Roche
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Country
0
0
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Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
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Contact person for public queries
Name
0
0
Query!
Address
0
0
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Country
0
0
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Phone
0
0
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Fax
0
0
Query!
Email
0
0
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02171429
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