NCT02163759: HIBISCUS I

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

Completed Phase 3 Results posted Last updated 23 July 2021

What this trial tests

Phase 3 trial testing Adalimumab in Ulcerative Colitis in 358 participants. Completed in 19 March 2020.

Timeline

4 November 2014

Primary endpoint
19 February 2020

19 March 2020

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	358
Start date	4 November 2014
Primary completion	19 February 2020
Estimated completion	19 March 2020
Sites	88 locations across France, Hong Kong, Slovakia, Russia, Ukraine, Serbia, Estonia, Poland

Drugs / interventions tested

• Adalimumab (ADALIMUMAB) — full drug profile →
• Adalimumab Placebo — full drug profile →
• Etrolizumab — full drug profile →
• Etrolizumab Placebo

Conditions studied

• Ulcerative Colitis — all drugs for Ulcerative Colitis →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

Adults 18 to 80, any sex, with Ulcerative Colitis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants in Remission at Week 10 With Etrolizumab as Compared With Placebo, as Determined by the Mayo Clinic Score (MCS), GA28948 Population Primary · 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 permitt

Group	Value	95% CI
Placebo	6.9	3.00 – 15.25
Etrolizumab	19.4	13.81 – 26.67

Percentage of Participants in Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 Population Secondary · 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 permitt

Group	Value	95% CI
Adalimumab	22.5	16.44 – 30.08
Etrolizumab	19.4	13.81 – 26.67

Percentage of Participants in Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population Secondary · 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 permitt

Group	Value	95% CI
Adalimumab	23.5	18.96 – 28.76
Etrolizumab	18.8	14.72 – 23.74

Percentage of Participants With Clinical Response at Week 10, as Determined by the MCS, GA28948 Population Secondary · 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 missin

Group	Value	95% CI
Placebo	50.0	38.75 – 61.25
Adalimumab	52.1	43.95 – 60.16
Etrolizumab	56.9	48.78 – 64.75

Percentage of Participants With Clinical Response at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population Secondary · 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 missin

Group	Value	95% CI
Adalimumab	53.3	47.54 – 59.04
Etrolizumab	54.7	48.92 – 60.36

Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10, as Determined by the MCS Endoscopy Subscore, GA28948 Population Secondary · 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 sco

Group	Value	95% CI
Placebo	22.2	14.17 – 33.09
Adalimumab	33.1	25.89 – 41.19
Etrolizumab	40.3	32.62 – 48.44

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 Secondary · 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 sco

Group	Value	95% CI
Adalimumab	37.9	32.46 – 43.65
Etrolizumab	40.1	34.57 – 45.83

Percentage of Participants in Endoscopic Remission at Week 10, as Determined by the MCS Endoscopy Subscore, GA28948 Population Secondary · 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

Group	Value	95% CI
Placebo	6.9	3.00 – 15.25
Adalimumab	20.4	14.61 – 27.79
Etrolizumab	20.8	15.00 – 28.18

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 Secondary · 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

Group	Value	95% CI
Adalimumab	23.5	18.96 – 28.76
Etrolizumab	20.2	15.97 – 25.23

Percentage of Participants With Histologic Remission at Week 10, as Determined by the Nancy Histological Index, GA28948 Population Secondary · 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 scori

Group	Value	95% CI
Placebo	16.1	9.00 – 27.21
Adalimumab	29.3	21.80 – 38.15
Etrolizumab	42.5	34.02 – 51.44

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 Secondary · 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 scori

Group	Value	95% CI
Adalimumab	36.5	30.57 – 42.92
Etrolizumab	36.8	30.85 – 43.27

Change From Baseline in the MCS Rectal Bleeding Subscore at Week 6, GA28948 Population Secondary · 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). Parti

Group	Value	95% CI
Placebo	-1.0	-1.0 – 0.0
Adalimumab	-1.0	-2.0 – 0.0
Etrolizumab	-1.0	-2.0 – 0.0

Adverse events — posted to ClinicalTrials.gov

Time frame: From Baseline until the end of study (up to 26 weeks). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 2/72 (3%)

Deaths: 0/72

Adalimumab

Serious: 3/142 (2%)

Deaths: 0/142

Etrolizumab

Serious: 8/144 (6%)

Deaths: 1/144

Serious adverse events (13 terms)

Reaction	System	Placebo	Adalimumab	Etrolizumab
Colitis ulcerative	Gastrointestinal disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Cardiac arrest	Cardiac disorders	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—
Eye infection toxoplasmal	Infections and infestations	—	—	—
Pneumonia	Infections and infestations	—	—	—
Pneumonia bacterial	Infections and infestations	—	—	—
Pyelonephritis acute	Infections and infestations	—	—	—
Procedural intestinal perforation	Injury, poisoning and procedural complications	—	—	—
Hypoalbuminaemia	Metabolism and nutrition disorders	—	—	—
Prostatitis	Reproductive system and breast disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Deep vein thrombosis	Vascular disorders	—	—	—

Other adverse events (2 terms — click to expand)

Reaction	System	Placebo	Adalimumab	Etrolizumab
Headache	Nervous system disorders	—	—	—
Colitis ulcerative	Gastrointestinal disorders	—	—	—

Most-reported serious reactions: Colitis ulcerative, Anaemia, Cardiac arrest, Cholelithiasis, Eye infection toxoplasmal, Pneumonia, Pneumonia bacterial, Pyelonephritis acute.

Data from ClinicalTrials.gov NCT02163759 adverse events section.

Sponsor's own description

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 naÏve 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 (GA28949; NCT02171429) was independently conducted.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting integrin pathways: mechanisms and advances in therapy.
   Pang X, He X, Qiu Z, Zhang H, et al · · 2023 · cited 704× · PMID 36588107 · DOI 10.1038/s41392-022-01259-6
2. Antibodies to watch in 2020.
   Kaplon H, Muralidharan M, Schneider Z, Reichert JM. · · 2020 · cited 332× · PMID 31847708 · DOI 10.1080/19420862.2019.1703531
3. Antibodies to watch in 2022.
   Kaplon H, Chenoweth A, Crescioli S, Reichert JM. · · 2022 · cited 245× · PMID 35030985 · DOI 10.1080/19420862.2021.2014296
4. Antibodies to watch in 2021.
   Kaplon H, Reichert JM. · · 2021 · cited 215× · PMID 33459118 · DOI 10.1080/19420862.2020.1860476
5. Antibodies to watch in 2018.
   Kaplon H, Reichert JM. · · 2018 · cited 179× · PMID 29300693 · DOI 10.1080/19420862.2018.1415671
6. Perspectives on Current and Novel Treatments for Inflammatory Bowel Disease.
   Na SY, Moon W. · · 2019 · cited 99× · PMID 31195433 · DOI 10.5009/gnl19019
7. A State-of-the-Art Review of New and Emerging Therapies for the Treatment of IBD.
   Chudy-Onwugaje KO, Christian KE, Farraye FA, Cross RK. · · 2019 · cited 87× · PMID 30445504 · DOI 10.1093/ibd/izy327
8. Etrolizumab versus adalimumab or placebo as induction therapy for moderately to severely active ulcerative colitis (HIBISCUS): two phase 3 randomised, controlled trials.
   Rubin DT, Dotan I, DuVall A, Bouhnik Y, et al · · 2022 · cited 75× · PMID 34798036 · DOI 10.1016/s2468-1253(21)00338-1