Etrolizumab versus adalimumab or placebo as induction therapy for moderately to severely active ulcerative colitis (HIBISCUS): two phase 3 randomised, controlled trials.
Adalimumab
/ adverse effects
Adolescent
Adult
Aged
Antibodies, Monoclonal, Humanized
/ adverse effects
Colitis, Ulcerative
/ chemically induced
Colonoscopy
Double-Blind Method
Female
Gastrointestinal Agents
/ adverse effects
Humans
Induction Chemotherapy
Male
Middle Aged
Placebos
/ therapeutic use
Remission Induction
Severity of Illness Index
Symptom Flare Up
Young Adult
Journal
The lancet. Gastroenterology & hepatology
ISSN: 2468-1253
Titre abrégé: Lancet Gastroenterol Hepatol
Pays: Netherlands
ID NLM: 101690683
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
16
06
2021
revised:
27
08
2021
accepted:
31
08
2021
pubmed:
20
11
2021
medline:
22
2
2022
entrez:
19
11
2021
Statut:
ppublish
Résumé
Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission relative to placebo in patients with moderately to severely active ulcerative colitis. The HIBISCUS studies aimed to compare the efficacy and safety of etrolizumab to adalimumab and placebo for induction of remission in patients with moderately to severely active ulcerative colitis. HIBISCUS I and HIBISCUS II were identically designed, multicentre, phase 3, randomised, double-blind, placebo-controlled and active-controlled studies of etrolizumab, adalimumab, and placebo in adult (18-80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. All patients had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In both studies, patients were randomly assigned (2:2:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks; subcutaneous adalimumab 160 mg on day 1, 80 mg at week 2, and 40 mg at weeks 4, 6, and 8; or placebo. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All patients and study site personnel were masked to treatment assignment. The primary endpoint was induction of remission at week 10 (defined as MCS of 2 or lower, with individual subscores of 1 or lower, and rectal bleeding subscore of 0) with etrolizumab compared with placebo. Pooled analyses of both studies comparing etrolizumab and adalimumab were examined for several clinical and endoscopic endpoints. Efficacy was analysed using a modified intent-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT02163759 (HIBISCUS I), NCT02171429 (HIBISCUS II). Between Nov 4, 2014, and May 25, 2020, each study screened 652 patients (HIBISCUS I) and 613 patients (HIBISCUS II). Each study enrolled and randomly assigned 358 patients (HIBISCUS I etrolizumab n=144, adalimumab n=142, placebo n=72; HIBISCUS II etrolizumab n=143; adalimumab n=143; placebo n=72). In HIBISCUS I, 28 (19·4%) of 144 patients in the etrolizumab group and five (6·9%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 12·3% (95% CI 1·6 to 20·6; p=0·017) in favour of etrolizumab. In HIBISCUS II, 26 (18·2%) of 143 patients in the etrolizumab group and eight (11·1%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 7·2% (95% CI -3·8 to 16·1; p=0·17). In the pooled analysis, etrolizumab was not superior to adalimumab for induction of remission, endoscopic improvement, clinical response, histological remission, or endoscopic remission; however, similar numerical results were observed in both groups. In HIBISCUS I, 50 (35%) of 144 patients in the etrolizumab group reported any adverse event, compared with 61 (43%) of 142 in the adalimumab group and 26 (36%) of 72 in the placebo group. In HIBISCUS II, 63 (44%) of 143 patients in the etrolizumab group reported any adverse event, as did 62 (43%) of 143 in the adalimumab group and 33 (46%) in the placebo group. The most common adverse event in all groups was ulcerative colitis flare. The incidence of serious adverse events in the pooled patient population was similar for etrolizumab (15 [5%] of 287) and placebo (seven [5%] of 144) and lower for adalimumab (six [2%] of 285). Two patients in the etrolizumab group died; neither death was deemed to be treatment related. Etrolizumab was superior to placebo for induction of remission in HIBISCUS I, but not in HIBISCUS II. Etrolizumab was well tolerated in both studies. F Hoffmann-La Roche.
Sections du résumé
BACKGROUND
Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission relative to placebo in patients with moderately to severely active ulcerative colitis. The HIBISCUS studies aimed to compare the efficacy and safety of etrolizumab to adalimumab and placebo for induction of remission in patients with moderately to severely active ulcerative colitis.
METHODS
HIBISCUS I and HIBISCUS II were identically designed, multicentre, phase 3, randomised, double-blind, placebo-controlled and active-controlled studies of etrolizumab, adalimumab, and placebo in adult (18-80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. All patients had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In both studies, patients were randomly assigned (2:2:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks; subcutaneous adalimumab 160 mg on day 1, 80 mg at week 2, and 40 mg at weeks 4, 6, and 8; or placebo. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All patients and study site personnel were masked to treatment assignment. The primary endpoint was induction of remission at week 10 (defined as MCS of 2 or lower, with individual subscores of 1 or lower, and rectal bleeding subscore of 0) with etrolizumab compared with placebo. Pooled analyses of both studies comparing etrolizumab and adalimumab were examined for several clinical and endoscopic endpoints. Efficacy was analysed using a modified intent-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT02163759 (HIBISCUS I), NCT02171429 (HIBISCUS II).
FINDINGS
Between Nov 4, 2014, and May 25, 2020, each study screened 652 patients (HIBISCUS I) and 613 patients (HIBISCUS II). Each study enrolled and randomly assigned 358 patients (HIBISCUS I etrolizumab n=144, adalimumab n=142, placebo n=72; HIBISCUS II etrolizumab n=143; adalimumab n=143; placebo n=72). In HIBISCUS I, 28 (19·4%) of 144 patients in the etrolizumab group and five (6·9%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 12·3% (95% CI 1·6 to 20·6; p=0·017) in favour of etrolizumab. In HIBISCUS II, 26 (18·2%) of 143 patients in the etrolizumab group and eight (11·1%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 7·2% (95% CI -3·8 to 16·1; p=0·17). In the pooled analysis, etrolizumab was not superior to adalimumab for induction of remission, endoscopic improvement, clinical response, histological remission, or endoscopic remission; however, similar numerical results were observed in both groups. In HIBISCUS I, 50 (35%) of 144 patients in the etrolizumab group reported any adverse event, compared with 61 (43%) of 142 in the adalimumab group and 26 (36%) of 72 in the placebo group. In HIBISCUS II, 63 (44%) of 143 patients in the etrolizumab group reported any adverse event, as did 62 (43%) of 143 in the adalimumab group and 33 (46%) in the placebo group. The most common adverse event in all groups was ulcerative colitis flare. The incidence of serious adverse events in the pooled patient population was similar for etrolizumab (15 [5%] of 287) and placebo (seven [5%] of 144) and lower for adalimumab (six [2%] of 285). Two patients in the etrolizumab group died; neither death was deemed to be treatment related.
INTERPRETATION
Etrolizumab was superior to placebo for induction of remission in HIBISCUS I, but not in HIBISCUS II. Etrolizumab was well tolerated in both studies.
FUNDING
F Hoffmann-La Roche.
Identifiants
pubmed: 34798036
pii: S2468-1253(21)00338-1
doi: 10.1016/S2468-1253(21)00338-1
pii:
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Gastrointestinal Agents
0
Placebos
0
Adalimumab
FYS6T7F842
etrolizumab
I2A72G2V3J
Banques de données
ClinicalTrials.gov
['NCT02163759', 'NCT02171429']
Types de publication
Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
17-27Investigateurs
Abdulkhakov Rustem
(A)
Abu Bakar Norasiah
(AB)
Aguilar Humberto
(A)
Aizenberg Diego
(A)
Akpinar Hale
(A)
Akriviadis Evangelos
(A)
Alexeeva Olga
(A)
Alikhanov Bagdadi
(A)
Alvarisqueta Andres
(A)
Ananthakrishnan Ashwin
(A)
Andrews Jane
(A)
Arlukowicz Tomasz
(A)
Atkinson Nathan
(A)
Atug Ozlen
(A)
Bafutto Mauro
(B)
Balaz Jozef
(B)
Bamias George
(B)
Banic Marko
(B)
Baranovsky Andrey
(B)
Barbalaco Neto Guerino
(BN)
Basaranoglu Metin
(B)
Baum Curtis
(B)
Baydanov Stefan
(B)
Bennetts William
(B)
Besisik Fatih
(B)
Bhaskar Sudhir
(B)
Bielasik Andrzej
(B)
Bilianskyi Leonid
(B)
Bilir Bahri
(B)
Blaha Pavol
(B)
Bohman Verle
(B)
Borissova Julia
(B)
Borzan Vladimir
(B)
Bosques-Padilla Francisco
(BP)
Bouhnik Yoram
(B)
Brooker James
(B)
Budko Tetiana
(B)
Budzak Igor
(B)
Bunganic Ivan
(B)
Chapman Jonathon
(C)
Che' Aun Azlida
(CA)
Chernykh Tatiana
(C)
Chiorean Michael
(C)
Chopey Ivan
(C)
Christodoulou Dimitrios
(C)
Chu Pui Shan
(C)
Chumakova Galina
(C)
Cummins Andrew
(C)
Cunliffe Robert
(C)
Cvetkovic Mirjana
(C)
Dagli Ulku
(D)
Danilkiewicz Wit Cezary
(D)
Datsenko Olena
(D)
de Magalhães Francesconi Carlos Fernando
(MF)
Debinski Henry
(D)
Deminova Elena
(D)
Derova Jelena
(D)
Ding John Nik
(D)
Dmitrieva Julia
(D)
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(D)
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(D)
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(D)
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(D)
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(DG)
DuVall George Aaron
(D)
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(D)
Ennis Craig
(E)
Erzin Yusuf
(E)
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(F)
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(F)
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(F)
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(F)
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(F)
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(F)
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(G)
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Déclaration de conflit d'intérêts
Declaration of interests DTR reports personal fees from AbbVie, AltruBio, Biomica, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos, Dizal Pharmaceuticals, GalenPharma/Atlantica, Gilead Sciences, GlaxoSmithKline, InDex Pharmaceuticals, Janssen Pharmaceuticals, Eli Lilly, Pfizer, Prometheus Laboratories, Reistone Biopharma, Roche/Genentech, Takeda, and TECHLAB; and grants from Takeda, outside the submitted work. ID reports personal fees from Abbott, AbbVie, Arena Pharmaceuticals, Cambridge Healthcare, Celgene/Bristol Myers Squibb, Celltrion, MSD, Falk Pharma, Food Industries Association, Gilead Sciences, Integra Holdings, Janssen Pharmaceuticals, Neopharm, Nestle, Pfizer, Rafa Laboratories, Roche/Genentech, Sangamo, Sublimity, Sandoz, Takeda, and Wild Biotech; and grants from Altman Research and Pfizer, outside the submitted work. YB reports consulting fees from AbbVie, Amgen, Biogaran, Biogen, Boehringer Ingelheim, Celltrion, Ferring, Fresenius Kabi, Gilead Sciences, Hospira, Janssen Pharmaceuticals, Eli Lilly, Mayoly Spindler Pharma, Merck, MSD, Norgine, Pfizer, Roche, Sandoz, Sanofi, Shire, Takeda, and UCB; and grants from AbbVie, Ferring, Hospira, Janssen Pharmaceuticals, MSD, and Takeda. GR-S reports consulting fees from AbbVie, Celgene, Janssen, MSD, Novartis, Pfizer, and Takeda; speaker fees from AbbVie, Janssen Pharmaceuticals, Pfizer, and Takeda; and grants from AbbVie, Janssen Pharmaceuticals, and Shire. PDRH reports consulting fees from AbbVie, Eli Lilly, and Pfizer. DSM reports consulting fees from GI Reviewers. PA, AS, AC, KC-J, SL, and JM are employees of Roche/Genentech and receive Roche stocks as a part of their compensation. ST and YSO were employees of Roche/Genentech at the time of this work, and received salary and stock options during the time of this study. JP reports consulting fees from AbbVie, Arena, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, MSD, Nestle, Oppilan, Pfizer, Progenity, Roche/Genentech, Takeda, Theravance, and TiGenix; and speaker fees from Abbott, Biogen, Janssen Pharmaceuticals, MSD, Roche/Genentech, Pfizer, and Takeda. AD declares no competing interests.