Abstract

Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study

Lancet Gastroenterol Hepatol. 2022 Feb;7(2):118-127.doi: 10.1016/S2468-1253(21)00294-6. Epub 2021 Nov 17.

 

Silvio Danese 1Jean-Frederic Colombel 2Milan Lukas 3Javier P Gisbert 4Geert D'Haens 5Bu'hussain Hayee 6Remo Panaccione 7Hyun-Soo Kim 8Walter Reinisch 9Helen Tyrrell 10Young S Oh 11Swati Tole 11Akiko Chai 11Kirsten Chamberlain-James 10Meina Tao Tang 11Stefan Schreiber 12GARDENIA Study Group

GARDENIA Study Group: Nazimuddin AbooTariq AhmadXavier Aldeguer ManteMatthieu AllezSven AlmerRomain AltweggMontserrat Andreu GarciaRamesh ArasaradnamSandro ArdizzoneAlessandro ArmuzziIan ArnottGuy AumaisIrit Avni-BironPeter BarrowIan BealesFernando Bermejo San JoseAbraham BezuidenhoutLivia BianconeMichael BlaekerStuart BloomBernd BokemeyerFabrizio BossaPeter BossuytGuillaume BouguenYoram BouhnikGerd BoumaRaymond BourdagesArnaud BourreilleChristian BoustiereTomas BrabecStephan BrandCarsten BueningAnthony BuissonGuillaume CadiotXavier Calvet CalvoFranck CarbonnelDaniel CarpioJae Hee CheonNaoki ChibaCamelia ChioncelNicoleta-Claudia CimpoeruMartin ClodiGino Roberto CorazzaRocco CosintinoJose CotterThomas CreedFraser CummingsSilvio DaneseGian Luigi De' AngelisMarc De MaeyerMilind DesaiEtienne DesiletsPierre DesreumauxOlivier DewitGeert D'HaensJohanna DinterEcaterina Daniela DobruTomas DoudaDan Lucian DumitrascuMatthias EbertAna Echarri PiudoMagdy ElkhashabChang Soo EunBrian FeaganRoland FejesCatarina FidalgoSigal FishmanBernard FlouriéSharyle FowlerWalter FriesCsaba FulopMathurin FumeryGyula G KissSonja GassnerDaniel GayaBastianello GermanàLiliana Simona GheorgheCyrielle Gilletta de Saint JosephPaolo GionchettiAdrian-Eugen GoldisRaquel GonçalvesJean-Charles GrimaudTibor GyökeresHerve HagegeAndrei HaidarHeinz HartmannPeter HasselblattBuhussain HayeeXavier HebuternePer HellströmPieter HindryckxHelena HlavovaFrank HoentjenStefanie HowaldtLudek HrdlickaKyu Chan HuhMaria Isabel Iborra ColominoFlorentina Ionita-RaduPeter IrvingJørgen JahnsenByungIk JangJeroen JansenSeong Woo JeonRodrigo Jover MartinezPascal JuilleratPer KarlénArthur KaserRadan KeilDeepak KejariwalDan KeretReena KhannaDongwoo KimDuk Hwan KimHyo-Jong KimHyun-Soo KimJoo Sung KimKueongok KimKyung-Jo KimSung Kook KimYoung-Ho KimJochen KlausAnna KohnVladimir KojeckyJa Seol KooRobert KozakMilan KremerTunde KristofFrederik KrugerDavid LaharieAdi Lahat-ZokEvgeny LandaJonghun LeeKang-Moon LeeKook Lae LeeYooJin LeeFrank LenzeWee Chian LimJimmy LimdiJames LindsayPilar Lopez SerranoEdouard LouisStefan LuethMilan LukasGiovanni MaconiFazia ManaSteven MannJohn MansfieldSantino MarchiMarco MarinoJohn MarshallMaria Dolores Martin ArranzRadu-Bogdan MateescuJohn McLaughlinSimon McLaughlinEhud MelzerJessica MertensPaul MitrutTamas MolnarVinciane MulsPushpakaran MunuswamyCharles MurrayTimna NaftaliVisvakuren NaidooYusuf NanabhayLucian NegreanuAugustin NguyenThomas OchsenkuehnAmbrogio OrlandoRemo PanaccioneJulian Panes DiazMaya ParitskyDong Il ParkJihye ParkLuca PastorelliMarkus Peck-RadosavljevicFarhad PeeraniJavier Perez GisbertLaurent Peyrin-BirouletLaurence PiconMarieke PierikTerry PonichFrancisco PortelaMaartens Jeroen PrinsIstvan RaczKhan Fareed RahmanJean-Marie ReimundMax ReinshagenXavier RoblinRodolfo RoccaFrancesca RogaiGerhard RoglerAgnes SalamonEnnaliza SalazarZoltan SalloSunil SamuelMiquel de Los Santos Sans CuffiEdoardo Vincenzo SavarinoVincenzo SavarinoGuillaume SavoyeStefan SchreiberAndrada SeiceanChristian SelingerDavid Martins SerraHang Hock ShimSungJae ShinBritta SiegmundJesse SiffledeenWayne SimmondsJan SmidJose SollanoGeun Am SongAlexander SpeightIoan SporeaDirk StaessenGeorge StancuAlan SteelDavid StepekVictor StoicaAndreas SturmGyorgy SzekelyTeck Kiang TanCarlos Taxonera SamsoJohn ThomsonMichal TichyGabor Tamas TothZsolt TulassayMarcello VangeliMarta VargaAna VieiraStephanie ViennotErica VillaPetr VitekHarald VogelsangPetr VyhnalekPeter WahabJens WalldorfByong Duk YeChristopher Ziady

 
     

Author information

1Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy.

2Icahn School of Medicine, Mount Sinai, New York City, NY, USA.

3Clinical and Research Centre for Inflammatory Bowel Diseases, ISCARE IVF Clinical Center Ceskomoravská, Prague, Czech Republic.

4Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.

5Department of Gastroenterology, Imelda Hospital, Amsterdam University Medical Center, Amsterdam, Netherlands.

6King's College Hospital Denmark Hill London, London, UK.

7University of Calgary, Calgary, AB, Canada.

8Department of Internal Medicine 20, Yonsei University, Wonju, South Korea.

9Medical University of Vienna, Vienna, Austria.

10Roche, Welwyn Garden City, UK.

11Genentech, South San Francisco, CA, USA.

12Christian-Albrechts University, Kiel, Germany. Electronic address: s.schreiber@mucosa.de.

Abstract

Background: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis.

Methods: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) 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. Patients were required to have 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. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment.

Findings: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment.

Interpretation: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint.

Funding: F Hoffmann-La Roche.

 

 

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