Lancet. 2024 Nov 21:S0140-6736(24)01762-8. doi: 10.1016/S0140-6736(24)01762-8.Online ahead of print.

Marc Ferrante ¹, Geert D'Haens ², Vipul Jairath ³, Silvio Danese ⁴, Minhu Chen ⁵, Subrata Ghosh ⁶, Tadakazu Hisamatsu ⁷, Jaroslaw Kierkus ⁸, Britta Siegmund ⁹, Sonja Michelle Bragg ¹⁰, Wallace Crandall ¹⁰, Frederick Durand ¹⁰, Emily Hon ¹⁰, Zhantao Lin ¹⁰, Michelle Ugolini Lopes ¹⁰, Nathan Morris ¹⁰, Marijana Protic ¹⁰, Hilde Carlier ¹⁰, Bruce E Sands ¹¹; VIVID Study Group

Collaborators

• VIVID Study Group: 

Emiliano Tron, Fernanda Dorado Dorado, Lena Thin, Rupert Leong, Hans Seltenreich, Britt Christensen, Anthony Croft, Simon Ghaly, Robert Koch, Walter Reinisch, Sonja Heeren, Peter Bossuyt, Marc Ferrante, Fabio Luiz Maximiano, Ligia Yukie Sassaki, Carolina Baia, Debora Poli, Alexandre de Sousa Carlos, Carlos Fernando de Magalhaes Francesconi, Alexander De Sa Rolim, Julio Razera, Joaquim Simoes Neto, Rodrigo Rocco, Jonathas Stifft, Jonathan Soldera, Genoile Silva, Cintia Mendes Clemente, Sandra Di Felice Boratto, Luciana Teixeira de Campos, Marcelo Rodrigues Borba, Gregory Rosenfeld, Terry Ponich, Allen Lim, Chadwick Williams, Bruce Musgrave, Stephane Gauthier, Wenjia Liu, Chengdang Wang, Hong Guo, Chunxiao Chen, Yan Chen Chen, Qian Cao, Jie Zhong, Min Xu, Yufang Wang, Changqing Zheng, Xiang Gao, Youxiang Chen, Yinglei Miao, Lin Wang, Deliang Liu, Bangmao Wang, Zhengji Song, Xiaowei Liu, Baili Chen, Yi Jiang, Qiang Zhan, Kaiguang Zhang, Hong Shen, Zhaotao Li, Xiaoyan Wang, Mei Wang Wang, De'an Tian, Lei Chen, Wen Tang, Vladimir Borzan, Zeljko Krznaric, Miroslava Volfova, Jiri Pumprla, Lucie Veberova, Michal Tichy, Jan Gregar, David Stepek, Jan Ulbrych, Pavel Drastich, Zdenek Papik, Jan Matous, Martin Lukas, Radka Koskova, Jan Fallingborg, Romain Altwegg, Ginette Fotsing, David Laharie, Stephane Nancey, Laurent Peyrin, Stefan Schreiber, Jörg Hoffmann, Ursula Seidler, Lars Fechner, Katrin Arelin, Christel Contzen, Guido Trenn, Thomas Schaum, Katrin Schoettker, Oliver Bachmann, Jens Encke, Michael Ibe, Christian Jakobeit, Marta Varga, Agnes Salamon, Andras Kafony, Gyula Horvat, Zsanett Heringh, Katalin Bezzegh, Ferenc Izbeki, Laszlo Szalai, Robert Schnabel, Jayanta Samanta, Rupa Banerjee, Ganesh Subramanian, Shrikant Mukewar, Naresh Kumar Bansal, Ajit Sood, Ravi Shankar Bagepally, Porika Shravan Kumar, Pankaj Shrimal, Saumin Shah, Nitin Pai, Vineet Ahuja, Ehud Melzer, Nimer Assy, Eran Goldin, Haim Shirin, Arik Segal, Adi Lahat, Simone Saibeni, Francesco Luzza, Silvio Danese, Flavio Caprioli, Maria Laura Annunziata, Massimo Fantini, Koichiro Matsuda, Sho Takagi, Shuji Kanmura, Mitsuhide Goto, Toshifumi Ashida, Nobuaki Nishimata, Kazuhiko Kawakami, Yoh Ishiguro Ishiguro, Atsuo Maemoto Maemoto, Yuji Naito Naito, Hideaki Naoe, Hiroshi Nakase, Tomohiro Iida, Junichi Akiyama, Masao Yoshioka, Yasuhiko Abe, Ken Takeuchi, Mikio Kawai, Fumihito Hirai, Noriyuki Horiki, Sang Hyoung Park, Dong Ii Park, Sang Bum Kang, Min Kyu Jung, Byung Ik Jang, Yoo Jin Lee, SungJae Shin, Tae-Oh Kim, Hyun-Soo Kim, Bo-In Lee, Jonghun Lee, Hyo Jong Kim, Chang Hwan Choi, Dongwoo Kim, Chang Soo Eun, Ben Kang, Juris Pokrotnieks, Gediminas Kiudelis, Karina Ramirez, Jose Luis Vega Fonseca, Robert Laheij, Jaroslaw Kierkus, Maria Klopocka, Zbigniew Wylegala, Beata Mroziak, Katarzyna Wojcik, Bartosz Korczowski, Beata Gawdis, Wit Danilkiewicz, Magdalena Olszanecka, Jolanta Krzykowska, Zofia Jamrozik, Malgorzata Duszynska, Agnieszka Ciesiolkiewicz, Malgorzata Baluta, Marek Horynski, Jaroslaw Leszczyszyn, Grzegorz Rozumek, Lukasz Firkowski, Marzena Konopko, Jakub Orleanski, Rafal Filip, Anna Wiechowska, Krzysztof Niezgoda, Radu Mateescu, Eugeniu Craciun, Camelia Chioncel, Marioara Musat, Theodor Alexandru Voiosu, Vasily Trofimov, Oksana Shchukina, Anatoly Pershko, Olga Fedorishina, Galina Chumakova, Igor Bakulin, Marina Osipenko, Denis Nikolin, Olga Barysheva, Olga Alexeeva, Konstantin Zakharov, Irina Khodareva, Alexander Tkachev, Alexey Golovenko, Veronika Popova, Vladimir Kashnikov, Maria Vershinina, Pavel Makarchuk, Ekaterina Valuyskikh, Slobodanka Crevar, Petar Svorcan, Tatjana Radakovic, Tibor Hlavaty, Ivan Bunganic, Miroslav Fedurco, Iveta Kalisova, Jozef Balaz, Lubomir Mihalkanin, Maria Dolores Martin Arranz, Luis De Teresa Parreno, Miquel Sans Cuffi, Alejandro Hernandez Camba, Stephan Brand, Pascal Juillerat, Frank Seibold, Hakan Demirci, Ahmet Tezel, Halis Simsek, Murat Kiyici, Can Gonen, Sadettin Hulagu, Tarkan Karakan, Ayhan Cekin, Engin Altintas, Kadri Guven, Hale Akpinar, Yasemin Ozin, Yusuf Erzin, Mehmet Demir, Tuncer Temel, Tetiana Lohdanidi, Valeriy Ivanov, Olha Ivanishyn, Oleksandr Golovchenko, Oksana Gerasymenko, Svitlana Danyliuk, Vira Vyshyvanyuk, Olena Datsenko, Mykola Stanislavchuk, Yaroslava Rishko, Olga Kyrychenko, Dmytro Donets, Yana Shapovalova, Andriy Yurkiv, Oleksandr Oliinyk, Nataliia Tsarynna, Oleksandr Fediv, Yevgen Poplyonkin, Arthur Kaser, Syed Hoque, Hawys Thomas, Shalini Iyengar, Frederic Newman, Ronald Fogel, Peder Pedersen, Chad Gonzales, Gregory McCord, Michael Galambos, Paul Lamb, Jeffrey Schneider, Bal Raj Bhandari, Michael Weiss, Christine Thai, Michael Shapiro, Ziad Younes, Narayanachar Murali, Jason Hou, Todd Williams, Omer Khalid, Connie Hsu, Christopher Bartalos, Calin Arimie, Syed Mumtaz, Israel Crespo, Renee Marchioni Beery, Anne Tuskey, Ryan Gaible, Alan Cutler, Anita Afzali, Kevin Stuart, Eric Ibegbu, Moises Irizarry-Roman, Kimberly Harris, Kwadwo Agyei, Frances Jones, Aasim Sheikh, Liam Zakko, Erica Cohen, George Duvall, Houssam Al Kharrat, Robert Wohlman, William Holderman, Alan Schulman, Sheldon Lidofsky, Peter Wayne, Luis Victores, Christian Stone, Kenolisa Onwueme, Monika Fischer, Shabana Shahid, Keith Moore, Jeffry Katz, Jeff Bullock, Julien Fahed

Author information

¹Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. Electronic address: marc.ferrante@uzleuven.be.

²Inflammatory Bowel Disease Centre, Amsterdam University Medical Center, Amsterdam, Netherlands.

³Department of Medicine, Division of Gastroenterology, Western University, London, ON, Canada.

⁴Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital, Milan, Italy.

⁵Division of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

⁶APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland.

⁷Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan.

⁸Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.

⁹Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany.

¹⁰Eli Lilly and Company, Indianapolis, IN, USA.

¹¹Dr Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Abstract

Background: Mirikizumab, a humanised monoclonal antibody that inhibits IL-23p19, is effective in moderate-to-severe ulcerative colitis. We aimed to evaluate the efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease.

Methods: VIVID-1 was a global phase 3, randomised, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study. The study enrolled adult patients at 324 sites (hospitals or medical centres, clinical practices, and clinical research sites) in 33 countries across Europe, Asia, North America, Central America, South America, and Australia. Adult patients with moderately-to-severely active Crohn's disease and previous inadequate response, loss of response, or intolerance to one or more approved biological therapies or conventional therapies were randomly assigned 6:3:2 to receive mirikizumab 900 mg intravenously at weeks 0, 4, and 8, then 300 mg subcutaneously every 4 weeks from weeks 12 to 52; ustekinumab about 6 mg/kg intravenously at week 0, then 90 mg subcutaneously every 8 weeks from weeks 8 to 52; or placebo. The coprimary endpoints assessing superiority of mirikizumab over placebo were composite endpoints: patient-reported outcome (PRO) clinical response at week 12 and endoscopic response at week 52 (endoscopic response-composite), and PRO clinical response at week 12 and Crohn's Disease Activity Index (CDAI) clinical remission at week 52 (CDAI clinical remission-composite). The adjusted risk differences were calculated, and the comparison was performed by the Cochran-Mantel-Haenszel test. Non-responder imputation was used. VIVID-1 was registered on ClinicalTrials.gov, NCT03926130, and is now complete.

Findings: Between July 23, 2019, and Aug 23, 2023, 1150 patients were randomly assigned and received study treatment (safety population); 1065 patients were included in the efficacy population and received mirikizumab (n=579), ustekinumab (n=287), or placebo (n=199). Both coprimary endpoints were met: endoscopic response-composite was reached in 220 (38·0%) of 579 patients on mirikizumab versus 18 (9·0%) of 199 on placebo (99·5% CI 20·6-36·8; p<0·0001); CDAI clinical remission-composite was reached in 263 (45·4%) of 579 patients on mirikizumab versus 39 (19·6%) of 199 patients on placebo (99·5% CI 15·9-35·6; p<0·0001). The incidence rates of overall adverse events and discontinuations in patients treated with mirikizumab were lower compared with placebo. The most common adverse event across the three groups was COVID-19. Serious adverse events were reported in 65 (10·3%) of 630 patients on mirikizumab, 33 (10·7%) of 309 patients on ustekinumab, and 36 (17·1%) of 211 patients on placebo. There were three deaths during VIVID-1, one in the ustekinumab group, and two in the placebo group, including one in a placebo non-responder who switched to mirikizumab after week 12. None of the deaths were considered related to the study drug. The safety of mirikizumab in Crohn's disease was consistent with its known favourable profile.

Interpretation: Mirikizumab was safe and effective as induction and maintenance treatment for patients with moderately-to-severely active Crohn's disease who had intolerance, inadequate response, or loss of response to standard therapy.

Funding: Eli Lilly and Company.