Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Amelia Evoli, Paolo Emilio Alboini, James F Howard, Kimiaki Utsugisawa, Michael Benatar, Hiroyuki Murai, Richard J Barohn, Isabel Illa, Saiju Jacob, John Vissing, Ted M Burns, John T Kissel, Srikanth Muppidi, Richard J Nowak, Fanny O'Brien, Jing-Jing Wang, Renato Mantegazza, Claudio Gabriel Mazia, Miguel Wilken, Carolina OrteaJuliet Saba, Marcelo Rugiero, Mariela Bettini, Gonzalo Vidal, Alejandra Dalila Garcia, Phillipa Lamont, Wai-Kuen Leong, Heidi Boterhoven, Beverly Fyfe, Leslie Roberts, Mahi Jasinarachchi, Natasha Willlems, Julia Wanschitz, Wolfgang Löscher, Jan De Bleecker, Guy Van Den Abeele, Kathy De Koning, Katrien De Mey, Rudy Mercelis, Linda Wagemaekers, Delphine Mahieu, Philip Van Damme, Charlotte Smetcoren, Olivier Stevens, Sarah Verjans, Ann D'Hondt, Petra Tilkin, Alzira Alves De Siqueira Carvalho, Rosa Hasan, Igor Dias Brockhausen, David Feder, Daniel Ambrosio, Ana Paula Melo, Rosana Rocha, Bruno Rosa, Thabata Veiga, Luiz Augusto Da Silva, Jordana Gonçalves Geraldo, Maria Da Penha Morita Ananias, Erica Nogueira Coelho, Gabriel Paiva, Marina Pozo, Natalia Prando, Debora Dada Martineli Torres, Cristiani Fernanda Butinhao, Erica Coelho, Luciana Renata Cubas Volpe, Gustavo Duran, Tamires Cristina Gomes Da Silva, Luiz Otavio Maia Gonçalves, Lucas Eduardo Pazetto, Luciana Souza Duca, Tomás Augusto Suriane Fialho, Maurício André Gheller Friedrich, Alexandre Guerreiro, Henrique Mohr, Maurer Pereira Martins, Daiane Da Cruz Pacheco, Ana Paula Macagnan, Aline De Cassia Santos, Acary Souza Bulle Oliveira, Ana Carolina Amaral De Andrade, Marcelo Annes, Valeria Cavalcante Lino, Wladimir Pinto, Carolina Miranda, Fernanda Carrara, Iandra Souza, Angela Genge, Rami Massie, Natasha Campbell, Vera Bril, Hans Katzberg, Mehran Soltani, Eduardo Ng, Zaeem Siddiqi, Celile Phan, Derrick Blackmore, Stanislav Vohanka, Josef Bednarik, Magda Chmelikova, Marek Cierny, Stanislava Toncrova, Jana Junkerova, Barbora Kurkova, Katarina Reguliova, Olga Zapletalova, Jiri Pitha, Iveta Novakova, Michaela Tyblova, Marcela Wolfova, Ivana Jurajdova, Henning Andersen, Thomas Harbo, Lotte Vinge, Anita Mogensen, Joan Højgaard, Nanna Witting, Anne Mette Autzen, Jane Pedersen, Markus Färkkilä, Sari Atula, Anne Nyrhinen, Juha-Pekka Erälinna, Mikko Laaksonen, Olli Oksaranta, Jaana Eriksson, Tuula Harrison, Claude Desnuelle, Sabrina Sacconi, Marie-Hélène Soriani, Sonia Decressac, Julie Moutarde, Pauline Lahaut, Guilhem Solé, Gwendal Le Masson, Anne-Cécile Wielanek-Bachelet, Morgane Gaboreau, Caroline Moreau, Amy Wilson, Christophe Vial, Françoise Bouhour, Helene Gervais-Bernard, Hélène Merle, Caroline Hourquin, Arnaud Lacour, Olivier Outteryck, Patrick Vermersch, Hélène Zephir, Edouard Millois, Michel Deneve, Fabienne Deruelle, Benedikt Schoser, Stephan Wenninger, Martin Stangel, Sascha Alvermann, Stefan Gingele, Thomas Skripuletz, Kurt-Wolfram Suehs, Corinna Trebst, Karin Fricke, Sotirios Papagiannopoulos, Sevasti Bostantzopoulou, Nicholas Vlaikidis, Martha Zampaki, Nikoletta 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Namie Taichi, Emiko Tsuda, Takashi Hayashi, Shin Hisahara, Tomihiro Imai, Jun Kawamata, Takashi Murahara, Masaki Saitoh, Shun Shimohama, Shuichiro Suzuki, Daisuke Yamamoto, Shingo Konno, Tomomi Imamura, Masashi Inoue, Mayumi Murata, Hiroshi Nakazora, Ritsu Nakayama, Yasuko Ikeda, Miki Ogawa, Maoko Shirane, Takashi Kanda, Motoharu Kawai, Michiaki Koga, Junichi Ogasawara, Masatoshi Omoto, Yasuteru Sano, Hideki Arima, Sachie Fukui, Shigemi Shimose, Hirokazu Shinozaki, Masanori Watanabe, Chieko Yoshikawa, Anneke Van Der Kooi, Marianne De Visser, Tamar Gibson, Jos Maessen, Marc De Baets, Catherine Faber, Maria Johanna Keijzers, Monique Miesen, Anna Kostera-Pruszczyk, Anna Kaminska, Byung-Jo Kim, Chang Nyoung Lee, Yong Seo Koo, Hung Youl Seok, Hoo Nam Kang, Hyejin Ra, Byoung Joon Kim, Eun Bin Cho, Hyelim Lee, Ju-Hong Min, Jinmyoung Seok, Da Yoon Koh, Juyoung Kwon, Jieun Lee, Sangae Park, Yoon-Ho Hong, Jae-Sung Lim, Miri Kim, Seung Min Kim, Yool-Hee Kim, Hyung Seok Lee, Ha Young Shin, Eun Bi Hwang, Miju Shin, Denis Sazonov, Asya Yarmoschuk, Larisa Babenko, Nadezhda Malkova, Anna Melnikova, Denis Korobko, Evgeniya Kosykh, Dmitry Pokhabov, Yulia Nesterova, Vladislav Abramov, Victor Balyazin, Carlos Casasnovas Pons, Maria Alberti Aguilo, Christian Homedes-Pedret, Natalia Julia Palacios, Ana Lazaro, Exuperio Diez Tejedor, Mireya Fernandez-Fournier, Pedro Lopez Ruiz, Francisco Javier Rodriguez De Rivera, Maria Salvado Figueras, Josep Gamez, Maria Salvado, Elena Cortes Vicente, Jordi Diaz-Manera, Luis Querol Gutierrez, Ricardo Rojas Garcia, Nuria Vidal, Elisabet Arribas-Ibar, Fredrik Piehl, Albert Hietala, Lena Bjarbo, Christopher Lindberg, Daniel Jons, Blanka Andersson, Ihsan Sengun, Pinar Ozcelik, Celal Tuga, Muzeyyen Ugur, Cavit Boz, Didem Altiparmak, Sibel Gazioglu, Cigdem Ozen Aydin, Sevim Erdem-Ozdamar, Can Ebru Bekircan-Kurt, Ezgi Yilmaz, Nazire Pinar Acar, Yagmur Caliskan, Husnu Efendi, Seda Aydinlik, Hakan Cavus, Cansu Semiz, Ozlem Tun, Murat Terzi, Baki Dogan, Musa 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Edward Hartmann, Brandy Quarles, Nicole Smalley, Anthony Amato, Thomas Cochrane, Mohammed Salajegheh, Kristen Roe, Katherine Amato, Shirli Toska, Gil Wolfe, Nicholas Silvestri, Kara Patrick, Karen Zakalik, Jonathan Katz, Robert Miller, Marguerite Engel, Elena Bravver, Benjamin Brooks, Sarah Plevka, Maryanne Burdette, Mohammad Sanjak, Megan Kramer, Joanne Nemeth, Clara Schommer, Vern Juel, Jeffrey Guptill, Lisa Hobson-Webb, Kate Beck, Donna Carnes, John Loor, Amanda Anderson, Dale Lange, Eliz Agopian, Jonathan Goldstein, Erin Manning, Lindsay Kaplan, Shara Holzberg, Nicole Kassebaum, Robert Pascuzzi, Cynthia Bodkin, John Kincaid, Riley Snook, Sandra Guinrich, Angela Micheels, Vinay Chaudhry, Andrea Corse, Betsy Mosmiller, Doreen Ho, Jayashri Srinivasan, Michael Vytopil, Nicholas Ventura, Stephanie Scala, Cynthia Carter, Craig Donahue, Carol Herbert, Elaine Weiner, Jonathan Mckinnon, Laura Haar, Naya Mckinnon, Karan Alcon, Kevin Daniels, Nadia Sattar, Dennis Jeffery, Kaitlyn Mckenna, Amanda Guidon, William David, Christina Dheel, Mark Levine-Weinberg, Catherine Nigro, Ericka Simpson, Stanley H Appel, Eugene Lai, Luis Lay, Milvia Pleitez, Sharon Halton, Casey Faigle, Lisa Thompson, Mark Sivak, Susan Shin, Joan Bratton, Daniel Jacobs, Gavin Brown, Ibrez Bandukwala, Morris Brown, Jennifer Kane, Ira Blount, Miriam Freimer, J. Chad Hoyle, Julie Agriesti, Julie Khoury, Tessa Marburger, Harpreet Kaur, Diana Dimitrova, Michelle Mellion, George Sachs, Brigid Crabtree, Roseann Keo, Ele Kim Perez, Sandra Taber, James Gilchrist, Angela Andoin, Taylor Darnell, Neelam Goyal, Sarada Sakamuri, Yuen T So, Lesly Welsh Welsh, Ratna Bhavaraju-Sanka, Alejandro Tobon Gonzalez, Floyd Jones, Amy Saklad, Sharon Nations, Jaya Trivedi, Steve Hopkins, Mohamed Kazamel, Mohammad Alsharabati, Liang Lu, Sandi Mumfrey-Thomas, Amy Woodall, David Richman, Janelle Butters, Molly Lindsay, Tahseen Mozaffar, Tiyonnoh Cash, Namita Goyal, Gulmohor Roy, Veena Mathew, Fatima Maqsood, Brian Minton, H. 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179 Citazioni (Scopus)

Abstract

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II–IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference −11·7, 95% CI −24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.
Lingua originaleEnglish
pagine (da-a)976-986
Numero di pagine11
RivistaLANCET NEUROLOGY
Volume16
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized
  • Autoantibodies
  • Double-Blind Method
  • Drug Resistance
  • Female
  • Humans
  • Male
  • Middle Aged
  • Myasthenia Gravis
  • Neurology (clinical)
  • Outcome Assessment (Health Care)
  • Receptors, Cholinergic
  • Severity of Illness Index

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