1. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial
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Lucy Lam, Jiri Pitha, John Vissing, Laura Fionda, Denis Korobko, Michael Pulley, Tony Vangeneugden, Silvia Bonanno, Nobuhiro Ido, Jerrica Farias, Jafar Shabanpour, James Gilchrist, Girolamo Alfieri, Gyorgyi Szabo, Carlayne E. Jackson, Eduardo Ng, Csilla Rozsa, Hans D. Katzberg, Carlo Antozzi, Aleksandra Golenia, Sayaka Ishida, Temur Margania, Andrzej Szczudlik, Richard J. Barohn, Mari Suzuki., Robert Henegar, Kaoru Sakuma, Evanthia Bernitsas, Elena Lapochka, Yukiko Ozawa, Tomihiro Imai, Debbie Hastings, Antonio Guglietta, Benjamin Frishberg, Elena Antipenko, Vera Bril, Stanislav Vohanka, Isela Hernandez, Ivo Bozovic, Ilona Vergunova, Lorenzo Maggi, Andreas Meisel, Ali Malekniazi, Tahseen Mozaffar, Emmanuelle Salort-Campana, Yasmin Camberos, Jan J.G.M. Verschuuren, Masayuki Masuda, Masanori Takahashi, Yoshihiko Okubo, Marek Smilowski, Yasushi Suzuki, Mary Wagoner, Andrew Heim, David Bors, Chiho Watanabe, Fiammetta Vanoli, Antonio Reia, Zubair Quraishi, Omar Jawdat, Makoto Samukawa, Gregory Sahagian, Gedeonne Margo Jakab, Eiichi Nomura, Samantha Colgan, Cindy Benzel, Ayako Mori, Annabel M. Ruiter, Ratna Bharavaju-Sanka, Roman Shakarishvili, Victoria Cannon, Malkova Nadezhda, Tomas Horak, Anna Kostera-Pruszczyk, Eniko Szabo, Emilien Delmont, Alexander Tsiskaridze, Lubna Daniyal, Vidosava Rakocevic Stojanovic, Szilvia Toth, Siegfried Kohler, Iveta Novakova, Katherine Roath, Kazuna Ikeda, Salma Akhter, Claudia Heibutzki, Martijn R. Tannemaat, Marta Pinkosz, Mads Peter Godtfeldt Stemmerik, Chafic Karam, Irys Caristo, Carolyn Paiz, Josef Bednarik, Monika Frasinska, Stefania Morino, Norianne Pimentel, Kanako Minemoto, Rekha Pillai, Linda Wagemaekers, Annelien De Pue, Irina Poverennova, Katerina Reguliova, Jana Junkerova, Angela Marsili, Anne-Marie Peters, Maren Wyckmans, Michaela Tyblova, Debbie Eggleston, Anne Mette Ostergaard Autzen, Takamichi Sugimoto, Kuldeep Kumar Khatri, Niraja Suresh, Jan De Bleecker, Lea Gerischer, Grazyna Zwolinska, Kevin R Keene, Yosuke Onishi, Francesco Saccà, Zaeem A. Siddiqi, Marjolein Van Heur, Jeffrey Statland, Tatiana Romanova, Diana Dimitrova, Stojan Peric, Tomoko Tsuda, Cathy Bailey, Lubov Urtaeva, Lizzie Zafirakos, Katherine Ruzhansky, Tomoya Kubota, Angela Campanella, Nadezhda Kuznetsova, Sarah Jones, Giovanni Antonini, Hiroyuki Murai, Luca Leonardi, Alan R. Berger, Jonathan Baets, Peter Ulrichts, Said R. Beydoun, Michala Jakubikova, Mamatha Pasnoor, James F. Howard, Leila Darki, Katerina Havelkova, Namita Goyal, Akiyuki Uzawa, Tia Nguyen, Miki Takaki, Matteo Garibaldi, Manisha Kak, Ivonne Turner, Aude-Marie Grapperon, Mageda Horakova, Yuebing Li, Ivana Basta, Lech Szczechowski, Shabber Mannan, Aneta Pasko, Caroline Vinck, Riccardo Giossi, Rudolf Mercelis, Ivana Jurajdova, Lesly Welsh, Małgorzata Bilińska, Marek Halas, Dragana Lavrnic, Kimiaki Utsugisawa, Todd Levine, Erik Velasquez, Daisuke Yamamoto, Constantine Farmakidis, John Anthony Morren, Sarah Hoffman, Manisha Chopra, Shingo Konno, Rita Frangiamore, Kelly Jia, Jana Horakova, Anna Melnikova, Piotr Szczudlik, Ali Habib, Giorgia Puorro, Michael D. Weiss, Robert P. Lisak, Hiroyuki Naito, Shahram Attarian, Hiroko Nakamura, Shin Hisahara, Mazen M. Dimachkie, Genya Watanabe, Duaa Jabari, Ekaterina Bulatova, Angela Genge, Makiko Naito, Melissa Currence, Henning Andersen, Katrien De Mey, Kathy de Koning, Yuen T. So, Chiara Pane, Renato Mantegazza, Rebecca Traub, Manato Yasuda, Amy Visser, Dike Remstedt, Yuka Takematsu, Frauke Stascheit, Ayumi Kamei, Tuan Vu, Tulio E. Bertorini, Ludivine Kouton, Neelam Goyal, Flicia Mada, Nizar Chahin, Mihiro Shimizu, Srikanth Muppidi, and Erina Sugano
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Population ,fc fragment ,Placebo ,Antibodies, Monoclonal, Humanized ,law.invention ,efgartigimod ,myasthenia gravis ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,Activities of Daily Living ,Myasthenia Gravis ,medicine ,Clinical endpoint ,Humans ,Receptors, Cholinergic ,Dosing ,Longitudinal Studies ,education ,Biology ,Autoantibodies ,education.field_of_study ,business.industry ,Headache ,Antibodies, Monoclonal ,Middle Aged ,medicine.disease ,Myasthenia gravis ,3. Good health ,Immunoglobulin Fc Fragments ,Clinical trial ,Chemistry ,030104 developmental biology ,Tolerability ,Female ,Human medicine ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p
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- 2020