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Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

医学 脊髓性肌萎缩 安慰剂 萎缩 临床终点 物理疗法 不利影响 内科学 随机对照试验 物理医学与康复 疾病 病理 替代医学
作者
Eugenio Mercuri,Nicolas Deconinck,Elena Mazzone,A. Nascimento,Maryam Oskoui,Kayoko Saito,Carole Vuillerot,Giovanni Baranello,Odile Boespflug‐Tanguy,Nathalie Goemans,Janbernd Kirschner,Anna Kostera‐Pruszczyk,Laurent Servais,Marianne Gerber,Ksenija Gorni,Omar Khwaja,Heidemarie Kletzl,R. Scalco,Hannah Staunton,Wai Yin Yeung,Carmen Martín,Paulo Fontoura,John Day,Joseph J. Volpe,John Posner,Ulrich Kellner,Rosaline C. M. Quinlivan,Aurore Daron,Stéphanie Delstanche,Romain Bruninx,Fabian Dal Farra,O. Schneider,Nicolas Deconinck,Irina Balikova,Patricia Delbeke,Inge Joniau,Valentine Tahon,Sylvia Wittevrongel,Elke De Vos,Nathalie Goemans,Ingele Casteels,Liesbeth De Waele,Irina Balikova,Cathérine Cassiman,Lies Prové,David Kinoo,Lisa Vancampenhout,M. van den Hauwe,Annelies Van Impe,Alexandra Prufer de Queiroz Campos Araújo,Aline Chacon Pereira,Flávia Nardes,Lorena Haefeli,Júlia Dutra Rossetto,Marcos Ferreira Rebel,Jaqueline Almeida Pereira,Craig Campbell,Sapna Sharan,Wendy L. McDonald,Cheryl Scholtes,Jean K. Mah,Maria Sframeli,Angela W. Chiu,Jane Hagel,Maryam Oskoui,Raquel Beneish,Gaela Cariou-Palmer,Connie Pham,Daniela Toffoli,Stéphanie Arpin,Sarah Turgeon Desilets,Yi Wang,Chaoping Hu,Jianfeng Huan,Qian Chen,Li Shen,Ying Xiao,Zhenxuan Zhou,Hui Li,Sujuan Wang,Hui Xiong,Xingzhi Chang,Hui Dong,Ying Liu,Tian Sang,Cuijie Wei,Jing Wen,Yiwen Cao,Xingyao Ly,Jing Wen,Jingjing Zhao,Wenzhu Li,Lun Qin,Nina Barišić,Martina Galiot Delić,Petra Kristina Ivkić,Nenad Vukojević,Ivana Kern,B Najdanović,Marin Skugor,Laurent Servais,Odile Boespflug‐Tanguy,Teresa Gidaro,A. Seferian,Silvana De Lucia,Emmanuel Barreau,Nabila M'Nafek,Marta Momtchilova,Helene Peche,Carole Valherie,Allison Grange,Charlotte Lilien,Darko Milaščević,Shotaro Tachibana,Claudia Ravelli,Ruxandra Cardaş,Jessica Taytard,Guillaume Aubertin,Laure Vanden Brande,Jean‐Baptiste Davion,Stéphanie Coopman,Ikram Bouacha,Philippe Debruyne,Sabine Defoort,Gilles Derlyn,Florian Leroy,Loïc Danjoux,J Guilbaud,Isabelle Desguerre,Christine Barnérias,Michaëla Semeraro,Dominique Brémond‐Gignac,Lenaïc Bruère,Maxence Rateaux,Élodie Deladrière,Virginie Germa,Yann Péréon,Sandra Mercie,Fanny Billaud,Lucie Le Goff,Guy Letellier,Carole Vuillerot,Aurélie Portefaix,Camille De-Montferrand,Laure Le-Goff,Stéphanie Fontaine,Manel Saidi,N. Bouzid,Aurélie Barrière,Marie Tinat,Janbernd Kirschner,Michelle Dreesbach,Wolf A. Lagrèze,Bettina Michaelis,Fanni Molnár,Dorina Seger,Sibylle Emilie Vogt,Enrico Bertini,Adele D’Amico,Sergio Petroni,Anna Maria Bonetti,Adelina Carlesi,Irene Mizzoni,Claudio Bruno,Enrico Priolo,Giuseppe Rao,Simone Morando,Paola Tacchetti,Ambra Zuffi,Giacomo P. Comi,Roberta Brusa,Stefania Corti,Velardo Daniele,Alessandra Govoni,Francesca Magri,Valeria Minorini,Silvia Osnaghi,Francesca Abbati,Federica Fassini,Michaela Foà,Amaqlia Lopopolo,Megi Meneri,Francesca Zoppas,Valeria Parente,Giovanni Baranello,Riccardo Masson,Stefania Bianchi Marzoli,Diletta Santarsiero,Myriam Garcia Sierra,Gemma Tremolada,Maria Teresa Arnoldi,M. E. F Viganó,Riccardo Zanin,Eugenio Mercuri,Laura Antonaci,Roberto De Sanctis,Marika Pane,Maria Carmela Pera,Giulia Maria Amorelli,Costanza Barresi,G. D'Amico,Lorenzo Orazi,Giorgia Coratti,Kazuhiro Haginoya,Atsuko Kato,Yuko Morishita,Ryutaro Kira,Kiyomu Akiyama,Miwako Goto,Yujiro Mori,Misato Okamoto,Saki Tsutsui,Yuta Takatsuji,Aya Tanaka,Hirofumi Komaki,Miina Omori,Ippei Suzuki,Mizuki Takeuchi,Daisuke Todoroki,Seji Watanabe,Tomoko Matsubayashi,Emi Inakazu,Hiroe Nagura,Akira Suzuki,Manami Usui,Nobutsune Ishikawa,Yousuke Harada,Kenichi Fudeyasu,Kazuhiko Hirata,Kana Michiue,Kazuyuki Ueda,Kayoko Saito,Junko Fujitani,Reiko Arakawa,Kozue Takano,Shigeko Yashiro,Maiko Seki,Nozomi Sano,Koji Fukuyama,Yuki Matsumoto,Hirofumi Miyazaki,Minoru Shibata,Kyoko Kobayashi,Yukie Nakamura,Yasuhiro Takeshima,Moe Kuma,Anna Kostera‐Pruszczyk,Anna Frączek,Maria Jędrzejowska,Anna Łusakowska,Agnieszka Czeszyk-Piotrowicz,Wojciech Hautz,Klaudia Rakusiewicz,Małgorzata Burlewicz,Zuzanna Gierlak-Wojcicka,Malwina Kępa,Adam Sikorski,Marcin Sobieraj,Maria Mazurkiewicz-Bełdzińska,Anna Lemska,Sandra Modrzejewska,Mateusz Koberda,Urszula Stodolska-Koberda,Agnieszka Waskowska,Jagoda Kolendo,Agnieszka Sobierajska-Rek,Barbara Steinborn,Magdalena Dalz,J Grabowska,Wojciech Hajduk,Justyna Janasiewicz-Karachitos,Monika Klimas,Marcin Stopa,Ewa Gajewska,Beata Pusz,D. Vlodavets,Evgenia Melnik,Natalya Leppenen,Nataliya Yupatova,Anastasya Monakhova,Yulia Papina,Olga Shidlovsckaia,Vedrana Milić Rašić,V. Branković,Ana Kosać,Olivera Djokić,Vesna Jakšić,Ana Pepić,Jelena Martinović,Francina Munell,Eduardo F. Tizzano,Nieves Martín Begué,Charlotte Wolley-Dod,Olaia Subirà,Bernat Planas Pascual,Esther Toro-Tamargo,Marcos Madruga Garrido,José David Medina Romero,M Salinas,A. Nascimento Osorio,Ana Díaz Cortés,Enrique Jiménez Gañan,Simone Dowon Suh,Julita Medina Cantillo,O. Moya,Nuria Padros,Sandra Roca Urraca,Hugo Gonzalez Valdivia,Samuel Ignacio Pascual Pascual,Sofía de Manuel,Susana Noval Martín,Paul Burnham,Sandra Espinosa,M. Moreno,Haluk Topaloğlu,İbrahim Öncel,Nesibe Eroglu Ertugru,Bahadır Konuşkan,Bora Eldem,Sibel Kadayıfçılar,İ. Alemdaroğlu,Ayşe Karaduman,O. Yılmaz,Neslihan Bilgin,Seher Sari,Claudia A. Chiriboga,John J. Lee,Donnielle Rome-Martin,John Day,Shannon Beres,Tina Duong,Richard Gee,Sally Dunaway Young,Sabine Fuerst‐Recktenwald,Anne Marquet,Nicoletta Milani Muelhardt,Dylan Trundell
出处
期刊:Lancet Neurology [Elsevier]
卷期号:21 (1): 42-52 被引量:125
标识
DOI:10.1016/s1474-4422(21)00367-7
摘要

Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy.In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing.Between Oct 9, 2017, and Sept 4, 2018, 180 patients were randomly assigned to receive risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included. At month 12, the least squares mean change from baseline in 32-item Motor Function Measure was 1·36 (95% CI 0·61 to 2·11) in the risdiplam group and -0·19 (-1·22 to 0·84) in the placebo group, with a treatment difference of 1·55 (0·30 to 2·81, p=0·016) in favour of risdiplam. 120 patients who received risdiplam and 60 who received placebo were included in safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 [21%] of 120 patients who received risdiplam vs ten [17%] of 60 patients who received placebo), diarrhoea (20 [17%] vs five [8%]), rash (20 [17%] vs one [2%]), mouth and aphthous ulcers (eight [7%] vs 0), urinary tract infection (eight [7%] vs 0), and arthralgias (six [5%] vs 0). The incidence of serious adverse events was similar between treatment groups (24 [20%] of 120 patients in the risdiplam group; 11 [18%] of 60 patients in the placebo group), with the exception of pneumonia (nine [8%] in the risdiplam group; one [2%] in the placebo group).Risdiplam resulted in a significant improvement in motor function compared with placebo in patients aged 2-25 years with type 2 or non-ambulant type 3 spinal muscular atrophy. Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilised in older individuals, which requires confirmation in further studies. SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam.F Hoffmann-La Roche.
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