作者
Timothy Harrison,Pascal Chanez,Francesco Menzella,Giorgio Walter Canonica,Renaud Louis,Borja G. Cosío,Njira Lugogo,Arjun Mohan,Annie Burden,Lawrence McDermott,Esther Garcia Gil,James Zangrilli,Wolfgang Pohl,Robert Voves,Maud Deschampheleire,Renaud Louis,Jean-Louis Corhay,Rudi Peché,Kenneth R. Chapman,Amarjit Cheema,Delbert R. Dorscheid,J. Mark FitzGerald,Rémi Gagnon,William Patrick Killorn,Ronald Olivenstein,George Philteos,Clare D. Ramsey,Julia Rolf,Brandie Walker,Ole Hilberg,Tina Skjold,Ingrid Louise Titlestad,Auli Hakulinen,Maritta Kilpeläinen,M. Ben Hayoun,Philippe Bonniaud,Arnaud Bourdin,Pascal Chanez,Frédéric de Blay,Gaëtan Deslée,Gilles Devouassoux,A. Didier,Y. Douadi,Stéphanie Fry,Gilles Garcia,Pierre‐Olivier Girodet,Christophe Leroyer,A. Magnan,Guillaume Mahay,C. Nocent,Christophe Pison,Pauline-Marie Roux,Camille Taillé,Juliana-Angelica Tiotiu,Ekkehard Beck,Margret Jandl,Christian Kaehler,Frank Käßner,Frank Koesters,Juliane Kronsbein,Thomas Schaum,Christian Schulz,Dirk Skowasch,Christian Taube,Tobias Welte,A de Roux,Bianca Beghé,Francesco Blasi,Giorgio Walter Canonica,Giovanna Elisiana Carpagnano,Cristiano Caruso,Angelo Corsico,Elio Constantino,Nunzio Crimi,Piero Maestrelli,Francesco Menzella,Manlio Milanese,Alberto Papi,Girolamo Pelaia,Laura Pini,Pierachille Santus,Eleonora Savi,Nicola Scichilone,Gianenrico Senna,Giuseppe Spadaro,Adriano Vaghi,Steven Gans,Jurgen Hölters,Bas Langeveld,Willem R. Pieters,Gerald Staaks,Ilonka van Veen,Jan Willem van den Berg,Gunnar Einvik,Sverre Lehmann,Ismael Ali García,Carlos Almonacid,Irina Bobolea,Paloma Campo Mozo,Gustavo de Luiz,Christian Domingo,José María Echave-Sustaeta María-Tomé,Juan Luis García‐Rivero,Borja García-Cosío Piqueras,A. Gómez-Bastero Fernández,Ruperto González‐Pérez,Aythamy Henríquez Santa,Carlos Martínez‐Rivera,Xavier Muñoz,Jacinto Ramos,José Gregorio Soto Campos,Carmen Vidal Pan,Nikolai Stenfors,Alf Tunsäter,Ines Vinge,Rekha Chaudhuri,Timothy Harrison,Adel Mansur,Shuaib Nasser,Monica Nordstrom,Paul Pfeffer,Dinesh Saralaya,Philip Short,Arun Adlakha,Oral Alpan,Francis Averill,Anil Badhwar,Jose Bardelas,B D Baxter,George Bensch,William Berger,Jonathan A. Bernstein,Tracy Bridges,Ryan Brimeyer,William J. Calhoun,Edward J. Campbell,W. Brett Cherry,Geoffrey Chupp,Lee Clore,John R. Cohn,Jeremy Cole,John J. Condemi,James Cury,Benjamin Davis,Samuel DeLeon,Luis DeLaCruz,Joseph D. Diaz,David Erb,Emeka Eziri,Faisal Fakih,Douglas Fiedler,David A. Fost,Stephen B. Fritz,Erika González,Brad Goodman,Peter A. Gottlieb,Gregory Gottschlich,Richard Gower,Rizan Hajal,James B. Harris,Hengameh Heidarian-Raissy,Albrecht Heyder,David A. Hill,Fernando Holguín,Iftikhar Hussain,Jonathan Illowite,Joshua Jacobs,Mikell Jarratt,Harold B. Kaiser,Neil L. Kao,Ravindra Kashyap,David Kaufman,Edward Kent,Kenneth Kim,Ryan Klein,Monica Kraft,Ritsu Kono,Shahrukh Kureishy,Jeffrey Leflein,Mila A. Leong,Huamin Li,Robert Y. Lin,Njira Lugogo,Michael Marcus,Diego Jose Maselli Caceres,Vinay Mehta,Curtis J. Mello,Mark Millard,Aaron P. Milstone,Arjun Mohan,Wendy C. Moore,Mark Moss,Nayla Mumneh,Thomas D. O’Brien,David Ostransky,Michael Palumbo,Purvi Parikh,Sudhir Parikh,Amit Patel,Guido O. Pérez,W PLESKOW,Bruce M. Prenner,Dileep Puppala,John Ramey,Joan Reibman,Ramón López de los Reyes,Emory Robinette,Ileana Rodicio,Stephen Ryan,Sudhir Sekhsaria,Barry Sigal,Vinay Sikand,Weily Soong,Selwyn Spangenthal,Roy St. John,Gary C. Steven,Vijay Subramaniam,Kaharu Sumino,Eric Sztejman,Ricardo Tan,Tonny Tanus,Charles S. Thompson,C.E. Thornblade,Manuel Villareal,Sally E. Wenzel,Heidi Zafra,Tomasz M. Ziedalski
摘要
Background ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Findings Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39–0·65; p<0·0001) over the 24-week treatment period and provided clinically meaningful and statistically significant improvement from baseline to week 24 in SGRQ total score versus placebo (least squares mean change from baseline −8·11 (95% CI −11·41 to −4·82; p<0·0001), with similar differences at earlier timepoints. Benralizumab improved FEV1, PEF, ACQ-6, CGI-C, PGI-C, PSIA, and SNOT-22 at week 24 versus placebo, with differences observed early (within weeks 1 to 4). Adverse events were reported for 271 (63%) of 427 patients on benralizumab versus 143 (62%) of 229 patients on placebo. The most commonly reported adverse events for the 427 patients receiving benralizumab (frequency >5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Interpretation Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. Funding AstraZeneca.