Esmirtazapine treatment of postmenopausal vasomotor symptoms: two randomized controlled trials

Abstract

Objectives: Two identical 12-week, randomized, double-blind, placebo-controlled, multi-arm, parallel-group Phase III studies (Study P012, NCT00560833; Study P013, NCT00535288) evaluated the efficacy and safety of esmirtazapine, an investigational medicine, for the treatment of moderate to severe vasomotor symptoms (VMS) in postmenopausal women.

Methods: Participants were randomized to placebo or esmirtazapine (2.25, 4.5, 9.0, or 18.0 mg). Co-primary efficacy endpoints (daily frequency and severity of moderate to severe VMS, both at weeks 4 and 12) were based on participative LogPad daily diaries. Adverse events (AEs) were recorded.

Results: In Studies P012 and P013, 942 and 946 participants were randomized, respectively. Compared with placebo, esmirtazapine significantly reduced the mean daily frequency by 1.4–2.2 moderate to severe VMS at weeks 4 and 12 (both ≥4.5 mg) and mean daily severity by 0.06–0.08 symptoms at weeks 4 (≥4.5 mg) and 12 (9.0 mg P012; 18.0 mg P013 only). Esmirtazapine was generally well tolerated with a more favorable safety profile at lower doses. Somnolence and fatigue were the most frequently reported AEs.

Conclusions: Esmirtazapine reduced the frequency and severity of moderate to severe VMS associated with menopause and was generally well tolerated in the study population.

摘要

目的：两项相同的12周随机双盲安慰剂对照多臂平行组III期临床试验研究（研究P012, NCT00560833；研究P013, NCT00535288）评价研究药物艾司米尔他扎平治疗绝经后妇女中重度血管舒缩症状(VMS)的疗效和安全性。

方法：随机分为安慰剂组和艾司米尔他扎平组 (2.25 mg、4.5 mg、9.0 mg或18.0 mg)。联合主要疗效终点(第4周和第12周, 中度至重度VMS的每日频率和严重程度)均基于参与者的每日日志记录。同时记录不良事件(AEs)。

结果：在P012和P013研究中, 942名和946名参与者分别被随机分组。与安慰剂相比, 艾司米尔他扎平在第4周和第12周（两项试验都是≥4.5 mg）显着降低了中重度VMS症状的平均每日频率1.4-2.2, 并且在第4周（≥4.5 mg）和第12周（研究012中9.0mg；研究013中18.0mg）时, 中重度VMS症状的平均每日严重程度降低0.06-0.08。在较低剂量下, 艾司米尔他扎平通常具有良好的耐受性和较好的安全性。嗜睡和疲劳是被记录的最常见不良反应。

结论：艾司米尔他扎平能够降低更年期中重度血管舒缩症状的发生频率和严重程度, 并在研究人群中普遍耐受性良好。

Keywords:

• Esmirtazapine
• hot flush
• menopause
• vasomotor symptoms

Acknowledgements

Medical writing support, under the direction of the authors, was provided by Adele Blair, PhD, of CMC AFFINITY, a division of McCann Health Medical Communications Ltd, Glasgow, UK, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, in accordance with Good Publication Practice (GPP3) guidelines. Christopher Lines, PhD, from Merck & Co., Inc., Kennilworth, NJ, USA provided comments on the manuscript. The authors thank Dr Willem Bergink, Dr Elisabet Stet, Dr Jolanda Elbers, Dr Marcel Hekking, and the study investigators for their contributions to the studies.

List of investigators for Study P012: Australia: JA Eden, Sydney Menopause Centre, Randwick; S Davis, Women’s Health Program, Prahran; E Farrell, Monash Medical Centre, Clayton; M Hickey, King Edward Memorial Hospital for Women, Perth; R Norman, Repromed, Dulwich; Canada: C Bouchard, Clinique RSF Inc., Quebec, QC; CK Yuen, Manitoba Clinical Medical Corporation, Winnipeg, MB; CH Derzko, St. Michael’s Hospital, Toronto, ON; Chile: R Massai, Instituto Chileno de Medicina Reproductiva, Santiago; M Villarroel, Clinica Alemana, Santiago; Finland: HR Rautiainen, Lääkärikeskus Gyneko Oy, Oulu; SK Korhonen, SPR Lääkäriasema, Mikkeli; E Varila, Suomen Terveystalo Oyj, Tampere; MLR Rantala, Adenova Lääkärikeskus, Espoo; France: A-I Richet, private practice, Paris; M-LB Bollengier, private practice, Lille; D Wiel-Masson, private practice, Chartres; J Sentenac, private practice, Talence; C Matuchansky, private practice, Maisons Laffitte; M-C Ehret-Mentré, private practice, Strasbourg; Germany: H-J Ahrendt, Ahrendt (private practice), Magdeburg; MD Chatsiproios, CGG-Centrum für ganzheitliche Gynäkologie, Mannheim; R Landthaler, Kreiskrankenhaus Krumbach – Gynäkologische Praxis, Krumbach; P Hadji, Philipps-Universität Marburg, Marburg; H Gerlach, Praxis Central, Essen; Italy: GBM Melis, P.O. S Giovanni di Dio, Cagliari; R Nappi, Policlinico San Matteo, Pavia; D De Aloysio, Policlinico S. Orsola – Malpighi, Bologna; P Sismondi, Ospedale Mauriziano, Torino; F Pansini, Centro di Servizio e Ricerca per lo Studio della Menopausa e dell’Osteoporosi dell’Università degli Studi di Ferrara, Ferrara; Mexico: S Uscanga, Hospital Mariajose, Colonia Roma; S Carranza Lira, Hospital de Gineco Obstetricia Dr. Luis Castelazo Ayala, Colonia Tizapàn; D Ortiz, Comité Mexicano para la Prevención de la Osteoporosis A. C., Colonia Hipódromo; Poland: J Tomaszewski, Prywatna Klinika Polozniczo – Ginekologiczna, Bialystok; M Koziara, Specjalistyczny Osrodek Medycyny Wieku Dojrzalego, Warsaw; A Jakimiuk, Samodzielny Publiczny Szpital Kliniczny, Lublin; M Elias, Neipubliczny Zaklad Opieki Zdrowotnej E-Med, Wroclaw; M Spaczynski, Ginekologiczno-Polozniczy Szpital Kliniczny, Poznan; T Niemiec, Instytut Matki I Dziecka, Warszawa; B Grzechocinska, Szpital Kliniczny, Warszawa; K Dynowski, Szpital Bielanski, Warszawa; Sweden: B-M Landgren, Karolinska Universitetssjukhus/Huddinge, Stockholm; S-E Olsson, Danderyds sjukhus, Danderyd; L Mattsson, Sahlgrenska Universitetssjukhuset/Östra, Göteborg; M Bixo, Norrlands Universitetssjukhus, Umeå; G Samsioe, Universitetssjukhuset Lund, Lund; M Hammar, Universitetssjukhuset Linköping, Linköping; USA: S Drosman, Genesis Center for Clinical Research, San Diego, CA; A Waldbaum, Downtown Women’s Healthcare, Denver, CO; JA Simon, Women’s Health Research Center, Laurel, MD; JC Mayer, University of South Florida, Tampa, FL; J Gersten, New Age Medical Research Corporation, Miami, FL; J Ballard, Northern Indiana Women’s Health Research, South Bend, IN; S Hendrix, Wayne State University, Detroit, MI; W Utian, Rapid Medical Research, Inc., Cleveland, OH; J Jensen, Oregon Health & Sciences University, Portland, OR; L Seidman, Philadelphia Women’s Research, Philadelphia, PA; WP Jennings, Radiant Research San Antonio, San Antonio, TX; W Larson, Radiant Research – Tacoma, Lakewood, WA.

List of investigators for Study P013: Belgium: M Dhont, Universitair Ziekenhuis Gent, Gent; H De Gezelle, De Gezelle Private Practice, Afsnee (Gent); A Saey, Saey Private Practice, Renaix/Ronse; B Pornel, Brussels Menopause Center, Bruxelles; Brazil: M Badalotti, Hospital São Lucas, Porto Alegre; C Reggiani, Hospital de Clínicas da UFPR, Curitiba; R Ferriani, Centro de Saúde Escola Professor Dr Joel Domingues Machado da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto; Canada: G Achyuthan, University of Regina Allied Health Centre, Regina, SK; B Hauck, Hauck’s Private Practice, Calgary, AB; M Moreau, Centre d’étude Clinique Montréal Inc., Montreal, QC; E Jolly, Ottawa Hospital – Riverside Campus, Ottawa, ON; Czech Republic: D Kolarik, Facultní Nemocnice Na Bulovce, Prague; P Strnad, Facultní Nemocnice v Motole, Prague; J Jenicek, Lekarsky dum, Prague; C Born, Privatni Gynekologicka Ambulance, Plzen; V Mulac, Nestatni zdravotnicke zarizeni, Beroun; T Reslova, Ordinace pro gynekologii a porodnictvi, Hradec Kralove; Denmark: S Christau, private clinic, Virum; A Peen, Speciallaegernes Hus, Aarhus; A Vedsted-Jakobsen, private clinic, Hillesrød; Hungary: Z Szabo, Semmelweis Hospital, Miskolc; L Rokay, János Selye Hospital, Komárom; P Osvath, Kenezy Gyula County Hospital, Debrecen; N Acs, Semmelweis University, Budapest; G Gyovai, University Affiliated General Hospital, Szentes; The Netherlands: MJ van de Mooren, Academisch Ziekenhuis Vrije Universiteit, Amsterdam; D van Duren, Menox Menopause Research, Nijmegen; GL Bremer, JUSTUS medische expertise, Eindhoven; Norway: BCS Eriksen, private practice, Haugesund; MEU Østerberg, Din Doktor, Fredrikstad; L Meyer, Volvat Medisinske Senter AS, Hamar; T Lunde, private practice, Larvik; T Sørdal, MEDICUS – et helseforetak, Trondheim; A Bjertnaes, Risvollan Legesenter, Trondheim; A Tandberg, Bekkestua Legesenter, Bekkestua; HE Ipsen, Hans Ejner Ipsen/Private Clinic, Ålesund; Slovak Republic: S Lukacin, Fakultna nemocnica L. Pasteura, Kosice; D Milly, Private Out Patient Gynecology Clinic, Bratislava; H Gasparik, Nemocnice Myjava, Myjava; F Balint, Privatni Gynekologicka Ambulance, Michalovce; Spain: F Baro, Hospital General Universitari Vall d'Hebron, Barcelona; S Palacios, Instituto Palacios de Salud y Medicina de la Mujer, Madrid; J Ferrer, Hospital Central Asturias, Oviedo; F Nohales, Hospital Francisco Borja de Gandia, Gandía; R Sánchez, Diatros Diagnósticos y Tratamientos Avanzados S.L., Gavà; F Quereda, Hospital Universitario San Juan de Alicante, San Juan de Alicante; Switzerland: M Birkhaeuser, Inselspital, Universitäts-Frauenklinik, Bern; J Bitzer, Universitätsspital Basel Frauenklinik, Basel; UK: J Rymer, Guy's Hospital, London; D Sturdee, Solihull Hospital, Solihull; E Morris, Norfolk & Norwich University Hospital, Norwich; R Brown, Compass House Medical Centre, Brixham, Devon; P Rovira, Kirkham Medical Practice, Torquay, Devon; USA: CK Skokos, The Woman’s Clinic, P.A., Little Rock, AR; WD Koltun, Medical Center for Clinical Research, San Diego, CA; S Johnson, University of Iowa, Iowa City, IA; SG Swanson, Women’s Clinic of Lincoln PC, Lincoln, NE; JC Gallagher, Creighton University Medical Center, Omaha, NE; R Lobo, Columbia Medical Center, New York, NY; M Gass, Holmes Hospital/Reproductive Medicine Research, Cincinnati, OH; BF Fuller, Medford Women's Clinic, LLP, Medford, OR; S Kreis, Waco OB/GYN, Waco, TX; P Amato, Baylor College of Medicine, REI Research, Houston, TX; DF Archer, Eastern Virginia Medical School, Norfolk, VA; R Kroll, Women’s Clinical Research Center, Seattle, WA.

Conflict of interest

M. Birkhaeuser has no disclosures to make. J. Bitzer has participated in advisory boards for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. At the time the studies were conducted, S. Braat and Y. Ramos were employees of Organon, a subsidiary of Akzo Nobel at the time of study conduct, and subsequently of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Additional information

Funding

Funding for this research was provided by Organon, a subsidiary of Akzo Nobel at the time of study conduct, and subsequently of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.