Two Phase III randomised double-blind studies of fixed-dose TC-5214 (dexmecamylamine) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to prior antidepressant therapy

Abstract

Objectives. To evaluate the neuronal nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy in patients with major depressive disorder (MDD) and inadequate response to prior antidepressant treatment. Methods. Study 004 (D4130C00004) and Study 005 (D4130C00005) comprised an 8-week open-label antidepressant (SSRI/SNRI) treatment period followed by an 8-week randomised, active treatment with twice-daily TC-5214 (0.5, 2 or 4 mg in Study 004; 0.1, 1 or 4 mg in Study 005) or placebo, adjunct to ongoing SSRI/SNRI. Primary efficacy endpoint was change in MADRS total score from randomisation (Week 8) to treatment end (Week 16). Secondary endpoints included MADRS response and remission, and changes in SDS and HAM-D-17-item scores. Safety and tolerability were monitored throughout. Results. Studies 004 and 005 randomised 640 and 696 patients, respectively, to TC-5214 or placebo. No statistically significant improvements in MADRS total score or any secondary endpoints were seen with TC-5214 versus placebo in either study at treatment end. The most commonly reported adverse events (> 10%) with TC-5214 were constipation, dizziness and dry mouth. Conclusions. TC-5214 adjunct to antidepressant was generally well tolerated. However, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy.

Key words::

• Adjunct therapy
• antidepressant
• major depressive disorder
• nicotinic channel modulator
• TC-5214

Acknowledgements

These studies were supported by AstraZeneca Pharmaceuticals in co-development with Targacept, Inc., and registered at ClinicalTrials.gov (D4130C 00004 study identifier number NCT01153347; D4130C00005 study identifier number NCT011 97508). The authors would like to thank Emma Robinson from Complete Medical Communications, who provided medical writing support funded by AstraZeneca.

The following investigators were involved in the studies:

Study 004

India: Ramanathan Sathianathan, Sandip Shah, Nadukuru Raju, Anjanappa Jagadish, Rohan Kusumgar, Sanjay Phadke, Hongaly Chandrashekhar, Bakul Buch Chandrakant, PSVN Sharma, Anil Kumar Tambi, Bandana Gupta, Mahesh Gowda, Hitendra A Gandhi, Dattatreya Dhavale, Vishal Indla, Rakesh Yadav, Jitendra K Trivedi, Pradip Vaghasiya, Umesh Nagapurkar, Ravish Thunga, Mahesh Chudgar, Vinay Barhale, Keshava Pai, Vaishal Vora, Venu Gopal Jhanwar, Sathyanarayana Rao, Vijay Nagecha, RK Mahendru, Himanshu Sharma, PK Kiran Kumar, Kaustubh Joag, Ramanand Satapathy, Suresh Kumar Kota, Darmavaram Rama Vijaykumar, Dinesan Narayanan, Sunil Mittal, Chellamuthu Ramasubramanian, IVL Narasi Rao. USA: Guy Brannon, Andrew Cutler, Mark DiBuono, Don DeFrancisco, Edward Friedman, Paul Gross, Karl Jacobs, Michael Johnson, Mary Knesevich, David Krefetz, Joseph Kwentus, Mark Lerman, Edward Logue, Morteza Marandi, Donald Garcia Jr, Vishaal Mehra, Janice Miller, Susan McElroy, Paul Miller, Charles Morin, George Konis, Margarita Nunez, Jennifer Lytle, Scott Segal, Tram Tran-Johnson, Mahmoud Okasha, David Walling, Blaise Wolfrum, John Murphy, Susan Weston, John Zajecka, George Papakostas, John Prater, John Beyer, Beal Essink, Amit Vijapura, Adam Lowy, David Franklin, Jackie Coombe-Moore, Olga Brawman-Mintzer, Americo Padilla, Fares Arguello, Diab Almhana, Michael McManus, James Igleburger, Nilesh Patel, Sarah Atkinson, Joel Breving, Alexander Bystritsky, Linda Harper, Mark Joyce, Valentin Isacescu, Gregory Kaczenski, Raymond Manning, Alan Yeo, Mary Stedman, Cherian Verghese, Steven Bupp, Jerry Steiert, Ashraf Attalla, Ira Glick, Jelena Kunovac, Cosme Jr. Lozano, Amal Chakraburtty, James Whalen, Joseph Kline Jr, Deborah Gould, Tracy Schillerstrom, Diana Koziupa, Lorena Wallhausser, Andrew Klymiuk, James Knutson, Louis Kopolow, Robert Lehman, Syed Mustafa, David Krakow, Dwight St Clair, Robert Buynak, Asif Habib, Mark Hernandez, Haydn Thomas, Randall Sullivan, Arifulla Khan, John Tran, Thomas Grugle, Charles Montano, Laurence Radin, David Chen, Ashok Patel, Brij Vaid, Paul Wylie, Charmaine Semeniuk, Valerie Arnold, Michael Banov, Bijan Bastani, Brian Bortnick, Barbara Diaz.

Study 005

Argentina: Eugenio Miguel Velasco, Marcelo Cetkovich Bakmas, Ricardo Marcelo Corral, Miguel Marquez, Andres Mega, Carlos Morra, Rolando Salinas, Edith Serfaty. Brazil: Hamilton Grabowski, Fabio Lopes Rocha, Joao Alberto Oliveira Campos, Irismar Reis de Oliveira, Sandra Ruschel. Bulgaria: Mladen Mantarkov, Vihra Milanova, Temenuzhka Dechkova-Novakova, Luchezar Hranov, Georgi Krastev, Emil Kaludiev, Georgi Parchev, Loris Sayan, Georgui Popov, Rinaldo Shishkov, Stefan Todorov, Maria Alexandrova, Svetlozar Georgiev, Tsveteslava Galabova. Chile: Jaime Solis, Sergio Gloger, Veronica Larach, Marcela Rojas, Luis Alberto Barra Ahumada. Colombia: Claudia Rocio Vanegas, Carlos Miranda, Dora Cardona, Rodrigo Nel Cordoba, Pablo Lema Medina. Croatia: Miro Jakovljevic, Gordan Makaric, Darko Perusic, Danijel Buljan, Tanja Franciskovic, Goran Dodig, Vlado Jukic, Dragica Kozaric-Kovacic, Miroslav Herceg, Neven Henigsberg. France: Jean.Albert Meynard, Bruno Millet, Philippe Leclercq, Daniel Bonnaffoux, Philippe Desbonnet, Christophe Dufour, Joel Gailledreau, Dideh Bassiri, Thierry Loiseau, Jacques Louvrier, Wissam El Hage, Frédéric Grabli, David Modavi, Joel Pon, Philippe Courtet, Francis Gheysen, Paule Khalifa, Pierre Legoubey, Jean-Yves Metzger. Germany: Frank Godemann, Günther Niklewski, Ralf Bitter, Heike Benes, Peter Emrich, Ilja Spellmann, Irma Schoell, Ruediger Schellenberg, Wolfgang Mattern, Johannes Boehringer, Klaus Sallach, Juergen Gebauer, Angelika Christopher, Reinhard Huentemann, Alexander Schulze, Eugen Schlegel, Jana Thomsen. Hungary: Agnes Fuchs, Erika Szadoczky, Istvan Kecskes, Csilla Varga, Laszlo Csekey, Gabor Feller. Peru: Zoila Pacheco, Jorge Pizarro, William Aguilar Rivera, Carlos Ordoñez. Poland: Marek Domanski, Ryszard Wardenski, Aleksander Araszkiewicz, Agnieszka Nowakowska-Rudzka, Mariusz Perucki, Leszek Bidzan, Dariusz Malicki, Jerzy Landowski, Mieczyslaw Janiszewski, Jacek Dobryniewski, Robert Kucharski. Romania: Delia Marina Podea, Simona Claudia Tamasan, Gheorghe Oros, Elena Tocari, Dorina Valerica Sima, Ioana Miclutia, Maria Silvia Trandafir, Elena Gherman, Cristina Anasta Iordache. Russia: Alexey Agarkov, Lubov Gluskina, Alexander Kotsubinskyi, Eugeny Abritalin, Anatoly Bogdanov, Alexey Bobrov, Mark Burkin, Gregory Neznamov, Vladimir Tochilov, Nikolay Govorin, Marina Nesterova, Nikolay Neznanov, Oleg Shiryaev, Vitaliy Tadtaev, Elena Zagoruyko, Anna Vasilyeva. South Africa: Karien Botha, Gretha Brink, Thabo J Lerumo, Bernard Janse van Rensburg, Pravitha Miseer, Alfred Le Clus, Lynette Nel, Hilda Russouw, Juan Schronen, Ian Taylor, Johannes Van der Westhuizen, Christiaan Van Jaarsveldt, Gert Venter, Donald Wilson, Paul Janus (JP) Pretorius, Gideon (Deon) Jordaan, Hermanus Jordaan. Serbia: Milorad Curcic, Vladimir Diligenski, Svetlana Drezgic Vukic, Miroslava Jasovic Gasic, Goran Mihajlovic, Milutin Nenadovic, Dusica Lecic Tosevski, Grozdanko Grbesa. Slovakia: Jan Pecenak, Jan Duzek, Maria Hastova, Peter Korcsog, Nada Kuriackova, Kvetoslav Moravcik, Abdul Mohammad Shinwari, Livia Vavrusova, Peter Molcan, Eva Janikova, Rastislav Korba. Spain: Javier Correas Lauffer, Jaime De la Torre, Cristobal Gastó, Celso Iglesias, Diego José Palao Vidal, Pedro Sopelana, Josep Gascon, Francisco Jose Montilla Garcia. Ukraine: Yuliya Blazhevych, Vladislav Demchenko, Gennadiy Zilberblat, Sofiya Rymsha, Volodymyr Abramov, Svitlana Moroz, Nataliya Maruta, Pavlo Palamarchuk, Viktoriya Verbenko, Oleksandr Filts, Olena Venger, Andrii Skrypnikov.

Statement of interest

Hans-Jürgen Möller has received grants or is a consultant for and on the speakers bureaus of AstraZeneca, Bristol-Myers Squibb, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Cilag, Lundbeck, Merck, Novartis, Organon, Pfizer, Sanofi-Aventis, Schering-Plough, Schwabe, Sepracor, Servier and Wyeth.

Koen Demyttenaere has received honoraria from, or has been an advisor/consultant to, or on the speakers bureaus for: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Glaxo SmithKline, Lundbeck, Otsuka, Servier, Takeda and Wyeth.

Raj Tummala is an employee of AstraZeneca.

Bengt Olausson was an employee of AstraZeneca at the time this study was conceived, conducted and completed.

Hans Eriksson, Johan Szamosi and Ellis Wilson were employees of AstraZeneca at the time this study was conceived, conducted and completed and hold stock in AstraZeneca.

David Hosford is an employee of Targacept, Inc.

Geoffrey Dunbar was an employee of Targacept, Inc. at the time this study was conceived, conducted and completed.