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Purpose: To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial-onset seizures (POS).
Methods: Two identical, randomized, placebo-controlled, double-blind studies were conducted in adults with POS uncontrolled for ≥1 year. Therapy-refractory epilepsy patients (≥16 years) remained on stable doses of prescribed antiepileptic drugs (≤2) for an 8-week prospective baseline phase and were then randomized (1:1:1) to carisbamate 200 mg/day, carisbamate 400 mg/day, or placebo, for a 12-week double-blind phase. Primary efficacy end points were percent reduction in seizure frequency and responder rate (patients with ≥50% reduction in POS frequency) during the double-blind phase compared with the prospective baseline phase.
Results: Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16–75 years) and 36 years (study 2, range 16–74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment-emergent adverse events (≥5% in any group), those with an incidence exceeding placebo (≥3%) were dizziness (400 mg/day group) and somnolence.
Conclusions: Carisbamate 400 mg/day was effective in patients with refractory partial-onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well-tolerated in both studies.
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RWJ-333369 (S-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is a novel therapeutic agent, initially developed by SK Biopharmaceuticals, under development for the treatment of epilepsy.
Dr. Madhavi Patil (SIRO Clinpharm Pvt. Ltd.) provided writing assistance and Dr. Wendy P. Battisti (Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) provided additional editorial support for this manuscript. We thank Dr. Peter Zannikos (Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) for his contributions in support of the pharmacokinetic data.
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
We thank the following investigators for their participation in this study: Argentina: Herrera, Gustavo, M.D.; Mesri, Jacobo, M.D.; Palacios Claudio, M.D.; and Thomson, Alfredo, M.D. Australia: Berkovic, Sam, M.B.B.S. F.R.A.C.P.; Bleasel, Andrew, M.B.B.S. F.R.A.C.P.; Cook, Mark, M.B.B.S. F.R.A.C.P.; Mclaughlin, Daniel, M.B.B.S. F.R.A.C.P.; O`brien, Terrence, M.B.B.S. F.R.A.C.P.; and Somerville, Ernest, M.B.B.S. F.R.A.C.P. Croatia: Hajnsek, Sanja, M.D., Ph.D. and Lusic, Ivo, M.D., Ph.D. Czech Republic: Hon, Petr, M.D.; Hovorka, Jiri, M.D., Ph.D.; Kalina, Miroslav, M.D.; Marusic, Petr, M.D., Ph.D.; Muzikova, Alena, M.D.; Rektor, Ivan, M.D., Ph.D.; Vysata, Oldrich, M.D.; and Vyskocilova, Dana, M.D. Finland: Kalviainen, Reeta, M.D.; Koivisto, Keijo, D.Med.Sc.; and Peltola, Jukka, D.Med.Sc. Germany: Elger, Christian, M.D.; Hagemann, Georg, M.D.; Hufnagel, Andreas, M.D.; Lerche, Holger, M.D.; Meencke, Heinz Joachim, M.D.; Schmitz, Bettina, M.D.; and Steinhoff, Bernhard, M.D. India: Jain, Satish, M.D.; Kulkarni, Rahul, M.D.; Meena, Angamuthu Kanikannad, M.D.; Pandit, Lekha, M.D.; Ravat, Sangeeta, M.D.; Shah, Arun, M.B.B.S.; Singh, Maneesh Kumar, M.D.; and Singh, Gagandeep, M.D. Malaysia: Lim, Kheng Seang, M.B.B.S. M.R.C.P. and Viswanathan, Shanthi, M.B.B.S. M.C.R.P. People’s Republic of China: Ding, Meiping, M.D.; Hong, Zhen, M.D.; Wang, Yuping, M.D.; Zhao, Zhongxin, M.D.; and Zhou, Liemin, M.D. Republic of Korea: Hong, Seung Bong, M.D., Ph.D.; Kang, Joong Koo, M.D., Ph.D.; Lee, Byung-in; and Lee, Sang-kun, M.D., Ph.D. Russia: Avakyan, Gagik, M.D.; Barbarash, Olga, M.D., Ph.D.; Belova, Anna, M.D.; Grigoryeva, Elena, M.D., Ph.D.; Kalinin, Vladimir, M.D., Ph.D.; Maslova, Natalia, M.D.; Neznanov, Nikolay, M.D.; Petrukhin, Andrey, M.D.; Pizova, Natalia, M.D.; Poverennova, Irina, M.D.; Reshetko, Olga, M.D.; Suchkov, Yuri, M.D.; and Yakupov, Eduard, M.D. Sweden: Ben-menachem, Elinor, M.D., Ph.D.; Kallen, Kristina, M.D., Ph.D.; Landtblom, Anne-marie, M.D., Ph.D. and Tomson, Torbjorn, M.D., Ph.D. United States of America: Bell, William, M.D.; Brower, Richard, M.D.; Cochran, John, M.D.; Drazkowski, Joseph, M.D.; Friedman, Sheri, M.D.; Halford, Jonathan, M.D.; Harden, Cynthia, M.D.; Holmes, Gregory, M.D.; Imbus, Charles, M.D.; Inglese, Christopher, M.D.; Jackel, Roy, M.D.; Jacobson, Mercedes, M.D.; Kanner, Andres, M.D.; Kirzinger, Stephen, M.D.; Kudrow, David, M.D.; Labiner, David, M.D.; Moore, David, M.D.; Neer, Jody, M.D.; Rosenfeld, William, M.D.; Shah, Aash, M.D.; Sheth, Raj, M.D.; Shnekar, Bassel, M.D.; Sperling, Michael, M.D.; Todorov, Alexandre, M.D.; and Ziman, Ronald, M.D..
EPY 3002:Bulgaria: Ganeva, Guergana, M.D.; Minchev, Dimitar, M.D.; and Naydenov, Valcho, M.D. Canada: Arts, Rudolf, M.D.; Carlen, Peter, M.D.; Desbiens, Richard, M.D.; Mclachlan, Richard, M.D.; Schneiderman, Jacob, M.D. and Wiebe, Sam, M.D. Hong Kong: Kwan, Patrick, M.D. Hungary: Balogh, Attila; Csiba, László, M.D.; Csányi, Attila, M.D.; Horvath, ágnes, M.D.; Rajna, Péter, M.D.; Rásonyi, György, M.D.; and Sólyom, András, M.D. India: Murthy, Jagarlapudi Murali Krishna, M.D.; Prabhakar, Subhasini, M.D.; Shankar, Nellikunja, M.D.; Sinha, Sanjib, M.D.; Sridharan, Ramaratnam, M.D.; Srinivasa, Rangashetty, MBBS; Velmurugendran, Cungaiper, M.D.; Vengamma, Bhuma, MBBS Norway: Kristensen, Terje, M.D.; and Nakken, Karl Otto, M.D. PhD; People’s Republic of China: Liao, Weiping, M.D.; Wang, Xuefeng, M.D.; Wu, Liwen, M.D.; and Zhou, Dong, M.D. Poland: Blaszczyk, Barbara, M.D., Ph.D.; Chwedorowicz, Roman, M.D.; Czapinski, Piotr, M.D.; Czlonkowska, Anna, M.D.; Fryze, Waldemar, M.D., Ph.D.; Jedrzejczak, Joanna, M.D., Ph.D.; Kapustecki, Janusz, M.D., Ph.D.; Kazibutowska, Zofia, M.D.; Kleczkowska, Magdalena, M.D.; Kowalski, Jacek, M.D., Ph.D.; Pruchnik-wolinska, Danuta, M.D., Ph.D.; and Stelmasiak, Zbigniew, M.D. Taiwan: Hsieh, Pei-yuan, M.D., M.S.; Lai, Shung-lon, M.D., Ph.D.; Liou, Horng-huei, M.D., Ph.D.; Tsai, Jing-jane, M.D. Dr. Med.; Wu, Tony, M.D. MS; and Yen, Der-jen, M.D. M.S. Thailand: Boonyapisit, Kanokwan, M.D.; Chinvarun, Yotin, M.D., Ph.D.; and Tiamkao, Somsak, M.D. Ukraine: Bitenskyy, Valeriy, M.D. Ph.D.; Buchakchyys`ka, Natalia, M.D. Ph.D.; Demchenko, Vladislav, M.D.; Dubenko, Andriy, M.D. Ph.D.; Goloborodko, Alla, M.D. Ph.D.; Golubkov, Oleg, M.D. Ph.D.; Ipatov, Anatoliy, M.D. Ph.D.; Kharchuk, Sergey, M.D. Ph.D.; Lytovchenko, Tetyana, M.D. Ph.D.; Marienko, Lidiya, M.D. Ph.D.; Smolanka, Volodymyr, M.D. Ph.D.; Smolko, Nadiya, M.D. Ph.D.; Studzinskyy, Oleg, M.D. Ph.D.; and Verbenko, Viktoriya, M.D. Ph.D. United States of America: Abou-khalil, Bassell, M.D.; Brandes, Jan, M.D.; Burch, John, M.D.; Chung, Steven, M.D.; Fisch, Bruce, M.D.; Frucht, Michael, M.D.; Gurru, Mandher, M.D.; Herrman, Craig, M.D.; Ko, David, M.D.; Leroy, Robert, M.D.; Liow, Kore, M.D.; Penovich, Patricia, M.D.; Rogin, Joanne, M.D.; Shojaei-moghaddam, Jalil, M.D.; So, Norman K, M.D.; Syed, Athar, M.D.; and Van Orman, Colin, M.D..
Conflict of interest: Dr. Sperling and Ms. Cramer were consultants in the design of both the studies, and have received honoraria from Johnson & Johnson Pharmaceutical Research & Development, L.L.C. for consulting. Dr. Halford was a principal investigator for study 1 and has received honoraria from Johnson & Johnson Pharmaceutical Research & Development, L.L.C. for consulting. Dr. Patrick Kwan was a principal investigator for study 2, has provided advisory board service and participated in speakers’ bureau of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Dr. Kälviäinen was an investigator for study 1, has provided advisory board service and participated in speakers’ bureau of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Drs. Greenspan, Schmitt, Yuen, Haas and Novak are employed by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Dr. Cook received salary support through a contract between the University of Wisconsin and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Some of these data were previously presented at American Epilepsy Society, December 2008.
Study support: Funded by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, U.S.A.