Comment
*Dieter Riemann, Kai Spiegelhalder
6
Department of Clinical Psychology and Psychophysiology/Sleep Medicine, Centre for Mental Disorders, Freiburg University Medical Centre, Hauptstr 5, 79104 Freiburg, Germany [email protected]
7
DR acted as a consultant for Abbvie in 2013. KS declares that he has no competing of interests. The work of both authors is supported by DFG (Deutsche Forschungsgemeinschaft; German Research Council), BMBF (Bundesministerium für Bildung und Forschung; German Ministry for Education and Research), FRIAS (Freiburg University Institute for Advanced Studies), European Union, and the Else Kröner-Fresenius-Stiftung (Else Kröner Fresenius Foundation). 1
2 3
4 5
Michelson D, Snyder E, Paradis E et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; published online March 27. http://dx.doi. org/10.1016/ S1474-4422(14)70053-5. Morin, CM, Benca R. Chronic insomnia. Lancet 2012; 379: 1129–41. Riemann D, Spiegelhalder K, Feige B, et al. The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Med Rev 2010; 14: 19–31. APA. Diagnostic and statistical manual of mental disorders—5th edition (DSM-5). Washington, DC: American Psychiatric Association, 2013. Riemann D, Perlis, ML. The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev 2009; 13: 205–14.
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9
10 11 12
13
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Duendar Y, Dodd S, Strobl J, et al. Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Hum Psychopharmacol 2004; 19: 305–22. Glass J, Lanctôt KL, Hermann N, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005; 331: 1–7. Buscemi N, Vandermeer B, Friesen C, et al. The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of RCTs. J Gen Intern Med 2007; 22: 1335–50. Huedo-Medina T, Kirsch I, Klonizakis M, et al. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ 2012; 345: 1–13. Mieda M, Sakurai T. Overview of orexin/hypocretin system. Prog Brain Res 2012; 198: 5–14. Farkas R. Suvorexant safety and efficacy—FDA preliminary conclusions. http://www.fda.gov/downloads/.../UCM354215.pdf (accessed March 18). Herring WJ, Snyder E, Budd K, Hutzelmann J, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 2012; 79: 2265–74. Actelion. Actelion and GSK discontinue clinical development of almorexant. http://www1.actelion.com/en/our-company/news-andevents/index.page?newsId=1483135 (accessed March 18). Tafti M. Reply to ‘promotion of sleep by targeting the orexin system in rats, dogs and humans’. Nature Med 2007; 13: 525–26.
Daclizumab in multiple sclerosis: a high-yield extension study Monoclonal antibodies have emerged as effective treatments for patients with multiple sclerosis. They bind to specific proteins on the surface of the immune cells that are involved in the cascade of events leading to pathological changes associated with the disease: rituximab, ocrelizumab, and ofatumumab target CD20 (also known as MS4A1), which is present on only B cells; alemtuzumab binds to CD52 on the surface of many types of white cells; and natalizumab binds to the alpha-4 integrin (ITGA4) on the surface of lymphocytes, thereby reducing the movement of these cells across the vascular endothelium. Common features of monoclonal antibodies are that they target an antigen expressed on peripheral lymphocytes, and so they have a long washout period and the effects after cessation of treatment are unpredictable. For example, a return of disease activity with relapses and gadolinium-enhancing lesions,1 and T2 lesions2 have been described after interruption of natalizumab treatment. Daclizumab is a monoclonal antibody that has previously been studied in phase 2 trials (CHOICE and SELECT)3,4 and is now being investigated in phase 3 trials (NCT01462318 and NCT01064401). Daclizumab binds to and blocks the α subunit of the high-affinity IL2 receptor CD25, which is expressed on the surface of activated www.thelancet.com/neurology Vol 13 May 2014
T cells. The main mechanism of action is thought to be an increase in number of CD56bright natural killer cells.3 In The Lancet Neurology, Gavin Giovannoni and colleagues present findings5 from the 1-year SELECTION extension study of the SELECT trial.4 In the SELECT trial, the efficacy and safety of treatment with daclizumab high-yield process (HYP) over 1 year was assessed in patients with relapsing-remitting multiple sclerosis.4 621 patients—an unusually high number for a phase 2 trial—were randomly assigned to receive placebo, 150 mg daclizumab HYP, or 300 mg daclizumab HYP. The annualised relapse rate—the primary endpoint—was lower for patients who received either dose of daclizumab HYP than for those who received placebo.4 These positive results in a population of patients with moderate disability and intermediate disease activity were followed by a study extension in the 1-year SELECTION trial.5 Typically, patients in extension studies are kept on the same active drugs as the original trial or are switched from placebo to the active compound. However, the SELECTION extension study had a novel design. In addition to the treatment initiation group (patients given placebo in SELECT were randomly assigned to receive either 150 mg or 300 mg daclizumab HYP in
Published Online March 19, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70056-0 See Articles page 472
443
Comment
year 2), patients who had received daclizumab HYP in SELECT underwent a randomised withdrawal procedure. They entered either a continuous treatment group (continued with the same dose of daclizumab HYP that they received in SELECT) or a washout and re-initiation group (washout period of 24 weeks in which patients received placebo, before resuming their original dose of daclizumab HYP for 32 weeks). This third group uniquely enabled investigation of the pharmacodynamic effects of the drug (through washout) and the possibility of a rebound of disease activity. Similar to the results of SELECT,4 Giovannoni and colleagues reported reductions in the treatment initiation group from year 1 to year 2 in the annualised relapse rate (0·434, 95% CI 0·347–0·544 vs 0·179, 0·123–0·261; p
*Dieter Riemann, Kai Spiegelhalder
6
Department of Clinical Psychology and Psychophysiology/Sleep Medicine, Centre for Mental Disorders, Freiburg University Medical Centre, Hauptstr 5, 79104 Freiburg, Germany [email protected]
7
DR acted as a consultant for Abbvie in 2013. KS declares that he has no competing of interests. The work of both authors is supported by DFG (Deutsche Forschungsgemeinschaft; German Research Council), BMBF (Bundesministerium für Bildung und Forschung; German Ministry for Education and Research), FRIAS (Freiburg University Institute for Advanced Studies), European Union, and the Else Kröner-Fresenius-Stiftung (Else Kröner Fresenius Foundation). 1
2 3
4 5
Michelson D, Snyder E, Paradis E et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; published online March 27. http://dx.doi. org/10.1016/ S1474-4422(14)70053-5. Morin, CM, Benca R. Chronic insomnia. Lancet 2012; 379: 1129–41. Riemann D, Spiegelhalder K, Feige B, et al. The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Med Rev 2010; 14: 19–31. APA. Diagnostic and statistical manual of mental disorders—5th edition (DSM-5). Washington, DC: American Psychiatric Association, 2013. Riemann D, Perlis, ML. The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev 2009; 13: 205–14.
8
9
10 11 12
13
14
Duendar Y, Dodd S, Strobl J, et al. Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Hum Psychopharmacol 2004; 19: 305–22. Glass J, Lanctôt KL, Hermann N, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005; 331: 1–7. Buscemi N, Vandermeer B, Friesen C, et al. The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of RCTs. J Gen Intern Med 2007; 22: 1335–50. Huedo-Medina T, Kirsch I, Klonizakis M, et al. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ 2012; 345: 1–13. Mieda M, Sakurai T. Overview of orexin/hypocretin system. Prog Brain Res 2012; 198: 5–14. Farkas R. Suvorexant safety and efficacy—FDA preliminary conclusions. http://www.fda.gov/downloads/.../UCM354215.pdf (accessed March 18). Herring WJ, Snyder E, Budd K, Hutzelmann J, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 2012; 79: 2265–74. Actelion. Actelion and GSK discontinue clinical development of almorexant. http://www1.actelion.com/en/our-company/news-andevents/index.page?newsId=1483135 (accessed March 18). Tafti M. Reply to ‘promotion of sleep by targeting the orexin system in rats, dogs and humans’. Nature Med 2007; 13: 525–26.
Daclizumab in multiple sclerosis: a high-yield extension study Monoclonal antibodies have emerged as effective treatments for patients with multiple sclerosis. They bind to specific proteins on the surface of the immune cells that are involved in the cascade of events leading to pathological changes associated with the disease: rituximab, ocrelizumab, and ofatumumab target CD20 (also known as MS4A1), which is present on only B cells; alemtuzumab binds to CD52 on the surface of many types of white cells; and natalizumab binds to the alpha-4 integrin (ITGA4) on the surface of lymphocytes, thereby reducing the movement of these cells across the vascular endothelium. Common features of monoclonal antibodies are that they target an antigen expressed on peripheral lymphocytes, and so they have a long washout period and the effects after cessation of treatment are unpredictable. For example, a return of disease activity with relapses and gadolinium-enhancing lesions,1 and T2 lesions2 have been described after interruption of natalizumab treatment. Daclizumab is a monoclonal antibody that has previously been studied in phase 2 trials (CHOICE and SELECT)3,4 and is now being investigated in phase 3 trials (NCT01462318 and NCT01064401). Daclizumab binds to and blocks the α subunit of the high-affinity IL2 receptor CD25, which is expressed on the surface of activated www.thelancet.com/neurology Vol 13 May 2014
T cells. The main mechanism of action is thought to be an increase in number of CD56bright natural killer cells.3 In The Lancet Neurology, Gavin Giovannoni and colleagues present findings5 from the 1-year SELECTION extension study of the SELECT trial.4 In the SELECT trial, the efficacy and safety of treatment with daclizumab high-yield process (HYP) over 1 year was assessed in patients with relapsing-remitting multiple sclerosis.4 621 patients—an unusually high number for a phase 2 trial—were randomly assigned to receive placebo, 150 mg daclizumab HYP, or 300 mg daclizumab HYP. The annualised relapse rate—the primary endpoint—was lower for patients who received either dose of daclizumab HYP than for those who received placebo.4 These positive results in a population of patients with moderate disability and intermediate disease activity were followed by a study extension in the 1-year SELECTION trial.5 Typically, patients in extension studies are kept on the same active drugs as the original trial or are switched from placebo to the active compound. However, the SELECTION extension study had a novel design. In addition to the treatment initiation group (patients given placebo in SELECT were randomly assigned to receive either 150 mg or 300 mg daclizumab HYP in
Published Online March 19, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70056-0 See Articles page 472
443
Comment
year 2), patients who had received daclizumab HYP in SELECT underwent a randomised withdrawal procedure. They entered either a continuous treatment group (continued with the same dose of daclizumab HYP that they received in SELECT) or a washout and re-initiation group (washout period of 24 weeks in which patients received placebo, before resuming their original dose of daclizumab HYP for 32 weeks). This third group uniquely enabled investigation of the pharmacodynamic effects of the drug (through washout) and the possibility of a rebound of disease activity. Similar to the results of SELECT,4 Giovannoni and colleagues reported reductions in the treatment initiation group from year 1 to year 2 in the annualised relapse rate (0·434, 95% CI 0·347–0·544 vs 0·179, 0·123–0·261; p
