BG Weinshenker Dr Greenberg has received consulting fees from Chugai, Novartis, EMD Serono and Medimmune. He has received grant support from the NIH, PCORI, Biogen and the Guthy Jackson Charitable Foundation. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. References 1. Kimbrough DJ, Fujihara K, Jacob A, et al. Treatment of neuromyelitis optica: Review and
recommendations. Mult Scler Rel Dis 2012; 1: 180–187. 2. Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007; 6: 1045–1053. 3. Messe SR, Sansing LH, Cucchiara BL, et al. Prophylactic antiepileptic drug use is associated with poor outcome following ICH. Neurocrit Care 2009; 11: 38–44. 4. Smith CM. Origin and uses of primum non nocere – above all, do no harm! J Clin Pharmacol 2005; 45: 371–377.57 7 MSJ0010.1177/1352458515579217Multiple Sclerosis JournalBM Greenbergresearch-article2015
Placebo Studies should not be Undertaken in Neuromyelitis Optica: Commentary
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Multiple Sclerosis Journal 2015, Vol. 21(6) 693–694 DOI: 10.1177/ 1352458515580402 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Brian G Weinshenker
Definitive phase 3 clinical trials for neuromyelitis optica (NMO), previously unthinkable, have become feasible and have actually begun in 2014.1 This achievement has resulted because of key advances over the past 15 years, including: (1) definitive diagnosis and separation of NMO from multiple sclerosis in the majority of patients at an early point in the disease before major irreversible disability; (2) recognition of a comprehensive spectrum of disease presentations aided by a specific biomarker, aquaporin-4 IgG; (3) rational selection of treatments based on understanding of the pathogenesis of NMO. However, progress is threatened by conflicting concerns regarding the need for and the acceptability of placebo-controlled clinical trials in NMO. Regulators in different jurisdictions have provided less than consistent guidance, in part due to differing opinions expressed to them by NMO experts on the subject. Palace and Greenberg nicely summarize the issues. Palace argues that the risk of even a single attack of irreversible disability cannot be asked from a patient given current knowledge and that observational studies in NMO and in a variety of other antibodymediated diseases adequately establish a standard of therapy for NMO; “reinventing the wheel” by conducting placebo-controlled studies is unnecessary. Greenberg argues that the evidence from retrospective studies is potentially flawed, backed up by previous experience from other diseases, for which the efficacy of agents presumed to be effective was
disproven in placebo-controlled clinical trials. He contends that the expanding spectrum of NMO does not allow us to assume that the severity of attacks for contemporary NMO is adequately documented in studies of decades ago; furthermore, arguing that current therapies are a standard of treatment ignores their potential safety risks. Theoretically, newer, targeted immunotherapies, such as monoclonal antibodies, may be safer than older less specific immunosuppressive treatments, though long-term studies will be required to establish the safety even of specific agents. Unexpectedly high frequency of certain infections2 and paradoxical autoimmunity3 have been observed with MS monoclonal antibody treatments.
Correspondence to: Brian G Weinshenker Professor of Neurology, Mayo Clinic, 200 First Street SW Rochester, MN 55905, USA. [email protected] Brian G Weinshenker Mayo Clinic, Rochester, USA
The arguments on both sides are meritorious. But what is the path forward? As one who previously espoused Palace’s arguments but has been convinced that placebo-controlled studies for NMO are acceptable under certain circumstances, I was most swayed by the fundamental principle that placebo-controlled trials are the standard for scientific rigor and having such an evidence base at an early point in therapeutic development for a disease is worthwhile. Treatments such as thymectomy for non-thymoma myasthenia gravis have been performed for decades despite no definitive study and continuing controversy about its efficacy.4 Although a clinical trial has been started years after being considered a standard of practice in many centers.5 enrollment has been difficult and did not meet targets. We may
http://msj.sagepub.com 693
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
Multiple Sclerosis Journal 21(6) never have an answer about this important issue. Had sham-controlled studies been conducted when thymectomy was first proposed as effective, this controversy could have been answered long ago. Yes, even a single attack of NMO may be permanently disabling. But when an attack is promptly recognized and treatment instituted, including plasma exchange when corticosteroids fail, major disability is usually avoided.6 Prompt recognition and aggressive treatment of attacks is generally expedited and more rigorously followed in the context of a clinical trial than in routine clinical practice. Other mitigating strategies to reduce adverse consequences to a patient include limiting duration of the placebo phase and withdrawal from the controlled phase of the study after a single event.1 As Palace suggests, this may reduce the informativeness of the study, as a patient contributes only a single event; however, the informativeness may be compromised to an even greater extent in an active comparative study to another effective agent. We need to know not only whether new treatments are more effective than placebo, but whether they are superior to existing treatments which are bound to be much less expensive than newer treatments; although treatments such as azathioprine, mycophenolate mofetil and rituximab, the most commonly used maintenance treatments for NMO, are associated with risks, they have a reasonable risk:benefit strategy based on decades of experience not only in NMO but in a variety of autoimmune diseases for which they are used. Therefore, although placebo-controlled studies are necessary, comparison to existing empiric therapies currently in use will also be necessary. However, concurrent comparison of multiple arms in a single trial for pair-wise comparison may lead to inordinately large sample sizes, especially if powered for detecting superiority in “time to first attack”. So, both arguments are correct; both placebo-controlled and active comparison trials are necessary to comprehensively address optimal efficacy for NMO. To establish a baseline, comparison to placebo will be necessary. Active comparison studies will then be able to build on this foundation and placebo-controlled trials may no longer be necessary once a true standard of treatment is established. As many of the safety issues may only be evident over the long term, prolonged follow-up of patients in trials is necessary, particularly for new agents without a well-established safety profile. Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Given the prevalence of NMO, generally 1−5/100,000 worldwide, the NMO community must come together
and cooperate to successfully enroll these studies. Agreement and standardization of entry criteria endpoints across clinical trials will facilitate comparison of results across trials, and potentially even facilitate a common placebo group and movement efficiently from trial to trial.1 A thorough discussion of the pros and cons of placebo-controlled studies for NMO is important and valuable; “getting stuck” is not. We need to move ahead rationally, methodically and cooperatively. Conflict of interest Member data safety monitoring boards: Novartis, Biogen Idec and Mitsubishi; Adjudication panel member: MedImmune. Consultant: Elan, GlaxoSmithKline, Ono, CHORD Therapeutics, and Chugai. Editorial board membership: Neurology, the Canadian Journal of Neurological Sciences, and the Turkish Journal of Neurology. Research support: Guthy-Jackson Charitable Foundation. Royalties and patent: RSR Ltd. and Oxford University for a patent regarding AQP4-associated antibodies for diagnosis of neuromyelitis optica. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1.
Weinshenker BG, Barron G, Behne, JM., et al. Challenges and opportunities in designing clinical trials for neuromyelitis optica. Neurology 2015 (forthcoming).
2.
Kleinschmidt-DeMasters BK, Miravalle A, Schowinsky J, et al. Update on PML and PML-IRIS occurring in multiple sclerosis patients treated with natalizumab. J Neuropath Exp Neurol 2012; 71: 604–617.
3.
Coles AJ. Alemtuzumab therapy for multiple sclerosis. Neurotherapeutics 2013; 10: 29–33.
4.
Benatar M, Verdugo RJ and Salinas RA. Thymectomy for non-thymomatous myasthenia gravis. Cochrane Database Syst Rev 2013; 10: CD008111.
5.
Kaminski HJ, Jaretzki A, 3rd, Swan A and NewsomDavis J. Development of a thymectomy trial in nonthymomatous myasthenia gravis patients receiving immunosuppressive therapy. Annals of the New York Academy of Sciences 2003; 998: 473–480.
6.
Kimbrough DJ, Fujihara K, Jacob A, et al. Treatment of neuromyelitis optica: Review and recommendations. Multiple Sclerosis and Related Disorders 2012; 1: 180–187.580402 MSJ0010.1177/1352458515580402Multiple Sclerosis JournalBG Weinshenkerresearch-article2015
694 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
recommendations. Mult Scler Rel Dis 2012; 1: 180–187. 2. Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007; 6: 1045–1053. 3. Messe SR, Sansing LH, Cucchiara BL, et al. Prophylactic antiepileptic drug use is associated with poor outcome following ICH. Neurocrit Care 2009; 11: 38–44. 4. Smith CM. Origin and uses of primum non nocere – above all, do no harm! J Clin Pharmacol 2005; 45: 371–377.57 7 MSJ0010.1177/1352458515579217Multiple Sclerosis JournalBM Greenbergresearch-article2015
Placebo Studies should not be Undertaken in Neuromyelitis Optica: Commentary
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Multiple Sclerosis Journal 2015, Vol. 21(6) 693–694 DOI: 10.1177/ 1352458515580402 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Brian G Weinshenker
Definitive phase 3 clinical trials for neuromyelitis optica (NMO), previously unthinkable, have become feasible and have actually begun in 2014.1 This achievement has resulted because of key advances over the past 15 years, including: (1) definitive diagnosis and separation of NMO from multiple sclerosis in the majority of patients at an early point in the disease before major irreversible disability; (2) recognition of a comprehensive spectrum of disease presentations aided by a specific biomarker, aquaporin-4 IgG; (3) rational selection of treatments based on understanding of the pathogenesis of NMO. However, progress is threatened by conflicting concerns regarding the need for and the acceptability of placebo-controlled clinical trials in NMO. Regulators in different jurisdictions have provided less than consistent guidance, in part due to differing opinions expressed to them by NMO experts on the subject. Palace and Greenberg nicely summarize the issues. Palace argues that the risk of even a single attack of irreversible disability cannot be asked from a patient given current knowledge and that observational studies in NMO and in a variety of other antibodymediated diseases adequately establish a standard of therapy for NMO; “reinventing the wheel” by conducting placebo-controlled studies is unnecessary. Greenberg argues that the evidence from retrospective studies is potentially flawed, backed up by previous experience from other diseases, for which the efficacy of agents presumed to be effective was
disproven in placebo-controlled clinical trials. He contends that the expanding spectrum of NMO does not allow us to assume that the severity of attacks for contemporary NMO is adequately documented in studies of decades ago; furthermore, arguing that current therapies are a standard of treatment ignores their potential safety risks. Theoretically, newer, targeted immunotherapies, such as monoclonal antibodies, may be safer than older less specific immunosuppressive treatments, though long-term studies will be required to establish the safety even of specific agents. Unexpectedly high frequency of certain infections2 and paradoxical autoimmunity3 have been observed with MS monoclonal antibody treatments.
Correspondence to: Brian G Weinshenker Professor of Neurology, Mayo Clinic, 200 First Street SW Rochester, MN 55905, USA. [email protected] Brian G Weinshenker Mayo Clinic, Rochester, USA
The arguments on both sides are meritorious. But what is the path forward? As one who previously espoused Palace’s arguments but has been convinced that placebo-controlled studies for NMO are acceptable under certain circumstances, I was most swayed by the fundamental principle that placebo-controlled trials are the standard for scientific rigor and having such an evidence base at an early point in therapeutic development for a disease is worthwhile. Treatments such as thymectomy for non-thymoma myasthenia gravis have been performed for decades despite no definitive study and continuing controversy about its efficacy.4 Although a clinical trial has been started years after being considered a standard of practice in many centers.5 enrollment has been difficult and did not meet targets. We may
http://msj.sagepub.com 693
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
Multiple Sclerosis Journal 21(6) never have an answer about this important issue. Had sham-controlled studies been conducted when thymectomy was first proposed as effective, this controversy could have been answered long ago. Yes, even a single attack of NMO may be permanently disabling. But when an attack is promptly recognized and treatment instituted, including plasma exchange when corticosteroids fail, major disability is usually avoided.6 Prompt recognition and aggressive treatment of attacks is generally expedited and more rigorously followed in the context of a clinical trial than in routine clinical practice. Other mitigating strategies to reduce adverse consequences to a patient include limiting duration of the placebo phase and withdrawal from the controlled phase of the study after a single event.1 As Palace suggests, this may reduce the informativeness of the study, as a patient contributes only a single event; however, the informativeness may be compromised to an even greater extent in an active comparative study to another effective agent. We need to know not only whether new treatments are more effective than placebo, but whether they are superior to existing treatments which are bound to be much less expensive than newer treatments; although treatments such as azathioprine, mycophenolate mofetil and rituximab, the most commonly used maintenance treatments for NMO, are associated with risks, they have a reasonable risk:benefit strategy based on decades of experience not only in NMO but in a variety of autoimmune diseases for which they are used. Therefore, although placebo-controlled studies are necessary, comparison to existing empiric therapies currently in use will also be necessary. However, concurrent comparison of multiple arms in a single trial for pair-wise comparison may lead to inordinately large sample sizes, especially if powered for detecting superiority in “time to first attack”. So, both arguments are correct; both placebo-controlled and active comparison trials are necessary to comprehensively address optimal efficacy for NMO. To establish a baseline, comparison to placebo will be necessary. Active comparison studies will then be able to build on this foundation and placebo-controlled trials may no longer be necessary once a true standard of treatment is established. As many of the safety issues may only be evident over the long term, prolonged follow-up of patients in trials is necessary, particularly for new agents without a well-established safety profile. Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Given the prevalence of NMO, generally 1−5/100,000 worldwide, the NMO community must come together
and cooperate to successfully enroll these studies. Agreement and standardization of entry criteria endpoints across clinical trials will facilitate comparison of results across trials, and potentially even facilitate a common placebo group and movement efficiently from trial to trial.1 A thorough discussion of the pros and cons of placebo-controlled studies for NMO is important and valuable; “getting stuck” is not. We need to move ahead rationally, methodically and cooperatively. Conflict of interest Member data safety monitoring boards: Novartis, Biogen Idec and Mitsubishi; Adjudication panel member: MedImmune. Consultant: Elan, GlaxoSmithKline, Ono, CHORD Therapeutics, and Chugai. Editorial board membership: Neurology, the Canadian Journal of Neurological Sciences, and the Turkish Journal of Neurology. Research support: Guthy-Jackson Charitable Foundation. Royalties and patent: RSR Ltd. and Oxford University for a patent regarding AQP4-associated antibodies for diagnosis of neuromyelitis optica. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1.
Weinshenker BG, Barron G, Behne, JM., et al. Challenges and opportunities in designing clinical trials for neuromyelitis optica. Neurology 2015 (forthcoming).
2.
Kleinschmidt-DeMasters BK, Miravalle A, Schowinsky J, et al. Update on PML and PML-IRIS occurring in multiple sclerosis patients treated with natalizumab. J Neuropath Exp Neurol 2012; 71: 604–617.
3.
Coles AJ. Alemtuzumab therapy for multiple sclerosis. Neurotherapeutics 2013; 10: 29–33.
4.
Benatar M, Verdugo RJ and Salinas RA. Thymectomy for non-thymomatous myasthenia gravis. Cochrane Database Syst Rev 2013; 10: CD008111.
5.
Kaminski HJ, Jaretzki A, 3rd, Swan A and NewsomDavis J. Development of a thymectomy trial in nonthymomatous myasthenia gravis patients receiving immunosuppressive therapy. Annals of the New York Academy of Sciences 2003; 998: 473–480.
6.
Kimbrough DJ, Fujihara K, Jacob A, et al. Treatment of neuromyelitis optica: Review and recommendations. Multiple Sclerosis and Related Disorders 2012; 1: 180–187.580402 MSJ0010.1177/1352458515580402Multiple Sclerosis JournalBG Weinshenkerresearch-article2015
694 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CALGARY on May 27, 2015
