Research in context
Evidence before this study
A search from inception to Jan 31, 2014, with no restriction on language, was done in the MEDLINE, Embase, and Cochrane databases, using the search terms ([neuromyelitis optica] OR [NMO] OR [NMOSD] OR [Devic's disease]). The search identified 2438 articles, which were screened for relevance with regard to treatment options, and 105 studies were included in a review of the evidence.
Most of the 105 studies were small, retrospective, observational studies with no comparator that rarely included sufficient detail on the trial methodology to evaluate selection bias, information bias, or confounding factors. After the identification of highly specific serum autoantibodies against the aquaporin-4 water channel expressed on astrocytes in the CNS in 2004, and the altered diagnostic criteria for patients with neuromyelitis optica spectrum disorder (NMOSD) in 2006, the characteristics of patients included in trials before and after these landmarks differed. Moreover, no safety data were reported in most of these studies; therefore, no benefit–risk assessments could be done, and the dosing regimens and durations of therapy differed greatly. Finally, no unified and accepted definition of an NMOSD attack was used.
Of the studies identified, seven summarised the effects of the immunosuppressant azathioprine, with or without corticosteroid treatment; all seven were uncontrolled case studies, three of which reported large multicentre retrospective case studies. Significant reductions in annualised relapse rate (ARR) were reported before and after treatment in six out of seven of these case studies. Ten uncontrolled, retrospective case series reported on the use of rituximab, an anti-CD20, B cell-depleting antibody in patients with NMOSD (134 patients in total). Nine of these studies reported an apparent reduction in ARR, and seven out of eight studies claimed an improvement on the Expanded Disability Status Scale (EDSS) after treatment.
The use of cyclophosphamide with or without steroids was examined in three uncontrolled, retrospective cases (12 patients in total), methotrexate with or without steroids was examined in two small case studies, and mitoxantrone with or without corticosteroids was examined in a further three case studies. In all but one of these studies, disease stabilisation was observed. One study reported that cyclophosphamide was ineffective and was associated with adverse events.
A further ten small case studies assessed an additional eight therapies, including mycophenolate mofetil, eculizumab, and natalizumab. Most of these studies reported reductions in ARR and EDSS scores without a reference control group, although subsequent studies have suggested that natalizumab treatment in NMOSD might be ineffective, and possibly harmful.
All of these studies were limited by bias inherent to the study design, and none of them were randomised. Therefore, although reductions in ARR or EDSS scores could be caused by treatment effect, they could also be attributed to regression to the mean, selection bias, or both.
Added value of this study
To date, no approved therapies exist for NMOSD, and randomised controlled trials have only recently been initiated. Currently, medications are used empirically to prevent and treat attacks. Although guidelines recommend the use of immunosuppressants in NMOSD, only low-level clinical evidence supporting this practice is available, based exclusively on uncontrolled or retrospective studies. Without randomised controlled studies, the benefits and risks associated with the use of off-label medications in NMOSD are not well established. Thus, there is a clear unmet need for effective, evidence-based treatments to delay or prevent attacks in NMOSD. N-MOmentum is a double-blind, randomised placebo-controlled phase 2/3 study assessing the efficacy and safety of inebilizumab in patients with NMOSD. The trial was designed to be acceptable to patients, physicians, ethics boards, and regulatory authorities, with safety as a key consideration, and it included independent study oversight and objective adjudication of NMOSD attacks according to predefined criteria.
Implications of all the available evidence
N-MOmentum is the first large, randomised controlled trial of any disease-modifying therapy to demonstrate superiority over placebo in reducing the risk of an NMOSD attack, disability worsening, MRI lesion activity, and disease-related hospitalisations in patients with NMOSD.