Is it ethical to use teriflunomide as an active comparator in phase 3 trials?

Ethical concerns have been raised about the practice of using teriflunomide, an oral licensed disease-modifying therapy, as an active comparator in phase 3 multiple sclerosis (MS) trials. The assumption is based on the perceived low efficacy of teriflunomide as judged by its effect on relapses and focal MRI activity. However, when you look beyond focal inflammation, teriflunomide has a robust impact on disability progression and a similar effect to the anti-CD20 monoclonal antibody therapies on slowing down the accelerated brain volume loss associated with MS. Teriflunomide is also more effective when used second or third line. The other classes of disease-modifying therapies have problems with their use as active comparators in clinical trials. Using a non-inferiority or equivalence trial design has its own unique set of regulatory and ethical challenges and is not necessarily a solution. There are also economic, altruistic and pragmatic reasons for continuing to use teriflunomide as an active comparator in MS clinical trials. An online survey indicates that the majority of the MS community feels it is still ethical to randomise subjects to teriflunomide and that procedures can be put in place to protect trial subjects randomised to teriflunomide. Therefore, we still have equipoise, and teriflunomide comparator trials are ethical.

CNS resilience in the progression of MS.

Resilience; Progressive multiple sclerosis; Genomics.

Myopia in late adolescence and subsequent multiple sclerosis among men.

BACKGROUND: Risk factors such as low vitamin D level has been implicated in the etiology of multiple sclerosis (MS) and may be relevant to myopia, such that there may be an association between myopia and MS. METHODS: Using linked Swedish national register data, we conducted a cohort study of men who were born in Sweden between 1950 and 1992, lived in Sweden between 1990 and 2018, and enrolled in military conscription assessment (n = 1,847,754). Myopia was defined based on the spherical equivalent refraction measured at conscription assessment, around age 18 years. Multiple sclerosis was identified using the Patient Register. Cox regression produced hazard ratios (HR) with 95% confidence intervals (95% CI), with adjustment for demographic and childhood socioeconomic characteristics and residential region. Due to changes in the assessment of refractive error, the analysis was stratified into two groups by the year of conscription assessment: 1969-1997 and 1997-2010. RESULTS: Among 1,559,859 individuals during a maximum of 48 years of follow-up from age 20 to 68 years (44,715,603 person-years), there were 3,134 MS events, and the incidence rate 7.0 (95% CI [6.8, 7.3] per 100,000 person-years). Among individuals with conscription assessments during 1997-2010, there were 380 MS events. There was no evidence of an association between myopia and MS, with HR 1.09 (95% CI 0.83, 1.43). Among individuals who underwent conscription assessment in 1969-1997, there were 2754 MS events. After adjusting for all covariates, there was no evidence of an association between myopia and MS (HR 0.99 [95% CI 0.91, 1.09]). CONCLUSION: Myopia in late adolescence is not associated with a subsequent raised risk of MS and thus there does not appear to be important shared risk factors.