Short-Term Relapse Quantitation as a Fully Surrogate Endpoint for Long-Term Sustained Progression of Disability in RRMS Patients Treated with Natalizumab

Abstract

Time to sustained worsening in the expanded disability status scale as the standard for evaluating the accumulation of disability has been used as a measure of clinical efficacy in many relapsing-remitting multiple sclerosis (RRMS) clinical trials. However, this measurement usually requires a large sample and long-term study to demonstrate the treatment effect. Annualized relapse rate or time to first relapse is also widely used as alternative measurements of clinical efficacy. A formal statistical validation of short-term relapse activity as a surrogate endpoint for long-term sustained progression of disability could potentially permit smaller, shorter, and less expensive clinical trials in RRMS. Four statistical validation/evaluation approaches consistently showed that relapse activity through one year of treatment serves as statistically valid surrogate endpoint for time to sustained progression of disability. The analysis demonstrates that long-term sustained progression of disability can be predicted by short-term relapse measures with 4 consistent validations of statistical approaches, including a formal statistical hypothesis test. This was demonstrated in a large phase III trial of natalizumab and showed that the beneficial clinical effect of natalizumab on sustained progression of disability at 2 years in patients with RRMS can be predicted by the total number of relapses at 1 year.

Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS

“…However, these disease-modifying therapies have a series of side effects. The use of glucocorticoids, for example, has caused muscle atrophy (26), osteoporosis, obesity, cataracts, necrosis of the femoral head and immunosuppression (27), while IFN-b and natalizumab were respectively predicted to have 62% and 80% annual recurrence and 2-year disability deterioration in MS patients receiving their first treatment (28,29). The development of a new, personalized medicine is therefore urgent.…”

Unraveling treatment response in multiple sclerosis

“…According to different studies, the treatment effect on relapses in the first treatment year predicted ;62% and ;80% of the treatment effect on the 2-year disability worsening in IFN-βand natalizumab-treated patients, respectively. 24,25 In analogy, the treatment effect on new T2 lesions in the first treatment year predicted ;60% of the treatment effect on relapses 26 and ;57% of the treatment effect on the 2-year disability worsening. 27 A combined measure of 1-year changes in MRI lesions and relapses predicted 100% of the treatment effect on 2-year disability worsening in IFN-β-treated patients.…”

Time to first relapse as an endpoint in multiple sclerosis clinical trials

“…In patients with multiple sclerosis (MS), clinical relapses represent the most reliable marker of disease activity and several drugs have been approved for the treatment of relapsing MS on the basis of relapse rate reductions [1][2][3][4][5][6] that were detected in Phase III trials. Moreover, recent work 7,8 shows that the effects of interferon (IFN) beta-1a and natalizumab on the progression of MS-related disability are largely mediated by the effects seen on relapses, lending further support to the use of relapse-related outcomes as the primary endpoints in MS trials.…”