Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review

Abstract

BackgroundSo far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population.ObjectiveThe aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator.MethodsA systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year’s duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared.ResultsOf 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately.ConclusionOptimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression.

Heterogeneity of Multiple Sclerosis Lesions in Multislice Myelin Water Imaging

“…In PPMS-patients, lesions seem to differ in number and underlying pathology [ 14 ]. Compared to RRMS-patients, PPMS-patients seem to have fewer brain T2-lesions and less CELs [ 26 ]. The lesions are believed to contain fewer inflammatory cells [ 27 ], show less acute axonal damage [ 28 ] and partly hold extensive remyelination in a large proportion of the lesion area [ 29 ], which might rather explain higher MWF values in lesions of PPMS-patients.…”

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

“…Lack of efficacy, inappropriate patients’ selection, short study period, and non-optimal primary outcome are the major causes of the negative results (75). The ORATORIO study was the first phase 3 study to meet its primary endpoint in PPMS (4) (Table 1).…”

Interferon β-Mediated Protective Functions of Microglia in Central Nervous System Autoimmunity

“…Relapsing-remitting MS (RRMS) represents the most common disease course. A minority of about 15% of all patients develops primary-progressive MS (PPMS) characterized by continuous deterioration of neurologic function in the absence of acute exacerbations [2]. Although the etiology of MS remains elusive, it is well established that the immune system is involved in demyelination leading to axonal injury and loss [3,4,5,6].…”

“…Notably, beside its approval for RRMS, Ocrelizumab has been additionally licensed for treating PPMS. Progress in MS therapies have been reviewed in detail before and is therefore not further discussed here [2,43,44,45,46,47].…”