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Characteristics of the patients identified by each of these definitions are shown in Table 4.

Clinical Trials for MS and Rheumatoid Arthritis with Umbilical Cord Mesenchymal Stem Cells

The two definitions that led to the earliest diagnosis of SPMS were both based on the 3-strata criterion of progression magnitude Fig. In addition, they used a minimum EDSS score of 3 combined with a confirmation period of 6 months or a minimum EDSS score of 4 in combination with a confirmation period of 3 months. According to these definitions half of the patients were diagnosed with SPMS within Timeliness of diagnosis and disability burden.

A Time from disease onset to secondary progression Kaplan-Meier estimate. In addition, AUC during the progressive phase is shown open squares. Error bars represent the IQR. The annualized relapse rates were 0. When analysing the progressive disease phase exclusively, mean relapse rates varied between 0. In comparison, the patients diagnosed versus not diagnosed by the treating physician showed an annualized relapse rate of 0. Patients with progressive disease experienced a higher overall burden of disability, expressed as the annualized area under the EDSS-time curve compared with non-progressive patients Fig.

Also, the median increase in the overall disability burden the annualized AUC change ranged from 1. Patients with ongoing relapses or contrast-enhancing MRI lesions after the diagnosis of SPMS did not tend to accumulate more disability compared with patients without episodic inflammatory activity Supplementary Table 3. In this analysis from the prospective observational MSBase cohort study, we have identified an objective definition of SPMS with the best performance from a pool of candidate definitions. Importantly, it enabled the diagnosis of SPMS more than 3 years earlier than the diagnosis date assigned by the treating physicians.

Currently, there is no gold-standard objective definition of SPMS. We therefore used a consensus diagnosis of SPMS as one of the comparators for the evaluated definitions. In keeping with previous studies, we observed good agreement among neurologists when determining the conversion to SPMS in selected patients with extended follow-up and high visit density Amato et al.


However, consensus on the date of conversion to SPMS was only moderate and the variability in the time of the diagnosed conversion was remarkable even among the three neurologists with a largely similar view of the SPMS diagnosis. Such a period has been described previously and may be required to distinguish fluctuations from true disability progression Katz Sand et al. Our proposed objective definition of SPMS minimises this period of uncertainty, which could reduce an important source of bias in studies where SPMS is an inclusion criterion or an outcome.

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As expected, specificity and sensitivity of the operational definitions varied broadly when compared with the consensus diagnosis. It is not surprising that the definitions with the best accuracy defined minimal EDSS and pyramidal FS scores and also required confirmation within the FS leading to progression.

Omitting a minimal pyramidal FS score and confirmation within the leading FS resulted in a lower diagnostic accuracy, which could not be easily overcome by using more stringent requirements for other criteria, such as the required confirmation time. While using a definition without the FS information represents a pragmatic approach where this information is not available, we strongly advocate utilization of FS scores. This not only increases diagnostic accuracy of the definition but also enables review of the internal validity of EDSS scores.

While correction for disability progression attributable to preceding relapse activity improved accuracy, excluding patients with a higher number of relapses after the diagnosis had no relevant impact. For the analysis in the complete dataset, we used the proportion of patients diagnosed with SPMS and a set of unfavourable long-term outcomes as to assess sensitivities and specificities. It has been previously demonstrated that the most important determinant of progression stability is the required confirmation time and that disability metrics based on short-term confirmed progression overestimated the long-term accumulation of irreversible disability Kalincik et al.

However, patients with progressive multiple sclerosis and higher EDSS score were less likely to regress. This finding can be explained by the properties of the EDSS, which is known to have less variability at higher stages of disability and also by the fact that there is less fluctuation once a patient has reached a certain level of disability Weinshenker et al. We also found that the exclusion of progression events that were related to preceding relapse activity was a critical factor of progression stability.

On the other hand, we observed that replacement of the 3-strata progression paradigm by the more stringent criterion of a progression magnitude of 2 EDSS steps led to fewer identified patients without increasing the proportion of patients reaching the predefined disability outcomes. The median time from disease onset until conversion to SPMS has been reported as 15 years in the London, Ontario cohort and 19 years in the Lyon and Gothenburg cohorts, whereas contemporary cohorts have shown a shift towards a longer time to conversion Confavreux et al.

Multiple Sclerosis Advances In Clinical Trial Design Treatment And Future Perspectives

Similarly, we also found a substantially longer time from disease onset to SPMS compared to the mentioned natural history studies. It has been previously suggested that the trend towards slower disability progression may represent a flux in the patient population seen in multiple sclerosis clinics, and might also be driven by an increased recognition of the disease, changing diagnostic criteria, availability of more potent immunomodulatory drugs, as well as improving management of chronic disease Tremlett et al. In addition, MSBase is not a natural history cohort, and the population seen in the tertiary multiple sclerosis centres contributing to MSBase is enriched for patients with active relapsing-remitting disease and treated with immunomodulatory agents.

Finally, there is well known heterogeneity among observational studies in terms of design, data collection, definition of outcomes, and analysis Tremlett et al. This implies a systematic difference in the use of diagnostic criteria, which again proves the need for a unified, validated SPMS definition.

Clinical trials in multiple sclerosis: milestones

None of the shortlisted definitions excluded patients with ongoing relapses, which may raise concerns about an increased proportion of patients with disease activity in the selected populations. However, compared with the data available from treatment trials in SPMS, the observed annualised relapse rates during the progressive phase 0.

This suggests that our proposed definition of SPMS does not result in an overrepresentation of patients with inflammatory activity. In combination with the substantially greater disability burden among the patients identified by the shortlisted definitions, this implies that the identified patients continue to accumulate further disability that is not directly associated with episodic CNS inflammation. We conclude that the definition using a 3-strata progression paradigm, with a minimum EDSS of 4 and a confirmation time of 3 months had the best overall performance out of the candidate definitions.

Relapse rate and accumulation of new disability during the progressive multiple sclerosis were greater in the patients diagnosed by the objective definition than those with an SPMS diagnosis by the treating physicians. These findings confirm that neurologists wait until substantial disability has been accumulated and episodic disease activity has ceased before the SPMS diagnosis is confidently assigned, one motivation probably being their desire for patients to remain on disease-modifying therapy, which in some jurisdictions is not allowed after diagnosis of SPMS.

While the effect of a diagnostic delay invoked by this conservative approach is negligible in clinical practice, it can introduce a significant bias in clinical trial settings.

Search for progressive multiple sclerosis treatment is gathering momentum

The main limitation of our study overlaps with the limitations of the EDSS. The score is weighted towards motor and lower limb functions, which leads to a decreased sensitivity for detecting more subtle forms of disease progression. Our proposed definition of SPMS is therefore likely to be rather conservative.

To adjust for the well-known non-linearity of the scale, we stratified the required magnitude of the progression by the level of pre-existing disability Amato and Ponziani, The EDSS is burdened with a relatively low intra- and inter-rater reliability, especially at the lower end of the scale Amato et al. As our study involved 81 centres over long follow-up periods, this probably led to inflation of the EDSS variance.

On the other hand, we aimed to mitigate variance through the requirement of Neurostatus certification and its impact through the size of the study population. Furthermore, all of the shortlisted definitions required minimal EDSS levels, thus restricting evaluation of progression to the higher EDSS steps, which are known to be relatively more stable Hohol et al.

In addition, confirmation after defined time periods and within FS scores were used to further improve EDSS stability.

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In clinical practice, SPMS is typically diagnosed retrospectively. As the time-point when the diagnosis is assigned is not recorded in MSBase, we were unable to analyse the period of uncertainty in the complete dataset. Hence, we used an estimate from sample patients, which probably still underestimated the lag to the diagnosis, as the sample was selected with the intention of maximising follow-up duration and visit density.

While this sample cannot be regarded as being representative of the full MSBase cohort, it provides an optimal setting for the comparison of the tested definitions of SPMS to clinical judgement. The relatively poor availability of MRI data hindered conclusive assessment of disease activity in the progressive patients. On the other hand, it forced us to focus our analysis on clinical data, which facilitated development of an accessible and easy-to-use definition for SPMS. Our objective definition of SPMS based on the EDSS and information about preceding relapses provides a tool for a reproducible, accurate and timely SPMS diagnosis that requires a very short confirmation period and can also be easily applied retrospectively to longitudinal data.

If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in SPMS. This study was financially supported by the National Health and Medical Research Council practitioner fellowship , project grants and and centre for research excellence , the University of Melbourne Faculty of Medicine, Dentistry and Health Sciences research fellowship and Biogen Fellowship in MS Registries Research.

The study was conducted separately and apart from the guidance of the sponsors. Supplementary material is available at Brain online. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

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Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Patients and methods. Supplementary material. Editor's Choice. Defining secondary progressive multiple sclerosis Johannes Lorscheider. Oxford Academic. Google Scholar. Katherine Buzzard. Vilija Jokubaitis. Tim Spelman. Eva Havrdova. Dana Horakova. Maria Trojano. Guillermo Izquierdo. Marc Girard. Pierre Duquette. Alexandre Prat. Alessandra Lugaresi.