Secondary Progressive Multiple Sclerosis Trials Research Articles

Spatial patterns of brain lesions assessed through covariance estimations of lesional voxels in multiple Sclerosis: The SPACE-MS technique

Predicting disability in progressive multiple sclerosis (MS) is extremely challenging. Although there is some evidence that the spatial distribution of white matter (WM) lesions may play a role in disability accumulation, the lack of well-established quantitative metrics that characterise these aspects of MS pathology makes it difficult to assess their relevance for clinical progression. This study introduces a novel approach, called SPACE-MS, to quantitatively characterise spatial distributional features of brain MS lesions, so that these can be assessed as predictors of disability accumulation. In SPACE-MS, the covariance matrix of the spatial positions of each patient’s lesional voxels is computed and its eigenvalues extracted. These are combined to derive rotationally-invariant metrics known to be common and robust descriptors of ellipsoid shape such as anisotropy, planarity and sphericity. Additionally, SPACE-MS metrics include a neuraxis caudality index, which we defined for the whole-brain lesion mask as well as for the most caudal brain lesion. These indicate how distant from the supplementary motor cortex (along the neuraxis) the whole-brain mask or the most caudal brain lesions are.We applied SPACE-MS to data from 515 patients involved in three studies: the MS-SMART (NCT01910259) and MS-STAT1 (NCT00647348) secondary progressive MS trials, and an observational study of primary and secondary progressive MS. Patients were assessed on motor and cognitive disability scales and underwent structural brain MRI (1.5/3.0 T), at baseline and after 2 years. The MRI protocol included 3DT1-weighted (1x1x1mm3) and 2DT2-weighted (1x1x3mm3) anatomical imaging. WM lesions were semiautomatically segmented on the T2-weighted scans, deriving whole-brain lesion masks. After co-registering the masks to the T1 images, SPACE-MS metrics were calculated and analysed through a series of multiple linear regression models, which were built to assess the ability of spatial distributional metrics to explain concurrent and future disability after adjusting for confounders.Patients whose WM lesions laid more caudally along the neuraxis or were more isotropically distributed in the brain (i.e. with whole-brain lesion masks displaying a high sphericity index) at baseline had greater motor and/or cognitive disability at baseline and over time, independently of brain lesion load and atrophy measures. In conclusion, here we introduced the SPACE-MS approach, which we showed is able to capture clinically relevant spatial distributional features of MS lesions independently of the sheer amount of lesions and brain tissue loss. Location of lesions in lower parts of the brain, where neurite density is particularly high, such as in the cerebellum and brainstem, and greater spatial spreading of lesions (i.e. more isotropic whole-brain lesion masks), possibly reflecting a higher number of WM tracts involved, are associated with clinical deterioration in progressive MS. The usefulness of the SPACE-MS approach, here demonstrated in MS, may be explored in other conditions also characterised by the presence of brain WM lesions.

Disease-modifying treatment of secondary progressive multiple sclerosis

HintergrundBei der Multiplen Sklerose (MS) besteht ein Krankheitskontinuum vom klinisch isolierten Syndrom über die schubförmig-remittierende MS zur sekundär progredienten MS (SPMS). Es bestehen zahlreiche Therapieansätze mit Wirksamkeit auf die schubförmigen und fokal-entzündlichen Krankheitsaspekte, während die Therapie der sekundären Progredienz und der mit ihr assoziierten Aspekte der Pathologie weiterhin eine Herausforderung darstellt.Ziel der ArbeitÜbersicht der aktuellen Optionen zur krankheitsmodifizierenden Therapie der SPMS.Material und MethodenErgebnisse randomisierter klinischer Studien werden substanzspezifisch dargestellt und bewertet.ErgebnisseRandomisierte klinische Studien zur Behinderungszunahme bei SPMS zeigten für β‑Interferone widersprüchliche, für Natalizumab negative Ergebnisse. Orales Cladribin und Ocrelizumab reduzierten die Behinderungszunahme bei schubförmiger MS, wurden jedoch nicht gezielt in einer SPMS-Population untersucht. Positive Ergebnisse zu Mitoxantron sind für heutige SPMS-Patienten mit Blick auf das Nebenwirkungsprofil nur bedingt relevant. Für das Blut-Hirn-Schranken-gängige Siponimod wurde in der EXPAND-Studie bei typischen SPMS-Patienten eine signifikante Reduktion des Risikos der Behinderungsprogression nachgewiesen. Subgruppenanalysen sprechen für eine noch höhere Wirksamkeit von Siponimod bei jüngeren Patienten mit aktiver SPMS.DiskussionFür den Einsatz bisheriger krankheitsmodifizierender Therapien bei SPMS besteht begrenzte Evidenz. Mit Siponimod steht eine neue Option zur Therapie der aktiven SPMS zur Verfügung, definiert durch Schübe oder fokal-entzündliche MRT-Aktivität. Für die Indikationsstellung sind einerseits die frühe Erkennung einer schubunabhängigen Progression, andererseits die Abgrenzung der aktiven SPMS von einer nicht aktiven Erkrankung von entscheidender Bedeutung.

Is the Symbol Digit Modalities Test a useful outcome in secondary progressive multiple sclerosis?

It is unclear which cognitive outcome measure is the most useful for clinical trials in multiple sclerosis. To investigate the usefulness of the Symbol Digit Modalities Test (SDMT) as a clinical outcome measure in secondary progressive multiple sclerosis (SPMS), we describe the frequency of worsening and improvement events in a large randomized controlled trial (RCT) dataset. Using original trial data from the ASCEND trial (n=889), a recent large RCT in SPMS, we describe worsening and similarly defined improvement with and without 3-month confirmation on the SDMT in the whole trial cohort and unconfirmed worsening and improvement on the Paced Auditory Serial Addition Test (PASAT) in a smaller subset (n=107). Somewhat unexpectedly, SDMT scores steadily increased throughout the 2years of follow-up in this trial. There were overall few SDMT worsening events throughout the trial (generally fewer than 10% of participants), but improvement events steadily increased from around 50% of participants with improvement at 12weeks to more than 70% at 84weeks and beyond. PASAT scores followed a similar pattern. In this well-characterized clinical trial cohort, the SDMT does not reflect the steady cognitive decline that patients with SPMS experience. Both SDMT and PASAT scores improve throughout follow-up, possibly due to a practice effect. The SDMT may not be a useful outcome measure of disease progression in 2-year clinical trials in SPMS.

Reliability of Outcome Measures in Clinical Trials in Secondary Progressive Multiple Sclerosis.

To investigate the reliability of clinical outcomes in secondary progressive multiple sclerosis (SPMS) trials, we compared the frequency of progression and improvement events on different clinical outcome measures in the placebo arms of 2 large randomized controlled trial (RCT) datasets. Using original trial data from the placebo arms of IMPACT (International MS Secondary Progressive Avonex Controlled Trial) and ASCEND (A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis), 2 large RCTs in SPMS, we compared disability progression and similarly defined improvement with and without 3- or 6-month confirmation on the outcome measures Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and their combinations. In both datasets, the EDSS showed the highest rates of improvement over time, and the smallest difference between progression and improvement rates, followed by the T25FW and the 9HPT. For the T25FW and 9HPT, improvement rates were fairly stable over time and remained at below or around the 10% level. For the EDSS, improvement rates increased in parallel with disability progression rates. All investigated outcome measures in SPMS showed some evidence of random variation and measurement error, the T25FW and 9HPT less so than the more established outcome EDSS. Our findings are relevant for the design and critical appraisal of trials in SPMS.

Machine learning in secondary progressive multiple sclerosis: an improved predictive model for short-term disability progression.

BackgroundEnhanced prediction of progression in secondary progressive multiple sclerosis (SPMS) could improve clinical trial design. Machine learning (ML) algorithms are methods for training predictive models with minimal human intervention.ObjectiveTo evaluate individual and ensemble model performance built using decision tree (DT)-based algorithms compared to logistic regression (LR) and support vector machines (SVMs) for predicting SPMS disability progression.MethodsSPMS participants (n = 485) enrolled in a 2-year placebo-controlled (negative) trial assessing the efficacy of MBP8298 were classified as progressors if a 6-month sustained increase in Expanded Disability Status Scale (EDSS) (≥1.0 or ≥0.5 for a baseline of ≤5.5 or ≥6.0 respectively) was observed. Variables included EDSS, Multiple Sclerosis Functional Composite component scores, T2 lesion volume, brain parenchymal fraction, disease duration, age, and sex. Area under the receiver operating characteristic curve (AUC) was the primary outcome for model evaluation.ResultsThree DT-based models had greater AUCs (61.8%, 60.7%, and 60.2%) than independent and ensemble SVM (52.4% and 51.0%) and LR (49.5% and 51.1%).ConclusionSPMS disability progression was best predicted by non-parametric ML. If confirmed, ML could select those with highest progression risk for inclusion in SPMS trial cohorts and reduce the number of low-risk individuals exposed to experimental therapies.

Clinical outcome measures in SPMS trials: An analysis of the IMPACT and ASCEND original trial data sets

Background: Still too little is known about the natural history of clinical outcome measures beyond the Expanded Disability Status Scale (EDSS), such as the timed 25-foot walk (T25FW) and nine-hole peg test (9HPT) in secondary progressive multiple sclerosis (SPMS). Objective: To describe progression on the EDSS, T25FW, 9HPT, and their combinations. To investigate the association of the baseline characteristics age, sex, EDSS, T25FW, gadolinium-enhancing lesions, and relapse activity with EDSS and T25FW progression. Methods: Using original trial data from the placebo arms of the IMPACT and ASCEND randomized controlled trials, we describe disability progression (with and without 3- or 6-month confirmation). We investigated the association of selected baseline characteristics with EDSS and T25FW progression over 2 years using binary logistic regression. Results: T25FW was the single outcome measure with the largest proportion of patients progressing, followed by EDSS and 9HPT. EDSS and T25FW at baseline were associated with EDSS and T25FW progression in both data sets. Age and relapse activity were only mild and inconsistent predictors, while sex and gadolinium enhancement at baseline did not predict disability progression in either data set. Conclusion: Our analyses inform the selection of primary outcome measures as well as inclusion criteria for clinical trials in SPMS.

Can We Treat Secondary Progressive Multiple Sclerosis Now?

Secondary progressive multiple sclerosis (SPMS) is characterized by progressive accumulation of disability without intermittent recovery. Treatment of these patients is challenging due to limited understanding of pathogenesis and fewer therapeutic options. This article summarizes difficulties in defining and conducting trials in SPMS, review major clinical trials on therapies approved and unapproved in SPMS and lastly, therapies in pipeline for use in SPMS.

Longitudinal optical coherence tomography study of optic atrophy in secondary progressive multiple sclerosis: Results from a clinical trial cohort

Background: Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS). Objective: Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort. Methods: Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy. Results: Mean RNFL and GCIPL values of patients (n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (−0.31 µm/year) and GCIPL (−0.29 µm/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 µm was associated with greater annualized RNFL atrophy (−0.85 µm/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy. Conclusion: This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations.

Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis.

It is well recognised that the majority of the impact of multiple sclerosis (MS), both personal and societal, arises in the progressive phase where disability accumulates inexorably. As such, progressive MS (PMS) has been the target of pharmacological therapies for many years. However, there are no current licensed treatments for PMS. This stands in marked contrast to relapsing remitting MS (RRMS) where trials have resulted in numerous licensed therapies. PMS has proven to be a more difficult challenge compared to RRMS and this review focuses on secondary progressive MS (SPMS), where relapses occur before the onset of gradual, irreversible disability, and not primary progressive MS where disability accumulation occurs without prior relapses. Although there are similarities between the two forms, in both cases pinpointing when PMS starts is difficult in a condition in which disability can vary from day to day. There is also an overlap between the pathology of relapsing and progressive MS and this has contributed to the lack of well-defined outcomes, both surrogates and clinically relevant outcomes in PMS. In this review, we used the search term 'randomised controlled clinical drug trials in secondary progressive MS' in publications since 1988 together with recently completed trials where results were available. We found 34 trials involving 21 different molecules, of which 38% were successful in reaching their primary outcome. In general, the trials were well designed (e.g. double blind) with sample sizes ranging from 35 to 1949 subjects. The majority were parallel group, but there were also multi-arm and multidose trials as well as the more recent use of adaptive designs. The disability outcome most commonly used was the Expanded Disability Status Scale (EDSS) in all phases, but also magnetic resonance imaging (MRI)-measured brain atrophy has been utilised as a surrogate endpoint in phase II studies. The majority of the treatments tested in SPMS over the years were initially successful in RRMS. This has a number of implications in terms of targeting SPMS, but principally implies that the optimal strategy to target SPMS is to utilise the prodrome of relapses to initiate a therapy that will aim to both prevent progression and slow its accumulation. This approach is in agreement with the early targeting of MS but requires treatments that are both effective and safe if it is to be used before disability is a major problem. Recent successes will hopefully result in the first licensed therapy for PMS and enable us to test this approach.

A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis

MRI measures of tissue atrophy within the central nervous system may reflect the neurodegenerative process which underpins the progressive phase of multiple sclerosis (MS). There has been limited longitudinal investigation of MRI-detected atrophy in secondary progressive MS. This study includes 56 subjects with secondary progressive MS. Subjects were followed up for 2 years and MRI analysis was conducted at 12 month intervals using the following measures: (1) whole brain (WB) volume change; (2) grey and white matter (WM) volumes; (3) central brain volume; (4) upper cervical spinal cord (SC) area; (5) T2 lesion volumes. Clinical measures included the Expanded Disability Status Scale and the MS Functional Composite. All volumetric MRI measures were assessed for sensitivity, responsiveness, reliability and correlation with disability. The mean annual atrophy rate of WB was 0.59% per year and this was the most responsive atrophy measure assessed. Grey matter (GM) atrophy (-1.18% per year) was greater and more responsive than WM atrophy (0.12% per year). The SC demonstrated the highest atrophy rate at 1.63% per year. WB, GM and SC atrophy all correlated with change in the Multiple Sclerosis Functional Composite z score (r = 0.35, 0.42, 0.34), and GM atrophy was the only correlate of change in the 9 Hole Peg Test and Paced Auditory Serial Addition Test performance. None of the MRI measures correlated with Expanded Disability Status Score progression. Measures of WB, GM and SC atrophy all have attributes for use as surrogate markers in secondary progressive MS trials and improvement in the reliability of the GM and SC volume measurements may enhance these further.

MRI as an outcome in multiple sclerosis clinical trials

T2-weighted and gadolinium enhanced T1-weighted MRI scans measure plaque burden and breakdown of the blood-brain barrier, respectively, in multiple sclerosis (MS) lesions. These have become widely used outcome measures for monitoring disease activity in clinical trials and clinical practice. However, their use as surrogates or biomarkers for disability and relapses, key clinical outcome measures, has remained incompletely validated. In a clinical trial database comprised of 31 relapsing-remitting and secondary progressive MS trial placebo groups, we assessed relationships between 1) T2 lesion load (TLL) change and disability change and 2) gadolinium enhancement of MS lesions and on-study relapses with univariate and multivariate analyses. In relapsing-remitting MS, TLL change (n = 223) made no independent contribution to predicting change in disability from baseline to trials' end. Similarly, inclusion of gadolinium enhancing lesions (n = 170) into multivariate models did not independently contribute to the predictive value for on-trial relapses. In secondary progressive MS, a small effect of TLL was found for disability change (n = 355) but in multivariate analysis this accounted for less than 5% of the variance in end-of-trial disability. Results were replicated in independent datasets, more than doubling effective sample sizes. MRI measures widely used in trials of relapsing-remitting and progressive multiple sclerosis add little if anything independently to the clinically relevant relapse and disability outcomes. These results reemphasize the importance of validating potential surrogate markers against clinical measures and highlight the need for better MRI markers of disease activity and progression.

Dirucotide (MBP8298) for the treatment of multiple sclerosis

Multiple sclerosis (MS) is a chronic and debilitating disease affecting approximately 2.5 million people worldwide, and safe and effective treatment options are sorely lacking. While there are several currently approved drugs that have shown some efficacy at reducing the relapse rate in patients with the relapsing–remitting form of the disease, the impact of this outcome relative to long-term disease progression is unknown. Effective treatment for those with primary or secondary progressive MS is practically nonexistent. Dirucotide (MBP8298) is a synthetic peptide that has shown promise at increasing time to progression with little or no associated toxicity in Phase II studies. The drug is specifically designed to induce tolerance in patients with HLA types DR2 and/or DR4, although patients with other HLA subtypes may also benefit. Dirucotide is now being evaluated in two large Phase III secondary progressive MS trials, as well as a smaller Phase II relapsing–remitting MS trial.

Disability as an outcome in MS clinical trials

Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Preventing progressive disability is the key therapeutic goal but there remains no validated definition for its measurement in a trial context. Meanwhile, MS trials continue to shorten and to depend on unvalidated surrogates. Since there have been no treatment claims for improving unremitting disability, worsening of disability in the placebo/control arm must occur for effectiveness on this outcome to be shown. We examined widely-used clinical surrogates of long-term disability progression in individual patients with MS within a unique database from the placebo arms of 31 randomized clinical trials. Detection of treatment effects in secondary progressive MS trials is undermined by noise in disability measurement. Whereas existing measures can be partially validated in secondary progressive MS, this is not the case in relapsing-remitting MS. Here, examination of widely used definitions of treatment failure demonstrated that disability progression was no more likely than similarly defined improvement. Existing definitions of disease progression in short-term intervention trials in relapsing-remitting patients reflect random variation, measurement error, and remitting relapses. Clinical surrogates of unremitting disability used in trials of relapsing-remitting multiple sclerosis cannot be validated. Trials have been too short or degrees of disability change too small to measure the key outcomes. These analyses highlight the difficulty in determining effectiveness of therapy in chronic diseases.

Does interferon beta help in secondary progressive MS?

Most patients with multiple sclerosis (MS) present with a relapsing-remitting (RR) course but eventually exhibit gradual worsening with progressive disability, secondary progressive MS (SP-MS).1 Three pivotal trials of interferon beta (IFNβ) in SP-MS have been published: the European Study Group on Interferon Beta-1b in Secondary Progressive MS (Eu IFNβ-1b),2 the Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MS (SPECTRIMS),3 and the International MS Secondary Progressive Avonex Controlled Trial (IMPACT) of IFNβ-1a.4 A fourth trial, the North American Study Group on Interferon Beta-1b in Secondary Progressive MS (NA IFNβ-1b),5 is reported in this issue of Neurology . A companion paper presents a pooled analysis of the Eu and NA IFNβ-1b studies.6 All four trials demonstrated benefit on relapses and MRI lesion activity. The magnitude of benefit on these endpoints was comparable with that seen in trials of RR-MS. However, the results on disability progression differed among the SP-MS trials. In the Eu IFNβ-1b study, IFNβ treatment slowed worsening on the Kurtzke Expanded Disability Status Scale (EDSS), whereas the NA IFNβ-1b, SPECTRIMS, and IMPACT studies showed no benefit on this endpoint. Modest benefit on disability progression was shown in IMPACT using the Multiple Sclerosis Functional Composite7 as the primary outcome measure. The Eu and NA IFNβ-1b studies provide a unique opportunity to dissect …