Trials In Relapsing-remitting Multiple Sclerosis Research Articles

Do efficacy results obtained from randomized controlled trials translate to effectiveness data from observational studies for relapsing-remitting multiple sclerosis?

Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example. A systematic review of randomized controlled trials and observational studies was conducted. The primary outcome was the annualized relapse rate. Using (network) meta-analysis together with posterior predictive distributions, the drug-specific rate ratios from the network of randomized controlled trials were compared with those from the network of observational studies. Effect estimates from 26 observational studies showed greater magnitudes and were less precise compared to estimates obtained from 21 randomized controlled trials. Twenty of the 28 treatment comparisons between designs had similar rate ratios. Seven inconsistencies in observed rate ratios could be attributed to two specific disease-modifying therapies. In this case study, estimates from observational studies predominantly agreed with estimates from randomized controlled trials given their posterior predictive distributions. Multiple observational studies together may therefore supplement additional pivotal randomized controlled trials in relapsing-remitting multiple sclerosis, for instance facilitating the extrapolation of trial results to the broader patient population.

Association Between Improved Serum Fatty Acid Profiles and Cognitive Function During a Dietary Intervention Trial in Relapsing-Remitting Multiple Sclerosis.

Cognitive impairment is a common multiple sclerosis (MS)-related symptom that impacts quality of life (QOL). Diet interventions are shown to be beneficial in managing QOL, and the intake of essential fatty acids is linked with improved cognitive function. However, the effect of diets on serum fatty acid profiles and cognitive function is unknown. A previous randomized, parallel-arm trial recruited participants with relapsing-remitting MS (N = 77). Study visits included 4 time points: run-in, baseline, 12 weeks, and 24 weeks. During the run-in phase, participants followed their usual diet and were then randomly assigned to either a modified paleolithic (Wahls) or a low saturated fat (Swank) diet at baseline. Assessments at study visits included cognitive function assessed by Symbol Digit Modalities Test-Oral (SDMT-O) and Perceived Deficits Questionnaire (PDQ), and serum fatty acids, including eicosapentaenoic (EPA), docosahexaenoic (DHA), and arachidonic (ARA) acids. Both groups had significant improvements in all serum fatty acids (P < .01), except for ARA, as well as SDMT-O at 24-weeks (P < .05), total PDQ at 12 and 24 weeks (P < .01) compared with baseline values. The 12-week changes in ω-3 (EPA + DHA) index and EPA serum fatty acids were associated with SDMT-O changes (P ≤ .05); however, the changes in fatty acid levels did not mediate the effect of the diets on SDMT-O or PDQ (P > .05). Both diets led to improvements in serum fatty acid profiles and cognitive function, with associations between the 12-week ω-3 (EPA + DHA) index and EPA changes with SDMT-O.

Emulating randomised clinical trials in relapsing-remitting multiple sclerosis with non-randomised real-world evidence: an application using data from the MSBase Registry

BackgroundTo mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE...

Association of age and inflammatory disease activity in the pivotal natalizumab clinical trials in relapsing-remitting multiple sclerosis

BackgroundFocal inflammatory disease activity in relapsing-remitting multiple sclerosis (RRMS) diminishes with increasing age. Here we use patient-level data from randomised controlled trials (RCTs) of natalizumab treatment in RRMS to investigate...

Association between improved metabolic risk factors and perceived fatigue during dietary intervention trial in relapsing-remitting multiple sclerosis: A secondary analysis of the WAVES trial.

Preliminary dietary intervention trials with the low-saturated fat (Swank) and modified Paleolithic elimination (Wahls) diets have shown favorable effects on fatigue among people with multiple sclerosis (MS); however, their impact on metabolic health is unknown. To evaluate the impact of the Swank and Wahls diets on markers of metabolic health and to determine the association and mediation effect between changes in metabolic health and perceived fatigue among people with relapsing-remitting MS (RRMS). As part of a randomized parallel-arm trial, vital signs, blood metabolic biomarkers, and the fatigue scale for motor and cognitive functions (FSMC) were collected from participants with relapsing-remitting MS (n = 77) at four study visits spaced 12 weeks apart: (1) run-in, (2) baseline, (3) 12-weeks, and (4) 24-weeks. Participants followed their usual diet at run-in, then were randomized at baseline to either the Swank or Wahls diets and followed for 24 weeks. Both groups had significant reductions in weight, body mass index (BMI), total cholesterol, and low-density lipoprotein (LDL) at 12- and 24-weeks compared to respective baseline values (p ≤ 0.04 for all). The Swank group also had a significant reduction in high-density lipoprotein (HDL) at 12- and 24-weeks (p = 0.0001 and p = 0.02, respectively), while the Wahls group had significant reductions in diastolic blood pressure (DBP). In addition, both groups had significant reductions in FSMC total perceived fatigue and the motor and cognitive fatigue subscales at 12- and 24-weeks (p ≤ 0.01 for all); however, change in the cognitive subscale was not significant at 12-weeks in the Swank group (p = 0.06). Furthermore, the favorable effects, of both diets, on markers of metabolic health were not associated with and did not mediate the effect of the diets on perceived fatigue (p > 0.05 for all). Both diets lead to significant reductions in perceived fatigue, weight, BMI, total cholesterol, and LDL, but the significant reductions in perceived fatigue were independent of changes in markers of metabolic health.

034 Updated safety analysis of ocrelizumab in multiple sclerosis

BackgroundOngoing safety reporting is crucial to understanding the long-term benefit-risk profile of ocrelizumab in multiple sclerosis (MS). Safety/efficacy of ocrelizumab have been characterised in Phase II (NCT00676715) and III (NCT01247324/NCT01412333/NCT01194570) trials in relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS). Here, we report safety evaluations from ocrelizumab clinical trials and open-label extensions up to January 2019, and selected post-marketing data.MethodsSafety outcomes are reported for the ocrelizumab all-exposure population in Phase II/III and ongoing Phase IIIb trials. To account for different exposure lengths, rates per 100 patient years (PY) are presented.ResultsIn clinical trials, 4,611 patients with MS received ocrelizumab (14,329 PY exposure). Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 252 (249–254); serious AEs, 7.33(6.89–7.79); infections, 76.7 (75.3–78.2); serious infections, 1.99 (1.77–2.23); malignancies, 0.46 (0.35–0.58); and AEs leading to discontinuation, 1.08 (0.92–1.27). Updated ocrelizumab all-exposure population data and selected post-marketing data will be presented.ConclusionsReported event rates in the ocrelizumab all-exposure clinical trial population and post-mar- keting settings remain generally consistent with the controlled treatment period in RMS/PPMS populations. Regular reporting of long-term safety data will continue.k.schmierer@qmul.ac.uk

Association of Age With Contrast-Enhancing Lesions Across the Multiple Sclerosis Disease Spectrum.

To investigate the association of age and the presence of contrast-enhancing lesions (CELs) on cranial MRI scans in different disease courses of multiple sclerosis (MS), we describe the frequency of CELs as a function of age in 4 large randomized controlled trial (RCT) datasets. Using original trial data from CombiRx (Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis; clinicaltrials.gov identifier NCT00211887), a trial in relapsing-remitting MS; ASCEND (A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis; clinicaltrials.gov identifier NCT01416181), a trial in secondary progressive MS; and the 2 primary progressive MS trials PROMISE and INFORMS; clinicaltrials.gov identifier NCT00731692), we describe the occurrence of CELs per age group at baseline for the entire trial cohort and at 1 year follow-up in the treatment arms. CombiRx included 1,008, ASCEND 889, PROMISE 943, and INFORMS 970 participants. At baseline, CEL frequency differed between datasets according to disease course: 39.6% of CombiRx, 23.9% of ASCEND, 14.0% of PROMISE, and 12.3% of INFORMS participants had CELs. This distribution by disease course was largely preserved within each age group. In all datasets, there was an almost linear decrease of the percentage of participants with CELs with advancing age. After 1 year of experimental treatment, CEL occurrence was reduced in all trial datasets, and almost absent in ASCEND. The decrease of CEL occurrence with advancing age was preserved in CombiRx, PROMISE, and INFORMS after 1 year of treatment. We investigated the association of the baseline factors age, disease duration, sex, and EDSS with having CELs at baseline with multivariable binary logistic regression models. Age was the only characteristic associated with the risk of CELs at baseline in all datasets, with higher age associated with a lower risk of CELs (odds ratios for having CELs at baseline per year increase in age: CombiRx: 0.96, 95% confidence interval [CI] 0.95-0.98; ASCEND: 0.94, 95% CI 0.92-0.97; PROMISE: 0.94, 95% CI 0.91-0.96; INFORMS: 0.97, 95% CI 0.94-0.99). Our analysis of 4 large, well-characterized RCT datasets shows that the association of age and CEL occurrence is a general phenomenon across the spectrum of MS disease courses. Our findings should be replicated in real-world MS datasets.

Neurofilament light levels are associated with long-term outcomes in multiple sclerosis

Background: Neurofilament light chain (NfL) is a promising marker of disease activity/treatment response in multiple sclerosis (MS), although its predictive value for long-term clinical outcomes remains unclear. Objective: We measured NfL from a phase 3 trial in relapsing-remitting MS and investigated its association with outcomes after 8 and 15 years. Methods: NfL concentrations were measured by single molecule array assay in cerebrospinal fluid (CSF) from MS patients (n = 235) in a 2-year randomized clinical trial (RCT) of intramuscular interferon β-1a, and in serum (n = 164) from the extension study. Results: Year 2 CSF and Year 3 serum NfL were associated with brain parenchymal fraction (BPF) change over 8 years (p < 0.0001, r = −0.46; p < 0.05. r = −0.36, respectively) and were predictive of reaching Expanded Disability Status Scale (EDSS) ⩾ 6.0 at Year 8 (odds ratio (OR) (upper vs lower tertile) = 3.4; 95% confidence interval (CI) = 1.2–9.9, p < 0.05; OR = 11.0, 95% CI = 2.0–114.6; p < 0.01, respectively). Serum NfL concentration (Year 4) was predictive of reaching EDSS score ⩾6.0 at 15 years (OR (upper vs lower tertile) = 4.9; 95% CI = 1.4–20.4; p < 0.05). NfL concentrations were complementary to 2-year BPF change in predicting long-term outcomes. Conclusion: Serum and CSF NfL concentrations were associated with long-term clinical outcomes in MS patients and are promising biomarkers for disease severity stratification supporting treatment decisions.

Disability Outcome Measures in Phase III Clinical Trials in Multiple Sclerosis.

Accumulating neurological disability has a substantial impact on the lives of patients with multiple sclerosis (MS). As well as the established Expanded Disability Status Scale (EDSS), several other outcome measures are now available for assessing disability progression in MS. This review extends the findings of a previous analysis of relapsing-remitting MS (RRMS) trials published up to 2012, to determine whether there has been a shift in outcome measures used to assess disability in phase III clinical trials in RRMS and progressive MS. Forty relevant trials were identified (RRMS, n = 16; progressive MS, n = 18; other/mixed phenotypes, n = 6). Sustained EDSS worsening, particularly over 3 months, was included as an endpoint in almost all identified trials. Other disability-related endpoints included the Multiple Sclerosis Functional Composite z-score and scores for the physical component summary of the Multiple Sclerosis Impact Scale and Medical Outcomes Study Short-Form (36-item) Health Survey. Tests assessing manual dexterity, ambulation, vision and cognition were also employed, and in some trials, composite endpoints were used. However, there was no obvious trend in choice of disability outcome measures over time. Sustained EDSS worsening over short time periods continues to be the most widely used measure of disability progression in pivotal MS trials, despite its well-recognised limitations. A new tool set is needed for use in MS clinical trials that detects the benefit of potential treatments that slow (or reverse) progressive disability.Electronic supplementary materialThe online version of this article (10.1007/s40263-018-0530-8) contains supplementary material, which is available to authorized users.

Efficacy and Safety of 2 Doses of Ponesimod (10 and 20 mg o.d.): Interim Analysis of a Phase II Extension Trial in Relapsing-remitting Multiple Sclerosis (P3.398)

Efficacy and Safety of 2 Doses of Ponesimod (10 and 20 mg o.d.): Interim Analysis of a Phase II Extension Trial in Relapsing-remitting Multiple Sclerosis (P3.398)

The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis.

BackgroundThe quantification of brain atrophy in relapsing-remitting multiple sclerosis (RRMS) may serve as a marker of disease progression and treatment response. We compared the association between first-line (FL) or second-line (SL) disease-modifying drugs (DMDs) and brain volume changes over time in RRMS.Materials and MethodsWe reviewed clinical trials in RRMS between January 1, 1995 and June 1, 2014 that assessed the effect of DMDs and reported data on brain atrophy in Medline, Embase, the Cochrane database and meeting abstracts. First, we designed a meta-analysis to directly compare the percentage brain volume change (PBVC) between FLDMDs and SLDMDs at 24 months. Second, we conducted an observational and longitudinal linear regression analysis of a 48-month follow-up period. Sensitivity analyses considering PBVC between 12 and 48 months were also performed.ResultsAmong the 272 studies identified, 117 were analyzed and 35 (18,140 patients) were included in the analysis. Based on the meta-analysis, atrophy was greater for the use of an FLDMD than that of an SLDMD at 24 months (primary endpoint mean difference, -0.86; 95% confidence interval: -1.57–-0.15; P = 0.02). Based on the linear regression analysis, the annual PBVC significantly differed between SLDMDs and placebo (-0.27%/y and -0.50%/y, respectively, P = 0.046) but not between FLDMDs (-0.33%/y) and placebo (P = 0.11) or between FLDMDs and SLDMDs (P = 0.49). Based on sensitivity analysis, the annual PBVC was reduced for SLDMDs compared with placebo (-0.14%/y and -0.56%/y, respectively, P<0.001) and FLDMDs (-0.46%/y, P<0.005), but no difference was detected between FLDMDs and placebo (P = 0.12).ConclusionsSLDMDs were associated with reduced PBVC slope over time in RRMS, regardless of the period considered. These results provide new insights into the mechanisms underlying atrophy progression in RRMS.

B cell-directed therapies in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory neurological disease of the CNS that goes along with demyelination and neurodegeneration. It is probably caused by an autoimmune response against the CNS, which emerges from the interplay of genetic and environmental factors. Although major progress has been made in the treatment of MS, it is still the leading cause for acquired nontraumatic neurological disability in young adults. Several therapeutic agents have been approved for the treatment of relapsing-remitting MS (RRMS), aiming at the reduction of relapses and a delay in disability progression. Three therapeutic monoclonal antibodies targeting CD20-positive B cells (rituximab, ocrelizumab and ofatumumab) were investigated in MRI-based Phase II and Phase III trials in RRMS, providing consistent evidence for a disease-ameliorating effect of B cell depleting therapies in MS. Here, we discuss the role of B cells and review current and future therapeutic approaches to target B cells in MS.

Clinical trials in relapsing-remitting multiple sclerosis (a new proposal for dealing with basic problems and restrictions)

The natural course of multiple sclerosis is characterized by a high variability of pattern, relapse rate and different progression indices. They also present a dramatic impact on the interpretation of treatment trials. Older reports, based on uncontrolled observations are therefore of little value. Currently it is generally accepted that a proper treatment trial should be double blinded and, although probably controversial, that it should be compared with a group of MS patients treated with placebo. Such an approach would be easily acceptable to prove the effectiveness of recently discovered disease modifying drugs. We know that current standard methods of therapy with interferon beta or glatiramer acetate are able to decrease the relapse rate at least by one third, to elongate the intervals between the relapses and to decrease the progression indices. Currently MS is considered a generalized degenerative disease. The lesions are persistent, therefore immunomodulatory treatment has to be started as early as possible. An alternative approach, somewhat suggestive for the use of placebo trials, seems to be a comparison of proposed new drug therapy group with a group of patients treated with a generally accepted reference drug, such as interferon beta or glatiramer acetate, including all clinical and MRI measures.

Neurosurgical Approaches in Demyelinating Disorders; Where are We Now?

Demyelinating diseases of the central nervous system (CNS) are a group of autoimmune disorders affecting the myelin sheets of CNS neurons resulting in different neurological deficits and disability. Multiple sclerosis (MS), Devic’s disease, progressive multifocal leukoencephalopathy, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) are among the most common types of demyelinating disorders. Currently MS is the leading cause of neurological disability in young population after trauma . The incidence and prevalence of MS is increasing worldwide primarily due to increase the incidence in female population. Globally, the median estimated incidence of MS is 5.2 (range: 0.5-20.6) per 100,000 p-yrs, the median estimated prevalence of MS is 112.0 (with a range of 5.2-335) per 100,000 p-yrs, and the average disease duration is 20.2 years (range: 7.6-36.2). In Iran, the prevalence and incidence of MS is estimated to be 54.51 and 5.87 per 100,000. Diagnosis of demyelinating disorders is a controversial issue and several criteria has been introduced for the aforementioned subject. Diagnostic criteria for clinically definite MS require documentation of two or more episodes of symptoms and two or more signs that reflect pathology in anatomically noncontiguous white matter tracts of the CNS. The second may be documented by abnormal paraclinical tests such as MRI or evoked potentials (EPs).&#x0D; The standard treatment for patients with demyelinating disorders and especially MS is the medical management. Recent large placebo-controlled trials in relapsing-remitting multiple sclerosis have shown efficacy of new oral disease-modifying drugs, teriflunomide and dimethyl fumarate, with similar or better efficacy than the injectable disease-modifying drugs, IFN-β and glatiramer acetate. In addition, the new oral drugs seem to have a favorable safety profile. Further, the monoclonal antibody alemtuzumab, which in clinical trials has shown superiority to subcutaneous IFN-β 1a, has been approved in Europe. In acute exacerbation and flare up of the disease, methylprednisolone pulse is the only approved treatment.&#x0D; Although the standard of treatment of MS and other demyelinating disorders is medical, but neurosurgical procedures especially the functional neurosurgical interventions has found their way in management of patients with demyelinating disorders. These interventions are used to treat the complications of MS and demyelinating disorders such as tremor, trigeminal neuralgia, movement disorders and neuropathic pains. Most of these interventions are stereotactic in order to obtain precise targeting of a special deep brain nucleus. The first application of deep brain stimulation (DBS) in patients with MS was for treatment of tremor. Recently it has been demonstrated that DBS of ventral intermediate (VIM) nucleus of thalamus results in alleviation of severe, disabling tremor in patients with MS. Other experiments have also demonstrated decreased tremor and improved quality of life in MS patients responsive to DBS.&#x0D; Neuropathic pain and trigeminal neuralgia are among the other complications of demyelinating disorders which are associated with disability and decreased quality of life. Several investigations have shown that DBS of thalamic nuclei would be effective in treatment of neuropathic pain in patients with MS, although the results are controversial and need further investigations. The trigeminal neuralgia is often treated by microsurgical decompression of the trigeminal nerve. However this approach is not effective in patients with demyelinating disorders as they have different pathology. Case series have shown that Gamma Knife surgery (GKS) is an effective and safe treatment for trigeminal neuralgia in patients with MS. No clinical trial is available for comparing the results and outcome between GKS and microsurgical approach. However results of case series are favorable.&#x0D; There are still other field that could be approached surgically in patients with demyelinating disorders. Recent bodies of evidence have demonstrated a link between cervical cord plaques and discopathy in those with MS which needs further investigation. Tumefactive demyelinating lesions (TDL) are another issues observed in patients with MS which have unknown course and pathology. The link between demyelinating disorders and brain tumors is also another issues which deserves further investigation. To take a long story short, although the role of functional neurosurgical procedures in management of patients with demyelinating disorders especially MS is still limited, but there is optimistic horizons for growing role of neurosurgical procedures in management of different complications of demyelinating disorders refractory to medical therapy.Â

Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials.

No subgroups of patients with higher treatment effects have been clearly detected in multiple sclerosis (MS). The aim of the present work was to evaluate whether there are subgroups of relapsing-remitting MS (RRMS) patients who are more responsive to treatments. All published randomized clinical trials in RRMS reporting a subgroup analysis of treatment effect were collected. Two main outcomes, the annualized relapse rate (ARR) and the disability progression, were studied. The treatment effect in each subgroup was reported as a relative effect (RE), defined as the treatment effect in the subgroup relative to the overall effect. A meta-analysis was run to compare the RE between subgroups. Six trials (6693 RRMS patients) were included. Treatment effects on ARR were significantly higher in younger than in older subjects (RE = 0.83 vs. RE = 1.30, P < 0.001), in patients with than those without gadolinium activity (RE = 0.86 vs. RE = 1.15, P = 0.005) and in patients with lower than in those with higher Expanded Disability Status Scale (RE = 0.96 vs. RE = 1.23, P = 0.02), and on disability progression in younger than in older subjects (RE = 0.82 vs. RE = 1.28, P = 0.017). This study formally shows that in RRMS higher treatment effects are associated with characteristics of earlier (lower age and Expanded Disability Status Scale) and more active (higher gadolinium activity) disease.

Regression to the mean and predictors of MRI disease activity in RRMS placebo cohorts--is there a place for baseline-to-treatment studies in MS?

BackgroundGadolinium-enhancing (GD+) lesions and T2 lesions are MRI outcomes for phase-2 treatment trials in relapsing-remitting Multiple Sclerosis (RRMS). Little is known about predictors of lesion development and regression-to-the-mean, which is an important aspect in early baseline-to-treatment trials.ObjectivesTo quantify regression-to-the-mean and identify predictors of MRI lesion development in placebo cohorts.Methods21 Phase-2 and Phase-3 trials were identified by a systematic literature research. Random-effects meta-analyses were performed to estimate development of T2 and GD+ after 6 months (phase-2) or 2 years (phase-3). Predictors of lesion development were evaluated with mixed-effect meta-regression.ResultsThe mean number of GD+-lesions per scan was similar after 6 months (1.19, 95%CI: 0.87-1.51) and 2 years (1.19, 95%CI: 1.00-1.39). 39% of the patients were without new T2-lesion after 6 month and 19% after 2 years (95%CI: 12-25%). Mean number of baseline GD+-lesions was the best predictor for new lesions after 6 months.ConclusionBaseline GD-enhancing lesions predict evolution of Gd- and T2 lesions after 6 months and might be used to control for regression to the mean effects. Overall, proof-of-concept studies with a baseline to treatment design have to face a regression to 1.2 GD+lesions per scan within 6 months.

New management algorithms in multiple sclerosis.

Our current treatment algorithms include only IFN-β and glatiramer as available first-line disease-modifying drugs and natalizumab and fingolimod as second-line therapies. Today, 10 drugs have been approved in Europe and nine in the United States making the choice of therapy more complex. The purpose of the review has been to work out new management algorithms for treatment of relapsing-remitting multiple sclerosis including new oral therapies and therapeutic monoclonal antibodies. Recent large placebo-controlled trials in relapsing-remitting multiple sclerosis have shown efficacy of new oral disease-modifying drugs, teriflunomide and dimethyl fumarate, with similar or better efficacy than the injectable disease-modifying drugs, IFN-β and glatiramer acetate. In addition, the new oral drugs seem to have a favorable safety profile. Further, the monoclonal antibody alemtuzumab, which in clinical trials has shown superiority to subcutaneous IFN-β 1a, has been approved in Europe, but not yet in the United States. In de novo-treated patients, the injectables, IFN-β and glatiramer acetate, will to a great extent be replaced by the new orals, dimethyl fumarate and teriflunomide. However, patients who are stable on an injectable with no or minor side-effects could continue their current therapy. Alemtuzumab should be used as a second-line therapy.

Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis

To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS). We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression. Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R(2) = 0.48, p = 0.001) and on active MRI lesions (R(2) = 0.61, p < 0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R(2) = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression. In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination.

MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials

A meta-analysis of randomised trials in relapsing-remitting multiple sclerosis published in 2009 showed a quantitative relation between the treatment effects detected on MRI lesions and clinical relapses. We aimed to validate that relation using data from a large and independent set of clinical trials in multiple sclerosis. We searched Medline for clinical trials that assessed disease-modifying drugs for relapsing-remitting multiple sclerosis published from Sept 1, 2008, to Oct 31, 2012. We extracted data for the treatment effects on MRI lesions and on relapses from each trial, and the correlation of log transformed relative measures of these treatment effects was assessed with a weighted linear regression analysis. The R(2) value was estimated to quantify the strength of the correlation, and we used an interaction test to test for a difference in slope from the previously estimated equation. We also ran several sensitivity analyses. We identified 31 eligible trials, which provided data for 18 901 patients with relapsing-remitting multiple sclerosis. The regression equation derived using data from these studies showed a relation between the concurrent treatment effects on MRI lesions and relapses (slope=0·52; R(2)=0·71), much the same as was previously estimated (pinteraction=0·45). Analysis of trials that tested the same drugs in phase 2 and phase 3 studies showed that the effects on MRI lesions over short follow-up periods (6-9 months) can also predict the effects on relapses over longer follow-up periods (12-24 months), with reported effects on relapses that were within the 95% prediction intervals in eight of nine trials. Our findings indicate that the effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions, implying that the use of MRI markers as primary endpoints in future clinical trials of treatments for multiple sclerosis can be considered, in specific situations, such as in trials testing generics or biosimilars of drugs with a well known mechanism of action or in paediatric trials testing drugs already approved for adults. None.

Long-Term Efficacy and Safety of Ocrelizumab in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS): Week 96 Results of a Phase II, Randomized, Multicenter Trial (S30.006)

Objective: Ocrelizumab reduced gadolinium-enhancing lesions (primary endpoint) by ≥89% and annualized relapse rate (ARR) by ≥73% vs placebo by Week 24, in a Phase II trial in RRMS. Background To determine long-term efficacy and safety of ocrelizumab up to Week 96. Design/Methods: RRMS patients (n=220) were randomized (1:1:1:1) to intravenous ocrelizumab (days 1, 15) total dose 600 mg (A), 2000 mg (B), placebo (C), or open-label weekly intramuscular interferon beta-1a 30 μg (D). At Weeks 24, 48, and 72, all patients received open-label ocrelizumab: groups A, C, and D received 600 mg/cycle; group B received 1000 mg at Weeks 24 and 48, then 600 mg at Week 72. MRI follow-up occurred only with groups A and B. Results: 183 patients completed 96 weeks. From Weeks 0–96, the ARR was 0.18 [95% CI: 0.11–0.31] and 0.22 [95% CI: 0.13–0.35] for groups A and B; 78.2% and 80.0% of patients, respectively, were relapse-free and 67.3% and 76.4% had no relapses or confirmed EDSS progression (9clinical disease activity free9). ARRs reduced during Weeks 24 to 96 in patients switched from placebo to ocrelizumab (group C) from 0.64 to 0.20 [95% CI: 0.12–0.33] and from 0.36 to 0.16 [95% CI: 0.09–0.28] in those switched from interferon beta-1a to ocrelizumab (group D). At Week 96 there were no gadolinium-enhancing lesions in groups A and B with 1.1% and 1.2% reduction in brain volume, respectively, from Weeks 12–96. Serious infection rates were similar for all groups and did not increase with time on treatment. There were no opportunistic infections or imbalance in rate of serious adverse events across groups over 96 weeks. Conclusions: Ocrelizumab substantially reduced MRI and clinical measures of MS disease activity over 96 weeks. Switching from interferon beta-1a or placebo to ocrelizumab produced similar sustained benefits. Disclosure: Dr. Hauser has received personal compensation for activities with BioMarin, Novartis and Receptos as a consultant and serving on a scientific advisory board.Dr. Hauser has received personal compensation in an editorial capacity for the journal Annals of Neurology and Harrison9s Internal Medical textbook.Dr. Hauser has received compensation for serving on the scientific advisory board of Receptos. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Li has received personal compensation for activities with Genzyme, Novartis and Nuron as a consultant.Dr. Li has receved research support from Angiotech, Bayer, Berlex-Schering, Bio-MS, Boehringer-Ingelheim, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences,Sanofi-Aventis, Transition Therapeutics, and Novartis. Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex. Dr. Calabresi has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Barkhof has received personal compensation for activities with Novartis, Biogen Idec, Merck-Serono, and Bayer-Schering as a consultant. Mr. Wells has received personal compensation for activities with Roche as an employee. Dr. Leppert has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Leppert has received compensation for serving on the University of British Columbia MS/MRI Research Group of Angiotech, Bayer, Berlex-Schering, Bio-MS, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences, Sanofi-Aventis, and Transition Therapeutics. Dr. Leppert holds stock and/or stock options in F. Hoffmann La Roche Ltd., which sponsored research in which Dr. Leppert was involved as an investigator. Dr. Glanzman has received personal compensation for activities with Hoffmann-LaRoche LTD. Dr. Tinbergen has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Tinbergen holds stock and/or stock options in Roche Diagnostics Corporation.