Predicting the On-Study Relapse Rate for Multiple Sclerosis Patients in Clinical Trials

Background: The annual relapse rate has been commonly used as a primary efficacy endpoint in phase III multiple sclerosis (MS) clinical trials. The aim of this study was to determine the relative contribution of different possible prognostic factors available at baseline to the on-study relapse rate in MS. Methods: A total of 821 patients from the placebo arms of the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database were available for this analysis. The univariate relationships between on-study relapse rate and the baseline demographic, clinical, and MRI-based predictors were assessed. The multiple relationships were then examined using a Poisson regression model. Two predictor subsets were selected. Subset 1 included age at disease onset, disease duration, gender, Expanded Disability Status Scale (EDSS) at baseline, number of relapses in the last 24 months prior to baseline, and the disease course (RR and SP). Subset 2 consisted of Subset 1 plus gadolinium enhancement status in MRI. The number of patients for developing the models with no missing values was 727 for Subset 1 and 306 for Subset 2. Results:The univariate relationships show that the on-study relapse rate was higher for younger and for female patients, for RR patients than for SP patients, and for patients with positive enhancement status at entry (Wilcoxon test, p<0.05). A higher on-study relapse rate was associated with a shorter disease duration, lower entry EDSS, more pre-study relapses and more enhancing lesions in T1 at entry. The fitted Poisson model shows that disease duration (estimate=-0.02) and previous relapse number (estimate=0.59 for 1, 0.91 for 2 and 1.45 for 3 or more relapses vs 0 relapse) remain. We were able to confirm these findings in a second, independent dataset. Conclusions: The relapse number prior to entry into clinical trials together with disease duration are the best predictors for the on-study relapse rate. Disease course and gadolinium enhancement status, given the other covariates, have no significant influence on the on-study relapse rate

Treating Systematic Errors in Multiple Sclerosis Data

Multiple sclerosis (MS) is characterized by high variability between patients and, more importantly here, within an individual over time. This makes categorization and prognosis difficult. Moreover, it is unclear to what degree this intra-individual variation reflects the long-term course of irreversible disability and what is attributable to short-term processes such as relapses, to interrater variability and to measurement error. Any investigation and prediction of the medium or long term evolution of irreversible disability in individual patients is therefore confronted with the problem of systematic error in addition to random fluctuations. The approach described in this article aims to assist in detecting relapses in disease curves and in identifying the underlying disease course. To this end neurological knowledge was transformed into simple rules which were then implemented into computer algorithms for pre-editing disease curves. Based on simulations it is shown that pre-editing time series of disability measured with the Expanded Disability Status Scale (EDSS) can lead to more robust and less biased estimates for important disease characteristics, such as baseline EDSS and time to reach certain EDSS levels or sustained progression

Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions.

BACKGROUND:Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS). OBJECTIVE:To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations. METHODS:We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients. RESULTS:Compared with RMS patients, PPMS patients had higher numbers of SELs (p = 0.002) and higher T2 volumes of SELs (p &lt; 0.001). SELs were devoid of gadolinium enhancement. Compared with areas of T2 lesions not classified as SEL, SELs had significantly lower T1 intensity at baseline and larger decrease in T1 intensity over time. CONCLUSION:We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS

Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis.

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum

Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis

Multiple sclerosis; Patient safety; Medical careEsclerosis múltiple; Seguridad del paciente; Atención médicaEsclerosi múltiple; Seguretat del pacient; Atenció mèdicaBackground and Objectives To report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings. Methods Safety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources. Results At data cutoff (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient-years [PY] of exposure) in clinical trials. Rates per 100 PY (95% confidence interval) of AEs (248; 246–251), serious AEs (7.3; 7.0–7.7), infusion-related reactions (25.9; 25.1–26.6), and infections (76.2; 74.9–77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81–2.23) and malignancies (0.46; 0.37–0.57), were consistent with the ranges reported in epidemiologic data. Discussion Continuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns, in a heterogeneous MS population. Classification of Evidence This analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.This work was supported by financial support from F. Hoffmann-La Roche Ltd, Basel, Switzerland, for the study and publication of the manuscript

No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a.

BackgroundNo evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS).ObjectiveThe objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status.MethodsNEDA was assessed in a modified intent-to-treat population (n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β-1a; 44 μg).ResultsNEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% (p &lt; 0.001), from Week 0‒24 by 33% (p &lt; 0.001) and from Week 24‒96 by 72% (p &lt; 0.001). Among patients with disease activity during Weeks 0‒24, 66.4% vs 24.3% achieved NEDA during Weeks 24‒96 in the ocrelizumab and IFN β-1a groups (relative increase: 177%; p &lt; 0.001).ConclusionSuperior efficacy with ocrelizumab compared with IFN β-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN β-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab

The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis.

The recently completed European trial of interferon beta-1b (IFN beta -1b) in patients with secondary progressive multiple sclerosis (SP multiple sclerosis) has given an opportunity to assess the impact of treatment on cerebral atrophy using serial MRI. Unenhanced T-1-weighted brain imaging was acquired in a subgroup of 95 patients from five of the European centres; imaging was performed at 6-month intervals from month 0 to month 36. A blinded observer measured cerebral volume on four contiguous 5 mm cerebral hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation. There was a significant and progressive reduction in cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P = 0.34 between groups). Exploratory subgroup analyses indicated that patients without gadolinium (Gd) enhancement at the baseline had a greater reduction of cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFN beta -1b 1.8%, P < 0.05) whereas those with Gd-enhancing lesions showed a trend to greater reduction of cerebral volume if the patient was on IFN<beta>-1b (placebo 2.6%, IFN beta -1b, 3.7%; P > 0.05). These results are consistent with ongoing tissue loss in both arms of this study of secondary progressive multiple sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFN beta. The different pattern seen in patients with and without baseline gadolinium enhancement suggests that part of the cerebral volume reduction observed in IFN beta -treated patients may be due to the anti-inflammatory/antioedematous effect of the drug. Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on cerebral atrophy in this population of patients with advanced disease