Patient subgroup analyses of the treatment effect of subcutaneous interferon ?-1a on development of multiple sclerosis in the randomized controlled REFLEX study.
ABSTRACT: The REFLEX study (NCT00404352) established that subcutaneous (sc) interferon (IFN) ?-1a reduced the risks of McDonald MS (2005 criteria) and clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event suggestive of MS. The aim of this subgroup analysis was to assess the treatment effect of sc IFN ?-1a in patient subgroups defined by baseline disease and demographic characteristics (age, sex, use of steroids at the first event, classification of first event as mono- or multifocal, presence/absence of gadolinium-enhancing lesions, count of <9 or ?9 T2 lesions), and by diagnosis of MS using the revised McDonald 2010 MS criteria. Patients were randomized to the serum-free formulation of IFN ?-1a, 44 ?g sc three times weekly or once weekly, or placebo, for 24 months or until diagnosis of CDMS. Treatment effects of sc IFN ?-1a on McDonald 2005 MS and CDMS in the predefined subgroups were similar to effects found in the intent-to-treat population. McDonald 2010 MS was retrospectively diagnosed in 37.7 % of patients at baseline. Both regimens of sc IFN ?-1a significantly reduced the risk versus placebo of McDonald 2005 MS and CDMS, irrespective of McDonald 2010 status at baseline (risk reductions between 29 and 51 %). The effect of sc IFN ?-1a was not substantially influenced by baseline patient demographic and disease characteristics, or baseline presence/absence of McDonald 2010 MS.
Project description:OBJECTIVE:To assess the prognostic role of serum neurofilament light chains (NfL) for clinically defined multiple sclerosis (CDMS) and McDonald 2017 multiple sclerosis (MS) in patients with clinically isolated syndromes (CIS). METHODS:We retrospectively analyzed data of patients admitted to our neurologic department between 2000 and 2015 for a first demyelinating event. We evaluated baseline serum NfL in addition to CSF, MRI, and clinical data. RESULTS:Among 222 patients who were enrolled (mean follow-up 100.6 months), 45 patients (20%) developed CDMS and 141 patients (63.5%) developed 2017 MS at 2 years. Serum NfL (median 22.0, interquartile range 11.6-40.4 pg/mL) was noticeably increased in patients with a recent relapse, with a high number of T2 and gadolinium-enhancing lesions at baseline MRI. Serum NfL was prognostic for both CDMS and McDonald 2017 MS, with a threefold and a twofold respective reduction in CDMS and 2017 MS risk in those patients with low and extremely low levels of NfL. The results remained unchanged subsequent to adjustment for such established MS prognostic factors as oligoclonal bands, Gd-enhancing lesions, and a high T2 lesion load at baseline MRI. NfL was associated with disability at baseline but not at follow-up. CONCLUSIONS:Serum NfL have a prognostic value for CIS patient conversion to MS. NfL might play a twin role as biomarker in MS as peak level measurements can act as a quantitative marker of serious inflammatory activity, while steady-state levels can be a reflection of neurodegenerative and chronic inflammatory processes.
Project description:INTRODUCTION:Previous studies suggest that multiple sclerosis (MS) patients have a greater stroke risk than the general population but there is limited evidence of stroke risk in patients receiving disease-modifying treatment. We assessed stroke risk in MS patients treated with subcutaneous interferon-?1a (sc IFN-?1a) using pooled data from clinical trials and post-marketing surveillance. METHODS:Seventeen phase II-IV Merck KGaA-sponsored trials of sc IFN-?1a were assessed to estimate the stroke incidence rate (IR) and IR ratio (IRR) per 100 patient-years (PY), and associated 95% confidence intervals (CI). The association of treatment duration with stroke was assessed through a Cox model. IR, IRR, and hazard ratio (HR) were adjusted by age, sex, presence of any comorbidity, and MS duration. Individual case safety reports were retrieved from the Global Patient Safety Database. The reporting rates of stroke were calculated and classified as medically confirmed or non-medically confirmed according to the source of each report. RESULTS:In 17 clinical trials, 4412 patients were treated with sc IFN-?1a for a total of 10,622 PY and 1055 patients with placebo for 2005 PY. The IR/100 PY (95% CI) of stroke was 0.025 (0.004, 0.150) in sc IFN-?1a patients and 0.051 (0.008, 0.349) in placebo patients. The IRR for sc IFN-?1a vs placebo was 0.486 (0.238, 0.995) and the HR was 0.496 (0.235, 1.043) for time to stroke-related event for sc IFN-?1a treatment at any dose compared with placebo. Among sc IFN-?1a patients, the IRR in those treated for <?2 years was 0.602 (0.159, 2.277) and for ??2 years 0.469 (0.196, 1.124). Analysis of the safety database showed that the overall reporting rate for stroke was 13.286/10,000 PY. CONCLUSION:Safety data from both clinical trial and post-marketing settings indicate that treatment with sc IFN-?1a does not increase stroke risk in patients with MS. FUNDING:Merck KGaA, Darmstadt, Germany.
Project description:To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon ?-1a (SC IFN-?-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).The impact of alemtuzumab 12 mg vs SC IFN-?-1a 44 ?g on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-?-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-?-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-?-1a.Alemtuzumab demonstrated greater efficacy than SC IFN-?-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-?-1a in RRMS.NCT00530348 and NCT00548405.The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-?-1a on multiple MRI endpoints.
Project description:To determine the prognostic value of selected biomarkers in clinically isolated syndromes (CIS) for conversion to multiple sclerosis (MS) and disability accrual.Data were acquired from 2 CIS cohorts. The screening phase evaluated patients developing clinically definite MS (CIS-CDMS) and patients who remained as CIS during a 2-year minimum follow-up (CIS-CIS). We determined levels of neurofascin, semaphorin 3A, fetuin A, glial fibrillary acidic protein, and neurofilament light (NfL) and heavy chains in CSF (estimated mean [95% confidence interval; CI]). We evaluated associations between biomarker levels, conversion, disability, and magnetic resonance parameters. In the replication phase, we determined NfL levels (n = 155) using a 900 ng/L cutoff. Primary endpoints in uni- and multivariate analyses were CDMS and 2010 McDonald MS.The only biomarker showing significant differences in the screening was NfL (CIS-CDMS 1,553.1 [1,208.7-1,897.5] ng/L and CIS-CIS 499.0 [168.8-829.2] ng/L, p < 0.0001). The strongest associations were with brain parenchymal fraction change (rs = -0.892) and percentage brain volume change (rs = -0.842) at 5 years. NfL did not correlate with disability. In the replication phase, more NfL-positive patients, according to the cutoff, evolved to MS. Every 100-ng/L increase in NfL predicted CDMS (hazard ratio [HR] = 1.009, 95% CI 1.005-1.014) and McDonald MS (HR = 1.009, 95% CI 1.005-1.013), remaining significant for CDMS in the multivariate analysis (adjusted HR = 1.005, 95% CI 1.000-1.011). This risk was lower than the presence of oligoclonal bands or T2 lesions.NfL is a weak independent risk factor for MS. Its role as an axonal damage biomarker may be more relevant as suggested by its association with medium-term brain volume changes.
Project description:This study evaluated efficacy of subcutaneous (sc) interferon beta-1a (IFN ?-1a) 44 µg 3?×?weekly (tiw) in patients appearing to transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS). The PRISMS study included 560 patients with RRMS (EDSS 0-5.0;???2 relapses in previous 2 years), and the SPECTRIMS study included 618 patients with SPMS (EDSS 3.0-6.5 and???1-point increase in previous 2 years [??0.5 point if 6.0-6.5]) randomly assigned to sc IFN ?-1a 44 or 22 µg or placebo for 2-3 years, respectively. These post hoc analyses examined five subgroups of MS patients with EDSS 4.0-6.0: PRISMS (n?=?59), PRISMS/SPECTRIMS (n?=?335), PRISMS/SPECTRIMS with baseline disease activity (n?=?195; patients with either???1 relapse within 2 years before baseline or???1 gadolinium-enhancing lesion at baseline), PRISMS/SPECTRIMS without baseline disease activity (n?=?140), and PRISMS/SPECTRIMS with disease activity during the study (n?=?202). In the PRISMS and PRISMS/SPECTRIMS subgroups, sc IFN ?-1a delayed disability progression, although no significant effect was observed in PRISMS/SPECTRIMS subgroups with activity at baseline or activity during the study (regardless of baseline activity). In the PRISMS/SPECTRIMS subgroup, over year 1 (0-1) and 2 (0-2), sc IFN ?-1a 44 µg tiw significantly reduced annualized relapse rate (p???0.001), and relapse risk (p?<?0.05) versus placebo. Similar results were seen for the PRISMS/SPECTRIMS with baseline disease activity subgroup. Subcutaneous IFN ?-1a reduced T2 burden of disease and active T2 lesions in the PRISMS/SPECTRIMS subgroups overall, with and without baseline activity. In conclusion, these post hoc analyses indicate that effects of sc IFN ?-1a 44 µg tiw on clinical/MRI endpoints are preserved in a patient subgroup appearing to transition between RRMS and SPMS.
Project description:<h4>Objectives</h4>To investigate whether inclusion of lesions in the symptomatic region influences the performance of dissemination in space (DIS) criteria for a diagnosis of clinically definite multiple sclerosis (CDMS) in patients with a clinically isolated syndrome (CIS).<h4>Methods</h4>We studied 30 patients with CIS with brainstem/cerebellar and spinal cord syndromes who had MRI scans at the time of CIS and were followed up for the development of CDMS. We retrospectively applied the McDonald 2010 DIS criteria (excluding all lesions in the symptomatic region) to baseline MRI scans and 2 modified DIS criteria: (1) the inclusion of asymptomatic lesions in the symptomatic region in DIS, and (2) the inclusion of any lesion in the symptomatic region in DIS. The performance of the McDonald 2010 DIS criteria and the 2 modified criteria for the development of CDMS was compared.<h4>Results</h4>The sensitivity, specificity, and accuracy of the DIS criteria was, respectively, 73%, 73%, and 73% for the McDonald 2010 criteria, 80%, 73%, and 77% when asymptomatic lesions in the symptomatic region were included, and 87%, 73%, and 80% when any lesion in the symptomatic region was included in DIS.<h4>Conclusions</h4>Including lesions in the symptomatic region in DIS increases the sensitivity of MRI criteria for diagnosing multiple sclerosis without compromising specificity. These findings may help inform future revisions of the diagnostic criteria for multiple sclerosis.<h4>Classification of evidence</h4>This study provides Class II evidence that for patients with CIS, including lesions in the symptomatic region as part of the criteria for DIS does not significantly increase the accuracy for predicting the development of CDMS. The study lacks the precision to detect an important change in accuracy.
Project description:Longitudinal studies have shown that brain white matter lesions are strong predictors of the conversion of unilateral optic neuritis to multiple sclerosis (MS) in Caucasian populations. Consequently brain MRI criteria have been developed to improve the prediction of the development of clinically definite multiple sclerosis (CDMS). In Asian populations, optic neuritis may be the first sign of classical or optic-spinal MS. These signs add to the uncertainty regarding brain MRI changes with respect to the course of unilateral optic neuritis. The aim of this study was to examine the association between brain lesion activity and conversion to CDMS in Chinese patients with unilateral optic neuritis. A small prospective cohort study of 40 consecutive Chinese patients who presented with unilateral optic neuritis was conducted. Brain lesion activity was recorded as the incidence of Gd-enhanced lesions and new T2 lesions. Brain lesions on MRI that were characteristic of MS were defined according to the 2010 revisions of the McDonald criteria. The primary endpoint was the development of CDMS. We found that nineteen patients (48%) had brain lesions that were characteristic of MS on the initial scan. One of these patients (3%) had Gd-enhanced brain lesions. A significantly lower percentage of the patients (10%, p<0.001) presented with new T2 brain lesions on the second scan. During a median of 5 years of follow-up, seven patients (18%) developed CDMS. There was no significant difference in the conversion rate to CDMS between patients with and without brain lesions that were characteristic of MS (4/19 and 3/21, respectively; Fisher exact test, one-sided, p = 0.44). We conclude that brain lesions characteristic of MS are common in Chinese patients with unilateral optic neuritis; however, these patients exhibit low lesion activity. The predictive value of brain lesion activity for CDMS requires investigation in additional patients.
Project description:To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.Alemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a-treated patients.In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.
Project description:Importance:In 2017, the International Panel on Diagnosis of Multiple Sclerosis revised the McDonald 2010 criteria for the diagnosis of multiple sclerosis (MS). The new criteria are easier to apply and could lead to more and earlier diagnoses. It is important to validate these criteria globally for their accuracy in clinical practice. Objective:To evaluate the diagnostic accuracy of the 2017 criteria vs the 2010 criteria in prediction of clinically definite MS in patients with a typical clinically isolated syndrome (CIS). Design, Setting and Patients:A total of 251 patients at Erasmus MC, Rotterdam, the Netherlands, in collaboration with several regional hospitals, fulfilled the inclusion criteria. Thirteen patients received another diagnosis early in the diagnostic process and therefore were excluded from the analyses. Nine patients with CIS declined to participate in the study. This left 229 patients who were included between March 2006 and August 2016 in this prospective CIS cohort. Patients underwent a baseline magnetic resonance imaging scan within 3 months after onset of symptoms and, if clinically required, a lumbar puncture was performed. Data were analyzed between December 2017 and January 2018. Main Outcomes and Measures:Sensitivity, specificity, accuracy, and positive and negative predictive value were calculated after 1, 3, and 5 years for the 2017 vs the 2010 criteria. Results:Among the 229 patients with CIS, 167 were women (73%), and the mean (SD) age was 33.5 (8.2) years. One hundred thirteen patients (49%) were diagnosed as having CDMS during a mean (SD) follow-up time of 65.3 (30.9) months. Sensitivity for the 2017 criteria was higher than for the 2010 criteria (68%; 95% CI, 57%-77% vs 36%; 95% CI, 27%-47%; P < .001), but specificity was lower (61%; 95% CI, 50%-71% vs 85%; 95% CI, 76%-92%; P < .001). Using the 2017 criteria, more MS diagnoses could be made at baseline (n = 97 [54%]; 95% CI, 47%-61% vs n = 46 [26%]; 95% CI, 20%-32%; P < .001). In the group with at least 5 years of follow-up, 33% of patients who were diagnosed as having MS using the 2017 criteria did not experience a second attack during follow-up vs 23% when using the 2010 criteria. Conclusions and Relevance:The 2017 revised McDonald criteria are associated with greater sensitivity but less specificity for a second attack than the previous 2010 criteria. The tradeoff is that it leads to a higher number of MS diagnoses in patients with a less active disease course.
Project description:The objective of this study was to assess the effect of treatment with interferon (IFN) β-1a, 44 µg subcutaneously (sc) three times weekly (tiw), on clinical and magnetic resonance imaging (MRI) outcomes in patients with relapsing multiple sclerosis (MS) following mitoxantrone therapy.This was an open-label, randomized, multicentre, rater-blinded, 96-week observational study conducted in Germany. Clinically stable patients with relapsing forms of MS, who had discontinued mitoxantrone treatment 1-6 months before study entry, were randomized to IFN β-1a sc 44 µg tiw, or no treatment. The primary endpoint was time to first relapse. Secondary endpoints included the number of relapse-free patients, disease activity assessed by MRI and time to 3-month confirmed Expanded Disability Status Scale (EDSS) progression, all at week 96.A total of 30 patients were randomized (intent-to-treat population: 14 IFN β-1a, 15 untreated; one patient from the safety population discontinued the study after 25 days owing to an adverse event and without providing any postbaseline efficacy data, and was thus excluded from the intent-to-treat population). Overall, 71.4% (10/14) of patients in the IFN β-1a group remained relapse free over 96 weeks, versus 46.7% (7/15) in the untreated group (p = 0.26). IFN β-1a delayed the time to first relapse versus no treatment (p = 0.14); time to first relapse (25th percentile) was 95.4 (IFN β-1a) versus 46.0 weeks (no treatment). Confirmed EDSS progression was observed in five patients in each treatment group. Mean change in EDSS score was 0.3 in both groups (p = 0.79). Changes in the number or volume of T1 and T2 lesions at week 96 were not significantly different between treatment groups (p > 0.05). There were no new or unexpected adverse events related to IFN β-1a treatment.Several endpoints appeared to show a benefit of IFN β-1a treatment, but no significant differences could be detected owing to the small sample. Therefore, these data only permit, at best, tentative conclusions about the disease course in patients with MS after de-escalation from mitoxantrone and continuation with or without IFN β-1a. Larger confirmatory studies are required.