Blood Neurofilament Light in Progressive Multiple Sclerosis: Post Hoc Analysis of 2 Randomized Controlled Trials.

BACKGROUND AND OBJECTIVES: To investigate the potential of plasma neurofilament light (pNfL) as a biomarker of disease progression and treatment response in progressive multiple sclerosis (PMS) with and without acute disease activity. METHODS: A post hoc blinded analysis of pNfL levels in 2 placebo-controlled, phase 3 studies in secondary progressive multiple sclerosis (SPMS; EXPAND) and primary progressive multiple sclerosis (PPMS; INFORMS) using siponimod and fingolimod, respectively, as active compounds was performed. pNfL levels were quantified using a single molecule array (Homebrew Simoa) immunoassay from stored ethylenediaminetetraacetic acid (EDTA) plasma samples of all patients who consented for exploratory biomarker analysis in either study; pNfL levels were divided into high (≥30 pg/mL) and low (<30 pg/mL) at baseline. We investigated the association of pNfL levels with disability progression, cognitive decline, and brain atrophy and their sensitivity to indicate treatment response through clinical measures. RESULTS: We analyzed pNfL in 4,185 samples from 1,452 patients with SPMS and 1,172 samples from 378 patients with PPMS. Baseline pNfL levels were higher in SPMS (geomean 32.1 pg/mL) than in PPMS (22.0 pg/mL; p < 0.0001). In both studies, higher baseline pNfL levels were associated with older age, higher Expanded Disability Status Scale score, more Gd+ lesions, and higher T2 lesion load (all p < 0.05). Independent of treatment, high vs low baseline pNfL levels were associated with significantly higher risks of confirmed 3-month (SPMS [32%], hazard ratio [95% CI] 1.32 [1.09-1.61]; PPMS [49%], 1.49 [1.05-2.12]) and 6-month disability progression (SPMS [26%], 1.26 [1.01-1.57]; PPMS [48%], 1.48 [1.01-2.17]), earlier wheelchair dependence (SPMS [50%], 1.50 [0.96-2.34]; PPMS [197%], 2.97 [1.44-6.10]), cognitive decline (SPMS [41%], 1.41 [1.09-1.84]), and higher rates of brain atrophy (mean change at month 24: SPMS, -0.92; PPMS, -1.39). Baseline pNfL levels were associated with future disability progression and the degree of brain atrophy regardless of presence or absence of acute disease activity (gadolinium-enhancing lesions or recent occurrence of relapses before baseline). pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo-treated patients and higher in those having experienced disability progression. DISCUSSION: pNfL was associated with future clinical and radiologic disability progression features at the group level. pNfL was reduced by treatment and may be a meaningful outcome measure in PMS studies. TRIAL REGISTRATION INFORMATION: EXPAND (ClinicalTrials.gov identifier: NCT01665144) and INFORMS (ClinicalTrials.gov identifier: NCT00731692).

Correction to: Long-Term Effect of Immediate Versus Delayed Fingolimod Treatment in Young Adult Patients with Relapsing-Remitting Multiple Sclerosis: Pooled Analysis from the FREEDOMS/FREEDOMSII Trials.

Figures 1a, 1b and 3 were published incorrectly in the original version. The corrected images are given as follows.

Long-term prognostic value of longitudinal measurements of blood neurofilament levels.

OBJECTIVE: To assess the long-term prognostic value of an integral of longitudinal measurements of plasma neurofilament light chain levels (NfLlong) over 12 and 24 months vs single neurofilament light chain (NfL) measurements in patients with relapsing-remitting MS (RRMS) and its additional value when combined with clinical and MRI measures. METHODS: This analysis included continuously fingolimod-treated patients with RRMS from the 24-month FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS)/12-month Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) phase 3 trials and their long-term extension, LONGTERMS. Patients were classified into high (≥30 pg/mL, n = 110) and low (<30 pg/mL, n = 164) NfL categories based on the baseline (BL) NfL value or the geometric mean NfLlong calculated over 12 and 24 months to predict disability-related outcomes and brain volume loss (BVL). The additional prognostic value of NfL was quantified using the area under the receiver operating characteristic (ROC) curve. RESULTS: A single high (vs low) NfL measure at BL was prognostic of a higher risk of reaching Expanded Disability Status Scale (EDSS) score ≥4 earlier (hazard ratio [HR] = 2.19; 95% CI = 1.21-3.97) and higher BVL over 120 months (difference: -1.12%; 95% CI = -2.07 to -0.17). When NfLlong was measured over 24 months, high NfL was associated with a higher risk of reaching EDSS score ≥4 (HR = 7.91; 95% CI = 2.99-20.92), accelerated 6-month confirmed disability worsening (HR = 3.14; 95% CI = 1.38-7.11), and 20% worsening in the Timed 25-Foot Walk Test (HR = 3.05; 95% CI = 1.38-6.70). Area under the ROC curve was consistently highest in models combining NfL with clinical and MRI measures. CONCLUSIONS: NfLlong had a higher prognostic value than single NfL assessments on long-term outcomes in RRMS. Combining it with clinical and MRI measures increased sensitivity and specificity to predict long-term disease outcomes. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that NfLlong was more strongly associated with long-term outcomes than single NfL assessments in patients with RRMS.

Long-Term Effect of Immediate Versus Delayed Fingolimod Treatment in Young Adult Patients with Relapsing-Remitting Multiple Sclerosis: Pooled Analysis from the FREEDOMS/FREEDOMS II Trials.

INTRODUCTION: Fingolimod has demonstrated clinical and MRI benefits versus placebo/interferon ß-1a in young adults with multiple sclerosis (MS). Here we report the long-term effects of fingolimod 0.5 mg on clinical and MRI outcomes in young adults with MS aged ≤ 30 years followed up for up to 8 years (96 months). METHODS: This post hoc analysis of pooled FREEDOMS/FREEDOMS II studies included patients who either received fingolimod 0.5 mg from randomization (immediate; N = 163) or switched from placebo to fingolimod at month (M) 24 (delayed; N = 147). The 6-month confirmed disability improvement [6m-CDI: based on Expanded Disability Status Scale (EDSS)], 6m-CDI-plus (6m-CDI+; EDSS, 9-Hole Peg Test, Timed 25-Foot Walk Test), 6-month confirmed disability progression (6m-CDP), time to EDSS score ≥ 4, annualized relapse rates (ARRs), new/newly enlarging T2 (neT2) lesions, and annual rate of brain volume loss (BVL) were analyzed from baseline to M24, M48, and M96. Cox regression and negative binomial regression models were used to analyze measured outcomes. RESULTS: At baseline, more than two-thirds of young adult patients were treatment naïve, had more than two relapses in the previous 2 years, and EDSS score < 2. From M0 to M96, a significantly higher proportion of young adult patients in the immediate group (vs. delayed group) achieved 6m-CDI (58.2% vs. 30.5%, p = 0.0206) and 6m-CDI+ (70.6% vs. 42.3%, p = 0.0149); significantly fewer patients reached 6m-CDP (20.1% vs. 34.7%, p = 0.0058) and EDSS ≥ 4 (24.1% vs. 34.1%, p = 0.0041). Up to M96, young adults in the immediate versus delayed group had lower ARRs (0.16 vs. 0.38, p < 0.0001) and a higher proportion of patients were free of neT2 lesions at M48 (31.0% vs. 5.0%, p = 0.0011). CONCLUSION: In young adult patients with MS, immediate versus delayed fingolimod treatment was associated with improved disease outcomes and greater long-term benefits in both disease activity and disability progression. FUNDING: Novartis Pharma AG.

Early initiation of fingolimod reduces the rate of severe relapses over the long term: Post hoc analysis from the FREEDOMS, FREEDOMS II, and TRANSFORMS studies.

BACKGROUND: Relapse frequency is often correlated with the prognosis of multiple sclerosis (MS). In patients with relapsing-remitting MS (RRMS), relapses vary in severity and may affect activities of daily living, require steroid intervention, or hospitalization. Incomplete recovery from relapses results in increasing disability. In pivotal phase III studies of fingolimod (FREEDOMS, FREEDOMS II, and TRANSFORMS), the frequency of overall and severe relapses was significantly reduced in patients with RRMS treated with fingolimod compared with placebo or intramuscular interferon ß-1a (IFN ß-1a). The objective of this study was to report the effect of early initiation of fingolimod on relapse severity in patients with RRMS. METHODS: This is a post hoc descriptive analysis of data from the pooled placebo-controlled FREEDOMS/FREEDOMS II studies and from the active-comparator TRANSFORMS study. Patients were analyzed under 2 groups: patients initially randomized to receive fingolimod 0.5 mg during the core phase and continued fingolimod 0.5 mg in the extension phase (immediate fingolimod group), and patients initially randomized to placebo or IFN ß-1a during the core phase and switched to fingolimod during the extension phase (delayed fingolimod group). Annualized relapse rate (ARR) was estimated for severe relapses (defined as Expanded Disability Status Scale increase of >1 point, or >2-point change in 1 or 2 Functional Systems, respectively, or >1-point change in >4 Functional Systems). ARR was also estimated for relapses that affected activities of daily living, required steroid use, or hospitalization. RESULTS: In the pooled FREEDOMS/FREEDOMS II extensions, the immediate fingolimod group showed sustained reductions in the proportion (core: 15.8% and extension: 9.3%) and in ARR over 4 years (0.032 and 0.015) for severe relapses, in relapses requiring steroids (0.149 and 0.123), hospitalization (0.049 and 0.039) and relapses affecting activities of daily living (0.155 and 0.112). In the TRANSFORMS extension, similar reductions were observed in the immedaite group for the proportion of severe relapses (core: 11.8% and extension: 9.8%). ARR remained low over 2 years for severe relapses (0.024 and 0.018), relapses affecting activities of daily living (0.112 and 0.109), relapses requiring steroids (0.156 and 0.161) and hospitalization (0.027 and 0.033). Results in the FREEDOMS/FREEDOMS II and TRANSFORMS extensions for the delayed group were similar. In the TRANSFORMS extension, the proportion of severe relapses were 18.0% (core) and 11.1% (extension); there were significant reductions in ARR for severe relapses (core: 0.079 and extension: 0.029), relapses requiring steroids (0.366 and 0.232), hospitalization (0.092 and 0.055), and relapses affecting activities of daily living (0.285 and 0.144) (all p < 0.0001). Complete recovery was reported for the majority of relapses during the core and extension phases in both the immediate and delayed fingolimod groups (Pooled FREEDOMS/FREEDOMS II: immediate group 59.7%-65.5% and delayed group 64.9%-67.7%; TRANSFORMS: 72.1%-80.0% and 65.4%-70.8%). CONCLUSIONS: In patients with RRMS, the frequency of severe relapses and relapse severity remained low in the immedaite fingolimod group over a period of 4 years. Reductions in the proportion of severe relapses post switch from IFN ß-1a or placebo to fingolimod underscore the clinical benefit and the relevance of an early initiation of fingolimod.

Blood neurofilament light chain as a biomarker of MS disease activity and treatment response.

OBJECTIVE: To assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis. METHODS: We measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-ß-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes. RESULTS: At baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.5 and 27.0 vs 16.9, p = 0.0001) and correlated with T2 lesion load and number of gadolinium-enhancing T1 lesions (p < 0.0001, both). Baseline NfL levels, treatment, and number of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all p < 0.01). High vs low baseline NfL levels were associated (estimate [95% confidence interval]) with an increased number of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51-4.60]; p = 0.0006), relapses (rate ratio: 2.53 [1.67-3.83]; p < 0.0001), brain volume loss (difference in means: -0.78% [-1.02 to -0.54]; p < 0.0001), and risk of confirmed disability worsening (hazard ratio: 1.94 [0.97-3.87]; p = 0.0605). Fingolimod significantly reduced NfL levels already at 6 months (vs placebo 0.73 [0.656-0.813] and IFN 0.789 [0.704-0.884]), which was sustained until the end of the studies (vs placebo 0.628 [0.552-0.714] and IFN 0.794 [0.705-0.894]; p < 0.001, both studies at all assessments). CONCLUSIONS: Blood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value. Our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response.

Efficacy of acupuncture for the prophylaxis of migraine: a multicentre randomised controlled clinical trial.

BACKGROUND: Our aim was to assess the efficacy of a part-standardised verum acupuncture procedure, in accordance with the rules of traditional Chinese medicine, compared with that of part-standardised sham acupuncture and standard migraine prophylaxis with beta blockers, calcium-channel blockers, or antiepileptic drugs in the reduction of migraine days 26 weeks after the start of treatment. METHODS: This study was a prospective, randomised, multicentre, double-blind, parallel-group, controlled, clinical trial, undertaken between April 2002 and July 2005. Patients who had two to six migraine attacks per month were randomly assigned verum acupuncture (n=313), sham acupuncture (n=339), or standard therapy (n=308). Patients received ten sessions of acupuncture treatment in 6 weeks or continuous prophylaxis with drugs. Primary outcome was the difference in migraine days between 4 weeks before randomisation and weeks 23-26 after randomisation. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN52683557. FINDINGS: Of 1295 patients screened, 960 were randomly assigned to a treatment group. Immediately after randomisation, 125 patients (106 from the standard group) withdrew their consent to study participation. 794 patients were analysed in the intention-to-treat popoulation and 443 in the per-protocol population. The primary outcome showed a mean reduction of 2 .3 days (95% CI 1.9-2.7) in the verum acupuncture group, 1.5 days (1.1-2.0) in the sham acupuncture group, and 2.1 days (1.5-2.7) in the standard therapy group. These differences were statistically significant compared with baseline (p<0.0001), but not across the treatment groups (p=0.09). The proportion of responders, defined as patients with a reduction of migraine days by at least 50%, 26 weeks after randomisation, was 47% in the verum group, 39% in the sham acupuncture group, and 40% in the standard group (p=0.133). INTERPRETATION: Treatment outcomes for migraine do not differ between patients treated with sham acupuncture, verum acupuncture, or standard therapy.

Short stent implantation for routine use is feasible in a high proportion of coronary interventions and yields a low restenosis rate.

Stent length predicts restenosis. The feasibility of using a short stent (<10 mm) routinely was investigated in 331 consecutive patients treated for 424 coronary artery lesions. A single short stent provided suitable coverage and achieved a residual stenosis <30%, with or without predilatation, in 252/424 lesions (59.4%). Longer stents were implanted in 58/424 lesions (13.7%), while only percutaneous transluminal coronary angioplasty was performed in 114/242 lesions (26.9%). Angiographic success and procedural success were achieved in 250/252 lesions (99.2%). Restenosis occurred in 36/231 lesions (15.6%) after short stenting, in 10/53 lesions (18.9%) after long stents, in 21/88 lesions (23.9%) after percutaneous transluminal coronary angioplasty, and in 67/372 lesions (18.0%) controlled angiographically. Only small vessel diameter predicted restenosis after short stenting. Thus, a single short stent implanted directly or after predilatation is sufficient to achieve an acceptable angiographic result in more than in nearly 60% of all treated lesions. Short stenting results in a low restenosis rate.