Dataset Information

Relapse Rate and MRI Activity in Young Adult Patients With Multiple Sclerosis: A Post Hoc Analysis of Phase 3 Fingolimod Trials.

ABSTRACT:

Background

Disease activity differs in young patients with multiple sclerosis (MS) compared with the overall adult MS population.

Objective

The objective of this paper is to evaluate the effect of fingolimod 0.5 mg on disease activity in young adults with MS from three randomized, double-blind Phase 3 trials.

Methods

Annualized relapse rate (ARR), number of new/newly enlarging T2 lesions (neT2), and no evidence of disease activity (NEDA-3) were estimated in the intent-to-treat population at age 20 (youngest) and 30 (young) and compared to the overall population. Models used included a negative binomial regression (ARR/neT2) and a logistic regression (NEDA), with age at baseline as a continuous covariate.

Results

ARRs were higher in younger patients (all p < 0.05), and significantly reduced with fingolimod versus placebo or interferon beta-1a (IFN β-1a), with the percentage reduction inversely proportional to age. Fingolimod was significantly associated with a lower number of neT2 lesions versus placebo/IFN in all age groups except versus IFN in the youngest patients. Regardless of age, fingolimod-treated patients were more likely to achieve NEDA-3 versus placebo/IFN β-1a, with strongest benefits in the youngest patients (all p < 0.05).

Conclusions

Young adults show higher levels of MS disease activity, and may particularly benefit from fingolimod treatment compared with the overall study population.

SUBMITTER: Gartner J

PROVIDER: S-EPMC5971396 | biostudies-literature | 2018 Apr-Jun

REPOSITORIES: biostudies-literature

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Publications

Relapse Rate and MRI Activity in Young Adult Patients With Multiple Sclerosis: A Post Hoc Analysis of Phase 3 Fingolimod Trials.

Gärtner Jutta J Chitnis Tanuja T Ghezzi Angelo A Pohl Daniela D Brück Wolfgang W Häring Dieter Adrian DA Karlsson Goeril G Putzki Norman N

Multiple sclerosis journal - experimental, translational and clinical 20180401 2

<h4>Background</h4>Disease activity differs in young patients with multiple sclerosis (MS) compared with the overall adult MS population.<h4>Objective</h4>The objective of this paper is to evaluate the effect of fingolimod 0.5 mg on disease activity in young adults with MS from three randomized, double-blind Phase 3 trials.<h4>Methods</h4>Annualized relapse rate (ARR), number of new/newly enlarging T2 lesions (neT2), and no evidence of disease activity (NEDA-3) were estimated in the intent-to-tr ...[more]

PMID: 29854416

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Project description:BACKGROUND:Fingolimod is a once-daily, orally administered therapy for relapsing forms of MS. It has been shown to reduce relapse rates significantly in all phase II and phase III clinical trials when compared with placebo and intramuscular interferon ?-1a (IFN?-1a IM). METHODS:This study compared annualized relapse rates (ARRs) associated with fingolimod, placebo and IFN?-1a IM, in patient subgroups from the pooled FREEDOMS, FREEDOMS II, and TRANSFORMS populations. This provided a large data set in which the efficacy of fingolimod could be assessed across a range of patient subgroups, including clinically relevant subgroups not previously analysed. RESULTS:Compared with placebo, fingolimod was associated with significantly lower ARRs across all patient subgroups with relative reductions in ARRs ranging from 35% (patients who had previously received treatment for their MS for up to 1 year; P<0.05) to 69% (patients with symptoms for less than 3 years before study entry; P<0.001). Other relative reductions in ARR compared with placebo included 64% in patients aged 40 years or younger and 63% in those naïve to treatment (P<0.001 for both). Compared with IFN?-1a IM, the greatest benefits to ARR were seen in patients aged 40 years or younger (55% relative ARR reduction, P<0.001) and in a small subgroup of patients who had previously received IFN? and glatiramer acetate (55% relative ARR reduction; P<0.05). Reductions in ARR compared with IFN?-1a IM were not statistically significant in men (33%, P=0.081), in patients aged over 40 years (23%, P=0.230) and in those who had received treatment prior to the study for 1 year or less (35%, P=0.108). Fingolimod was associated with significantly lower ARRs compared with placebo and with IFN?-1a IM irrespective of treatment status (treatment-naïve and previously treated for MS), and regardless of type of previous therapy. CONCLUSIONS:Fingolimod provided consistent efficacy benefits over placebo and IFN?-1a IM across a range of subgroups of patients with relapsing MS. The magnitude of the beneficial effect of fingolimod over IFN?-1a IM may depend on age, sex, and duration of previous treatment. These findings suggest that most benefit will be gained by patients who start fingolimod early in the disease course, but the findings also suggest that fingolimod treatment will benefit patients later in the disease course when they have already accrued disability.

Project description:Background and objectivesTo 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.MethodsA 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.ResultsWe 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.DiscussionpNfL 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 informationEXPAND (ClinicalTrials.gov identifier: NCT01665144) and INFORMS (ClinicalTrials.gov identifier: NCT00731692).

Project description:To determine whether basing the decision to initiate immediate vs delayed disease-modifying therapy (DMT) on extent of recovery after initial relapse affects long-term disability accumulation in a multiple sclerosis (MS) evidence-based setting. We analyzed the double-blind, placebo-controlled interferon beta-1a 30 mc once a week in clinically isolated syndrome and 10-year-follow-up extension trial. Good recovery after presenting relapse was defined as (1) full early recovery within 28 days of symptom onset (Expanded Disability Status Scale [EDSS] score of 0 at enrollment maintained ≥6 months) and (2) delayed good recovery (EDSS score > 0 at enrollment and improvement from peak deficit to 6th-month or 1-year visit ≥ median). Time from recovery assignment to future disability (EDSS score ≥ 2.5 or ≥4.0) was studied on a relapse-recovery-stratified age axis and immediate vs 3-year delayed treatment initiation with Kaplan-Meier statistics and hazard ratios (HRs). One hundred seventy-five/328 patients had good recovery (94 immediate and 81 delayed treatment); 153 did not have good recovery (77 immediate and 76 delayed treatment). HRs for EDSS score ≥2.5 outcome were: delayed treatment without good recovery as reference (HR = 1.0), delayed treatment with good recovery (HR6th-month: 0.67, p = 0.207; HR1st-year: 0.40, p = 0.027), immediate treatment without good recovery (HR6th-month: 0.56, p = 0.061; HR1st-year: 0.40, p = 0.011), and immediate treatment with good recovery (HR6th-month: 0.43, p = 0.014; HR1st-year: 0.48, p = 0.034). Placebo patients were switched to long-term treatment after 3 years, and insufficient EDSS score ≥4.0 outcome events were available to study. In patients with MS presenting without good recovery after the initial relapse, immediate DMT initiation favorably influences the likelihood of more ambulatory-benign disease akin to patients with good recovery after the initial relapse. This study provides Class III evidence that for patients with MS without good recovery after the initial relapse, immediate DMT initiation increases the likelihood of a benign disease course.

Project description:BackgroundA study was undertaken to evaluate remote monitoring via smartphone sensor-based tests in people with multiple sclerosis (PwMS). This analysis aimed to explore regional neural correlates of digital measures derived from these tests.MethodsIn a 24-week, non-randomized, interventional, feasibility study (NCT02952911), sensor-based tests on the Floodlight Proof-of-Concept app were used to assess cognition (smartphone-based electronic Symbol Digit Modalities Test), upper extremity function (Draw a Shape Test, Pinching Test), and gait and balance (Static Balance Test, Two-Minute Walk Test, U-Turn Test). In this post-hoc analysis, digital measures and standard clinical measures (e.g., Nine-Hole Peg Test [9HPT]) were correlated against regional structural magnetic resonance imaging outcomes. Seventy-six PwMS aged 18-55 years with an Expanded Disability Status Scale score of 0.0-5.5 were enrolled from two different sites (USA and Spain). Sixty-two PwMS were included in this analysis.ResultsWorse performance on digital and clinical measures was associated with smaller regional brain volumes and larger ventricular volumes. Whereas digital and clinical measures had many neural correlates in common (e.g., putamen, globus pallidus, caudate nucleus, lateral occipital cortex), some were observed only for digital measures. For example, Draw a Shape Test and Pinching Test measures, but not 9HPT score, correlated with volume of the hippocampus (r = 0.37 [drawing accuracy over time on the Draw a Shape Test]/ - 0.45 [touching asynchrony on the Pinching Test]), thalamus (r = 0.38/ - 0.41), and pons (r = 0.35/ - 0.35).ConclusionsMultiple neural correlates were identified for the digital measures in a cohort of people with early MS. Digital measures showed associations with brain regions that clinical measures were unable to demonstrate, thus providing potential novel information on functional ability compared with standard clinical assessments.

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Dataset Information

Relapse Rate and MRI Activity in Young Adult Patients With Multiple Sclerosis: A Post Hoc Analysis of Phase 3 Fingolimod Trials.

Background

Objective

Methods

Results

Conclusions

Publications

Relapse Rate and MRI Activity in Young Adult Patients With Multiple Sclerosis: A Post Hoc Analysis of Phase 3 Fingolimod Trials.

Similar Datasets

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