Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis

ObjectiveIn this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la Sclérose en Plaques.MethodsA total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated.ResultsThe confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio [OR] 0.60, p < 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54, p < 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, p < 0.001).ConclusionsAfter 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness.Classification of evidenceThis study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment.

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Discontinuation and comparative effectiveness of dimethyl fumarate and fingolimod in 2 centers

Neurology Clinical Practice ◽

10.1212/cpj.0000000000000487 ◽

2018 ◽

Vol 8 (4) ◽

pp. 292-301 ◽

Cited By ~ 15

Author(s):

Brandi Vollmer ◽

Daniel Ontaneda ◽

Anasua Bandyopadhyay ◽

Sam Cohn ◽

Kavita Nair ◽

...

Keyword(s):

Multiple Sclerosis ◽

Randomized Clinical Trials ◽

Brain Mri ◽

Cleveland Clinic ◽

Dimethyl Fumarate ◽

Oral Disease ◽

Clinical Population ◽

Practical Reasons ◽

Covariate Balance ◽

T2 Lesions

BackgroundDimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease-modifying therapies for relapsing multiple sclerosis (MS). Observational studies are valuable when randomized clinical trials cannot be done due to ethical or practical reasons. Two-site studies allow investigators to further ascertain external validity of previously examined treatment effect differences. Limited head-to-head 2-site studies exist comparing DMF and FTY.MethodsPatients prescribed DMF (n = 737) and FTY (n = 535) from 2 academic multiple sclerosis (MS) centers (Cleveland Clinic and University of Colorado) were identified. Discontinuation and disease activity endpoints were assessed using propensity score (PS) weighting. Covariates used in the PS model included demographics and clinical and MRI characteristics.ResultsPS weighting demonstrated excellent covariate balance. Discontinuation was more common in DMF (44.2%) compared to FTY (34.8%) over 24 months (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.21–1.99, p < 0.001). The leading cause for discontinuation was intolerability for both DMF (56.1% of DMF discontinuations) and FTY (46.2% of FTY discontinuations) (OR 1.65, 95% CI 1.21–2.25, p = 0.002). The proportion of patients with clinical relapses was low for both medications (DMF, 15.1%; FTY, 13.1%). There was no difference in the proportion of patients with relapses (OR 1.27, 95% CI 0.90–1.80, p = 0.174), gadolinium-enhancing lesions (OR 1.42, 95% CI 0.92–2.20, p = 0.114), or new T2 lesions on brain MRI (OR 1.13, 95% CI 0.83–1.55, p = 0.433).ConclusionsThis combined analysis suggests DMF and FTY have similar effectiveness in a large, 2-site clinical population over 24 months. Discontinuation of both DMTs was common and occurred more frequently with DMF, largely driven by intolerability.

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A comparative study of teriflunomide and dimethyl fumarate within the Swedish MS Registry

Multiple Sclerosis Journal ◽

10.1177/13524585211019649 ◽

2021 ◽

pp. 135245852110196

Author(s):

Jan Hillert ◽

Jon A Tsai ◽

Mona Nouhi ◽

Anna Glaser ◽

Tim Spelman

Keyword(s):

Multiple Sclerosis ◽

Real World ◽

Clinical Effectiveness ◽

Dimethyl Fumarate ◽

Population Based ◽

Life Outcomes ◽

Treatment Persistence ◽

Relapsing Remitting ◽

Relapsing Remitting Multiple Sclerosis

Background: Teriflunomide and dimethyl fumarate (DMF) are first-line disease-modifying treatments for multiple sclerosis with similar labels that are used in comparable populations. Objectives: The objective of this study was to compare the effectiveness and persistence of teriflunomide and DMF in a Swedish real-world setting. Methods: All relapsing-remitting multiple sclerosis (RRMS) patients in the Swedish MS registry initiating teriflunomide or DMF were included in the analysis. The primary endpoint was treatment persistence. Propensity score matching was used to adjust comparisons for baseline confounders. Results: A total of 353 teriflunomide patients were successfully matched to 353 DMF. There was no difference in the rate of overall treatment discontinuation by treatment group across the entire observation period (hazard ratio (HR) = 1.12; 95% confidence interval (CI) = 0.91–1.39; p = 0.277; reference = teriflunomide). Annualised relapse rate (ARR) was comparable ( p = 0.237) between DMF (0.07; 95% CI = 0.05–0.10) and teriflunomide (0.09; 95% CI = 0.07–0.12). There was no difference in time to first on-treatment relapse (HR = 0.78; 95% CI = 0.50–1.21), disability progression (HR = 0.55; 95% CI = 0.27–1.12) or confirmed improvement (HR = 1.17; 95% CI = 0.57–2.36). Conclusion: This population-based real-world study reports similarities in treatment persistence, clinical effectiveness and quality of life outcomes between teriflunomide and dimethyl fumarate.

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Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-319831 ◽

2019 ◽

Vol 90 (4) ◽

pp. 458-468 ◽

Cited By ~ 24

Author(s):

Tomas Kalincik ◽

Eva Kubala Havrdova ◽

Dana Horakova ◽

Guillermo Izquierdo ◽

Alexandre Prat ◽

...

Keyword(s):

Multiple Sclerosis ◽

Propensity Scores ◽

Negative Binomial ◽

Dimethyl Fumarate ◽

Survival Models ◽

Treatment Persistence ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis ◽

Relapse Rates

ObjectiveOral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.MethodsWe identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).ResultsThe eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).ConclusionThe effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.

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Effect of fingolimod on MRI outcomes in patients with paediatric-onset multiple sclerosis: results from the phase 3 PARADIGMS study

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-322138 ◽

2020 ◽

Vol 91 (5) ◽

pp. 483-492 ◽

Cited By ~ 3

Author(s):

Douglas L Arnold ◽

Brenda Banwell ◽

Amit Bar-Or ◽

Angelo Ghezzi ◽

Benjamin M Greenberg ◽

...

Keyword(s):

Multiple Sclerosis ◽

Early Treatment ◽

Brain Atrophy ◽

Treatment Discontinuation ◽

Interferon Β ◽

Phase 3 ◽

Once Daily ◽

T2 Lesions ◽

Superior Efficacy

ObjectivePARADIGMS demonstrated superior efficacy and comparable safety of fingolimod versus interferon β-1a (IFN β-1a) in paediatric-onset multiple sclerosis (PoMS). This study aimed to report all predefined MRI outcomes from this study.MethodsPatients with multiple sclerosis (MS) (aged 10–<18 years) were randomised to once-daily oral fingolimod (n=107) or once-weekly intramuscular IFN β-1a (n=108) in this flexible duration study. MRI was performed at baseline and every 6 months for up to 2 years or end of the study (EOS) in case of early treatment discontinuation/completion. Key MRI endpoints included the annualised rate of formation of new/newly enlarging T2 lesions, gadolinium-enhancing (Gd+) T1 lesions, new T1 hypointense lesions and combined unique active (CUA) lesions (6 months onward), changes in T2 and Gd+ T1 lesion volumes and annualised rate of brain atrophy (ARBA).ResultsOf the randomised patients, 107 each were treated with fingolimod and IFN β-1a for up to 2 years. Fingolimod reduced the annualised rate of formation of new/newly enlarging T2 lesions (52.6%, p<0.001), number of Gd+ T1 lesions per scan (66.0%, p<0.001), annualised rate of new T1 hypointense lesions (62.8%, p<0.001) and CUA lesions per scan (60.7%, p<0.001) versus IFN β-1a at EOS. The percent increases from baseline in T2 (18.4% vs 32.4%, p<0.001) and Gd+ T1 (–72.3% vs 4.9%, p=0.001) lesion volumes and ARBA (–0.48% vs −0.80%, p=0.014) were lower with fingolimod versus IFN β-1a, the latter partially due to accelerated atrophy in the IFN β-1a group.ConclusionFingolimod significantly reduced MRI activity and ARBA for up to 2 years versus IFN β-1a in PoMS.

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Preapproval and postapproval evidence on drugs for multiple sclerosis

Neurology ◽

10.1212/wnl.0000000000005561 ◽

2018 ◽

Vol 90 (21) ◽

pp. 964-973 ◽

Cited By ~ 8

Author(s):

Chiara Gerardi ◽

Vittorio Bertele' ◽

Silvia Rossi ◽

Silvio Garattini ◽

Rita Banzi

Keyword(s):

Multiple Sclerosis ◽

Clinical Effectiveness ◽

Dimethyl Fumarate ◽

New Drugs ◽

Cochrane Library ◽

European Medicines Agency ◽

The European Union ◽

Disability Progression ◽

Disease Modifying Drugs ◽

Approved Drugs

ObjectiveTo review the evidence supporting the European Union marketing authorization of drugs for multiple sclerosis (MS) and assess how far postmarketing research addresses information gaps at the time of approval.MethodsThrough its database, we identified drugs approved by the European Medicines Agency and gathered data on pivotal trials from the European Public Assessment Reports and corresponding publications. We searched Medline, Embase, Cochrane Library, and trial registries for postmarketing randomized controlled trials testing the drugs identified in any form of the disease.ResultsSince approval of interferon and glatiramer up to 2017, the Agency has examined 10 drugs for the treatment of MS, and 8 were included in this study: alemtuzumab, daclizumab, dimethyl fumarate, fampridine, fingolimod, peginterferon-β-1a, natalizumab, and teriflunomide. We analyzed 16 pivotal trials enrolling almost 16,000 participants. Eleven compared new drugs to placebo, 5 to interferon-β-1a. Annualized relapse rate was the primary outcome in two-thirds and coprimary with disability progression in the 2 studies of alemtuzumab. Of the 52 postmarketing trials, 24 reported final results and 28 were ongoing, terminated, or completed but no results were available. None directly compared the approved drugs, thus leaving their respective therapeutic values unknown. Data on the prevention of disease progression were scarce: none of the disease-modifying drugs showed any effect on disability progression.ConclusionThe lack of comparative evidence and data on clinical effectiveness hamper the assessment of therapeutic value and place in therapy of drugs approved for MS.

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

Multiple Sclerosis Journal ◽

10.1177/1352458518814117 ◽

2018 ◽

Vol 25 (14) ◽

pp. 1915-1925 ◽

Cited By ~ 24

Author(s):

Colm Elliott ◽

Jerry S Wolinsky ◽

Stephen L Hauser ◽

Ludwig Kappos ◽

Frederik Barkhof ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Multiple Sclerosis ◽

Magnetic Resonance ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Tissue Loss ◽

Jacobian Determinant ◽

Resonance Imaging ◽

T2 Lesions ◽

Magnetic Resonance Imaging Mri

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 < 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.

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060 Association of brain volume loss and neda outcomes in patients with relapsing multiple sclerosis in the opera i and opera ii studies (ENCORE)

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-anzan.59 ◽

2018 ◽

Vol 89 (6) ◽

pp. A25.1-A25

Author(s):

Anthony Traboulsee ◽

Douglas Arnold ◽

Eric C Klawiter ◽

Eva Havrdova ◽

Damian Fiore ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Activity ◽

Brain Tissue ◽

Repeated Measures ◽

Brain Volume ◽

Brain Mri ◽

Treatment Goal ◽

Volume Loss ◽

T2 Lesions ◽

Brain Volume Loss

IntroductionBrain volume loss (BVL) occurs in multiple sclerosis (MS) patients, reflecting irreversible tissue damage. No evidence of disease activity (NEDA), a composite measure assessing absence of clinical and magnetic resonance imaging (MRI) disease activity has emerged as important treatment goal in MS and may be associated with preservation of brain tissue and BVL prevention.MethodsPatients in OPERA-I/II (NCT01247324/NCT01412333) received 600 mg ocrelizumab (intravenous) very 24 weeks or 44 µg subcutaneous interferon beta-1a (IFNβ-1a) 3x-weekly for 96 weeks. Brain MRI assessments were completed at baseline and 24/48/96 Weeks. Brain volume normalised for head size was measured using SIENAX software. Percent change in whole brain volume (WBV) was determined using SIENA software, changes in cortical grey (GMV) and white (WMV) matter volumes were measured using validated, locally developed Jacobian integrator atrophy software. NEDA was defined as absence of relapses, 12-week confirmed disability progression, T1 Gd–enhancing lesions and new and/or enlarging T2-lesions. Changes from baseline in brain volume were examined in NEDA patients and those with evidence of disease activity (EDA), using the mixed-effects model for repeated measures method.ResultsThe analysis included 1520 patients (ocrelizumab-761; IFNβ-1a-759). Over 96 weeks, 569 (37%) patients [ocrelizumab-363 (48%); IFNβ-1a-206(27%); p<0.001] had NEDA. Compared with EDA patients, NEDA patients had significantly less WBV loss from baseline (30%-reduction; p<0.001). In the NEDA group, ocrelizumab patients had significantly less WBV loss (32%-reduction; p<0.001), WMV loss (34%-reduction; p=0.044) and GMV loss (30%-reduction; p<0.001) from baseline than IFNβ-1a patients. In the EDA group, ocrelizumab patients had significantly less WBV loss (11%-reduction; p=0.047) and GMV loss (21%-reduction; p<0.001) but not WMV loss (1.03%-increase; p=0.90) from baseline than IFNβ-1a patients.ConclusionThese findings highlight the importance of NEDA as treatment goal with respect to brain tissue preservation regardless of treatment choice. Ocrelizumab may confer additional benefits in NEDA patients NEDA beyond what is observed with IFNβ-1a.

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005 Filling in the gaps: precision MRI reporting in multiple sclerosis clinical practice

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-anzan.5 ◽

2018 ◽

Vol 89 (6) ◽

pp. A3.2-A4

Author(s):

Heidi Beadnall ◽

Yael Barnett ◽

Linda Ly ◽

Chenyu Wang ◽

Thibo Billiet ◽

...

Keyword(s):

Multiple Sclerosis ◽

Quantitative Data ◽

Clinical Decision Making ◽

Brain Mri ◽

Clinical Decision ◽

Quantitative Information ◽

Quantitative Mri ◽

Brain Volumes ◽

T2 Lesions ◽

Radiology Reports

IntroductionClinical multiple sclerosis (MS) magnetic resonance imaging (MRI) brain reports provide important information to neurologists. The quantitative data reported varies between centres and radiologists. Structured MRI reporting and formal quantitative MRI (QMRI) analysis may assist clinicians with patient management. The objective is to compare quantitative data derived from standard clinical reports, structured neuroradiologist reviews, local QMRI analyses and fully-automated MSmetrix QMRI analyses, in a longitudinal clinical MS cohort.MethodsClinical brain MRI scans separated by one-year minimum, from the same patient on the same scanner, were evaluated. Quantitative information was extracted from the clinical reports and structured neuroradiologist reviews. MRI scan-pairs were analysed locally by imaging-analysts and centrally by MSmetrix.Results50 MS patients, baseline age 39.02 (9.06) years, disease duration 9.11 (6.88) years and Expanded Disability Status Scale score 1.91 (1.62), were included. Compared to clinical reports, structured neuroradiologist reviews provided increased semi-/quantitative data; baseline T2 and T1 lesion burden (50% vs 100%; 2% vs 100%), baseline brain volume-loss (BVL; 72% vs 100%), new T1 lesions (0% vs 100%), regional brain atrophy (BA; 20% vs 100%). Lesion and brain volumes were not provided in radiology reports/reviews. Comparison of local and central QMRI revealed moderate-strong Pearson correlations for most metrics; Intra-class correlations varied more widely. Statistical consistency existed across all methods in detecting new T2 lesions. Radiologist-identified baseline BVL was associated with lower quantitatively-measured brain volumes. Local QMRI longitudinal BA rates >0.4% and >0.8%, were 48% and 26% respectively. Neuroradiologist review identified BA in 12%.ConclusionStructured neuroradiology review provided additional quantitative information over standard clinical reports. Quantitative data measured using local and MSmetrix pipelines were generally well associated but are not interchangeable. Longitudinal whole brain and regional atrophy is not reliably identified by radiologists and QMRI analysis provides a clear advantage in this regard. Structured reporting, and formal QMRI analysis, provide additional quantitative MRI data that may assist clinical decision-making in MS.

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Delayed-Release Dimethyl Fumarate Safety and Efficacy in Pediatric Patients With Relapsing-Remitting Multiple Sclerosis

Frontiers in Neurology ◽

10.3389/fneur.2020.606418 ◽

2021 ◽

Vol 11 ◽

Author(s):

Raed Alroughani ◽

Peter Huppke ◽

Maria Mazurkiewicz-Beldzinska ◽

Astrid Blaschek ◽

Martin Valis ◽

...

Keyword(s):

Multiple Sclerosis ◽

Pediatric Patients ◽

Dimethyl Fumarate ◽

Relative Reduction ◽

Hyperintense Lesion ◽

Safety And Efficacy ◽

Delayed Release ◽

T2 Lesions ◽

Relapsing Remitting Multiple Sclerosis

Background: Pediatric multiple sclerosis (MS) is rare: only 1.5–5% of MS cases are diagnosed before 18 years of age, and data on disease-modifying therapies (DMTs) for pediatric MS are limited. The CONNECTED study assessed the long-term safety and efficacy of treatment with delayed-release dimethyl fumarate (DMF), an oral MS DMT, in pediatric patients with MS.Methods: CONNECTED is the 96-week extension to FOCUS, a 24-week phase 2 study of patients aged 13–17 years; participants received DMF 240 mg twice daily. Endpoints included (primary) incidence of adverse events (AEs), serious AEs, and DMF discontinuations due to an AE, and (secondary) T2 hyperintense lesion incidence by magnetic resonance imaging and annualized relapse rate (ARR).Results: Twenty participants [median (range) age, 17 (14–18) years; 65% female] who completed FOCUS enrolled into CONNECTED; 17 (85%) completed CONNECTED. Eighteen participants (90%) experienced AEs: the most frequent was flushing (25%). None experienced infections or fever related to low lymphocyte counts. Three participants experienced four serious AEs; none led to DMF discontinuation. Twelve of 17 participants (71%) had no new/newly enlarged T2 lesions from weeks 16–24, two (12%) had one, and one each (6%) had two, three, or five or more lesions [median (range), 0 (0–6)]. Over the full 120-week treatment period, ARR was 0.2, an 84.5% relative reduction (n = 20; 95% confidence interval: 66.8–92.8; p < 0.0001) vs. the year before DMF initiation.Conclusions: The long-term safety and efficacy observed in CONNECTED was consistent with adults, suggesting pediatric and adolescent patients with MS might benefit from DMF treatment.

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