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  • 1
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 27, No. 10 ( 2021-09), p. 1564-1576
    Abstract: In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses. Objective: To distinguish siponimod’s direct effects on disability progression from those on relapses in the EXPAND phase 3 trial. Methods: Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod’s effects on 3- and 6-month confirmed disability progression were independent of on-study relapses. Results: Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%–20% and 29%–33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%–18% and 23% for 3- and 6-month confirmed disability progression, respectively. Conclusion: By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2008225-3
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  • 2
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 27, No. 14 ( 2021-12), p. 2219-2231
    Abstract: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). Objective and Methods: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5–1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo. Results: At 8 years’ follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%–43.1%) of assessed participants in the IFNβ-1a–fingolimod switch group and 41.9% (36.6%–47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a–fingolimod switch group than on continuous fingolimod (5.4% [3.0%–9.5%] vs 14.2% [10.8%–18.4%], p = 0.01). Conclusion: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2008225-3
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  • 3
    Online Resource
    Online Resource
    BMJ ; 2014
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 85, No. 10 ( 2014-10), p. e4.53-e4
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 85, No. 10 ( 2014-10), p. e4.53-e4
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    RVK:
    Language: English
    Publisher: BMJ
    Publication Date: 2014
    detail.hit.zdb_id: 1480429-3
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  • 4
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 94, No. 1 ( 2023-01), p. 1-9
    Abstract: Analyse the integrated safety profile of evobrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), using pooled data from multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) trials. Methods Phase II, randomised, double-blind, placebo-controlled trial data were analysed (N=1083; MS: n=213, 48 weeks (W); RA: n=390, 12W; SLE: n=480, 52W). The analysis included all patients who received ≥1 dose of evobrutinib (25 mg or 75 mg once daily, or 50 mg or 75 mgtwice daily) or placebo. Descriptive statistics and exposure-adjusted incidence rates (EAIR) were used to report treatment-emergent adverse events (TEAEs). Results Data from 1083 patients were pooled: evobrutinib, n=861; placebo, n=271 (sum 〉 1083 due to MS trial design: n=49 received both placebo (W0–24) and evobrutinib 25 mg (W25–48)); median follow-up time (pt-years): evobrutinib, 0.501; placebo, 0.463. Across indications, the proportion of patients with TEAEs and the EAIR were similar for evobrutinib and placebo (66.2% (247.6 events/100 pt-years) vs 62.4% (261.4 events/100 pt-years)). By indication, the EAIR (events/100 pt-years) of TEAEs for evobrutinib versus placebo were: MS: 119.7 vs 148.3; RA: 331.8 vs 306.8; SLE: 343.0 vs 302.1. Two fatal events occurred (in SLE). The serious infections EAIR was 2.7 and 2.1 events/100 pt-years for evobrutinib and placebo. For previously reported BTKi-class effects, the EAIR of transient elevated alanine aminotransferase/aspartate aminotransferase TEAEs (events/100 pt-years) with evobrutinib versus placebo was 4.8 vs 2.8/3.5 vs 0.7, respectively. IgG levels were similar in evobrutinib/placebo-treated patients. Conclusions This is the first BTKi-integrated safety analysis that includes patients with MS. Overall, evobrutinib treatment (all doses) was generally well tolerated across indications. Trial registration numbers NCT02975349 , NCT03233230 , NCT02975336 .
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    RVK:
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1480429-3
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  • 5
    Online Resource
    Online Resource
    Cambridge University Press (CUP) ; 2020
    In:  Proceedings of the Nutrition Society Vol. 79, No. OCE2 ( 2020)
    In: Proceedings of the Nutrition Society, Cambridge University Press (CUP), Vol. 79, No. OCE2 ( 2020)
    Abstract: In the rural region of northern Croatian county Koprivnica Krizevci, new school meals program “Smart meals for smart kids” was implemented since the beginning of 2019. Analysis of nutritional quality of standard school meals served in 18 primary schools indicated high consumption of cereal products, meat, particularly meat products, pastry and sweets, and lacking of fruits, vegetables, fish and legumes. New menu was designed with the aim of improving nutritional quality of schools’ meals through a new recipes based on gastronomy heritage, dietary habits and National guidelines, but also education and testing of children's acceptance. Initial step of the project was to test new menu through Pilot program in six schools during two weeks. Process was accompanied by educational activities through originally designed leaflet about healthy diet, new meals and nutritional benefits, and was distributed among all students. Children's acceptance of Pilot menu of 10 meals was analyzed on a 9-point pictured hedonic scale and qualitative discussion through focus groups. In every school questionnaire was distributed in 4 th (age 9 to 10) and 7 th grade (age 12 to 13). In total, 237 children filled out the questionnaire, 104 from 4 th grade and 133 from 7 th grade. In focus groups, 26 participated 14 students and 12 teachers. Results show that best accepted meals were Spaghetti Bolognese, Breaded fish with cabbage savoy and potatoes, and Chicken risotto. High acceptance of this meals can be explained by familiarity to the children, often being served at school, relatively simple dishes with lesser amount of known ingredients and adequate taste profile. Least preferred meals were Chickpea with barley and corn, and Gnocchi with turnip, these meals were in most schools served for the first time, ingredients were unfamiliar, and combination of tastes was not according to the children's preferences. Qualitative discussion revealed that children noticed the difference from standard meals, particularly increase in serving of fruits and different and new varieties of vegetables, and believe that new meals are healthier. They also liked the educational leaflet and think it is a good way of communicating about healthy diet. Teachers welcome the new menus, differences were noticeable in intensity of spiciness, new varieties of vegetables and legumes, and more served fruits. For a successful and sustainable Program follow-up, school meals should be adapted to children's dietary habits gradually with careful introduction of the new food and tastes, followed by continuous nutritional education.
    Type of Medium: Online Resource
    ISSN: 0029-6651 , 1475-2719
    Language: English
    Publisher: Cambridge University Press (CUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2016335-6
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  • 6
    In: Brain Sciences, MDPI AG, Vol. 12, No. 2 ( 2022-02-04), p. 215-
    Abstract: Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs). We assessed effectiveness by recording relapses, Expanded Disability Status Scale (EDSS) scores, and MRI activity. Of 637 patients enrolled, 505 completed the study (mean age, 42 years). Overall, 72.8% and 12.7% experienced AEs and SAEs respectively. The most common AEs were fatigue, headache, and urinary tract infection; no cases of PML were observed. Fingolimod treatment resulted in low disease activity. Patients with ≤8 weeks washout period had a markedly lower risk of relapses (4.5%) than those with 〉 8 weeks (51.4%). In patients switching from natalizumab to fingolimod, no new safety signals with overall low relapse activity were observed in patients with washout latencies of ≤8 weeks before fingolimod initiation. Fingolimod was found to be safe and effective in patients transitioning from natalizumab.
    Type of Medium: Online Resource
    ISSN: 2076-3425
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2651993-8
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  • 7
    In: Journal of Neuroimaging, Wiley, Vol. 29, No. 5 ( 2019-09), p. 615-623
    Abstract: Quantitative neuroimaging is an important part of multiple sclerosis research and clinical trials, and measures of lesion volume (LV) and brain atrophy are key clinical trial endpoints. However, translation of these endpoints to heterogeneous historical datasets and nonstandardized clinical routine imaging has been difficult. The NeuroSTREAM technique was recently introduced as a robust and broadly applicable surrogate for brain atrophy measurement, but no such surrogate currently exists for conventional T2‐LV. Therefore, we sought to develop a fully automated proxy for T2‐LV with similar analytic value but increased robustness to common issues arising in clinical routine imaging. METHODS We created an algorithm to identify salient central lesion volume (SCLV), comprised of the subset of lesion voxels within a specific distance to the lateral ventricles (centrality) and with intensity at least a quantitatively‐derived amount brighter than normal appearing tissue (salience). We evaluated this method on four datasets (clinical, inter‐scanner, scan‐rescan, and real‐world multi‐center), including 1.5T, 3T, Philips, Siemens, and GE scanners with heterogeneous protocols, to assess agreement with conventional T2‐LV, comparative relationship with disability, reliability across scanners and between scans, and applicability to real‐world scans. RESULTS SCLV correlated strongly with conventional T2‐LV in both research‐quality ( r = .90, P 〈 .001) and real‐world ( r = 0.87, P 〈 0.001) datasets. It also showed similar correlations with Expanded Disability Status Scale, as conventional T2‐LV ( r = 0.48 for T2‐LV vs. r = 0.45 for SCLV). Inter‐scanner reproducibility (ICC) was 0.86, p 〈 0.001 for SCLV compared to 0.84, p 〈 0.001 for conventional T2‐LV, whereas scan‐rescan ICC was 0.999 for SCLV versus 0.997 for T2‐LV. CONCLUSIONS SCLV is a robust, fully‐automated proxy for T2‐LV in situations where conventional T2‐LV is not easily or reliably calculated.
    Type of Medium: Online Resource
    ISSN: 1051-2284 , 1552-6569
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2035400-9
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  • 8
    In: JMIR Medical Informatics, JMIR Publications Inc., Vol. 8, No. 4 ( 2020-4-14), p. e17592-
    Abstract: There is an unmet need for a tool that helps to evaluate patients who are at risk of progressing from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS). A new tool supporting the evaluation of early signs suggestive of progression in multiple sclerosis (MS) has been developed. In the initial stage, concepts relevant to progression were identified using a mixed method approach involving regression on data from a real-world observational study and qualitative research with patients and physicians. The tool was drafted in a questionnaire format to assess these variables. Objective This study aimed to develop the scoring algorithm for the tool, using both quantitative and qualitative research methods. Methods The draft scoring algorithm was developed using two approaches: quantitative analysis of real-world data and qualitative analysis based on physician interviews and ranking and weighting exercises. Variables that were included in the draft tool and regarded as most clinically relevant were selected for inclusion in a multiple logistic regression. The analyses were run using physician-reported data and patient-reported data. Subsequently, a ranking and weighting exercise was conducted with 8 experienced neurologists as part of semistructured interviews. Physicians were presented with the variables included in the draft tool and were asked to rank them in order of strength of contribution to progression and assign a weight by providing a percentage of the overall contribution. Physicians were also asked to explain their ranking and weighting choices. Concordance between physicians was explored. Results Multiple logistic regression identified age, MS disease activity, and Expanded Disability Status Scale score as the most significant physician-reported predictors of progression to SPMS. Patient age, mobility, and self-care were identified as the strongest patient-reported predictors of progression to SPMS. In physician interviews, the variables ranked and weighted as most important were stability or worsening of symptoms, intermittent or persistent symptoms, and presence of ambulatory and cognitive symptoms. Across all physicians, the level of concordance was 0.278 (P 〈 .001), indicating a low to moderate, but statistically significant, level of agreement. Variables were categorized as high (n=8), moderate (n=8), or low (n=10) importance based on the findings from the different approaches described above. Accordingly, the respective questions in the tool were assigned a weight of “three,” “two,” or “one” to inform the draft scoring algorithm. Conclusions This study further confirms the need for a tool to provide a consistent, comprehensive approach across physicians to support the early evaluation of signs indicative of progression to SPMS. The novel and comprehensive approach to develop the draft scoring algorithm triangulates data obtained from ranking and weighting exercises, qualitative interviews, and a real-world observational study. Variables that go beyond the clinically most obvious impairment in lower limbs have been identified as relevant subtle/sensitive signs suggestive of progressive disease.
    Type of Medium: Online Resource
    ISSN: 2291-9694
    Language: English
    Publisher: JMIR Publications Inc.
    Publication Date: 2020
    detail.hit.zdb_id: 2798261-0
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  • 9
    Online Resource
    Online Resource
    American Medical Association (AMA) ; 2016
    In:  JAMA Neurology Vol. 73, No. 11 ( 2016-11-01), p. 1375-
    In: JAMA Neurology, American Medical Association (AMA), Vol. 73, No. 11 ( 2016-11-01), p. 1375-
    Type of Medium: Online Resource
    ISSN: 2168-6149
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2016
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  • 10
    In: JAMA Neurology, American Medical Association (AMA), Vol. 76, No. 11 ( 2019-11-01), p. 1359-
    Type of Medium: Online Resource
    ISSN: 2168-6149
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2019
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