A proof-of-concept application of a novel scoring approach for personalized medicine in multiple sclerosis

2019 ◽  
Vol 26 (9) ◽  
pp. 1064-1073
Author(s):  
Fabio Pellegrini ◽  
Massimiliano Copetti ◽  
Francesca Bovis ◽  
David Cheng ◽  
Robert Hyde ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Personalized Medicine ◽  
Treatment Response ◽  
Short Form ◽  
Combined Treatment ◽  
Patient Specific ◽  
Individual Treatment ◽  
Treatment Groups ◽  
Relapsing Remitting ◽  
Relapsing Remitting Multiple Sclerosis

Background: Stratified medicine methodologies based on subgroup analyses are often insufficiently powered. More powerful personalized medicine approaches are based on continuous scores. Objective: We deployed a patient-specific continuous score predicting treatment response in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Data from two independent randomized controlled trials (RCTs) were used to build and validate an individual treatment response (ITR) score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. Results: The ITR score for the combined treatment groups versus placebo detected differential clinical response in both RCTs. High responders in one RCT had a cross-validated ARR ratio of 0.29 (95% confidence interval (CI) = 0.13–0.55) versus 0.62 (95% CI = 0.47–0.83) for all other responders (heterogeneity p = 0.038) and were validated in the other RCT, with the corresponding ARR ratios of 0.31 (95% CI = 0.18–0.56) and 0.61 (95% CI = 0.47–0.79; heterogeneity p = 0.036). The strongest treatment effect modifiers were the Short Form-36 Physical Component Summary, age, Visual Function Test 2.5%, prior MS treatment and Expanded Disability Status Scale. Conclusion: Our modelling strategy detects and validates an ITR score and opens up avenues for building treatment response calculators that are also applicable in routine clinical practice.

Fatigue in multiple sclerosis: multidimensional assessment and response to symptomatic treatment

2004 ◽  
Vol 10 (4) ◽  
pp. 462-468 ◽  
Author(s):  
Alfredo Romani ◽  
Roberto Bergamaschi ◽  
Elisa Candeloro ◽  
Enrico Alfonsi ◽  
Roberto Callieco ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Test Scores ◽  
Rating Scale ◽  
Symptomatic Treatment ◽  
Cognitive Test ◽  
Treatment Groups ◽  
Impact Scale ◽  
Relapsing Remitting ◽  
Fatigue Severity ◽  
Relapsing Remitting Multiple Sclerosis

Sixty relapsing-remitting multiple sclerosis (MS) patients were selected on the basis of their score on the Fatigue Severity Scale (FSS) and formed two groups: 40 patients (fatigued MS; MSf) scored above the 75th percentile of a previously assessed representative MS sample (100 patients), and 20 age- and sex-matched patients (nonfatigued MS patients; MSnf) scored below the 25th percentile. The patients underwent clinical evaluation (Expanded Disability Status Scale (EDSS)), further assessment of fatigue (Fatigue Impact Scale), scales evaluating depression (Hamilton Depression Rating Scale (HDRS) and Beck’s Depression Inventory (BDI)) and neuropsychological tests. All patients were evaluated for muscle fatigability and central activation by means of a biomechanical test of sustained contraction; they also underwent somatosensory evoked potentials (SSEPs) and transcranial magnetic stimulation (TMS). The patients of the MSf subgroup were then randomized to one of the following two treatments: 4-aminopyridine (4-AP) 24 mg/day and fluoxetine (FLX) 20 mg/day. After a one-week titration this treatment proceeded for 8 weeks. At the end of the treatment, EDSS, fatigue and depression scores were further evaluated. At baseline, fatigue test scores consistently correlated with depression and cognitive test scores, but not with the fatigability test. Fatigue scores decreased in both treatment groups in a similar way. Due to the design of the study, this cannot be disjoined from a placebo effect. The changes of fatigue scores could not be predicted in the FLX group, whereas in the 4-AP group higher basal fatigability test scores were associated with greater reduction in fatigue scores.

ALEMTUZUMAB IMPROVES 3-YEAR QUALITY OF LIFE IN CARE-MS II

2015 ◽  
Vol 86 (11) ◽  
pp. e4.9-e4
Author(s):  
Alasdair Coles ◽  
Gavin Giovannoni ◽  
Thibault Moreau ◽  
Eva Havrdova ◽  
David Margolin ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Sclerosis ◽  
Short Form ◽  
Extension Study ◽  
Prior Therapy ◽  
Link Type ◽  
Relapsing Remitting ◽  
Emotional Aspects ◽  
Relapsing Remitting Multiple Sclerosis

In the 2-year, phase 3 CARE–MS II study (NCT00548405) of relapsing-remitting multiple sclerosis (RRMS) patients with inadequate efficacy response to prior therapy, alemtuzumab demonstrated superior efficacy and quality-of-life (QoL) improvements versus subcutaneous interferon beta-1a, with manageable safety. Here, QoL outcomes are examined in alemtuzumab-treated patients at Year 3 in an ongoing extension study (NCT00930553). 393 of 435 alemtuzumab 12 mg-treated patients entered the extension study; 80 received as-needed alemtuzumab retreatment during Year 3. Mean Functional Assessment of multiple sclerosis total score (scale 0–176) improved from baseline to year 3 (119.1 vs 124.8; P<0.0001), with 5 of 6 subscales significantly improved. Mean Short-Form 36–Item survey physical and mental component summary scores (scale 1–100) rose from baseline to Year 3 (42.7 vs 44.7; P<0.0001, and 44.9 vs 46.5; P=0.042, respectively), with 6 of 8 subscales improved, and 82% and 73% of patients, respectively, having a stable or improved score at Year 3. EuroQol 5–dimensional visual analogue scale score improved from baseline to Year 3 (70.1 vs 73.0; P=0.0045). Overall sustained improvement in physical, mental, and emotional aspects of QoL were observed through 3 years in this population of alemtuzumab-treated RRMS patients, even though most patients received only 2 alemtuzumab treatment courses.

scholarly journals A Controlled Trial of Mitoxantrone in Multiple Sclerosis: Serial MRI Evaluation at One Year

1994 ◽  
Vol 21 (3) ◽  
pp. 266-270 ◽  
Author(s):  
S. Bastianello ◽  
C. Pozzilli ◽  
F. D’Andrea ◽  
E. Millefiorini ◽  
M. Trojano ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Gadolinium Dtpa ◽  
Treatment Groups ◽  
Number Of Patients ◽  
Significant Difference ◽  
Relapsing Remitting ◽  
The Mean ◽  
Remitting Multiple Sclerosis ◽  
One Year ◽  
Relapsing Remitting Multiple Sclerosis

Abstract:We present the results of a randomized double-blinded placebo controlled, multicenter trial, of low-dose mitoxantrone (MX), after one year, in 25 patients with relapsing-remitting multiple sclerosis, who had serial enhanced magnetic resonance imaging (MRI). Treatment groups were balanced for age, gender, duration of illness and neurological disability. Five of the 13 MX patients and 10 of the 12 placebo patients had exacerbations during treatment (p < 0.02). The mean change in the extended disability status scale was not significantly different between the MX and placebo treatment groups. Serial Gadolinium-DTPA enhancedMRIdetected no significant difference between the MX treated and placebo groups in the mean total number of new, enlarging, or Gadolinium-DTPA enhancing lesions; there was a trend toward a reduction of new, enlarging and Gadolinium-DTPA enhancing lesions in MX patients. Despite this ameliorating effect, the results indicate that serial Gadolinium-DTPA enhanced MRI, performed over one year in a limited number of patients, could not provide conclusive evidence for a role of MX therapy in relapsing-remitting multiple sclerosis.

No evidence of disease activity in patients receiving daclizumab versus intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis in the DECIDE study

2016 ◽  
Vol 23 (13) ◽  
pp. 1736-1747 ◽  
Author(s):  
Ludwig Kappos ◽  
Eva Havrdova ◽  
Gavin Giovannoni ◽  
Bhupendra O Khatri ◽  
Susan A Gauthier ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Interferon Beta ◽  
Composite Endpoint ◽  
Logistic Regression Models ◽  
Treatment Groups ◽  
Therapeutic Decisions ◽  
Relapsing Remitting ◽  
Magnetic Resonance Imaging Mri ◽  
Relapsing Remitting Multiple Sclerosis

Background: No evidence of disease activity (NEDA) is a composite endpoint being increasingly applied as an outcome measure in clinical trials as well as proposed for individual therapeutic decisions in multiple sclerosis (MS). Objective: Assess the proportion of patients with relapsing-remitting MS achieving NEDA in the DECIDE study of daclizumab 150 mg subcutaneous versus intramuscular interferon beta-1a 30 µg for 96–144 weeks. Methods: NEDA was defined as no relapses, no onset of 12-week confirmed disability progression (CDP), no new/newly enlarging T2 hyperintense lesions (NET2), and no gadolinium-enhancing (Gd+) lesions. Logistic regression models adjusted for baseline covariates compared treatment groups for baseline to week 96, weeks 0–24, and weeks 24–96. Results: From baseline to week 96, more daclizumab versus intramuscular interferon beta-1a patients achieved NEDA (24.6% vs 14.2%; odds ratio (OR; 95% confidence interval): 2.059 (1.592−2.661); p < 0.0001). ORs for clinical NEDA (no relapses, no CDP) and magnetic resonance imaging (MRI) NEDA (no NET2, no Gd+ lesions) were 1.651 (1.357−2.007; p < 0.0001) and 2.051 (1.628−2.582; p < 0.0001), respectively. ORs in favor of daclizumab for weeks 24–96 were consistently higher than for weeks 0–24. Conclusion: More daclizumab versus intramuscular interferon beta-1a patients achieved NEDA early in DECIDE, with effects increasing over time.

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

Neurology ◽  
2019 ◽  
Vol 92 (10) ◽  
pp. e1007-e1015 ◽  
Author(s):  
Jens Kuhle ◽  
Harald Kropshofer ◽  
Dieter A. Haering ◽  
Uma Kundu ◽  
Rolf Meinert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Treatment Response ◽  
Light Chain ◽  
Healthy Controls ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
T2 Lesions ◽  
Relapsing Remitting ◽  
Relapsing Remitting Multiple Sclerosis

ObjectiveTo 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.MethodsWe 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]-β-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes.ResultsAt 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).ConclusionsBlood 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.

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