T1 Gd Research Articles

Serum neurofilament light chain correlations in patients with a first clinical demyelinating event in the REFLEX study: a post hoc analysis.

In REFLEX, subcutaneous interferon beta-1a (sc IFN β-1a) delayed the onset of multiple sclerosis (MS) in patients with a first clinical demyelinating event (FCDE). This post hoc analysis aimed to determine whether baseline serum neurofilament light (sNfL) chain can predict conversion to MS and whether correlations exist between baseline sNfL and magnetic resonance imaging (MRI) metrics. sNfL was measured for 494 patients who received sc IFN β-1a 44 μg once weekly (qw; n = 168), three times weekly (tiw; n = 161), or placebo (n = 165) over 24 months. Median baseline sNfL (26.1 pg/mL) was used to define high/low sNfL subgroups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox's proportional hazard model to determine factors influencing the risk of conversion to MS. Kaplan-Meier estimates calculated median time-to-conversion to MS (McDonald 2005 criteria) or clinically definite MS (CDMS; Poser criteria). Correlations between sNfL and MRI findings were assessed using Spearman's rank correlation coefficient (r). Multivariable models indicated that high baseline sNfL was associated with the likelihood of converting to MS and inversely to time-to-conversion (HR = 1.3, 95% CI: 1.03-1.64; p = 0.024). Significant additional factors affecting conversion to McDonald MS were on-study treatment (sc IFN β-1a/placebo; qw: HR = 0.59, 95% CI: 0.46-0.76; tiw: HR = 0.45, 95% CI: 0.34-0.59), classification of FCDE (monofocal/multifocal; HR = 0.69, 95% CI: 0.55-0.85), and most baseline imaging findings (T2 and T1 gadolinium-enhancing [Gd+] lesions; HR = 1.02, 95% CI: 1.01-1.03 and HR = 1.07, 95% CI: 1.03-1.11); all p ⩽ 0.001. Conversion to CDMS showed similar results. At month 24, sNfL was strongly correlated with a mean number of combined unique active (r = 0.71), new T2 (r = 0.72), and new T1 Gd+ (r = 0.60) lesions; weak correlations were observed between sNfL and clinical outcomes for all treatment groups. Higher baseline sNfL was associated with an increased risk of MS conversion, a risk that was mitigated by treatment with sc IFN β-1a tiw. ClinicalTrials.gov identifier: NCT00404352. Date registered: 28 November 2006.

Neurofilament Light Chain Levels and Disease Activity During Long-Term Treatment of Relapsing Multiple Sclerosis with the Bruton’s Tyrosine Kinase Inhibitor Evobrutinib (P1-3.011)

Neurofilament Light Chain Levels and Disease Activity During Long-Term Treatment of Relapsing Multiple Sclerosis with the Bruton’s Tyrosine Kinase Inhibitor Evobrutinib (P1-3.011)

Efficacy of Early Ofatumumab vs Late Switch From Teriflunomide: Subgroup Analysis of the ALITHIOS Open-label Extension Study by Previous Disease-Modifying Therapy Exposure and Age (P6-3.016)

Efficacy of Early Ofatumumab vs Late Switch From Teriflunomide: Subgroup Analysis of the ALITHIOS Open-label Extension Study by Previous Disease-Modifying Therapy Exposure and Age (P6-3.016)

Early Reduction of MRI Activity During 6 Months of Treatment With Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis: MAGNIFY-MS.

Background and ObjectivesThe onset of action for high-efficacy immunotherapies in multiple sclerosis (MS) is an important parameter. This study (MAGNIFY-MS) evaluates the onset of action of cladribine tablets by observing changes in combined unique active (CUA) MRI lesion counts during the first 6 months of treatment in patients with highly active relapsing MS.MethodsMRI was performed at screening, baseline, and at months 1, 2, 3, and 6 after initiating treatment with cladribine tablets 3.5 mg/kg. CUA lesion counts, defined as the sum of T1 gadolinium-enhancing (Gd+) lesions and new or enlarging active T2 lesions (without T1 Gd+), were compared between postbaseline and the baseline period and standardized to the period length and the number of MRIs performed.ResultsIncluded in this analysis were 270 patients who received ≥1 dose of cladribine tablets. After treatment initiation, significant reductions in mean CUA lesion counts were observed from month 1 onward compared with the baseline period (−1.193 between month 1 and month 6, −1.500 between month 2 and month 6, and −1.692 between month 3 and month 6; all p < 0.0001). Mean T1 Gd+ lesion counts were decreased from month 2 onward compared with baseline (−0.857 at month 2, −1.355 at month 3, and −1.449 at month 6; all p < 0.0001), whereas the proportion of patients without any CUA lesions increased from 52.0% between month 1 and month 6 to 80.5% between month 3 and month 6.DiscussionFindings suggest an early onset of action for cladribine tablets, with an increasing reduction in active MRI lesions over time.Trial Registration InformationNCT03364036; Date registered: December 06, 2017.Classification of EvidenceUsing frequent MRI assessments of the brain over the first 6 months of the MAGNIFY-MS study (NCT03364036), we aimed to determine the onset of action of cladribine tablets 3.5 mg/kg in adult patients with highly active relapsing MS. This study provides Class IV evidence that, in such patients, treatment with cladribine tablets is associated with an early onset of action with reductions in active MRI lesion counts from month 2 (day 60) onward, with an increasing reduction in such lesions over time.

Siponimod vs placebo in active secondary progressive multiple sclerosis: a post hoc analysis from the phase 3 EXPAND study

BackgroundSiponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS.MethodsPost hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND. Endpoints: 3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline–month 24; number of new/enlarging (N/E) T2 lesions over all visits.ResultsData from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p < 0.01); there was no significant effect on T25FW. Siponimod increased likelihood of 6-month confirmed SDMT improvement vs placebo (by 62%; p = 0.007) and reduced risk of 6-month confirmed SDMT worsening (by 27%; p = 0.060). Siponimod was associated with less increase in T2LV (1316.3 vs 13.3 mm3; p < 0.0001), and fewer T1 Gd + and N/E T2 lesions than placebo (85% and 80% reductions, respectively; p < 0.0001).ConclusionsIn aSPMS, siponimod reduced risk of disability progression and was associated with benefits on cognition and MRI outcomes vs placebo.Trial registrationClinicalTrials.gov number: NCT01665144.

ANGI-1 Impact of neoadjuvant bevacizumab on transcriptional factor for stemness, macrophage polarization, and oxygenation of tumor microenvironment in glioblastoma

Background: Previously we reported that bevacizumab (Bev) produces tumor oxygenation with immunosupportive tumor microenvironment (TME) and inhibition of stemness. To confirm whether those effects might contribute prolongation of clinical outcome, in the present study paired samples from same patients with newly diagnosed GBM who received Bev during its effectiveness and refractoriness were investigated by immunohistochemistry. Methods: Eighteen samples from 9 patients with newly diagnosed GBM who received preoperative neoadjuvant Bev (neoBev) followed by surgical operation and chemoradiotherapy in addition to salvage surgery after recurrence were investigated. Expressions of FOXM1, HIF-1, and CD163 were evaluated by immunohistochemistry. Overall survial (OS) were analyzed with the present cohort divided into two groups between good and poor responder (GR and PR, respectively) of Bev defined as tumor regression rate judged by T1 gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) images. Results: In the group of good responder of T1Gd (T1Gd-GR; defined as >38% of regression rate after neoBev), OS was prolonged compared with T1Gd-PR along with inhibition of FOXM1 expression and HIF-1a. In contrast, in the group of good responder of FLAIR (FLAIR-GR; defined as >54% of regression rate after neoBev), there were no significant differences of OS and FOXM1 expression between GR and PR. HIF-1a expression tended to be elevated in T1Gd-PR of initial tumors, T1Gd-GR of recurrent tumors, and FLAIR-PR of both initial and recurrent tumors.Conclusion: T1Gd-GR after neoBev might attribute to inhibition of FOXM1 and oxygenation. Bev might provide tumor oxygenation, leading to inhibition of stemness and M2 TAM infiltration during its effectiveness. These results suggested that Bev combined with immunotherapy for newly diagnosed GBM might provide clinical benefits including inhibition of stemness and induction of immunosupportive TME, when tumor volume assessed by T1 Gd. was significantly decreased following neoBev.

Four-year safety and effectiveness data from patients with multiple sclerosis treated with fingolimod: The Spanish GILENYA registry.

ObjectiveTo describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry.MethodsAn observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve.ResultsSix hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p<0.001). This significant reduction in the ARR continued to be observed in all subgroups. After 4 years, the EDSS showed a minimal deterioration, with the EDSS scores from year 1 to year 4 remaining mostly stable. The percentage of patients without T1 Gd+ lesions progressively increased from 45.6% during the year prior to fingolimod initiation to 88.2% at year 4. The proportion of patients free from new/enlarged T2 lesions after 4 years of fingolimod treatment was 80.3%. This trend in both radiological measures was also observed in the subgroups. Adverse events (AEs) were experienced by up to 41.6% of patients (most commonly: lymphopenia [12.5%] and urinary tract infection [3.7%]). Most AEs were mild in severity, 3.6% of patients had serious AEs.ConclusionsThe patient profile was similar to other observational studies. The results obtained from the long-term use of fingolimod showed that it was effective, regardless of prior DMT, and it had adequate safety results, with a positive benefit-risk balance.

Cladribine tablets versus other disease-modifying oral drugs in achieving no evidence of disease activity (NEDA) in multiple sclerosis–A systematic review and network meta-analysis

IntroductionAssuming full control of the relapsing-remitting multiple sclerosis (RRMS) is the main target for practitioners. Disease control could be defined as no clinical relapse, absence of 3-month confirmed disability progression expressed on the Expanded Disability Status Scale (EDSS), as well as no disease activity on magnetic resonance imaging (MRI). NEDA-3 (no evidence of disease activity) is a composite endpoint used primarily in clinical trials, comprising these 3 measurements of disease activity. The aim of this study is to compare cladribine tablets (CT) with oral disease-modifying drugs (DMDs) – fingolimod (FTY), dimethyl fumarate (DMF), and teriflunomide (TERI) – with regard to NEDA-3 and its clinical (relapse and disability progression) and MRI (no new T1 Gd+ lesions or no new T2 lesions or no enlargement of existing lesions) components occurrence during a 24-month follow-up. MethodsIn June 2018, a systematic review of MEDLINE, Embase and Cochrane database was performed. Due to the lack of head-to-head trials directly comparing cladribine tablets to oral drugs of interest, an indirect network meta-analysis (NMA) was applied, with placebo as a common comparator. NMA was performed with Bayesian approach and Markov chain Monte Carlo (MCMC) method for estimating posterior distributions. Additional data used in the analysis were taken from conference abstracts or post hoc analyses of pooled data from the clinical studies. ResultsSix randomised clinical trials (RCTs) presenting NEDA, with active treatment compared to placebo, were included in the NMA: CLARITY (CT), FREEDOMS and FREEDOMS II (FTY), CONFIRM and DEFINE (DMF) and TEMSO (TERI). The rate of NEDA-3 was significantly higher in cladribine tablets vs DMF: OR (odds ratio)=1.76 (95% CrI [credible intervals]: 1.02–3.03) and TERI: OR=2.78 (95% CrI: 1.60–4.83), but not vs FTY. For the MRI NEDA results were as follows – cladribine tablets vs DMF: OR=1.87 (95% CrI: 1.18–2.97); cladribine tablets vs TERI: OR=6.59 (95% CrI: 4.32–10.09); cladribine tablets vs FTY: OR=1.58 (95% CrI: 1.10–2.29). The comparison of clinical NEDA did not reach significance vs either DMF or TERI and evaluation vs FTY was not possible because of lack of data. ConclusionsCladribine in the form of tablets was significantly more effective in achieving NEDA-3 than DMF and TERI, but there was no significant difference vs FTY. Cladribine tablets was more effective than all oral comparators considering the MRI NEDA. For clinical NEDA, the superiority vs DMF and vs TERI was not confirmed, and vs FTY evaluation was not possible.

Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

BackgroundIn the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE).ObjectiveTo determine the timing of effects of cladribine tablets on lesion activity assessed by magnetic resonance imaging (MRI).MethodsThis post hoc analysis assessed the effect of cladribine tablets versus placebo in ORACLE-MS on secondary MRI endpoints including T1 gadolinium-enhancing (Gd+), new or enlarging T2 lesions, and combined unique active lesions assessed on MRI scans performed at screening and every 3 months thereafter.ResultsCompared to placebo, cladribine tablets 3.5 mg/kg treatment appeared to lead to a trend of reductions in the mean number of T1 Gd+ lesions by Week 13 (first post-baseline scan: 0.37 vs. 1.00), new or enlarging T2 (0.20 vs. 1.01) and combined unique active (0.29 vs. 1.91) lesions by Week 24. Low lesion counts were maintained with cladribine tablets throughout 96 weeks. Similar results were observed with the 5.25 mg/kg dosage.ConclusionIn participants with an FCDE, cladribine tablets appeared to reduce lesion numbers within 13 weeks (time of first evaluation).

Subgroup analysis of clinical and MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study

BackgroundIn the Phase 3, 96-week ORACLE-MS study, cladribine 10 mg tablets (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly reduced the rate of conversion to clinically definite multiple sclerosis (CDMS) per the Poser criteria (henceforth referred to as CDMS), multiple sclerosis (MS) per the 2005 McDonald criteria, and the number of new or persisting T1 gadolinium-enhancing (Gd+), new or enlarging T2, and combined unique active (CUA) lesions versus placebo in participants with a first clinical demyelinating event (FCDE). Patient demographic and disease characteristics may be predictors of disease progression. The current study analyzed the effect of cladribine tablets in subgroups of participants in the ORACLE-MS study by baseline demographics and disease characteristics. MethodsThis analysis retrospectively examined data collected from 616 participants enrolled in the ORACLE-MS study (placebo, n=206; cladribine tablets 3.5 mg/kg, n=206; cladribine tablets 5.25 mg/kg, n=204). Five subgroups were predetermined by baseline demographics, including sex, age (<30 or ≥30 years), classification of FCDE, and lesion characteristics, including absence or presence of T1 Gd+ lesions and number of T2 lesions (<9 or ≥9). Selected endpoints of the ORACLE-MS study were re-analyzed for these subgroups. The primary and main secondary endpoints were time to conversion to CDMS and MS (2005 McDonald criteria), respectively. Secondary magnetic resonance imaging (MRI) endpoints included cumulative T1 Gd+ and new or enlarging T2 lesions. Cox proportional hazards models were used to evaluate time to conversion to CDMS and MS (2005 McDonald criteria). This analysis focused primarily on the results for the cladribine tablets 3.5 mg/kg group because this dosage is approved for relapsing forms of MS. ResultsIn the overall intent-to-treat (ITT) population, cladribine tablets 3.5 mg/kg significantly reduced the risk of conversion to CDMS (hazard ratio [HR]=0.326; P<0.0001) and MS (2005 McDonald criteria; HR=0.485; P<0.0001) versus placebo. Similar effects of cladribine tablets on risk of conversion were observed in post hoc analyses of subgroups defined by various baseline characteristics. In both the ITT population and across subgroups, cladribine tablets 3.5 mg/kg reduced the numbers of cumulative T1 Gd+ (range of rate ratios: 0.106–0.399), new or enlarging T2 (range of rate ratios: 0.178–0.485), and CUA (range of rate ratios: 0.154–0.384) lesions versus placebo (all nominal P<0.03). Multivariate Cox proportional hazards models revealed that age (HR=0.577, nominal P<0.0001), FCDE classification (HR=0.738, nominal P=0.0043), presence of T1 Gd+ lesions (HR=0.554, nominal P<0.0001), and number of T2 lesions (HR=0.417, nominal P<0.0001) at baseline were factors associated with risk of conversion to MS (2005 McDonald criteria), whereas no baseline factors examined were associated with risk of conversion to CDMS. ConclusionIn this post hoc analysis of the ORACLE-MS study, cladribine tablets reduced the risk of conversion to multiple sclerosis and lesion burden in participants with an FCDE in the overall ITT population and multiple subgroups defined by baseline demographics and lesion characteristics.

Natalizumab versus fingolimod for patients with active relapsing-remitting multiple sclerosis: results from REVEAL, a prospective, randomised head-to-head study

ObjectiveTo directly compare the efficacy of natalizumab and fingolimod in patients with active relapsing-remitting multiple sclerosis.MethodsThis phase 4, randomised, rater- and sponsor-blinded, prospective, parallel-group, clinic-based head-to-head study was conducted at...

Detection of Coalescent Acute Mastoiditis on MRI in Comparison with CT

PurposeCurrent imaging standard for acute mastoiditis (AM) is contrast-enhanced computed tomography (CT), revealing inflammation-induced bone destruction, whereas magnetic resonance imaging (MRI) outperforms CT in detecting intracranial infection. Our aim was to compare the diagnostic performance of MRI with CT in detecting coalescent AM and see to which extent MRI alone would suffice to diagnose or rule out this condition.MethodsThe MR images of 32 patients with AM were retrospectively analyzed. Bone destruction was evaluated from T2 turbo spin echo (TSE) and T1 Gd magnetization-prepared rapid acquisition with gradient echo (MPRAGE) images. Intramastoid enhancement and diffusion restriction were evaluated subjectively and intramastoid apparent diffusion coefficient (ADC) values were measured. The MRI findings were compared with contrast-enhanced CT findings of the same patients within 48 h of the MR scan.ResultsDepending on the anatomical subsite, MRI detected definite bone defects with a sensitivity of 100% and a specificity of 54–82%. Exception was the inner cortical table where sensitivity was only 14% and specificity was 76%. Sensitivity for general coalescent mastoiditis remained 100% due to multiple coexisting lesions. The absence of intense enhancement and non-restricted diffusion had a high negative predictive value for coalescent mastoiditis: an intramastoid ADC above 1.2 × 10−3 mm2/s excluded coalescent mastoiditis with a negative predictive value of 92%.ConclusionThe MRI did not miss coalescent mastoiditis but was inferior to CT in direct estimation of bone defects. When enhancement and diffusion characteristics are also considered, MRI enables dividing patients into low, intermediate and high-risk categories with respect to coalescent mastoiditis, where only the intermediate risk group is likely to benefit from additional CT.

Efficacy and Safety of the Bruton's Tyrosine Kinase Inhibitor Evobrutinib in Patients with Relapsing Multiple Sclerosis Over 48 Weeks: A Randomized, Placebo-Controlled, Phase 2 Study

Evobrutinib (M2951) is a highly selective oral inhibitor of Bruton's tyrosine kinase, a key regulator of B cell and myeloid cell functions implicated in multiple sclerosis (MS). This was a Phase 2 study to compare evobrutinib with placebo in relapsing MS (RMS). In this double-blind study (NCT02975349), adults with RMS were randomized to evobrutinib 25 mg once-daily (QD), 75 mg QD, 75 mg twice-daily (BID), open-label dimethyl fumarate (240 mg BID; reference), or placebo for 48 weeks. Placebo-treated patients were switched to evobrutinib 25 mg QD after 24 weeks. Primary endpoint: total number of T1 gadolinium enhancing (T1 Gd+) lesions over Weeks 12–24. Secondary endpoints included annualized relapse rate (ARR), magnetic resonance imaging measures, and safety. The study received full patient and Institutional Review Board approval. Of 267 randomized patients, 227 (85.0%) completed 48 weeks. Evobrutinib 75 mg QD and BID significantly reduced the total number of T1 Gd+ lesions over Weeks 12–24 versus placebo (primary endpoint; Table). There was no evidence of change in effect on T1 Gd+ lesions (mean±SD; Wilcoxon signed-rank test) between Weeks 24 and 48 with evobrutinib 75 mg BID (0.24±0.88 to 0.49±1.22; p=0.23) or evobrutinib 75 mg QD (0.28±0.91 to 0.85±2.87; p=0.57). ARR (unadjusted [95% confidence interval]) over 48 weeks was 0.25 (0.12–0.44) for evobrutinib 75 mg QD, 0.11 (0.04–0.25) for 75 mg BID, and 0.37 (0.21–0.59) for placebo (Table). All evobrutinib doses appeared well-tolerated. Transaminase elevations were predominantly mild; some Grade 3–4 events were observed; all had their onset within the first 24 weeks; transaminase elevations were asymptomatic and reversible on evobrutinib withdrawal. To our knowledge, evobrutinib is the first BTK inhibitor to demonstrate disease activity reduction in MS. The observed benefit-risk profile of evobrutinib in this Phase 2 study supports further clinical development in RMS.

Evaluation of combination of multiple MRI sequences in the differential diagnosis of esophagus cancer

Objective To evaluate the role of combination of multiple MRI sequences in the differential diagnosis of esophagus cancer and to assess the accordance among radiologists with different experience. Methods Thirty-fifty patients underwent conventional MRI including T2 weighted (T2) sequences, gadolinium fat-suppressed T1 weighted sequences (post-contrast T1), and DWI sequences. Three radiologists with different experience determined the possibility of local recurrence (LR) on T2, T2+post-contrast T1, T2+DWI, and T2+post-contrast T1+DWI. ROC and Kappa were used. Results In total, 13 patients had LR. On T2WI, the ROC curve (AUC) achieved by the senior,intermediate and junior groups were 0.701,0.407,and 0.584, respectively.Compared with simple T2WI sequences, DWI and T1 Gd significantly improved the AUC value for the intermediate radiologist. The great difference was observed between radiologists of different experience (Kappa coefficient was from 0.227 to 0.884). Combination of multiple sequences significantly reduced the diagnostic differences between radiologists with different experience for the senior radiologists particularly. Conclusions The addition of DWI and T1 post-contrast MRI increased diagnostic ability for LR of esophagus cancer and reduced the diagnostic differences between radiologists with different experience compared to T2WI. Key words: Esophagus neoplasms; Magnetic resonance imaging; Diffusion-weighted imaging

Efficacy of cladribine tablets 3.5 mg/kg in patients with relapsing multiple sclerosis aged above and below 45 years; clarity and clarity extension

In CLARITY, cladribine tablets 10 mg, (cumulative dose 3.5 mg/kg [CT3.5] over 2 years [yrs]) were efficacious versus placebo in patients with relapsing multiple sclerosis (RMS). This was maintained without further treatment in CLARITY Extension. The effect of CT3.5 was evaluated in patients with RMS aged >45 and ≤ 45 yrs. CT3.5 and placebo treatment groups of CLARITY were stratified according to age (≤45 and > 45 yrs). Efficacy endpoints were qualifying relapse, all relapses, and MRI parameters. Equivalent analyses were conducted for patients who received CT3.5 in CLARITY and placebo in CLARITY Extension. In CLARITY, 649 patients were ≤ 45 yrs. (CT3.5 N = 330; mean age 34 yrs) and 221 were > 45 yrs. (CT3.5 N = 103; mean age 52 yrs). Annualised qualifying relapse rate (ARR) comparison at Week 96 showed that CT3.5 was associated with significant relative risk reduction versus placebo in both age groups. ‘All relapse’ data were comparable for the same age groups, respectively. Numbers of cumulative new T1 Gd + lesions at Week 96 were reduced with CT3.5 compared to placebo in both age groups. Mean numbers of active T2 lesions per patient per scan at Week 96 were also significantly reduced with CT3.5 versus placebo in both age groups (≤45 yrs.: −0.667 [95%CI −0.67, −0.50], p < .0001; >45 yrs.: -0.167 [95%CI -0.33, 0.00], p < .0001), as were mean numbers of CU lesions. CLARITY Extension: mean numbers of qualifying relapses in patients ≤45 yrs. (N = 76) and > 45 yrs. (N = 22) were 0.30 and 0.09, respectively. CT3.5 reduced relapse and MRI lesion frequency in patients aged ≤45 yrs. and > 45 yrs.

088 Cladribine tablets were associated with rapid onset of improvements in MRI outcomes in the ORACLE-MS trial

IntroductionIn ORACLE-MS (616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis), cladribine tablets (CT) 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly delayed the time-to-conversion to clinically definite multiple sclerosis (CDMS), and reduced new/persisting T1 gadolinium-enhancing (T1 Gd+), new/enlarged or active T2 and combined unique active (CUA) lesion number. Here, the timing of CT effect is evaluated.MethodsMRI scans were performed at screening and every 12 weeks, for non-converting CDMS subjects. MRI-based endpoints were analyzed using analysis of covariance (ANCOVA) and negative binomial models. The temporal effects of the first yearly treatment course of CT and placebo on T1 Gd+, active T2, and CUA lesions were evaluated.Results96 weeks: the reduction in mean T1 Gd+, active T2, or CUA lesion number per patient per scan was nominally significantly greater for CT versus placebo (p&lt;0.0001). Early change in Gd+ lesion volume (at Week 13) from baseline was CT, -155.73 mm3; placebo, -14.76 mm3. Comparatively larger reductions in mean active T2 and CUA lesion numbers with CT at Week 13 versus placebo were observed (active T2: CT, -1.25; placebo, -1.43; CUA: CT, -1.56; placebo, -2.41). The mean number of T1 Gd+ lesions at 13 weeks following CT was 0.37 versus 1.0 with placebo.ConclusionsMRI data from ORACLE-MS subjects suggest the first yearly treatment course of CT has a rapid onset of action, with beneficial treatment effects on active lesion number and volume evident by Week 13.

090 The effect of cladribine tablets on delaying the time to conversion to clinically definite multiple sclerosis (MS) or McDonald MS is consistent across subgroups in the ORACLE-MS study

IntroductionIn the Phase 3 ORACLE-MS trial in 616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis (MS), treatment with cladribine tablets 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years [CT3.5 and CT5.25, respectively]) significantly delayed time to conversion to clinically definite multiple sclerosis (CDMS) according to Poser criteria (67% or 62% risk reduction [RR], respectively) and time to conversion to 2005 McDonald MS (50% or 57% RR, respectively), versus placebo. The objective was to analyze the effect of cladribine tablets vs placebo on converstion to CDMS and McDonald MS across ORACLE-MS patient subgroups based on baseline characteristics.MethodsIn this post-hoc analysis, time-to-conversion to CDMS or McDonald MS over the double-blind period was analyzed for patients treated with CT5.25 (N=204), CT3.5 (N=206) or placebo (N=206) across different subgroups. Subgroups were defined by baseline characteristics which have been investigated as potential predictors of CDMS conversion (age [&lt;30 or ≥30 years], gender, first classification demyelinating event [monofocal or multifocal], presence of T1 Gd+ lesions and number of T2 lesions [&lt;9 or ≥9]).ResultsTreatment with CT3.5 or CT5.25 was consistently efficacious across the subgroups examined on conversion to CDMS versus placebo for most comparisons (RR range: CT3.5, 39%–72%; CT5.25, 36%–79%). Similarly, treatment effect of both doses on conversion to 2005 McDonald MS was consistent across subgroups (CT3.5,40%–59%;CT5.25,42%–79%).ConclusionsThe effect of cladribine tablets on delaying the time-to-conversion to CDMS, or to McDonald MS, is consistent across subgroups.

Effectiveness of Vitamin D Supplementation in the Management of Multiple Sclerosis: A Systematic Review.

Objective: to examine the extent of effect vitamin D in Multiple Sclerosis (MS) on pathology and symptoms. Methods: A literature search was performed in November 2018 (CRD42018103615). Eligibility criteria: randomised control trials in English from 2012 to 2018; a clinical diagnosis of MS; interventions containing vitamin D supplementation (vitamin D3 or calcitriol) in disease activity compared to a control/placebo; improvement in: serum 25(OH)D, relapse rates, disability status by Expanded Disability Status Scale (EDSS) scores, cytokine profile, quality of life, mobility, T2 lesion load and new T2 or T1 Gd enhancing lesions, safety and adverse effects. Risk of bias was evaluated. Results: Ten studies were selected. The study size ranged from 40 to 94 people. All studies evaluated the use of vitamin D supplementation (ranging from 10 to 98,000 IU), comparing to a placebo or low dose vitamin D. The duration of the intervention ranged from 12 to 96 weeks. One trial found a significant effect on EDSS score, three demonstrated a significant change in serum cytokines level, one found benefits to current enhancing lesions and three studies evaluating the safety and tolerability of vitamin D reported no serious adverse events. Disease measures improved to a greater extent overall in those with lower baseline serum 25(OH)D levels. Conclusions: As shown in 3 out of 10 studies, improvement in disease measures may be more apparent in those with lower baseline vitamin D levels.

One-pot embedding of iron oxides and Gd(III) complexes into silica nanoparticles—Morphology and aggregation effects on MRI dual contrasting ability

The present work introduces one-pot synthetic route to join ultra-small iron oxides (6 nm) with Gd(III) complexes in small (∼30 nm) silica nanoparticles with high longitudinal and transverse relaxivity values (r1 = 34.7 mM−1 s−1 and r2 = 64.7 mM−1 s−1 at 0.47 T). The design of the nanoparticles is based on the core-shell morphology, where the Gd(III) complexes were doped into the exterior silica layer. The doping mode is the reason for an efficient interfacial hydration and the small suppressing of r1 by iron oxides. The measurements on the whole body scanner at 1.5 T confirm the high contrasting abilities of T1 (Gd) and T2 (iron oxide) components in the nanoparticles. Poor aggregation behavior of the nanoparticles in water is due to high electrokinetic potential value (−78 mV). Greater aggregation of the nanoparticles in the buffer solutions of bovine serum albumin enhances the disturbing effect of iron oxides on the longitudinal relaxation and facilitates the transverse relaxation. The higher surface activity of the nanoparticles results in their greater cytotoxicity versus the silica coated iron oxides, although the cytotoxicity is low in the concentration range which is within the region of interest for MRI technique.

Predictive value of early magnetic resonance imaging measures is differentially affected by the dose of interferon beta-1a given subcutaneously three times a week: an exploratory analysis of the PRISMS study

BackgroundOn-treatment magnetic resonance imaging lesions may predict long-term clinical outcomes in patients receiving interferon β-1a. This study aimed to assess the effect of active T2 and T1 gadolinium-enhancing (Gd+) lesions on relapses and 3-month confirmed Expanded Disability Status Scale (EDSS) progression in the PRISMS clinical trial.MethodsExploratory analyses assessed whether active T2 and T1 Gd + lesions at Month 6, or active T2 lesions at Month 12, predicted clinical outcomes over 4 years in PRISMS.ResultsMean active T2 lesion number at Month 6 was significantly lower with interferon beta-1a given subcutaneously (IFN β-1a SC) 44 μg and 22 μg 3×/week (tiw) than with placebo (p < 0.0001). The presence of ≥4 versus 0 active T2 lesions predicted disability progression at Years 3–4 in the IFN β-1a SC 22 μg group only (p < 0.05), whereas the presence of ≥2 versus 0–1 active T2 lesions predicted disability progression in the placebo/delayed treatment (DTx) (Years 2–4; p < 0.05) and IFN β-1a SC 22 μg groups (Years 3–4; p < 0.05). Greater active T2 lesion number at 6 months predicted relapses in the placebo/DTx group only (≥4 vs. 0, Years 1–4; ≥2 vs. 0–1, Years 2–4; p < 0.05), and the presence of T1 Gd + lesions at 6 months predicted disability progression in the IFN β-1a SC 44 μg group only (Year 1; p < 0.05). The presence of ≥2 versus 0–1 active T2 lesions at 12 months predicted disability progression over 3 and 4 years in the IFN β-1a SC 44 μg group.ConclusionActive T2 lesions at 6 months predicted clinical outcomes in patients receiving placebo or IFN β-1a SC 22 μg, but not in those receiving IFN β-1a SC 44 μg. Active T2 lesions at 12 months may predict outcomes in those receiving IFN β-1a SC 44 μg and are possibly more suggestive of poor response to therapy than T2 results at 6 months.