Predicting long-term disability outcomes in patients with MS treated with teriflunomide in TEMSO

To predict long-term disability outcomes in TEMSO core (NCT00134563) and extension (NCT00803049) studies in patients with relapsing forms of MS treated with teriflunomide. Methods: A post hoc analysis was conducted in a subgroup of patients who received teriflunomide in the core study, had MRI and clinical relapse assessments at months 12 (n = 552) and 18, and entered the extension. Patients were allocated risk scores for disability worsening (DW) after 1 year of teriflunomide treatment: 0 = low risk; 1 = intermediate risk; and 2-3 = high risk, based on the occurrence of relapses (0 to 652) and/or active (new and enlarging) T 2 -weighted (T 2 w) lesions ( 643 or >3) after the 1-year MRI. Patients in the intermediate-risk group were reclassified as responders or nonresponders (low or high risk) according to relapses and T 2 w lesions on the 18-month MRI. Long-term risk (7 years) of DW was assessed by Kaplan-Meier survival curves. Results: In patients with a score of 2-3, the risk of 12-week-confirmed DW over 7 years was significantly higher vs those with a score of 0 (hazard ratio [HR] = 1.96, p = 0.0044). Patients reclassified as high risk at month 18 (18.6%) had a significantly higher risk of DW vs those in the low-risk group (81.4%; HR = 1.92; p = 0.0004). Conclusions: Over 80% of patients receiving teriflunomide were classified as low risk (responders) and had a significantly lower risk of DW than those at increased risk (nonresponders) over 7 years of follow-up in TEMSO. Close monitoring of relapses and active T 2 w lesions after short-term teriflunomide treatment predicts a differential rate of subsequent DW long term. ClinicalTrials.gov identifier: TEMSO, NCT00134563; TEMSO extension, NCT0080304

Predicting long-term disability outcomes in patients with MS treated with teriflunomide in TEMSO

To predict long-term disability outcomes in TEMSO core (NCT00134563) and extension (NCT00803049) studies in patients with relapsing forms of MS treated with teriflunomide. Methods: A post hoc analysis was conducted in a subgroup of patients who received teriflunomide in the core study, had MRI and clinical relapse assessments at months 12 (n = 552) and 18, and entered the extension. Patients were allocated risk scores for disability worsening (DW) after 1 year of teriflunomide treatment: 0 = low risk; 1 = intermediate risk; and 2-3 = high risk, based on the occurrence of relapses (0 to â¥2) and/or active (new and enlarging) T 2 -weighted (T 2 w) lesions (â¤3 or >3) after the 1-year MRI. Patients in the intermediate-risk group were reclassified as responders or nonresponders (low or high risk) according to relapses and T 2 w lesions on the 18-month MRI. Long-term risk (7 years) of DW was assessed by Kaplan-Meier survival curves. Results: In patients with a score of 2-3, the risk of 12-week-confirmed DW over 7 years was significantly higher vs those with a score of 0 (hazard ratio [HR] = 1.96, p = 0.0044). Patients reclassified as high risk at month 18 (18.6%) had a significantly higher risk of DW vs those in the low-risk group (81.4%; HR = 1.92; p = 0.0004). Conclusions: Over 80% of patients receiving teriflunomide were classified as low risk (responders) and had a significantly lower risk of DW than those at increased risk (nonresponders) over 7 years of follow-up in TEMSO. Close monitoring of relapses and active T 2 w lesions after short-term teriflunomide treatment predicts a differential rate of subsequent DW long term. ClinicalTrials.gov identifier: TEMSO, NCT00134563; TEMSO extension, NCT00803049

Interleukin-6 receptor blockade or TNFa inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials

Background: Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. Methods: Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ? 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes. Results: Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity tan patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was ? 0.28 (? 0.40, ? 0.16; nominal p < 0.0001) and ? 0.42 (? 0.54, ? 0.31; nominal p < 0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40mg at week 24 was ? 0.13 (? 0.22, ? 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ? 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA. Conclusions: In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings. Trial registration: ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date ofregistration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015. Arthritis Research & Therapy (2020) 22:20

Long-term safety and efficacy of teriflunomide : nine-year follow-up of the randomized TEMSO study

This study was funded by Sanofi Genzyme.OBJECTIVE: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). METHODS: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. RESULTS: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score ≤2.5; probability of 12-week disability progression ≤0.48). CONCLUSIONS: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.Publisher PDFPeer reviewe

Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings.

OBJECTIVE: To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy. METHODS: In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed. RESULTS: Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3-5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1-5: -0.48%, -0.22%, -0.10%, -0.19%, -0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter. CONCLUSIONS: Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years

Schätzung von Quantilen basierend auf dem zentralen Grenzwertsatz in der fast sicheren Version

Eines der grundlegenden Probleme der angewandten statistischen Entscheidungstheorie besteht in der Schätzung von Quantilen unbekannter Verteilungen. Das Hauptziel dieser Dissertation ist, eine neue Schätzmethode für Quantile vorzustellen, die auf der fast sicheren Version des zentralen Grenzwertsatzes (FSZGWS) basiert. Die Abhandlung formuliert und beweist den FSZGWS für eine allgemeine Klasse von Statistiken, nämlich Rang-Statistiken. Verschiedene, auf dem FSZGWS basierende Methoden des Testen von Hypothesen werden vorgestellt; zwei dieser Methoden werden an Hand von Simulationsstudien eingehend analysiert. Dabei werden die FSZGWS-Tests mit bekannten Testverfahren verglichen, und es wird eine höhere Güte der neuen Verfahren nachgewiesen. Insbesondere parametrische und nichtparametrischen Behrens-Fisher-Probleme werden in diesem Zusammenhang ausführlich untersucht

Comparative effectiveness of teriflunomide and dimethyl fumarate in patients with relapsing forms of MS in the retrospective real-world Teri-RADAR study.

AIM: Head-to-head clinical trials of teriflunomide (TFM) versus dimethyl fumarate (DMF) have not been conducted. OBJECTIVES: To compare the real-world effectiveness of TFM versus DMF. METHODS: Anonymized data were collected from patients with relapsing MS initiating treatment with teriflunomide (N = 50) or DMF (N = 50). RESULTS: On follow-up magnetic resonance imaging (MRI) compared with baseline, with TFM versus DMF treatment, the proportion of patients with new/enlarging T2 or gadolinium-enhancing lesions was 30.0 versus 40.0% (p = 0.2752). However, median annualized percent whole brain volume change was -0.1 versus -0.5 (p = 0.0212). There were no significant treatment differences on additional MRI and clinical end points and no unexpected safety signals. CONCLUSION: The effectiveness of teriflunomide was superior to DMF on whole brain atrophy and similar to DMF on other MRI/clinical end points