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

The Use of Biomaterials in Islet Transplantation

Pancreatic islet transplantation is a therapeutic option to replace destroyed β cells in autoimmune diabetes. Islets are transplanted into the liver via the portal vein; however, inflammation, the required immunosuppression, and lack of vasculature decrease early islet viability and function. Therefore, the use of accessory therapy and biomaterials to protect islets and improve islet function has definite therapeutic potential. Here we review the application of niche accessory cells and factors, as well as the use of biomaterials as carriers or capsules, for pancreatic islet transplantation

Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study

International audienceOBJECTIVE: The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of fingolimod 0.5 or 1.25 mg over interferon β-1a (IFNβ-1a) in patients with relapsing-remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. METHODS: Patients randomised to fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-fingolimod) in the extension, whereas those on IFNβ-1a were re-randomised (1:1) to fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous-fingolimod 0.5 mg and pooled IFN-switch groups. RESULTS: Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0-EOS: 0.17 vs 0.27). After switching to fingolimod (M0-12 vs M13-EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. CONCLUSIONS: These results support a continued effect of long-term fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNβ-1a to fingolimod. CLINICAL TRIAL REGISTRATION NO: NCT00340834

Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study.

BackgroundOzanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5.ObjectiveEvaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis.MethodsIn the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-daily ozanimod hydrochloride (0.5 or 1 mg) or placebo. After 24 weeks, participants could enter a 2-year, dose-blinded extension. Ozanimod-treated participants continued their assigned dose; placebo participants were re-randomized (1:1) to ozanimod hydrochloride 0.5 or 1 mg (equivalent to ozanimod 0.46 and 0.92 mg).ResultsA total of 223 (89.6%) of the 249 participants completed the blinded extension. At 2 years of the extension, the percentage of participants who were gadolinium-enhancing lesion-free ranged from 86.5% to 94.6%. Unadjusted annualized relapse rate during the blinded extension (week 24-end of treatment) was 0.32 for ozanimod hydrochloride 0.5 mg → ozanimod hydrochloride 0.5 mg, 0.18 for ozanimod hydrochloride 1 mg → ozanimod hydrochloride 1 mg, 0.30 for placebo → ozanimod hydrochloride 0.5 mg, and 0.18 for placebo → ozanimod hydrochloride 1 mg. No second-degree or higher atrioventricular block or serious opportunistic infection was reported.ConclusionOzanimod demonstrated sustained efficacy in participants continuing treatment up to 2 years and reached similar efficacy in participants who switched from placebo; no unexpected safety signals emerged

Unraveling the carbohydrate count in the treatment of diabetes mellitus.

O diabetes mellitus é uma condição crônica que requer gerenciamento continuo, trata-se de um grupo heterogêneo de distúrbios metabólicos que apresenta em comum a hiperglicemia. A terapia nutricional é um dos componentes fundamentais da abordagem terapêutica do diabetes, em virtude disso no contexto de alimentação saudável a contagem de carboidratos torna-se uma estratégia chave para o tratamento da doença. Logo, neste estudo objetivou-se realizar uma revisão de literatura com os principais pontos relacionados ao diabetes a fim de compreender a repercussão da contagem de carboidratos como dietoterapia, analisando e fornecendo informações a respeito destas repercussões. Foram pesquisados artigos por meio de bancos de dados PUBMED, LILACS-BIREME e SCIELO, com o fim de realizar uma leitura criteriosa e objetiva do material que serviu de base para análise da relação entre contagem de carboidratos como estratégia para o tratamento do diabetes mellitus. A alimentação do paciente diabético demanda bastante atenção, por ser um aspecto conflitante para o indivíduo e para a sua família. O método de contagem pode ser amplamente utilizado por todos os tipos de diabetes, é uma estratégia de planejamento alimentar com foco nos carboidratos, por este ser o principal nutriente a afetar a resposta glicêmica pós prandial, além de ser um método que proporciona inserção social e que respeita as necessidades nutricionais e hábitos alimentares do indivíduo com diabetes. Com isso qualquer indivíduo com diabetes pode utilizar contagem de carboidrato como um plano de refeição.Diabetes mellitus is a chronic condition that requires ongoing management. It is a heterogeneous group of metabolic disorders, which presents, in common, the hyperglycemia. Nutritional therapy is one of the fundamental components of the therapeutic approach to diabetes. Thus, in the healthy eating context, carbohydrate counting becomes a key strategy for the treatment of diabetes. Therefore, this study aimed to conduct a literature review with the main points related to diabetes in order to understand the impact of carbohydrate counting and diet therapy, analyzing and providing information about these repercussions. Articles from the databases PUBMED, LILACS-BIREME and SCIELO were collected in order to conduct a careful and objective reading of the material that formed the basis for the analysis of the relationship between carbohydrate counting and diabetes mellitus. The diet of the diabetic patient demands close attention, because it is a conflicting issue for the individual and his family. The counting method can be widely used by all types of diabetes, being also a meal planning strategy focused on carbohydrate, which is the main nutrient that affects the postprandial glycemic response. In addition, the counting method provides social integration, and respects the nutritional needs and eating habits of the individual with diabetes. With that anyone with diabetes can use carbohydrate counting as a meal plan

Rapid rates of magma generation at contemporaneous magma systems, Taupo Volcano, New Zealand: insights from U-Th model-age spectra in zircons

New and/or enlarged datasets of U–Th disequilibrium model ages from secondary ionization mass spectrometry (SIMS) analyses of zircons in eight eruptive units from the area of Taupo volcano, New Zealand, highlight the behavioural contrasts of two closely adjacent, contemporaneous but independent magma chambers. One yielded closely similar crystal-poor (‘Oruanui-type’) rhyolites, sampled in three small precursor eruptions (Tihoi, ‘New plinian’, Okaia) from ∼45 to 30 ka, then the major 27 ka Oruanui eruption. Three of the four eruptions had vents within the modern Lake Taupo, whereas the fourth (‘New plinian’) was sourced ∼20 km NNE of the other vents, fed by lateral magma migration. Samples from all four eruptions share a common model-age peak at ∼95 ka of antecrystic zircons. However, three of the four differ in younger pre-eruptive model-age peaks that require their parental melt-dominant bodies to have been physically extracted independently from a common mush zone represented by the ∼95 ka peak. A sample from a fifth eruption (‘New phreatoplinian’, also at ∼45 ka) shares an older 80–100 ka peak but has numerous older grains and distinctly contrasting Sr-isotopic characteristics to the ‘Oruanui-type’ magmas. The 530 km3 Oruanui melt-dominant body was produced in at most ∼3000 years as shown by differences in zircon model-age spectra and average ages between it and the 30 ka Okaia eruption, despite their coincidence in vent locations. The second suite of eruptions at ∼47, 28 and 16 ka ejected moderately crystal-rich biotite rhyolites from a second source chamber, which vented over a 15 km wide area NE of Taupo (overlapping with Maroa volcano). This second chamber is inferred to have comparable horizontal dimensions to the vent spacing. The three biotite rhyolites show unimodal model-age spectra that peak at 30, 15–25 and 6 kyr prior to each eruption, respectively, and underwent single cycles of melt generation and eruption with no recycling of significantly older antecrysts or xenocrysts ( 5 m3/s (Oruanui) and effectively drained the mush of melt in doing so (Oruanui vs post-Oruanui activity), probably mediated by active rifting processes and tectonic disruption of the mush pile. Comparisons of ‘magma residence times’ and discussion of the growth histories of large silicic chambers represented by volcanic or plutonic rocks are self-limited by the uncertainties in the respective SIMS analyses. Growth times of Miocene and older plutons dated by SIMS U–Pb techniques are comparable with the 2 Myr lifetime of the whole Taupo Volcanic Zone, and the associated 1σ SIMS analytical uncertainties exceed the lifetime of a volcano such as Taupo. Subtle details that indicate the rapidity of magma accumulation and recycling of crystals in the young Taupo system cannot be discerned in most pre-300 ka silicic systems. Averaging of SIMS model-age data further obscures subtle details that would allow discrimination of newly crystallized versus recycled zircons. Discussions of volcano–plutonic relationships and accumulation rates for large silicic melt-dominant bodies cannot rely on age data in isolation, but require knowledge of the stratigraphic and compositional settings