Early MRI results and odds of attaining 'no evidence of disease activity' status in MS patients treated with interferon β-1a in the EVIDENCE study

Abstract Introduction 'No evidence of disease activity' (NEDA) is increasingly used as a treatment target with disease-modifying drugs for relapsing multiple sclerosis. Methods This post-hoc analysis of the randomised EVIDENCE trial compared interferon beta-1a injected subcutaneously three times weekly (IFN β-1a SC tiw) with interferon β-1a injected intramuscularly once weekly (IFN β-1a IM qw) on NEDA and clinical activity-free (CAF) status. The influence of the frequency of magnetic resonance imaging (MRI) scanning on NEDA and the effect of baseline T1 gadolinium-enhancing (Gd +) lesions on NEDA and CAF were also investigated. Results More patients in the IFN β-1a SC tiw group achieved NEDA compared with the IFN β-1a IM qw group, although rates were lower when monthly MRI scans through 24 weeks were included (35.0% vs. 21.6%, respectively; p p p = 0.022), and CAF through Week 48 in patients receiving IFN β-1a SC tiw ( p = 0.024). Conclusions IFN β-1a SC tiw was associated with significantly higher rate of NEDA status compared with IFN β-1a IM qw. Baseline Gd + lesions augured less frequent CAF or NEDA status. Inclusion of more MRI scans in the analysis reduced rates of NEDA status

Pharmacodynamic biomarkers of long-term interferon beta-1a therapy in REFLEX and REFLEXION.

Abstract This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN β-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were analyzed. All investigated biomarkers were significantly upregulated 1.5–4-fold in response to sc IFN β-1a treatment versus baseline (p ≤ 0.008). The validity of MX1, 2'5'OAS, and IL-1RA as biomarkers of response to sc IFN β-1a was confirmed in this large patient cohort, with biomarkers consistently upregulated in a dose-dependent manner. Neopterin, TRAIL, and IP-10 were confirmed as biomarkers associated with long-term sc IFN β-1a treatment efficacy over 5 years

Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.

BACKGROUND: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. METHODS: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. RESULTS: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. CONCLUSION: Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.This study was sponsored by EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany (in the United States), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (rest of the world)

Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis : An Integrated Analysis of Safety

Introduction: Although use of contraception was pre-specified during cladribine clinical trials for multiple sclerosis, some pregnancies did occur. Objective: This analysis reports on pregnancy outcomes in the cladribine clinical development program. Methods: Pregnancy outcomes in female patients (direct pregnancies) and those arising from partner pregnancies (i.e., female partners of male study participants with multiple sclerosis) were evaluated from an integrated safety analysis of ten studies of cladribine in multiple sclerosis (nine clinical trials and a long-term safety registry), with patients treated with cladribine tablets, parenteral cladribine, or placebo (all-exposed cohort; 1976 patients received cladribine and 802 received placebo). Pregnancies that occurred during the 'at-risk' period for cladribine (during treatment or within 6 months thereafter) are reported as a separate group. Results: In the all-exposed cohort, 70 direct pregnancies occurred among 62 female patients (cladribine, n = 49; placebo, n = 21). Pregnancy outcomes were: live births (cladribine, n = 19 [38.8%]; placebo, n = 9 [42.9%]), elective terminations (cladribine, n = 14 [28.6%]; placebo, n = 4 [19.0%]), spontaneous abortions (cladribine, n = 11 [22.4%]; placebo, n = 5 [23.8%]), and therapeutic terminations (cladribine, n = 5 [10.2%]; placebo, n = 2 [9.5%]); in the remaining placebo recipient, the pregnancy outcome was unknown. There were two reports of congenital malformations (cladribine, n = 1; placebo, n = 1), both of which occurred with pregnancies arising > 2 years after exposure to the last dose of study medication. Sixteen direct pregnancies occurred during the 'at-risk' period for cladribine; outcomes for these were: live births, n = 3 (18.8%); elective terminations, n = 10 (62.5%); spontaneous abortions, n = 2 (12.5%); and therapeutic terminations, n = 1 (6.2%). Corresponding findings for direct pregnancies among placebo recipients were (n = 11): live births, n = 5 (45.5%); elective terminations, n = 2 (18.2%); spontaneous abortions, n = 3 (27.3%); and unknown, n = 1 (9.1%). No cases of congenital malformation were reported for pregnancies during the 'at-risk' period. There were an additional nine partner pregnancies in female partners of cladribine-treated male patients, all of which resulted in live births; of these, two pregnancies occurred within the 'at-risk' period for cladribine. Conclusions: While limited by the small number of pregnancies and related data from the cladribine clinical development program, highlighting the need for further study, the observations made in the present analysis were generally consistent with epidemiological data on pregnancy outcomes for the general population or women with multiple sclerosis. There were no congenital malformations in pregnancies that occurred during cladribine treatment or within 6 months after the last dose. As the data available for cladribine-exposed pregnancies in patients with multiple sclerosis are limited, a non-interventional post-authorization safety study has been initiated to obtain more information on this subject. Clinical Trial Registration: CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE MS: NCT00725985; ONWARD: NCT00436826; PREMIERE: NCT01013350

Associations between changes in ferritin levels and susceptibility-weighted imaging filtered phase in patients with relapsing–remitting multiple sclerosis over 24weeks of therapy with subcutaneous interferon beta-1a three times weekly

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Propuesta de Supply Chain Management y Logística para la empresa Almacén y Cerrajería el Lago

Con el desarrollo de este documento pretendemos demostrar y exponer cómo aplican las diferentes características y funciones de SCM y Logística al interior de una empresa, se demuestra que sin importar el tamaño de la empresa se puede aplicar un diseño logístico el cual permite optimizar recursos y mejorar en cada uno de los procesos, es por este motivo que se elige la empresa Almacén y cerrajería el lago, una empresa pymes (pequeña), la cual no contaba con ningún análisis ni diseño logístico, no contaba con procesos establecidos sino que se realizaba un proceso empírico que permitía realizar cada labor de forma mecánica y según la necesidad correspondiente.With the development of this document we intend to demonstrate and expose how the different characteristics and functions of SCM and Logistics are applied within a company, it is shown that regardless of the size of the company, a logistics design can be applied which allows optimizing resources and improving In each of the processes, it is for this reason that the company Almacén y cerrajería el lago was chosen, a SME (small) company, which did not have any analysis or logistical design, did not have established processes, but carried out a empirical process that allowed each task to be carried out mechanically and according to the corresponding need

Benefit-risk assessment of cladribine using multi-criteria decision analysis (MCDA) for patients with relapsing-remitting multiple sclerosis

Purpose: We applied Multi-Criteria Decision Analysis (MCDA) methods in a structured benefit–risk assessment of cladribine and newer approved disease-modifying drugs (DMDs) for patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Decision conferencing with clinical neurologists as decision makers was used to create an MCDA model that incorporated available evidence on DMDs for RRMS and clinical judgments about the relevance of the evidence. Benefit–risk assessments were conducted for DMDs in both patients with RRMS and patients with RRMS with high disease activity (HDA; defined as ≥2 relapses in the previous year). Treatment options included cladribine and recently approved DMDs available in European Union countries at the time of assessment (December 2015): alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide. To account for the relative importance of DMD effects, scores for the MCDA model were weighted to ensure that the most clinically important attributes carried more weight in the final benefit–risk calculation. The neurologists weighted different efficacy and safety profile attributes without any reference to individual DMDs to disassociate the assessment of weights with any specific DMD. The neurologists did not do direct comparisons between DMDs. Findings: The highest overall weighted preference value for the RRMS model was for dimethyl fumarate (63) followed closely by cladribine (62). For patients with RRMS and HDA, cladribine had the highest overall weighted preference value (76), followed by alemtuzumab (62) and natalizumab (61). The benefit–risk balance of cladribine in patients with RRMS and specifically patients with RRMS who exhibited HDA characterized by high relapse activity (≥2 relapses in the previous year) was more favorable than the other DMDs included in the model. Implications: The balance of high efficacy and the safety profile makes cladribine an important treatment option to consider, both in patients with RRMS and patients with HDA. Regular, single-country meetings could be organized to explore how differences in cultural values (scores and weights) and updated input data might affect the usefulness of MCDA in different, real-world, dynamic clinical settings

Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets.

BACKGROUND: Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage. METHODS: In the CLARITY study ( ClinicalTrials.gov NCT00213135), the effect of 2 years' treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS). RESULTS: Compared with placebo (-0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (-0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (-0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p < 0.001), with patients with lower PBVC/y showing the highest probability of remaining free from disability progression at 2 years and vice versa. CONCLUSIONS: Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates.ARES Trading SA, Aubonne, Switzerlan

Immunological and short-term brain volume changes in relapsing forms of multiple sclerosis treated with interferon beta-1a subcutaneously three times weekly: an open-label two-arm trial

Abstract Background Brain volume atrophy is observed in relapsing–remitting multiple sclerosis (RRMS). Methods Brain volume changes were evaluated in 23 patients with RRMS treated with interferon β-1a 44 μg given subcutaneously (SC) three times a week (tiw) and 15 healthy controls. Percentages of whole brain and tissue-specific volume change were measured from baseline (0 months) to 3 months, from 3 to 6 months, and from baseline to 6 months using SIENAX Multi Time Point (SX-MTP) algorithms. Immunological status of patients was also determined and correlations between subsets of T cells and changes in brain volume were assessed. Results Interferon β-1a 44 μg SC tiw in 23 patients with RRMS resulted in significant reductions in whole brain and gray matter tissue volume early in the treatment course (baseline to 3 months; mean change; –0.95 %; P = 0.030, –1.52 %; P = 0.004, respectively), suggesting a short-term treatment-induced pseudoatrophy effect. From baseline to 6 months, there were significant correlations observed between decreased T- cell expression of IL-17 F and decreased whole brain and brain tissue-specific volume. Conclusions These findings are consistent with the interpretation of the pseudoatrophy effect as resolution of inflammation following treatment initiation with interferon β-1a 44 μg SC tiw, rather than disease-related tissue loss. Trial registration ClinicalTrials.gov; NCT0108531