Background
Comparing real-world effectiveness and tolerability of therapies for relapsing-remitting multiple sclerosis is increasingly important, though average treatment effects fail to capture ...possible treatment effect heterogeneity. With the clinical course of the disease being highly heterogeneous across patients, precision medicine methods enable treatment response heterogeneity investigations.
Objective
To compare real-world effectiveness and discontinuation profiles between dimethyl fumarate and fingolimod while investigating treatment effect heterogeneity with precision medicine methods.
Methods
Adults initiating dimethyl fumarate or fingolimod as a second-line therapy were selected from a French registry. The primary outcome was annualized relapse rate at 12 months. Seven secondary outcomes relative to discontinuation and disease progression were considered. A precision medicine framework was used to characterize treatment effect heterogeneity.
Results
Annualized relapse rates at 12 months were similar for dimethyl fumarate and fingolimod. The odd of treatment persistence was 47% lower for patients treated with dimethyl fumarate relative to those treated with fingolimod (odds ratio: 0.53, 95% confidence interval: 0.39, 0.70). None of the five precision medicine scoring approaches identified treatment heterogeneity.
Conclusion
These findings substantiated the similar effectiveness and different discontinuation profiles for dimethyl fumarate and fingolimod as a second-line therapy for relapsing-remitting multiple sclerosis, with no significant effect heterogeneity observed.
En l’absence de données observationnelles françaises, Biogen a réalisé, avec l’OFSEP, une étude diméthylfumarate (DMF) versus fingolimod (FTY) chez les patients atteints de sclérose en plaques ...récurrente-rémittente (SEP-RR).
Comparer l’efficacité en vie réelle du DMF et du FTY chez des patients ayant une SEP-RR en échec d’un précèdent traitement par pondération inverse sur le score de propension (IPTW).
Étude comparative rétrospective sur la cohorte OFSEP. Les critères d’inclusions étaient : patients atteints de SEP-RR,>18 ans, ayant initiés DMF ou FTY, en échec d’au moins un précèdent traitement, entre le 15 janvier 2014 et le 15 décembre 2016, avec au moins un score EDSS disponible à l’initiation et 12 mois de suivi. L’analyse par IPTW a comparé l’efficacité clinique (poussées, handicap), radiologique et la maintenance du traitement.
Un total de1166 patients (554 DMF et 612 FTY) ont été inclus. Après pondération par IPTW aucune différence significative n’a été observée à 12 et 24 mois sur : le taux annualisé de poussées (TAP), critère principal à 12 mois, TAP ratio DMF vs FTY=1,06 (IC 95 % 0,78–1,43, p=0,7263), la progression du handicap (EDSS ponctuel) et les données IRM. Seuls les Résultats sur l’arrêt de traitement étaient significativement en faveur du FTY.
Ces résultats, similaires aux données étrangères publiées sur le sujet, viennent combler le manque de données comparatives chez les patients français atteints de SEP-RR. L’efficacité du DMF (poussées, handicap et activité IRM) est comparable à celle du FTY en conditions réelles d’utilisation chez les patients français ayant une SEP-RR active et en échec d’un précèdent traitement.
Cette étude en pratique courante a montré qu’il n’y avait pas de différence significative du DMF vs FTY sur l’effet global du traitement chez des patients partageant les mêmes caractéristiques.
Ce travail a été financé par Biogen et réalisé en utilisant les données de l’OFSEP. L’OFSEP a bénéficié d’une aide de l’État gérée par l’Agence Nationale de la Recherche au titre du programme Investissements d’Avenir portant la référence ANR-10-COHO-002. Observatoire Français de la Sclérose en plaques (OFSEP).
BACKGROUNDHuman herpesvirus 6 (HHV-6) is susceptible to latency and reactivation in hematopoietic stem cell transplant (HSCT) recipients. We investigated the incidence of HHV-6 DNAemia and factors ...related to HHV-6 DNAemia and death after allogeneic stem cell transplantations. We also explored the relationship between HHV-6 viral load and the presence of clinical signs.
METHODSData concerning age, sex, transplantation conditions, graft-versus-host disease (GVHD), treatments, clinical signs, outcome, HHV-6, and other infections were collected for a historical cohort of 390 HSCT performed between 1999 and 2008 in the Transplant Unit of Nancy University Hospital Center. Univariate analysis was used to evaluate influences between the different parameters.
RESULTSThe study included 220 of the 390 allogeneic HSCTs. For the analyzed period, 44 patients (n=44/220, 20%) presented HHV-6 DNAemia in whole blood, including three integrated forms. Fifteen percent (7/41) of HHV-6–positive patients presented clinical signs not related to higher viral load (P=0.164). The factors associated with HHV-6 DNAemia were as followscord blood transplantation (P<0.001), conditioning regimen (P=0.030), acute GVHD (P=0.003), and the type of prophylactic treatment for GVHD (P=0.001). HHV-6 DNAemia was not significantly associated with cytomegalovirus infection (P=0.937). HHV-6 DNAemia was not associated with death (P=0.151).
CONCLUSIONSHHV-6 DNAemia was not so frequent after allogeneic transplantation. Factors associated with HHV-6 DNAemia were similar to those for other infections. No abnormally high death rate was observed in the HHV-6 positive population. The presence of clinical signs did not appear to be statistically related to HHV-6 viral load.
Objectives:
The present study aimed to compare the projected long-term clinical and cost implications associated with liraglutide, sitagliptin and glimepiride in patients with type 2 diabetes ...mellitus failing to achieve glycemic control on metformin monotherapy in France.
Methods:
Clinical input data for the modeling analysis were taken from two randomized, controlled trials (LIRA-DPP4 and LEAD-2). Long-term (patient lifetime) projections of clinical outcomes and direct costs (2013 Euros; €) were made using a validated computer simulation model of type 2 diabetes. Costs were taken from published France-specific sources. Future costs and clinical benefits were discounted at 3% annually. Sensitivity analyses were performed.
Results:
Liraglutide was associated with an increase in quality-adjusted life expectancy of 0.25 quality-adjusted life years (QALYs) and an increase in mean direct healthcare costs of €2558 per patient compared with sitagliptin. In the comparison with glimepiride, liraglutide was associated with an increase in quality-adjusted life expectancy of 0.23 QALYs and an increase in direct costs of €4695. Based on these estimates, liraglutide was associated with an incremental cost-effectiveness ratio (ICER) of €10,275 per QALY gained vs sitagliptin and €20,709 per QALY gained vs glimepiride in France.
Conclusion:
Calculated ICERs for both comparisons fell below the commonly quoted willingness-to-pay threshold of €30,000 per QALY gained. Therefore, liraglutide is likely to be cost-effective vs sitagliptin and glimepiride from a healthcare payer perspective in France.
Background. Human herpesvirus 6 (HHV-6) is susceptible to latency and reactivation in hematopoietic stem cell transplant (HSCT) recipients. We investigated the incidence of HHV-6 DNAemia and factors ...related to HHV-6 DNAemia and death after allogeneic stem cell transplantations. We also explored the relationship between HHV-6 viral load and the presence of clinical signs.Methods. Data concerning age, sex, transplantation conditions, graft-versus-host disease (GVHD), treatments, clinical signs, outcome, HHV-6, and other infections were collected for a historical cohort of 390 HSCT performed between 1999 and 2008 in the Transplant Unit of Nancy University Hospital Center. Univariate analysis was used to evaluate influences between the different parameters.Results. The study included 220 of the 390 allogeneic HSCTs. For the analyzed period, 44 patients (n=44/220, 20%) presented HHV-6 DNAemia in whole blood, including three integrated forms. Fifteen percent (7/41) of HHV-6-positive patients presented clinical signs not related to higher viral load (P=0.164). The factors associated with HHV-6 DNAemia were as follows: cord blood transplantation (P<0.001), conditioning regimen (P=0.030), acute GVHD (P=0.003), and the type of prophylactic treatment for GVHD (P=0.001). HHV-6 DNAemia was not significantly associated with cytomegalovirus infection (P=0.937). HHV-6 DNAemia was not associated with death (P=0.151).Conclusions. HHV-6 DNAemia was not so frequent after allogeneic transplantation. Factors associated with HHV-6 DNAemia were similar to those for other infections. No abnormally high death rate was observed in the HHV-6 positive population. The presence of clinical signs did not appear to be statistically related to HHV-6 viral load.
Targeting tunas associated with drifting Fish Aggregating Devices (dFADs) raises questions on the sustainability of tropical tuna fisheries. To limit catches of juvenile tunas, multiple time-area ...dFADs-fishing moratoria have been implemented by ICCAT since 1998. In this study we assessed the effectiveness of two different dFADs time-area closures implemented for the protection of both bigeye and yellowfin tuna juveniles. Using Atlantic Ocean Tunas Tagging Program (AOTTP) data from 2016 to 2019, we estimated the relative risk for individuals tagged inside the moratorium strata to be recaptured inside in comparison to the recapture rate outside the spatio-temporal strata. AOTTP releases were not homogeneously distributed in terms of areas and school type, therefore to assess the effect of the moratorium without potential bias a matching procedure was used to rebalance the release areas. As a result of the matching procedure and subsequent filtering applied to the dataset, the number of bigeyes recaptures retained inside and outside the time-area closure were below the threshold from which any conclusion could be drawn. In contrast, our results show that a majority of yellowfin and skipjack tunas tagged within the closed area stayed within the closed area during the moratorium period. Consequently, the last moratorium can be considered as effective for these two species, at least during the months of fishing ban on dFADs.
Herein, we report a direct recycling process of the spent LiFePO4 by direct room temperature chemical lithiation. A fine characterization of a recovered LFP cathode from a spent commercial battery ...demonstrates that the end of life of the battery is mainly due to the lithium loss, while the structure of the LFP cathode material is globally preserved. It is shown here that such a cathode can be efficiently recovered by direct lithiation in solution using LiI in different solvents (acetonitrile, ethanol, cyclohexane, methanol, DMSO and propan-1,2-ol) with optimized experimental parameters. The best electrochemical performance is obtained with ethanol, one of the greenest and cheapest solvents, without any additional heat treatment. More interestingly, the regeneration of LFP can be achieved directly with the material cast onto its aluminum collector, which paves the way to more efficient recycling preserving the whole electrode formulation and avoiding a new electrode casting. The chemically lithiated LFP cathode in ethanol exhibits a full reversible capacity of ∼168 mAh/g vs. Li metal with a stable coulombic efficiency exceeding 98% for 25 cycles. In addition, this recovery process produces regenerated electrodes showing good electrochemical performance also at high current density.
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•Spent LiFePO4 is regenerated at room temperature via DCL.•No heat treatment is required.•Regenerated electrodes show excellent performance, even at high current density.•Optimal performance is achieved using cost-effective, eco-friendly ethanol solvent.•With DCL, LFP cathode is regenerated without removing aluminum collector.
Health information technology (HIT) can help coordinate health and social actors involved in patients' pathways. We assess five regional HIT-based programmes ('
' or TSN) introduced in France, ...covering the period 2012-2018.
This was a quasi-experimental controlled before/after mixed design. We used data from the French National Health Insurance database, qualitative and quantitative surveys, and information extracted from project documents and databases. We assessed the impact of TSN using four main impact indicators: emergency room visits, unplanned hospitalizations, avoidable hospitalizations and rehospitalization within 30 days. We also collected qualitative and secondary quantitative data covering perceived needs, knowledge, use, satisfaction, adoption and understanding of projects, pathway experience, impact on professional practices and appropriateness of hospitalizations.
TSN implemented a heterogeneous mix of HIT. Implementation was slower than expected and was not well documented. Users perceived the HIT as having a positive but weak overall effect. There were no significant differences in trends for the main impact indicators, nor on the appropriateness of hospitalizations, but favourable trends on secondary polypharmacy indicators.
If similar innovations take place in future, they should be based on a logical framework that defines causal, measurable links between services provided and expected impacts.
Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe ...(requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.
We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 death to 7 discharged from hospital) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021.
Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 20%), sarilumab 200 mg (n=159 38%), or sarilumab 400 mg (n=173 42%). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days 95% CI 9·0 to 15·0) and sarilumab 200 mg (10·0 days 9·0 to 12·0; hazard ratio HR 1·03 95% CI 0·75 to 1·40; log-rank p=0·96) or sarilumab 400 mg (10·0 days 9·0 to 13·0; HR 1·14 95% CI 0·84 to 1·54; log-rank p=0·34), or in proportions of patients alive (77 92% of 84 patients in the placebo group; 143 90% of 159 patients in the sarilumab 200 mg group; difference -1·7 -9·3 to 5·8; p=0·63 vs placebo; and 159 92% of 173 patients in the sarilumab 400 mg group; difference 0·2 -6·9 to 7·4; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% 95% CI -7·7 to 25·5; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group.
This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19.
Sanofi and Regeneron Pharmaceuticals.
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