ABSTRACT
Introduction (contexte de la recherche) Un algorithme relatif à la stratégie treat-to-target a récemment été développé pour guider l'utilisation des thérapies systémiques en vue du contrôle de la maladie chez l'adulte atteint d'une DA. Cet algorithme a mis en avant des critères visant à définir un objectif cible initial acceptable à 3 mois ainsi qu'un objectif cible optimal à 6 mois. Objectif Les objectifs de cette analyse sont d'utiliser l'algorithme lié à la stratégie treat-to-target pour évaluer l'efficacité de l'upadacitinib (UPA), chez des patients adultes atteints d'une DA modérée à sévère, traités par UPA 15mg ou 30mg par voie orale en monothérapie 1 fois par jour ;à partir des données poolées des études de phase III, randomisées, contrôlées en double aveugle vs placebo : Measure Up 1 (MU1, NCT03569293) et Measure Up 2 (MU2, NCT03607422) ;ainsi que de déterminer la proportion de patients atteints d'une DA modérée à sévère ayant obtenu une amélioration≥1 des principaux domaines de la DA (signes, symptômes et qualité de vie) aux semaines 2 et 16 dans les études MU1 et MU2. Méthodes L'atteinte de ces critères sous UPA (15mg et 30mg) en monothérapie, 1 fois par jour a été comparée au placebo chez les patients adultes, en utilisant les données poolées des études MU1et MU2 et l'imputation des non-répondeurs en intégrant l'imputation multiple pour les valeurs manquantes liées à l'épidémie de COVID-19. Résultats Une proportion plus élevée de patients traités par UPA (15mg et 30mg) vs placebo (p<0,001 pour tous) a atteint l'objectif cible initial acceptable de 3 mois à la semaine 2 (78,9 %, 82,6 % vs 25,0 %) et la semaine 16 (72,5 %, 80,2 % vs 22,9 %) ;et l'objectif cible optimal de 6 mois à la semaine 2 (52,8 %, 64,3 % vs 6,3 %) et la semaine 16 (56,2 %, 70,1 % vs 13,9 %). Conclusions Ces résultats semblent indiquer qu'UPA (15mg et 30mg) administré par voie orale, 1 fois par jour pourrait améliorer la prise en charge conventionnelle des patients souffrant d'une DA modérée à sévère, en permettant d'atteindre l'objectif cible optimal à 6 mois (signes, symptômes et qualité de vie) dès 16 semaines et même dès 2 semaines chez la plupart des patients.
ABSTRACT
Recommendations for a treat-to-target approach were recently developed to guide systemic therapy for disease control in adults with AD. Recommendations outlined criteria for a 3-month initial acceptable target goal: reduction from baseline ≥1 on a 5-level Patient Global Impression of Severity (PGIS) scale and ≥1 specific disease domain target (≥50% improvement from baseline in Eczema Area and Severity Index [EASI-50];≥50% reduction in Scoring of AD [SCORAD-50];and a reduction from baseline in Worst Pruritus Numerical Rating Scale [WP-NRS] ≥3, Dermatology Life Quality Index [DLQI] ≥4, or Patient Oriented Eczema Measure [POEM] ≥4);and a 6-month optimal target goal: PGIS ≤2 and ≥1 specific disease domain target (EASI-75 or EASI ≤7, SCORAD-75 or SCORAD ≤24, WP-NRS ≤4, DLQI ≤5, POEM ≤7). Achievement of these criteria with once-daily upadacitinib (15 mg and 30 mg) monotherapy was compared with placebo using integrated adult data from MU1 and MU2 trials and nonresponder imputation incorporating multiple imputation for missing values due to COVID-19. Greater proportions of patients treated with upadacitinib 15 mg;30 mg vs placebo (P <.001 for all) achieved the initial acceptable target goal at week 2 (78.9%;82.6% vs 25.0%) and week 16 (72.5%;80.2% vs 22.9%), and the optimal target goal at week 2 (52.8%;64.3% vs 6.3%) and week 16 (56.2%;70.1% vs 13.9%). These results suggest that once-daily oral upadacitinib (15 mg and 30 mg) may help improve standards of care in patients with moderate-to-severe AD by achieving 6-month target goals at 16 weeks and as early as 2 weeks for most patients.
ABSTRACT
The rapid development of artificial intelligence techniques is significantly promoting the resolution of various important decision-making issues such as material distribution, generation line optimization scheduling, and path planning. Currently, SARS-CoV-2 is raging over the world, and it is valuable to propose a vaccine distribution strategy to utilize limited vaccine resources rationally. In this paper, we aim to propose an optimal vaccine distribution strategy based on deep reinforcement learning(DRL) approaches. An End-to-End vaccine distribution model is proposed by combining the Deep Reinforcement Learning model and LinUCB algorithm to get an optimistic strategy of allocation. Experiment results demonstrated that vaccine distribution strategies based on this model show a strong capacity to control the epidemic and ensure stable government revenue compared with baseline strategies. © 2021 IEEE.
ABSTRACT
Atopic dermatitis (AD) is a chronic, recurrent, highly pruritic immune-mediated inflammatory disease, with an unmet need for additional effective therapies. Results from phase IIb and phase III clinical trials demonstrated that upadacitinib (UPA) was efficacious with a favourable benefit-risk profile vs. placebo (PBO) in the treatment of moderate-to-severe AD. Here, we analyse the efficacy and safety of UPA in adolescent and adult subgroups using data from three phase III studies. Data from three randomized, double-blind, placebo-controlled, multicentre phase III studies [Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422) and AD Up (NCT03568318)] were used to assess the efficacy and safety of UPA in adolescents and adults. Across the three studies, adolescents (aged 12 to < 18years) and adults (aged 18-75years) with moderate-to-severe AD were randomized 1: 1: 1 to UPA 15mg (UPA15), UPA 30mg (UPA30) or PBO orally once daily, either alone (Measure Up 1 and Measure Up 2) or with concomitant topical corticosteroids (AD Up). This analysis includes prespecified efficacy endpoints in adolescents and adults at week 16: achievement of 75% improvement in Eczema Area and Severity Index (EASI-75), validated Investigator's Global Assessment-Atopic Dermatitis score of clear or almost clear (vIGA-AD 0/1), Worst Pruritus Numerical Rating Scale (WP-NRS) improvement of ≥ 4, Dermatology Life Quality Index (DLQI) or Children's DLQI score of 0 or 1 (DLQI 0/1 or CDLQI 0/1), and Hospital Anxiety and Depression Scale (HADS)-Anxiety (HADS-A) < 8 and HADS-Depression (HADS-D) < 8. The primary approach for evaluating categorical endpoints was NRI-C (nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19). Safety was assessed as treatment-emergent adverse events (AEs) in all patients who received ≥ 1 dose of study drug and analysed as an integrated dataset for all three studies. In total, 124, 104 and 116 adolescents plus 723, 732 and 785 adults were randomized and treated in Measure Up 1, Measure Up 2 and AD Up, respectively. EASI-75 response rates at week 16 across adolescent and adult subgroups for both doses of UPA were consistent with the overall study population results;treatment with UPA30 yielded numerically better results than with UPA15. Most patients in both subgroups achieved EASI-75 with UPA15 (> 55%), and numerically greater proportions of patients achieved EASI-75 for UPA30 (> 72%), with response rates for both UPA doses demonstrating significantly better efficacy than PBO (≥ 30%). vIGA-AD 0/1 was achieved by > 38% and > 50% of patients receiving UPA15 and UPA30, respectively, in both subgroups, with response rates for both UPA doses demonstrating significantly better efficacy than PBO (< 12%). A WP-NRS improvement of ≥ 4 was achieved by > 33% of adolescents and > 42% of adults receiving UPA15 vs. > 50% of adolescents and > 60% of adults receiving UPA30, with response rates for both UPA doses demonstrating significantly better efficacy than PBO (< 16%). CDLQI 0/1 was achieved by > 13% (UPA15) and ≥ 19% (UPA30) of adolescents aged 12 to <16years, while DLQI 0/1 was achieved by ≥ 0% (UPA15) and ≥ 27% (UPA30) of adolescents aged 16 to <18years;most adolescent rates for DLQI 0/1 and CDLQI 0/1 were not significantly greater than PBO. In the adult subgroup, DLQI 0/1 was achieved by > 24% and > 37% receiving UPA15 and UPA30, respectively, both significantly greater than PBO. Achievement of HADS-A<8 and HADS-D<8 was comparable for adolescents and adults, with response rates for both UPA doses being significantly higher than PBO: ≥ 40% for UPA15 and > 41% for UPA30 in both subgroups. Rates of serious AEs and AEs leading to discontinuation were generally similar across treatment groups for both adolescents and adults. Rates of acne-the most common AE-were higher with UPA than PBO, and similar for adolescents and adults. Serious infections were reported infrequently (< 1%) with UPA in both adolescents and adults. Opportunistic infections were reported in < 1% of adults, with n ne in adolescents. Rates of herpes zoster virus infection were higher with UPA than PBO in both adolescents and adults. No adjudicated gastrointestinal perforation, major adverse cardiovascular events or venous thromboembolic events were reported in the UPA groups. No malignancies were reported in adolescents. Adolescent and adult responses to UPA15 and UPA30 treatment were consistent across clinical, quality-of-life and patient-reported outcome assessments, with similar and acceptable safety in both populations.