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Asif H Khan,1 Adeline Abbe,1 Bruno Falissard,2 Paulo Carita,1 Claus Bachert,3,4 Joaquim Mullol,5 Matthew Reaney,6 Jingdong Chao,7 Leda P Mannent,1 Nikhil Amin,7 Puneet Mahajan,8 Gianluca Pirozzi,8 Laurent Eckert1 1Sanofi, Chilly-Mazarin, France; 2Centre de recherche en epidémiologie et santé des populations (CESP), INSERM U1018, Paris, France; 3Upper Airways Research Laboratory, Ghent University, Ghent, Belgium; 4CLINTEC, Karolinska Institutet, Stockholm, Sweden; 5Rhinology Unit & Smell Clinic, ENT Department, Hospital Clínic, Universitat de Barcelona; Clinical and Experimental Respiratory Immunoallergy, IDIBAPS; and CIBERES, Barcelona, Catalonia, Spain; 6IQVIA, Reading, UK; 7Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 8Sanofi, Bridgewater, NJ, USACorrespondence: Asif H KhanSanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, 91380, FranceTel +33 1 60 49 77 77Email asif.khan@sanofi.comPurpose: Patient perspective is an important and increasingly sought-after complement to clinical assessment. The aim of this study was to transcribe individual patients’ experience of treatment in a dupilumab clinical trial through free-text responses with analysis using natural language processing (NLP) to obtain the unique perspective of patients on disease impact and unmet needs with existing treatment to inform future trial design.Patients and Methods: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) who were enrolled in a Phase IIa randomized controlled trial comparing dupilumab with placebo (NCT01920893) were invited to complete a self-assessment of treatment (SAT) tool at the end of treatment, asking, “What is your opinion on the treatment you had during the trial? What did you like or dislike about the treatment?” Free-text responses were analyzed for the overall cohort and according to treatment assignment using natural language processing including sentiment scoring. In a mixed-methods approach, quantitative patient-reported outcome (PRO) results were utilized to complement the qualitative analysis of free-text responses.Results: Of 60 patients enrolled in the study, 43 (71.6%) completed the SAT and responses from 37 patients were analyzed (placebo, n = 16; dupilumab, n = 21). Word analyses showed that the most common words were “smell,” “improve,” “staff,” “great,” “time,” and “good.” Across the whole cohort, “smell” was the most common symptom-related word. The words “smell” and “experience” were more likely to occur in patients treated with dupilumab. Patients treated with dupilumab also had more positive sentiment in their SAT responses than those who received placebo. The results from this qualitative analysis were reflected in quantitative PRO results.Conclusion: “Smell” was important to patients with CRSwNP, highlighting its importance as a patient-centric efficacy outcome measure in the context of clinical trials in CRSwNP.Trial Registration: ClinicalTrials.gov, NCT01920893. Registered 12 August 2013, https://www.clinicaltrials.gov/ct2/show/NCT01920893.Keywords: CRSwNP, free-text data mining, patient perspective, self-assessment, sense of smell

David Della-Morte,1,2 Francesco Cacciatore,3 Elisa Salsano,4 Gilda Pirozzi,4 Maria Teresa Del Genio,4 Iole D'Antonio,4 Gaetano Gargiulo,5 Raffaele Palmirotta,2 Fiorella Guadagni,2 Tatjana Rundek,1 Pasquale Abete41Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA; 2Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele, Rome, Italy; 3Istituto Scientifico di Campoli/Telese, Fondazione Salvatore Maugeri, IRCCS, Benevento, Italy; 4Dipartimento di Scienze Mediche Traslazionali, Università di Napoli "Federico II," Naples, Italy; 5AON, SS Antonio e Biagio e Cesare Arrigo, Struttura Complessa di Geriatria, Alessandria, ItalyAbstract: Stroke is one of the leading causes of death in industrialized countries for people older than 65 years of age. The reasons are still unclear. A reduction of endogenous mechanisms against ischemic insults has been proposed to explain this phenomenon. The “cerebral” ischemic preconditioning mechanism is characterized by a brief episode of ischemia that renders the brain more resistant against subsequent longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. This protective mechanism seems to be reduced with aging both in experimental and clinical studies. Alterations of mediators released and/or intracellular pathways may be responsible for age-related ischemic preconditioning reduction. Agents able to mimic the “cerebral” preconditioning effect may represent a new powerful tool for the treatment of acute ischemic stroke in the elderly. In this article, animal and human cerebral ischemic preconditioning, its age-related difference, and its potential therapeutical applications are discussed.Keywords: ischemic preconditioning, stroke, transient cerebral ischemic attack, mortality, elderly

BackgroundDupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428).ObjectivesTo characterize the pharmacokinetics of dupilumab, and long-term safety and efficacy in adolescents.MethodsThis was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 dupilumab weekly. Primary end points were dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI).ResultsForty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )].ConclusionsIn adolescents with moderate-to-severe AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52-week safety and efficacy data support long-term use of dupilumab in this patient population. What's already known about this topic? Adolescents with moderate-to-severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options. Dupilumab (monoclonal antibody against interleukin-4 receptor α) is approved for the treatment of adolescents with moderate-to-severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union). A 16-week, randomized, placebo-controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long-term safety and efficacy of dupilumab in adolescents with moderate-to-severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16-week dupilumab phase III trial. The data from these studies also support the use of dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16-week phase III monotherapy trial.