Summary Background Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic ...diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis. Methods In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov , NCT02260986. Findings Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% 125 patients who received dupilumab plus topical corticosteroids qw and 39% 41 patients who received dupilumab q2w plus topical corticosteroids vs 12% 39 patients who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% 204 and 69% 73 vs 23% 73; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids. Interpretation Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety. Funding Sanofi and Regeneron Pharmaceuticals Inc.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary Background Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with ...dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. Methods In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov , number NCT01859988. Findings Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week n=63, 300 mg every 2 weeks n=64, 200 mg every 2 weeks n=61, 300 mg every 4 weeks n=65, 100 mg every 4 weeks n=65; placebo n=61). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (−74% SE 5·16), 300 mg every 2 weeks (−68% 5·12), 200 mg every 2 weeks (−65% 5·19), 300 mg every 4 weeks (−64% 4·94), 100 mg every 4 weeks (−45% 4·99); placebo (−18% 5·20). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). Interpretation Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. Funding Sanofi and Regeneron Pharmaceuticals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objectives We sought to identify risk factors for mortality and morbidity during the Norwood hospitalization in newborn infants with hypoplastic left heart syndrome and other single right ventricle ...anomalies enrolled in the Single Ventricle Reconstruction trial. Methods Potential predictors for outcome included patient- and procedure-related variables and center volume and surgeon volume. Outcome variables occurring during the Norwood procedure and before hospital discharge or stage II procedure included mortality, end-organ complications, length of ventilation, and hospital length of stay. Univariate and multivariable Cox regression analyses were performed with bootstrapping to estimate reliability for mortality. Results Analysis included 549 subjects prospectively enrolled from 15 centers; 30-day and hospital mortality were 11.5% (63/549) and 16.0% (88/549), respectively. Independent risk factors for both 30-day and hospital mortality included lower birth weight, genetic abnormality, extracorporeal membrane oxygenation (ECMO) and open sternum on the day of the Norwood procedure. In addition, longer duration of deep hypothermic circulatory arrest was a risk factor for 30-day mortality. Shunt type at the end of the Norwood procedure was not a significant risk factor for 30-day or hospital mortality. Independent risk factors for postoperative renal failure (n = 46), sepsis (n = 93), increased length of ventilation, and hospital length of stay among survivors included genetic abnormality, lower center/surgeon volume, open sternum, and post-Norwood operations. Conclusions Innate patient factors, ECMO, open sternum, and lower center/surgeon volume are important risk factors for postoperative mortality and/or morbidity during the Norwood hospitalization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cause, timing, and location of death in the Single Ventricle Reconstruction trial Ohye, Richard G., MD; Schonbeck, Julie V., MSN, C-PNP; Eghtesady, Pirooz, MD, PhD ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
10/2012, Volume:
144, Issue:
4
Journal Article
Peer reviewed
Open access
Objectives The Single Ventricle Reconstruction trial randomized 555 subjects with a single right ventricle undergoing the Norwood procedure at 15 North American centers to receive either a modified ...Blalock-Taussig shunt or right ventricle-to-pulmonary artery shunt. Results demonstrated a rate of death or cardiac transplantation by 12 months postrandomization of 36% for the modified Blalock-Taussig shunt and 26% for the right ventricle-to-pulmonary artery shunt, consistent with other publications. Despite this high mortality rate, little is known about the circumstances surrounding these deaths. Methods There were 164 deaths within 12 months postrandomization. A committee adjudicated all deaths for cause and recorded the timing, location, and other factors for each event. Results The most common cause of death was cardiovascular (42%), followed by unknown cause (24%) and multisystem organ failure (7%). The median age at death for subjects dying during the 12 months was 1.6 months (interquartile range, 0.6 to 3.7 months), with the highest number of deaths occurring during hospitalization related to the Norwood procedure. The most common location of death was at a Single Ventricle Reconstruction trial hospital (74%), followed by home (13%). There were 29 sudden, unexpected deaths (18%), although in retrospect, 12 were preceded by a prodrome. Conclusions In infants with a single right ventricle undergoing staged repair, the majority of deaths within 12 months of the procedure are due to cardiovascular causes, occur in a hospital, and within the first few months of life. Increased understanding of the circumstances surrounding the deaths of these single ventricle patients may reduce the high mortality rate.
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Favorable clinical outcomes are difficult to achieve in long-standing persistent atrial fibrillation (LSPAF) with catheter ablation (CA). The CONVERGE (Convergence of Epicardial and Endocardial ...Ablation for the Treatment of Symptomatic Persistent Atrial FIbrillation) trial evaluated the effectiveness of hybrid convergent (HC) ablation vs endocardial CA.
The study sought to evaluate the safety and effectiveness of HC vs CA in the LSPAF subgroup from the CONVERGE trial.
The CONVERGE trial was a prospective, multicenter, randomized trial that enrolled 153 patients at 27 sites. A post hoc analysis was performed on LSPAF patients. The primary effectiveness was freedom from atrial arrhythmias off new or increased dose of previously failed or intolerant antiarrhythmic drugs (AADs) through 12 months. The primary safety endpoint was major adverse event incidence through 30 days with HC. Key secondary effectiveness measures included (1) percent of patients achieving ≥90% AF burden reduction vs baseline and (2) AF freedom.
Sixty-five patients (42.5% of total enrollment) had LSPAF; 38 in HC and 27 in CA. Primary effectiveness was 65.8% (95% confidence interval CI 50.7%–80.9%) with HC vs 37.0% (95% CI 5.1%–52.4%) with CA (P = .022). Through 18 months, these rates were 60.5% (95% CI 50.0%–76.1%) with HC vs 25.9% (95% CI 9.4%–42.5%) with CA (P = .006). Secondary effectiveness rates were higher than CA with HC at 12 and 18 months. Freedom from atrial arrhythmias off AADs was 52.6% (95% CI 36.8%–68.5%) and 47.4% (95% CI 31.5%–63.2%) with HC at 12 and 18 months vs 25.9% (95% CI 9.4%–42.5%) and 22.2% (95% CI 6.5%–37.9%) with CA, respectively (12 months: P = .031; 18 months: P = .038). Three (7.9%) major adverse events occurred within 30 days of HC.
Post hoc analysis demonstrated effectiveness and acceptable safety of HC compared with CA in LSPAF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background Moderate to severe atopic dermatitis (AD) is associated with substantial patient burden despite current therapies. Objective We sought to evaluate dupilumab treatment on patient-reported ...outcomes in adults with moderate to severe AD. Methods Adults (N = 380) with moderate to severe AD inadequately controlled by topical medications were randomized to 16 weeks of double-blind, subcutaneous treatment with dupilumab 100 mg every 4 weeks, 200 mg every 2 weeks, 300 mg every 2 weeks, 300 mg once weekly, or placebo. Patient-reported outcomes included pruritus numeric rating scale; patient-reported sleep item on Scoring AD scale; Patient-Oriented Eczema Measure; Hospital Anxiety and Depression Scale; Dermatology Life Quality Index; and 5-dimension 3-level EuroQol. Results Dupilumab reduced peak itch at 16 weeks relative to placebo by 1.1 to 3.2 points on numeric rating scale ( P < .0001 all doses, except 100 mg every 4 weeks P < .05); improved sleep and health-related quality of life on Dermatology Life Quality Index and 5-dimension 3-level EuroQol ( P < .05 all doses, except 100 mg every 4 weeks); and reduced anxiety and depression symptoms ( P < .05 all doses). Dupilumab's effects appeared early and achieved clinically relevant improvements without significant safety concerns. Limitations There are potential cultural differences affecting patient-reported outcome responses. Outcomes were secondary or exploratory end points. Conclusion Dupilumab produced early and sustained patient-reported and clinically relevant improvements in sleep, mental health, and health-related quality of life; the two 300-mg dose regimens resulted in greatest benefits.
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Objective To measure neurodevelopment at 3 years of age in children with single right-ventricle anomalies and to assess its relationship to Norwood shunt type, neurodevelopment at 14 months of age, ...and patient and medical factors. Study design All subjects in the Single Ventricle Reconstruction Trial who were alive without cardiac transplant were eligible for inclusion. The Ages and Stages Questionnaire (ASQ, n = 203) and other measures of behavior and quality of life were completed at age 3 years. Medical history, including measures of growth, feeding, and complications, was assessed through annual review of the records and phone interviews. The Bayley Scales of Infant Development, Second Edition (BSID-II) scores from age 14 months were also evaluated as predictors. Results Scores on each ASQ domain were significantly lower than normal ( P < .001). ASQ domain scores at 3 years of age varied nonlinearly with 14-month BSID-II. More complications, abnormal growth, and evidence of feeding, vision, or hearing problems were independently associated with lower ASQ scores, although models explained <30% of variation. Type of shunt was not associated with any ASQ domain score or with behavior or quality-of-life measures. Conclusion Children with single right-ventricle anomalies have impaired neurodevelopment at 3 years of age. Lower ASQ scores are associated with medical morbidity, and lower BSID-II scores but not with shunt type. Because only a modest percentage of variation in 3-year neurodevelopmental outcome could be predicted from early measures, however, all children with single right-ventricle anomalies should be followed longitudinally to improve recognition of delays.
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Background Data routinely captured in clinical registries may be leveraged to enhance efficiency of prospective research. The quality of registry data for this purpose has not been studied, however. ...We evaluated the completeness and accuracy of perioperative data within congenital heart centers’ local surgical registries. Methods Within 12 Pediatric Heart Network (PHN) sites, we evaluated 31 perioperative variables (and their subcategories, totaling 113 unique fields) collected via sites’ local clinical registries for submission to The Society of Thoracic Surgeons Database, compared with chart review by PHN research coordinators. Both used standard STS definitions. Data were collected on 10 subjects for 2 to 5 procedures/site and adjudicated by the study team. Completeness and accuracy (agreement of registry data with medical record review by PHN coordinator, adjudicated by the study team) were evaluated. Results A total of 56,500 data elements were collected on 500 subjects. With regard to data completeness, 3.1% of data elements were missing from the registry, 0.6% from coordinator-collected data, and 0.4% from both. Overall, registry data accuracy was 98%. In total, 94.7% of data elements were both complete/non-missing and accurate within the registry, although there was variation across data fields and sites. Mean total time for coordinator chart review per site was 49.1 hours versus 7.0 hours for registry query. Conclusions This study suggests that existing surgical registry data constitute a complete, accurate, and efficient information source for prospective research. Variability across data fields and sites also suggest areas for improvement in some areas of data quality.
Abstract Background Pulmonary emphysema is divided into 3 major subtypes at autopsy: centrilobular, paraseptal, and panlobular emphysema. These subtypes can be defined by visual assessment on ...computed tomography (CT); however, clinical characteristics of emphysema subtypes on CT are not well defined. We developed a reliable approach to visual assessment of emphysema subtypes on CT and examined if emphysema subtypes have distinct characteristics. Methods The Multi-Ethnic Study of Atherosclerosis COPD Study recruited smokers with chronic obstructive pulmonary disease (COPD) and controls ages 50-79 years with ≥10 pack-years. Participants underwent CT following a standardized protocol. Definitions of centrilobular, paraseptal, and panlobular emphysema were obtained by literature review. Six-minute walk distance and pulmonary function were performed following guidelines. Results Twenty-seven percent of 318 smokers had emphysema on CT. Interrater reliability of emphysema subtype was substantial (K: 0.70). Compared with participants without emphysema, individuals with centrilobular or panlobular emphysema had greater dyspnea, reduced walk distance, greater hyperinflation, and lower diffusing capacity. In contrast, individuals with paraseptal emphysema were similar to controls, except for male predominance. Centrilobular, but not panlobular or paraseptal, emphysema was associated with greater smoking history (+21 pack-years P <.001). Panlobular, but not other types of emphysema, was associated with reduced body mass index (−5 kg/m2 ; P = .01). Other than for dyspnea, these findings were independent of the forced expiratory volume in 1 second. Seventeen percent of smokers without COPD on spirometry had emphysema, which was independently associated with reduced walk distance. Conclusions Emphysema subtypes on CT are common in smokers with and without COPD. Centrilobular and panlobular emphysema, but not paraseptal emphysema, have considerable symptomatic and physiological consequences.
Background The adult burden of atopic dermatitis (AD) is poorly characterized. Objective We sought to characterize AD burden in adults with moderate to severe disease from the patient's perspective. ...Methods Patient-reported outcomes collected at screening in a phase 2b clinical trial of dupilumab included pruritus numeric rating scale, 5-Dimension Pruritus Scale, subjective components of SCORing AD, Patient-Oriented Eczema Measure, Hospital Anxiety and Depression Scale, Dermatology Life Quality Index, and 5-Dimension EuroQol. Results Most of the 380 patients had been living with AD for nearly all their lives, whereas approximately 40% were given a diagnosis as adults; 40.3% had asthma and 60.5% had other allergic conditions. Despite 48.2% of patients using systemic therapies in the past year, patients reported problems with itch frequency (85% of patients), duration (41.5% reported itching ≥18 h/d), and severity (6.5 of 10 on numeric rating scale); 55% reported AD-related sleep disturbances 5 d/wk or more. Hospital Anxiety and Depression Scale scores suggesting clinically relevant anxiety or depression were reported by 21.8% of patients. Quality of life was impaired on Dermatology Life Quality Index and 5-dimension EuroQol. Limitations This study had limited generalizability; conclusions may not reflect those with mild AD or not participating in a clinical trial. Conclusions Adults with moderate to severe AD report multidimensional burden including disease activity, patient-reported symptoms, comorbidities, and quality-of-life impact.
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