Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Long-term management options that specifically target the underlying inflammation in eosinophilic oesophagitis are needed. Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13; we aimed to assess its long-term efficacy and safety in adults and adolescents with eosinophilic oesophagitis enrolled in part B of the LIBERTY EoE TREET study who continued to part C (part B-C). METHODS: LIBERTY EoE TREET was a three-part, double-blind, randomised, placebo-controlled, phase 3 study conducted at 65 hospitals and private clinics across ten countries in Australia, Canada, Europe, and the USA. Adults or adolescents (aged ≥12 years) with a diagnosis of eosinophilic oesophagitis by endoscopic biopsy (peak oesophageal intraepithelial eosinophil count ≥15 eosinophils per high-power field [eos/hpf]) from at least one oesophageal region despite 8 weeks of high-dose proton-pump inhibitors (PPIs) and a Dysphagia Symptom Questionnaire (DSQ) score of at least 10 at baseline were eligible. In part B, patients were randomly (1:1:1) assigned to receive subcutaneous dupilumab 300 mg either weekly or every 2 weeks or weekly placebo until week 24. Randomisation was done centrally by interactive voice response system/web response system (IVRS/IWRS) in blocks and stratified according to age (<18 years vs ≥18 years) and use of PPI at randomisation (yes vs no). Patients, study sponsors, and investigators involved in the study were masked to the randomisation outcome. Eligible patients who received placebo in part B and continued to part C were randomly assigned again (1:1) to either weekly dupilumab (placebo/weekly dupilumab group) or dupilumab every 2 weeks (placebo/dupilumab every 2 weeks), with matching placebo alternating with dupilumab doses. Patients who were randomly assigned to one of the dupilumab dose regimens in part B remained on the same regimen in part C for an additional 28 weeks (weekly dupilumab/weekly dupilumab group or dupilumab every 2 weeks/dupilumab every 2 weeks group). Treatment assignment in part C was managed by IVRS/IWRS to maintain blinding of treatment assignment in part B. The primary endpoint of this trial has been reported; here, we report the week 52 outcomes of part B-C. Efficacy and safety analyses were done in the part C safety-analysis set, which included all patients who were randomised in part B, entered part C, and received any study drug in part C. This completed trial is registered with ClinicalTrials.gov, number NCT03633617. FINDINGS: Between Aug 12, 2019, and March 11, 2021, 240 patients were randomly assigned into part B, of whom 227 (74 in placebo group, 74 in weekly dupilumab group, and 79 in dupilumab every 2 weeks group) continued into part B-C and were included in the current analysis. 37 patients switched from placebo to weekly dupilumab, and 37 from placebo to dupilumab every 2 weeks; 74 patients continued on weekly dupilumab and 79 continued on dupilumab every 2 weeks. Of the patients who entered part B-C, 75 (33%) were adolescents, 145 (64%) male, 82 (36%) female, and 206 (91%) White. At week 52, 55 (85%) patients in the weekly dupilumab/weekly dupilumab group, 25 (68%) in the placebo/weekly dupilumab group, 54 (74%) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and 23 (72%) in the placebo/every 2 weeks dupilumab group achieved a peak oesophageal intraepithelial eosinophil count of 6 eos/hpf or less. Mean percent change from part B baseline in peak eosinophil count was -95·9% (95% CI -96·9 to -94·9) in the weekly dupilumab/weekly dupilumab group, -84·2% (-98·3 to -70·2) in the placebo/weekly dupilumab group, -84·8% (-94·3 to -75·2) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -91·2% (-95·9 to -86·5) in the placebo/every 2 weeks dupilumab group at week 52. At week 52, mean change from part B baseline in eosinophilic oesophagitis Histology Scoring System (HSS) grade score was -1·0 point (95% CI -1·1 to -0·9) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group; mean change in eosinophilic oesophagitis HSS stage score was -0·9 points (-1·0 to -0·8) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group. Similar improvements were observed in the every 2 weeks dupilumab groups. Mean absolute change from part B baseline in DSQ score was -30·3 points (95% CI -34·5 to -26·1) in the weekly dupilumab/weekly dupilumab group, -27·3 points (-32·1 to -22·4) in the placebo/weekly dupilumab group, -20·9% (-25·4 to -16·3) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -23·7% (-29·1 to -18·3) in the placebo/every 2 weeks dupilumab group at week 52. Mean change from part B baseline in endoscopic reference score was -5·4 points (95% CI -6·1 to -4·6) in the weekly dupilumab/weekly dupilumab group, -6·1 points (-7·3 to -4·9) in the placebo/weekly dupilumab group, -5·2% (-6·0 to -4·4) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -4·3% (-5·4 to -3·1) in the placebo/every 2 weeks dupilumab group at week 52. During part B-C, one (3%) patient in the placebo/weekly dupilumab group, one (1%) in the weekly dupilumab/weekly dupilumab group, and one (3%) in the placebo/every 2 weeks dupilumab group received rescue medication. One (3%) patient in the placebo/every 2 weeks dupilumab group and one (1%) in the dupilumab every 2 weeks/dupilumab every 2 weeks group underwent a rescue oesophageal dilation procedure. The most common treatment-emergent adverse events were injection-site reactions (ten [14%] in the weekly dupilumab/weekly dupilumab group and four [11%] in the placebo/weekly dupilumab group). INTERPRETATION: Improvements in histological, symptomatic, endoscopic, and molecular features of eosinophilic oesophagitis observed after 24 weeks of weekly dupilumab treatment were maintained or continued to improve to week 52. These findings reinforce the importance of weekly dupilumab, rather than every 2 weeks, for the improvement of symptoms in adults and adolescents with eosinophilic oesophagitis. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.

Burden of carbapenem non-susceptible infections in high-risk patients: systematic literature review and meta-analysis.

BACKGROUND: Owing to their resistance to an important class of antibiotics, the prevention and treatment of carbapenem-resistant (CR)/non-susceptible Gram-negative (GN) infections has become an important public health objective. We conducted a systematic review and meta-analysis of published literature to evaluate the burden of CR GN infections, focusing on high-risk patients such as transplant recipients, or patients with cancer, renal impairment, or sepsis. METHODS: MEDLINE®, Cochrane Central, and Embase® were searched between 2010 and March 2019. Abstracts and full-text articles were screened in duplicate. Random effects meta-analysis was conducted when reported outcomes were sufficiently similar. RESULTS: Twenty-six publications were eligible. Meta-analyses found increased mortality associated with CR infections among high-risk patients in both unadjusted analysis (8 studies; summary unadjusted odds ratio [OR]: 5.85; 95% confidence interval [CI]: 3.69, 9.26; I2 = 19.8%) and adjusted analysis (5 studies; summary hazard ratio [HR]: 4.67; 95% CI: 2.18, 9.99; I2 = 77.7%), compared to patients with carbapenem-susceptible (CS) infections or no infection. Increased mortality was also seen in subgroup analyses by length of follow-up (either short-term or long-term) or causative pathogen. A limited number of studies found that CR GN infections increased the risk for mechanical ventilation, adverse events such as graft failure or acute rejection in solid organ transplant recipients, increased renal failure or nephrotoxicity, and an increase in readmissions and costs, though the findings reported in the literature were not consistent. CONCLUSION: This systematic literature review and meta-analysis indicates that CR GN infections in high-risk patients are associated with increased mortality, emphasizing the need for antimicrobial stewardship and infection control in hospitals which treat high-risk patients and for the development of effective antimicrobials with favorable efficacy and safety profiles for the treatment of CR GN infections.

Contributing Factors to the Clinical and Economic Burden of Patients with Laboratory-Confirmed Carbapenem-Nonsusceptible Gram-Negative Urinary Tract Infections.

PURPOSE: We explored patient- and hospital-level predictor variables for worse clinical and economic outcomes in carbapenem-nonsusceptible urinary tract infections (UTIs). PATIENTS AND METHODS: We used electronic data (January 2013-September 2015; 78 US hospitals) from a large multicenter clinical database. Nonduplicate gram-negative isolates were considered carbapenem-nonsusceptible if they had resistant/intermediate susceptibility. Potential predictors of outcomes (mortality, 30-day readmissions, length of stay [LOS], hospital total cost, and net gain/loss per case) were examined using generalized linear mixed models. Significant predictors were identified based on statistical significance and model goodness-of-fit criteria. RESULTS: A total of 1439 carbapenem-nonsusceptible urine cases were identified. The mortality rate was 5.5%; the hospital readmission rate was 25.0%. Mean (standard deviation [SD]) LOS, total cost, and loss per case were 12 (14) days, $21,502 ($37,172), and $5828 ($26,540), respectively. Hospital-onset (vs community-onset) infection significantly impacted all outcomes: mortality (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.19-4.11; P=.01), 30-day readmissions (OR, 2.35; 95% CI, 1.49-3.71; P<.001), LOS (25.7 vs 10.2 days; P<.001), hospital total cost ($67,810 vs $22,141; P<.001), and loss per case (-$28,054 vs -$10,809; P<.001). Mechanical ventilation/intensive care unit status, neoplasms, and other underlying diseases were also common predictors for worse outcomes overall; polymicrobial infection was significantly associated with worse economic outcomes. Other key predictors were >1 prior hospitalization for 30-day readmissions, high Acute Laboratory Risk of Mortality Score for mortality, LOS, cost, and hospital teaching status for cost. CONCLUSION: Hospital-onset infections, polymicrobial infections, higher clinical severity, and underlying diseases are key predictors for worsened overall burden of carbapenem-nonsusceptible gram-negative UTIs.

Cost-effectiveness Analysis of Golimumab in the Treatment of Non-Radiographic Axial Spondyloarthritis in Scotland.

INTRODUCTION: The aim of this study is to assess the cost-effectiveness of golimumab for the treatment of non-radiographic axial spondyloarthritis (nr-axSpA) vs. conventional therapy and other tumor necrosis factor inhibitors from the Scottish payer perspective. METHODS: A model comprising a short-term decision tree and a long-term Markov model was developed to compare cost-effectiveness (incremental costs per quality-adjusted life-year [QALY]) for patients in Scotland with nr-axSpA treated by conventional therapy, adalimumab, certolizumab pegol, etanercept, or golimumab for a lifetime period. A network meta-analysis (NMA) was conducted to identify clinical and safety data for treatments and synthesize the available evidence into relative treatment effects between comparators. The probability of patients achieving an Assessment of SpondyloArthritis International Society 20/40% response criteria (ASAS20/ASAS40) or a 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index score (BASDAI50) at week 12 was obtained from the NMA for each of the comparators. Baseline health state utilities were based on the EQ-5D questionnaire collected in the golimumab GO-AHEAD study. The cost of treatment was calculated based on drug acquisition, drug administration, and initiation/monitoring costs. RESULTS: Golimumab resulted in an increase of 2.06 QALYs and additional cost of £39,770 compared with conventional therapy. Incremental cost per QALY gained was £19,280 for golimumab, which was lower than adalimumab (£19,737), etanercept (£20,089), and higher than certolizumab pegol (£18,710). Golimumab remained cost-effective throughout a range of sensitivity analyses where key assumptions were tested. CONCLUSIONS: From a Scottish perspective, golimumab was a cost-effective treatment for nr-axSpA compared with conventional therapy at a willingness-to-pay threshold of £30,000 per QALY. FUNDING: Merck & Co., Inc.