Blood eosinophils and fractional exhaled nitric oxide are prognostic and predictive biomarkers in childhood asthma.

BACKGROUND: Blood eosinophils and fractional exhaled nitric oxide (Feno) are prognostic biomarkers for exacerbations and predict lung function responses to dupilumab in adolescents and adults with asthma. OBJECTIVE: We evaluated the relationship between baseline blood eosinophils and Feno and response to dupilumab in children with asthma. METHODS: Children aged 6 to 11 years with uncontrolled moderate-to-severe asthma (n = 408) were randomized to receive dupilumab 100/200 mg by body weight or volume-matched placebo every 2 weeks for 52 weeks. Annualized exacerbation rate (AER) reduction and least squares mean change in prebronchodilator percent predicted forced expiratory volume in 1 second (ppFEV1) at week 12 were assessed according to cutoff baseline levels for Feno (<20 ppb vs ≥20 ppb) and blood eosinophil count (<150, ≥150 to <300, ≥300 to <500, and ≥500 cells/µL). Quadrant analyses in populations defined by biomarker thresholds and spline models across continuous end points assessed the relationship with Feno and eosinophil count. Interaction testing evaluated the independent roles of Feno and blood eosinophils as predictive markers. RESULTS: Exacerbation risk and magnitude of AER reduction increased in subgroups with higher baseline biomarker levels. Quadrant analyses revealed that disease of patients with either elevated Feno or eosinophil counts demonstrated a clinical response to dupilumab. Interaction testing indicated blood eosinophil counts or Feno independently added value as predictive biomarkers. CONCLUSIONS: In children with uncontrolled moderate-to-severe asthma, blood eosinophil counts and Feno are clinically relevant biomarkers to identify those at risk for asthma exacerbations, as well as those with disease with clinical response to dupilumab. TRIAL REGISTRATION: Liberty Asthma VOYAGE ClinicalTrials.gov NCT02948959.

Dupilumab Reduces Oral Corticosteroid Use in Patients With Corticosteroid-Dependent Severe Asthma: An Analysis of the Phase 3, Open-Label Extension TRAVERSE Trial.

BACKGROUND: Many patients with severe asthma require chronic corticosteroid treatment to maintain asthma control. RESEARCH QUESTION: Are the reduction in oral corticosteroid (OCS) use and the clinical efficacy observed with dupilumab treatment maintained long-term in patients with severe OCS-dependent asthma? STUDY DESIGN AND METHODS: The LIBERTY ASTHMA TRAVERSE study (ClinicalTrials.gov identifier: NCT02134028) was a multinational, multicenter, single-arm, open-label extension study in patients ≥ 12 years of age with asthma who participated in previous dupilumab studies. Treatment consisted of dupilumab 300 mg every 2 weeks for up to 96 weeks. In this analysis, we present the data from patients who initially enrolled in the LIBERTY ASTHMA VENTURE study (ClinicalTrials.gov identifier: NCT02528214), a 24-week placebo-controlled study of dupilumab in patients with OCS-dependent severe asthma, and continued in the TRAVERSE study. The subgroups analyzed were: those who received dupilumab in both (dupilumab/dupilumab group) and those who received placebo in the VENTURE study and dupilumab in the TRAVERSE study (placebo/dupilumab group). Outcomes included OCS use, exacerbation rates, and measures of lung function and asthma control. RESULTS: Ninety patients treated with dupilumab/dupilumab and 97 patients treated with placebo/dupilumab in the VENTURE study were enrolled and treated in the TRAVERSE study, with a mean OCS dosage of 11.0 mg/d (dupilumab) and 11.6 mg/d (placebo) at VENTURE study baseline. At TRAVERSE week 0, the mean daily OCS dosage was 3.1 mg/d and 6.4 mg/d (percentage decrease from the VENTURE study baseline, 68.8% and 41.3%) for the dupilumab/dupilumab group and placebo/dupilumab group, respectively, and decreased to 2.2 mg/d and 4.9 mg/d (78.3% and 53.4%) at week 48 and to 1.2 mg/d and 3.0 mg/d (89.3% and 74.4%) at week 96, respectively. Exacerbation rates were low during the TRAVERSE study. Further improvements from the VENTURE to TRAVERSE studies also were seen in FEV1 and 5-item Asthma Control Questionnaire scores. Safety findings were consistent with the known dupilumab safety profile. INTERPRETATION: In the open-label TRAVERSE study, dupilumab demonstrated the ability to sustain the OCS dosage reduction from the parent OCS-sparing study, while maintaining a low exacerbation rate and improved lung function. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT02134028 (TRAVERSE) and NCT02528214 (VENTURE); URL: www. CLINICALTRIALS: gov.

Preclinical and clinical experience with dupilumab on the correlates of live attenuated vaccines.

Background: The safety and tolerability of live attenuated vaccines in patients administered dupilumab for moderate-to-severe asthma have not been previously evaluated. During the LIBERTY ASTHMA TRAVERSE open-label extension study (ClinicalTrials.gov identifier NCT02134028), a yellow fever outbreak in Brazil required administration of a live attenuated vaccine to at-risk individuals. Objective: Our aim was to evaluate immune response to a live attenuated vaccine in the context of IL-4 receptor blockade (REGN1103, a dupilumab surrogate) in mice and in dupilumab-treated patients with moderate-to-severe asthma who participated in TRAVERSE. Methods: In the preclinical study, mice were coadministered REGN1103/isotype control and live attenuated influenza vaccine/control, followed by influenza virus challenge. During TRAVERSE, 37 patients discontinued dupilumab treatment and were administered 17D live attenuated yellow fever vaccine (YFV). Safety and tolerability data, dupilumab serum concentrations, and plaque reduction neutralization titers before and after vaccination were collected. Results: In the preclinical study, there was no impact of REGN1103 on vaccine efficacy in mice. In TRAVERSE, all 37 patients who received YFV achieved seroprotection despite most having therapeutic levels of dupilumab, with the magnitude of response appearing unrelated to prevaccination dupilumab concentrations. No instances of vaccine-related adverse events or vaccine hypersensitivity were reported in 36 patients; 1 patient reported nonserious body ache, malaise, and dizziness 7 days after vaccination but recovered fully. Conclusion: The preclinical model suggested that dupilumab does not affect the efficacy of live attenuated influenza vaccine. The live attenuated YFV did not raise safety concerns and appeared to be well tolerated in patients with asthma who recently discontinued dupilumab treatment, and dupilumab concentrations had no apparent impact on immunologic response to the vaccine.

Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study.

BACKGROUND: Clinical trials have shown treatment benefits of dupilumab in patients with uncontrolled asthma for up to 1 year. This study aimed to evaluate the long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma, as data for extended treatment with dupilumab beyond 1 year are not available. METHODS: TRAVERSE was an open-label extension study in 362 hospitals and clinical centres across 27 countries that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in adults and adolescents (aged 12-84 years) with moderate-to-severe or oral-corticosteroid-dependent severe asthma who had completed a previous dupilumab asthma study (phase 2A EXPEDITION, phase 2B DRI [P2b], phase 3 QUEST, or VENTURE). The primary endpoint was the number and percentage of patients with any treatment-emergent adverse events. Secondary endpoints included annualised exacerbation rate (AER) over the treatment period and change from parent study baseline in pre-bronchodilator FEV1, the five-item asthma control questionnaire (ACQ-5), the asthma quality of life questionnaire (AQLQ), type 2 biomarkers (blood eosinophils and serum total IgE), and anti-drug antibodies (ADAs). Statistical analyses were descriptive. We report safety in all enrolled patients, and efficacy in patients with non-oral-corticosteroid-dependent asthma and in subgroups, including patients with a type 2 inflammatory phenotype who received 148 weeks of treatment. This study is registered with ClinicalTrials.gov, NCT02134028. FINDINGS: Between Aug 5, 2014, and Oct 11, 2019, of 2302 patients assessed for eligibility, 2282 adults and adolescents were enrolled (median age 50 years, 62·1% female and 37·9% male). Safety during TRAVERSE was consistent with the known dupilumab safety profile. The proportion of patients reporting treatment-emergent adverse events throughout the study duration was similar to that observed in the parent studies and ranged from 76·3% to 94·7%. The most frequently reported treatment-emergent adverse events were nasopharyngitis (17·5-25·9%), injection-site erythema (2·2-23·4%), and bronchitis (9·3-19·0%). Serious asthma exacerbations (0·5-3·6%) and pneumonia (0·7-2·7%) were the most frequently reported serious adverse events. There were four treatment-emergent adverse events leading to death. Efficacy during TRAVERSE was also consistent with the results of parent studies. In patients who were non-oral-corticosteroid-dependent, AER remained low (0·277-0·327) across parent study and treatment groups, pre-bronchodilator FEV1 improvements were sustained to the end of treatment at week 96 (mean changes from parent study baseline ranged from 0·22 L [SD 0·44] to 0·33 L [0·44] across parent study and treatment groups), and improvements in ACQ-5 and AQLQ scores were sustained to the last timepoint assessed at week 48. Rapid improvements were observed in pre-bronchodilator FEV1 and sustained improvements were seen in all outcome measures for patients given dupilumab who previously received placebo in parent studies; further improvements in AER, asthma control, and health-related quality of life were observed in patients who continued receiving dupilumab. Blood eosinophils and serum total IgE decreased progressively. ADA status had no effect on safety or efficacy. In the subgroup of patients with a type 2 inflammatory phenotype followed-up for 148 weeks, AER decreased progressively, and initial lung function improvements were sustained over 148 weeks. INTERPRETATION: Data show that safety and efficacy of dupilumab in adult and adolescent patients with moderate-to-severe asthma are sustained when treatment is extended up to 148 weeks. These findings therefore support the long-term use of dupilumab in this patient population. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma.

BACKGROUND: Children with moderate-to-severe asthma continue to have disease complications despite the receipt of standard-of-care therapy. The monoclonal antibody dupilumab has been approved for the treatment of adults and adolescents with asthma as well as with other type 2 inflammatory diseases. METHODS: In this 52-week phase 3, randomized, double-blind, placebo-controlled trial, we assigned 408 children between the ages of 6 and 11 years who had uncontrolled moderate-to-severe asthma to receive a subcutaneous injection of dupilumab (at a dose of 100 mg for those weighing ≤30 kg and 200 mg for those weighing >30 kg) or matched placebo every 2 weeks. All the children continued to receive a stable dose of standard background therapy. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included the change from baseline in the percentage of predicted prebronchodilator forced expiratory volume in 1 second (ppFEV1) at week 12 and in the score on the Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) at week 24. End points were evaluated in the two primary efficacy populations who had either a type 2 inflammatory asthma phenotype (≥150 blood eosinophils per cubic millimeter or a fraction of exhaled nitric oxide of ≥20 ppb at baseline) or a blood eosinophil count of at least 300 cells per cubic millimeter at baseline. RESULTS: In patients with the type 2 inflammatory phenotype, the annualized rate of severe asthma exacerbations was 0.31 (95% confidence interval [CI], 0.22 to 0.42) with dupilumab and 0.75 (95% CI, 0.54 to 1.03) with placebo (relative risk reduction in the dupilumab group, 59.3%; 95% CI, 39.5 to 72.6; P<0.001). The mean (±SE) change from baseline in the ppFEV1 was 10.5±1.0 percentage points with dupilumab and 5.3±1.4 percentage points with placebo (mean difference, 5.2 percentage points; 95% CI, 2.1 to 8.3; P<0.001). Dupilumab also resulted in significantly better asthma control than placebo (P<0.001). Similar results were observed in the patients with an eosinophil count of at least 300 cells per cubic millimeter at baseline. The incidence of serious adverse events was similar in the two groups. CONCLUSIONS: Among children with uncontrolled moderate-to-severe asthma, those who received add-on dupilumab had fewer asthma exacerbations and better lung function and asthma control than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; Liberty Asthma VOYAGE ClinicalTrials.gov number, NCT02948959.).

Dupilumab improves upper and lower airway disease control in chronic rhinosinusitis with nasal polyps and asthma.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) and type 2 asthma share the same inflammatory pathophysiology and are frequent comorbidities. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin 4 and interleukin 13, which are key and central drivers of type 2 inflammation. OBJECTIVE: We report the effect of dupilumab vs placebo on outcome measures of the upper and lower airways and health-related quality of life (HRQoL) in the pooled population of patients with CRSwNP and comorbid asthma from the phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies. METHODS: In these randomized, double-blind, placebo-controlled trials, patients received subcutaneous dupilumab 300 mg (n = 438) or placebo (n = 286) every 2 weeks on a background of mometasone furoate nasal spray. Changes from baseline at week 24 in the upper and lower airway outcome measures are reported. RESULTS: Of the 724 patients randomized, 428 (59.1%) had comorbid asthma. In patients with asthma at week 24, dupilumab vs placebo improved the nasal polyp score (-2.04), patient-reported nasal congestion score (-1.04), Lund-Mackay computed tomography scan score (-6.43), peak nasal inspiratory flow (46.15 L/min), and 22-item sinonasal outcome test score (-21.42; all P < .001). The forced expiratory volume in 1 second and 6-item asthma control questionnaire scores were also markedly improved with dupilumab vs placebo. The most common adverse events (nasopharyngitis, headache, injection-site erythema, worsening of nasal polyposis, and asthma) were more frequent with placebo than dupilumab. CONCLUSION: Dupilumab improved upper and lower airway outcome measures and HRQoL in patients with severe CRSwNP and comorbid asthma and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52).

Design and monitoring of survival trials in complex scenarios.

This paper proposes an approach to design and monitor survival trials accounting for complex scenarios such as delayed treatment effect, treatment dilution, and treatment crossover. These scenarios often lead to non-proportional hazards, making study design and monitoring more difficult. We demonstrate that, with event times following piecewise exponential distributions, the log-rank statistic as well as its variance-covariance structure can be easily computed, which greatly simplifies study design and monitoring. As the number of pieces in the exponential distributions can be arbitrary, this approach can handle a wide range of scenarios. Three hypothetical examples are used to demonstrate its potential use.

Changes of myocardial lipidomics profiling in a rat model of diabetic cardiomyopathy using UPLC/Q-TOF/MS analysis.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious cardiac dysfunction induced by changes in the structure and contractility of the myocardium that are initiated in part by alterations in energy substrates. The underlying mechanisms of DCM are still under controversial. The observation of lipids, especially lipidomics profiling, can provide an insight into the know the biomarkers of DCM. The aim of our research was to detect changes of myocardial lipidomics profiling in a rat model of diabetic cardiomyopathy. METHODS: Diabetic cardiomyopathy was induced by feeding a high-sucrose/fat diet (HSFD) for 28 weeks and streptozotocin (30 mg/kg, intraperitoneally). The ultra-high-performance liquid chromatography (UPLC) coupled to quadruple time-of flight (QTOF) mass spectrometer was used to acquire and analyze the lipidomics profiling of myocardial tissue. Meanwhile, parameters of cardiac function were collected using cardiac catheterization, and the cardiac index was calculated, and fasting blood glucose and lipid levels were measured by an ultraviolet spectrophotometric method. RESULTS: We detected 3023 positive ion peaks and 300 negative ion peaks. Levels of phosphatidylcholine (PC) (22:6/18:2), PC (22:6/18:1), PC (20:4/16:1), PC (16:1/18:3), phosphatidylethanolamine (PE) (20:4/18:2), and PE (20:4/16:0) were down-regulated, and PC (20:2/18:2), PC (18:0/16:0), and PC (20:4/18:0) were up-regulated in DCM model rats, when compared with control rats. Cardiac functions signed as values of left ventricular systolic pressure, maximal uprising velocity of left ventricular pressure and maximal decreasing velocity of left ventricular pressure were injured by 21-44%, and the cardiac index was increased by 25%, and fasting blood glucose and lipids were increased by 34-368%. Meanwhile, the cardiac lipid-related biomarkers have significant correlation with changes of cardiac function and cardiac index. CONCLUSIONS: UPLC/Q-TOF/MS analysis data suggested changes of some potential lipid biomarkers in the development of cardiac dysfunction and hypertrophy of diabetic cardiomyopathy, which may serve as potential important targets for clinical diagnosis and therapeutic intervention of DCM in the future.

Example-based illustrations of design, conduct, analysis and result interpretation of multi-regional clinical trials.

Extensive research has been conducted in the Multi-Regional Clinical Trial (MRCT) area. To effectively apply an appropriate approach to a MRCT, we need to synthesize and understand the features of different approaches. In this paper, examples are used to illustrate considerations regarding design, conduct, analysis and interpretation of result of MRCTs. We start with a brief discussion of region definitions and the scenarios where different regions have differing requirements for a MRCT. We then compare different designs and models as well as the corresponding interpretation of the results. We highlight the importance of paying special attention to trial monitoring and conduct to prevent potential issues associated with the final trial results. Besides evaluating the overall treatment effect for the entire MRCT, we also consider other key analyses including quantification of regional treatment effects within a MRCT, and assessment of consistency of these regional treatment effects.

Sequential designs for individualized dosing in phase I cancer clinical trials.

This paper addresses dose finding in clinical trials where individuals exhibit biologic characteristics that alter the toxicity risks of the individuals. In these situations, instead of determining a dose that works for every patient, the trial aims to identify a dosing algorithm that prescribes dose according to the patient's biomarker or pharmacokinetic expression. Specifically, we aim to dose patients around a pre-specified level of area under the curve of irinotecan concentration using the patients' baseline phenotypes that predict drug clearance. We propose least squares recursion procedures to estimate the dosing algorithm sequentially with an aim to treat patients in the trial around the true unknown dosing algorithm, and introduce a novel application of an eigenvalue theory that guarantees convergence to the true dosing algorithms. Our simulation study demonstrates that using an eigenvalue constraint improves the efficiency of the recursion by as large as 40%, while concentrating in-trial patient allocation around the true dosing algorithm. We also provide practical guidance on design calibration, and design future irinotecan studies based on data from our first trial.

A case study of modeling and exposure-response prediction for count data.

Even with two doses of an experimental drug in Phase III studies, with the commonly used approach for assessing treatment effects of individual doses, it may still be difficult to determine the final commercial dose. In such a scenario, with plasma concentration data collected in the studies, a modeling approach can be applied to predict treatment effects at different plasma concentration levels. Through an established relationship between plasma concentration and dose, the treatment effects of doses not studied in the Phase III studies can then be predicted. The results can further be applied to justify the final dose confirmation or selection. In this article, a Phase III program example with count data as the primary endpoint in the multiple sclerosis area is used to illustrate the application of such a technique for dose confirmation. Several models, such as the overdispersion Poisson model, negative binomial model, and recurrent event models, are considered. The negative binomial model is preferable due to better data fitting and the capability of within-treatment assessment and between-treatment comparison.

Multi-regional clinical trial design and consistency assessment of treatment effects.

We can apply both fixed and random effects models to multi-regional clinical trial (MRCT) design and data analysis. Thoroughly, understanding the features of these models in an MRCT setting will help assessing their applicability to an MRCT. In this paper, we discuss the interpretations of trial results from these models. We also evaluate the impact of the number of regions and the sample size configuration across the regions on the required total sample size for the overall treatment effect assessment. For quantifying treatment effects of individual regions, the empirical shrinkage estimator and the James-Stein type shrinkage estimator associate with smaller variability compared with the regular sample estimator. We conduct computation and simulation to compare the performance of these estimators when they are applied to assess consistency of treatment effects across regions. We use a multinational trial example to illustrate the application of these methods.