Demonstrating efficacy and effectiveness in clinical studies with recurrent event as primary end point: a chronic obstructive pulmonary disease example.

Pivotal clinical trials of persistent disorders such as chronic obstructive pulmonary disease and severe asthma often utilize recurrent event (e.g., exacerbations) as primary study end point. Such infrequent and correlated end points usually have skewed distributions, which can result in clinical efficacy criterion being met even while clinical effectiveness may be poor. Patients, prescribers and, increasingly, payers want evidence of both a medicine's clinical efficacy and its effectiveness. This duality in evidentiary requirements is causing a shift from the traditional one-size-fits-all blockbuster drug development paradigm to newer patient-centric models. Using a simulated study, we illustrate how clinical studies using enrichment designs can collect and present such patient-centric evidence that will simultaneously demonstrate clinical efficacy and effectiveness, while increasing probability of trial success and overall efficiency.

Precision medicine in clinical practice.

In reports of clinical efficacies of new therapies in prospective randomized controlled trials, evidence showing proportion of respondents who meet the minimum clinically important difference in prespecified clinical end points are often not presented. Such reporting deficiency negatively impacts precision medicine practice in clinics. As all patient-centric decisions are binary, patients must be understood as individuals and not group averages. At any visit, a clinician must decide whether to prescribe or not to prescribe a unique therapy to a unique patient at that unique time. I submit my perspective here that reports of clinical evidence of drug efficacy must routinely include data and summary statistics from dichotomization of clinical end points at the prespecified minimum clinically important difference or higher cutoffs to inform personalized treatment decisions in clinics.

Relationship of Blood Eosinophil Count to Exacerbations in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Eosinophilic airway inflammation characterizes a chronic obstructive pulmonary disease (COPD) phenotype that requires more study. OBJECTIVE: To investigate the relationship of blood eosinophil count to exacerbations in COPD. METHODS: Using administrative pharmacy and health care utilization data from 2009 to 2012, we retrospectively identified patients 40 years or older with a COPD diagnosis, postbronchodilator FEV1/forced vital capacity ratio of less than 0.7, and a blood eosinophil count (N = 7,245). COPD exacerbations were defined as hospitalizations or emergency department visits with a primary diagnosis of COPD, or outpatient visits with systemic corticosteroid dispensing within ±14 days associated with an encounter code consistent with a COPD exacerbation. The relationship between the index blood eosinophil count and the rate of COPD exacerbations in the follow-up year was determined by multivariable analyses. RESULTS: Patients with COPD were predominantly male (57.1%), white (71.8%), often current or past smokers (75.4%), and had frequent comorbidities; 19.0% had eosinophil counts of greater than or equal to 300 cells/mm3, 76.1% were classified as moderate to very severe by lung function, and the COPD exacerbation rate was 0.38 per year (95% CI, 0.37-0.40). After adjustment for potential confounders, COPD exacerbations during 1-year follow-up were significantly greater for patients with blood eosinophil counts of greater than or equal to 300 cells/mm3 (rate ratio [RR], 1.25; 95% CI, 1.10-1.43), greater than or equal to 400 cells/mm3 (RR, 1.48; 95% CI, 1.26-1.75), and greater than or equal to 500 cells/mm3 (RR, 1.76; 95% CI, 1.45-2.14), respectively, compared with patients with eosinophils lower than the cutoffs. CONCLUSIONS: In this study, high blood eosinophil counts were an independent risk factor for future exacerbations in patients with COPD, a phenotype that might benefit from therapy directed at eosinophilic-driven disease and inflammation.

Burden of Chronic Oral Corticosteroid Use by Adults with Persistent Asthma.

BACKGROUND: Chronic oral corticosteroid (C-OCS) use in asthma is an indicator of disease severity, but its risk factors are largely unknown. OBJECTIVE: To describe patient characteristics and disease burden associated with C-OCS use by adults with persistent asthma. METHODS: We identified 9546 patients aged 18 to 64 years in a large managed care organization who met the Healthcare Effectiveness Data and Information Set 2-year criteria (2009-2010) for persistent asthma. A subgroup had blood eosinophil counts. We calculated cumulative OCS dispensed per patient in 2010 and examined the distribution of disease characteristics by average daily amounts of OCS dispensed. C-OCS use was defined as 2.5 mg/d or more. Baseline factors (2010) associated with C-OCS use during follow-up (2011) were investigated by multivariable Poisson regression. RESULTS: At baseline, 782 (8.2%) patients were C-OCS users. Compared with patients who received no or less than 2.5 mg/d OCS, C-OCS users were older and more often female and ethnic minorities; and had more comorbidities, asthma specialist care, greater step-care level, controllers, asthma exacerbations, and greater blood eosinophil counts (all P < .01). Baseline factors significantly associated with C-OCS use in the follow-up year included (1) demographic characteristics: older age, females, blacks versus whites, and whites versus others/unknown ethnicities; (2) disease burden: more asthma emergency department or hospitalization visits, greater step-care level, excessive short-acting ß2-agonist dispensed, theophylline use, asthma specialist care, and nasal polyposis; (3) greater blood eosinophil counts; and (4) most strongly, C-OCS use. CONCLUSIONS: C-OCS use was associated with more asthma burden, comorbidities, and greater blood eosinophil counts. Prior C-OCS use was the strongest predictor of future C-OCS use.

Characteristics and Outcomes of HEDIS-Defined Asthma Patients with COPD Diagnostic Coding.

BACKGROUND: Little is known of the disease burden of patients with persistent asthma (PA) who also have a chronic obstructive pulmonary disease (COPD) diagnosis code (AS-COPD). OBJECTIVE: The objective of this study was to characterize and compare patients with AS-COPD with those with PA without COPD diagnosis, and determine in AS-COPD the relationship between blood eosinophil count and future asthma exacerbations. METHODS: This retrospective cohort study used administrative pharmacy and health care utilization data to identify, characterize, and compare the burden and asthma exacerbations in adults with AS-COPD (N = 901) with those with PA (N = 2392). Negative binomial regression and Poisson regression models were used to evaluate the relationships between baseline blood eosinophil counts (high vs low) based on various cutoff points and asthma exacerbations in the follow-up year, adjusting for demographics, comorbidities, and asthma burden. RESULTS: Compared with patients with PA, those with AS-COPD were significantly (all P < .001) older, more frequently female, less well educated, more likely to be or have been a smoker, had more comorbidities, received more asthma controller medications, and had greater rates and frequencies of asthma exacerbations, but had similar blood eosinophil counts. The rate of asthma exacerbations/person-year in AS-COPD during follow-up was 1.61 (95% CI, 1.18-2.20). Patients with AS-COPD with a blood eosinophil count ≥400 cells/mm(3) had an increased rate of future asthma exacerbations compared with those whose blood eosinophil count was <400 cells/mm(3) (adjusted rate ratio, 1.44, 95% CI, 1.09-1.90). CONCLUSIONS: Compared with patients with PA, those with AS-COPD had more disease burden, but a similar relationship of high blood eosinophil count to more future asthma exacerbations. These findings suggest a common inflammatory component between AS-COPD and PA.

Self-reactive IgE exacerbates interferon responses associated with autoimmunity.

Canonically, immunoglobulin E (IgE) mediates allergic immune responses by triggering mast cells and basophils to release histamine and type 2 helper cytokines. Here we found that in human systemic lupus erythematosus (SLE), IgE antibodies specific for double-stranded DNA (dsDNA) activated plasmacytoid dendritic cells (pDCs), a type of cell of the immune system linked to viral defense, which led to the secretion of substantial amounts of interferon-α (IFN-α). The concentration of dsDNA-specific IgE found in patient serum correlated with disease severity and greatly potentiated pDC function by triggering phagocytosis via the high-affinity FcɛRI receptor for IgE, followed by Toll-like receptor 9 (TLR9)-mediated sensing of DNA in phagosomes. Our findings expand the known pathogenic mechanisms of IgE-mediated inflammation beyond those found in allergy and demonstrate that IgE can trigger interferon responses capable of exacerbating self-destructive autoimmune responses.

High blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma.

BACKGROUND: Exacerbation-associated uncontrolled asthma represents a major public health problem. The relationship of elevated blood eosinophils to this process needs study. OBJECTIVE: To determine whether a high blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma. METHODS: By using electronic pharmacy and health care data from Kaiser Permanente Southern California, 2392 patients, ages 18 to 64 years, were identified who met the Health Effectiveness Data and Information Set 2-year criteria for persistent asthma, did not manifest chronic obstructive pulmonary disease and other major illnesses, and had a blood eosinophil determination in 2010. Exacerbations (primary outcome) were defined as asthma outpatient visits that required systemic corticosteroid dispensing within ±7 days or asthma emergency department visits or hospitalizations. A period of ≥8 days defined a new exacerbation. Multivariate modelling used negative binomial and Poisson regression to examine the association between a blood eosinophil count determined in 2010 and risk of exacerbations, and ≥7 short-acting ß2-agonist (SABA) canisters dispensed (secondary outcome) in 2011 by adjusting for demographics, comorbidities, and asthma burden. RESULTS: The rate of asthma exacerbations in 2011 was 0.41 events per person year (95% CI, 0.37-0.45). Eosinophil count ≥400/mm(3) in 2010 was a risk factor for asthma exacerbations in 2011 (adjusted rate ratio 1.31 [95% CI, 1.07-1.60]; P = .009) and ≥7 SABA dispensed (adjusted risk ratio 1.17 [95% CI, 1.03-1.1.33]; P = .015). CONCLUSION: A high blood eosinophil count is a risk factor for increased future asthma exacerbations and excessive short-acting ß2-agonist use after adjustment of potential confounders in adults with persistent asthma, which suggests a higher disease burden in patients with asthma and with high blood eosinophil counts.

Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study.

BACKGROUND: Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations. In a phase 2b dose-ranging study, we aimed to assess the efficacy and safety of benralizumab, an anti-interleukin 5 receptor α monoclonal antibody that depletes blood and airway eosinophils, in adults with uncontrolled eosinophilic asthma. METHODS: We did a randomised, controlled, double-blind, dose-ranging phase 2b study. Eligible participants were adults aged 18-75 years with uncontrolled asthma using medium-dose or high-dose inhaled corticosteroids and longacting ß agonists, with two to six exacerbations in the past year. Current or former smokers were excluded. We used the ELEN index (an algorithm to predict elevated sputum eosinophils) or baseline fraction of exhaled nitric oxide to stratify patients by eosinophilic status, and with an interactive web-voice response system randomly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab, and non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg benralizumab. Study drugs were given as two subcutaneous injections every 4 weeks for the first three doses, then every 8 weeks, for 1 year. Patients, treating physicians, and study investigators were masked to treatment allocation. The primary endpoint was annual exacerbation rate in eosinophilic individuals after 1 year of follow-up. Analysis was by modified intention to treat. This study was designed with a two-sided α of 0·2 and powered at 78% for the primary outcome in the eosinophilic population. This study is registered with ClinicalTrials.gov, number NCT01238861. FINDINGS: Between Jan 3, 2011, and March 6, 2012, we randomly assigned 324 eosinophilic individuals to placebo (n=80) or benralizumab 2 mg dose (n=81), 20 mg dose, (n=81), or 100 mg dose (n=82), and 285 non-eosinophilic individuals to 100 mg benralizumab (n=142, 140 included in analysis) or placebo (n=143, 142 included in analysis). In eosinophilic individuals, benralizumab reduced exacerbation rates compared with placebo in the 100 mg group (0·34 vs 0·57, reduction 41%, 80% CI 11 to 60, p=0·096) but not in the 2 mg group (0·65 vs 0·57, difference -9%, 80% CI -59 to 26, p=0·781) or the 20 mg group (0·37 vs 0·57, reduction 36%, 80% CI 3 to 58, p=0·173). In patients with a baseline blood eosinophil cutoff of at least 300 cells per µL, exacerbation rates in the benralizumab 20 mg group (n=70) and 100 mg group (n=97) were lower than in the placebo group (n=83; 0·30 vs 0·68, reduction 57%, 80% CI 33 to 72, p=0·015 for 20 mg dose; 0·38 vs 0·68, difference 43%, 80% CI 18 to 60, p=0·049 for 100 mg dose). Our findings suggested that benralizumab 20 mg and 100 mg resided at the dose-response plateau. Treatment-emergent adverse events occurred in 277 (72%) of 385 participants receiving any benralizumab dose compared with 143 (65%) of 221 receiving placebo. Nasopharyngitis (44 [11%] patients receiving benralizumab vs 13 [6%] patients receiving placebo) and injection site reactions (60 [16%] vs eight [4%]) occurred more frequently with benralizumab than with placebo. INTERPRETATION: Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood eosinophils of at least 300 cells per µL, possibly due to targeting of the interleukin 5 receptor rather than interleukin 5 ligand. Further investigation of benralizumab treatment in phase 3 studies is warranted. FUNDING: MedImmune.

High blood eosinophil count is associated with more frequent asthma attacks in asthma patients.

BACKGROUND: The clinical importance of eosinophils in asthma has been shown by the observation of frequent exacerbation in patients with high sputum eosinophil counts and a corresponding decrease in exacerbations when anti-inflammatory therapy was adjusted to maintain low sputum eosinophil percentages. However, less is known of the relation between blood eosinophilia and asthma exacerbation. OBJECTIVE: To examine whether patients with asthma and a higher blood eosinophil count have more asthma attacks than those with a lower count. METHODS: The authors analyzed data from the National Health and Nutrition Examination Survey, an annual cross-sectional survey of the US general population. Patients with asthma and asthma attacks were identified based on participants' self-report or parental report. A high blood eosinophil count was defined using 200, 300, or 400 cells/µL as cutoffs. The primary analysis used data from 2001 through 2010 after adjusting for demographic variables, obesity, smoking, neutrophil level, and past treatment for wheezing. A secondary analysis used data from 2007 through 2010 and included recent treatment for asthma and fraction of exhaled nitric oxide level as additional adjustment variables. RESULTS: In survey years 2001 through 2010, 3,162 patients with asthma had blood eosinophil data and approximately half (54% of children and 52% of adults) reported an asthma attack in the previous year. In the primary analysis, higher blood eosinophil counts were associated with more asthma attacks in children but not in adults. The secondary analysis suggested an association in both children and adults. CONCLUSION: Patients with asthma with higher blood eosinophil counts experienced more asthma attacks than those with lower eosinophil counts.

High-resolution genomic profiles of human lung cancer.

Lung cancer is the leading cause of cancer mortality worldwide, yet there exists a limited view of the genetic lesions driving this disease. In this study, an integrated high-resolution survey of regional amplifications and deletions, coupled with gene-expression profiling of non-small-cell lung cancer subtypes, adenocarcinoma and squamous-cell carcinoma (SCC), identified 93 focal copy-number alterations, of which 21 span <0.5 megabases and contain a median of five genes. Whereas all known lung cancer genes/loci are contained in the dataset, most of these recurrent copy-number alterations are previously uncharacterized and include high-amplitude amplifications and homozygous deletions. Notably, despite their distinct histopathological phenotypes, adenocarcinoma and SCC genomic profiles showed a nearly complete overlap, with only one clear SCC-specific amplicon. Among the few genes residing within this amplicon and showing consistent overexpression in SCC is p63, a known regulator of squamous-cell differentiation. Furthermore, intersection with the published pancreatic cancer comparative genomic hybridization dataset yielded, among others, two focal amplicons on 8p12 and 20q11 common to both cancer types. Integrated DNA-RNA analyses identified WHSC1L1 and TPX2 as two candidates likely targeted for amplification in both pancreatic ductal adenocarcinoma and non-small-cell lung cancer.

Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification.

BACKGROUND: Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity. METHODS: Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration. RESULTS: Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion. CONCLUSIONS: These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.