Asthma Clinical Trials Research Articles

Proxy-reported questionnaires for young children with asthma: a structured review

Which proxy-reported outcome measures have been developed for use with children aged 6 years and younger to assess asthma symptoms, asthma control, and asthma-specific health-related quality of life, and do these questionnaires' measurement properties support their use as end-points in clinical trials? A two-phase literature search was conducted: 1) studies describing relevant questionnaires were identified, and the questionnaires were assessed against predefined criteria; 2) studies providing information on the measurement properties of questionnaires meeting the predefined inclusion criteria were identified. Literature sources included PubMed and EMBASE databases, scientific conference proceedings, a clinical trial registry, and a quality of life instrument database. The initial search of literature databases and conference abstracts identified 631 records. 20 paediatric asthma proxy-reported outcome instruments were identified; seven met the inclusion criteria: Childhood Asthma Control Test, Control de Asma en Niños Questionnaire, Pediatric Asthma Caregiver Diary, Pediatric Asthma Control Tool, PedsQL 3.0 Short-Form 22 Asthma Module, PedsQL Asthma Symptoms Scale, and Test for Respiratory and Asthma Control in Kids. Three proxy-reported outcome instruments were considered suitable for use as end-points in paediatric asthma clinical trials; the Pediatric Asthma Caregiver Diary possesses the strongest measurement properties of the three.

A Frailty Model in Crossover Studies with Time-to-Event Response Variable

In this article, we develop a model to study treatment, period, carryover, and other applicable effects in a crossover design with a time-to-event response variable. Because time-to-event outcomes on different treatment regimens within the crossover design are correlated for an individual, we adopt a proportional hazards frailty model. If the frailty is assumed to have a gamma distribution, and the hazard rates are piecewise constant, then the likelihood function can be determined via closed-form expressions. We illustrate the methodology via an application to a data set from an asthma clinical trial and run simulations that investigate sensitivity of the model to data generated from different distributions.

Asthma clinical trials of American Lung Association/Asthma Clinical Research Centers (ALA-ACRC): what have we learned in 12 years?

The American Lung Association Asthma Clinical Research Centers (ALA-ACRC) is a research network focused on performing clinical trials that directly affect medical care for adults and children with asthma. The group of eighteen clinical research centers and a data-coordinating center perform studies supported by the American Lung Association, the National Institute of Health/National Heart Lung and Blood Institute (NIH/NHLBI), and partnership with industry. The network has completed and published eight clinical trials (seven randomized control trials and one validation study of a diagnostic tool), numerous ancillary studies, and has four ongoing trials at the time of publication of this review. The network’s trials have focused on areas such as the relative merits of different adjunctive treatments for asthma not controlled on inhaled corticosteroids (ICS) alone, the effect of treatment of comorbid diseases on asthma care, and studies evaluating techniques used in the conduct of clinical trials of treatments for asthma. This review will describe the accomplishments of our network to date and the effect of those accomplishments on asthma care.

Six-month in vitro validation of a metered-dose inhaler electronic monitoring device: Implications for asthma clinical trial use

Six-month in vitro validation of a metered-dose inhaler electronic monitoring device: Implications for asthma clinical trial use

Chapter 15: Lessons learned from clinical trials of asthma

The preponderance of clinical data suggest that inhaled corticosteroids (ICSs) are the preferred therapy for the long-term management of asthma, whereas oral or parental corticosteroids and short-acting beta(2)-adrenergic agonists remain the mainstay treatment of acute exacerbations. Allergen and tobacco avoidance are tenets to the practice of allergy-immunology and are beneficial in the treatment of asthma. Failure to avoid animal danders or fungi to which a patient with asthma is allergic is a risk factor for a fatal attack. First introduced in the 1970s, ICSs are the mainstay of pharmacotherapy to control airway inflammation and bronchial hyperresponsiveness in children and adults with asthma. ICSs reduce symptoms, exacerbations, hospitalizations, and deaths while improving quality of life and lung function. When used in combination with an ICS, essentially all clinical trials have indicated that long-acting beta(2)-adrenergic agonists are effective and safe. Leukotriene modifiers (LTMs) are effective in the treatment of persistent asthma, exercise-induced asthma, and aspirin-induced asthma but, in general, are less efficacious than ICSs when used as monotherapy to control asthma symptoms. Nevertheless, some patients respond to LTMs better than ICSs so a personalized approach to asthma pharmacotherapy is recommended. Not only is conventional (subcutaneous) allergen immunotherapy effective in patients with allergic asthma, immunotherapy (subcutaneous or sublingual) administered for rhinoconjunctivitis in children has been shown to reduce the development of asthma.

Predicting Adolescent Asthma Research Participation Decisions From a Structural Equations Model of Protocol Factors

To examine similarities and differences in the process that parents and adolescents use to make decisions concerning participation in an asthma clinical trial. We hypothesized that a single conceptual model, tested through structural equations modeling, could explain adolescent assent and parent consent for adolescent research participation. One hundred nine adolescents enrolled with at least one parent and received an asthma evaluation from a pediatric asthma specialist and then evaluated a hypothetical asthma research protocol. Family members independently evaluated the protocol and made research participation decisions. Perceived risk, benefit, and compensation were direct predictors of participation decisions for parents and adolescents. Adolescents perceived direct study benefit from the relationship with the physician, however parents did not. Parent decisions were most strongly associated with perceived risk, and parents associated discomfort with risk more strongly than did adolescents. Protocol procedures contributed to perceptions of benefit and discomfort for parents and adolescents. Parent and adolescent research participation decisions are influenced by protocol variables in similar ways, although there are differences that account for disagreements within families. Findings may help investigators develop protocols that appeal to parents and adolescents and highlight issues of particular importance to address during the process of informed consent.

Placebo effect model in asthma clinical studies: longitudinal meta-analysis of forced expiratory volume in 1 second

Our objective was to describe the time course of the placebo effect in asthma and quantitatively investigate the affective factors of the placebo effect for the placebo response simulation during the asthma clinical study design. We conducted a systemic search of public data sources for the study-level forced expiratory volume in 1 second (FEV(1)) to build the placebo effect model for studies by oral or inhaled administrations simultaneously. The administration routes, types of inhalation device, mean patient age, mean male proportion, baseline FEV(1), disease severity, year of publication, inhaled corticosteroid status during the treatment, and dropout rate were tested as covariates. There are 34 literature sources containing 178 mean values for FEV(1) presenting the individual observations from about 3,703 patients. The exponential models adequately described the time course of placebo effect with the typical value of the maximum placebo effect (P(max)) of 0.060 L. Dropout rate incorporated in the residual error model and the disease severity (mild to moderate and moderate to severe) at baseline were covariates that remained in the final model. The placebo effect is adequately described by an exponential model over time. By incorporating the dropout rate in the residual error model, the estimation precision was improved. The model could predict the placebo response profile in mild to severe asthmatic patients for the asthma clinical study design and could also be a structure model of the placebo effect for the pure drug effect evaluation in the asthma clinical trials.

Asthma outcomes: Pulmonary physiology

Outcomes of pulmonary physiology have a central place in asthma clinical research. At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to provide recommendations on the use of pulmonary function measures as asthma outcomes that should be assessed in a standardized fashion in future asthma clinical trials and studies to allow for cross-study comparisons. Our subcommittee conducted a comprehensive search of PubMed to identify studies that focused on the validation of various airway response tests used in asthma clinical research. The subcommittee classified the instruments as core (to be required in future studies), supplemental (to be used according to study aims and in a standardized fashion), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. A list of pulmonary physiology outcomes that applies to both adults and children older than 6 years was created. These outcomes were then categorized into core, supplemental, and emerging. Spirometric outcomes (FEV(1), forced vital capacity, and FEV(1)/forced vital capacity ratio) are proposed as core outcomes for study population characterization, for observational studies, and for prospective clinical trials. Bronchodilator reversibility and prebronchodilator and postbronchodilator FEV(1) also are core outcomes for study population characterization and observational studies. The subcommittee considers pulmonary physiology outcomes of central importance in asthma and proposes spirometric outcomes as core outcomes for all future NIH-initiated asthma clinical research.

Asthma outcomes: Biomarkers

Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects. National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies. We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health-organized workshop convened in March 2010 and finalized in September 2011. Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (Feno), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures. The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories.

Adherence to inhaled corticosteroids: An ancillary study of the Childhood Asthma Management Program clinical trial

Information comparing subjective and objective measurements of adherence to study medications and the effects of adherence on treatment-related differences in asthma clinical trials are limited. We sought to compare subjective and objective measurements of children's adherence to inhaled corticosteroids or placebo and to determine whether adherence to study medications modified treatment-related differences in outcomes. In an ancillary study conducted in 3 of 8 Childhood Asthma Management Program Clinical Centers, adherence was assessed by using self-reported and objective data in 5- to 12-year-old children with mild or moderate asthma who were randomly assigned to 200 μg of inhaled budesonide twice per day (n = 84) or placebo (n = 56) for 4 years. The κ statistic was used to evaluate agreement between self-reported adherence (daily diary cards) and objectively measured adherence (number of doses left in study inhalers). Multivariable analyses were used to determine whether adherence to study treatment modified treatment-related differences in outcomes. Adherence of less than 80% was seen in 75% of 140 children when adherence was measured objectively but only in 6% of children when measured by means of self-report. There was poor agreement between objective and subjective measurements of adherence of at least 80% (κ = 0.00; 95% CI, -0.05 to 0.04); self-reported adherence over the 4-year period generally overestimated objectively measured adherence (93.6% vs 60.8%, P < .0001). There was little evidence to indicate that adherence modified treatment-related differences in outcomes. Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment.

Asthma outcome measures

Asthma is a common chronic disease with underlying inflammation of the airway. Advances in science have led to increased understanding of the heterogeneous nature of asthma and its complex mechanisms. Traditionally, asthma-practice guidelines have focused on optimizing lung function and the US FDA has required increases in lung function and reduction of exacerbation as primary outcomes in clinical trials of new asthma therapeutics. Improved lung function is a critical indicator of bronchodilator therapy, but the importance of long-term asthma control while maintained on controller medication is increasingly emphasized. The NIH asthma guidelines suggest the use of patient-reported outcomes, including health-related quality-of-life measures, to assess asthma control. Clinical practices and research studies concerning asthma can benefit from harmonizing the major outcome measures so that comparisons across studies can be made. In this article, we review common asthma outcome measures with a focus on recent efforts to harmonize outcomes for therapeutic clinical trials in asthma.

Efficacy of budesonide/formoterol pressurized metered-dose inhaler versus budesonide pressurized metered-dose inhaler alone in Hispanic adults and adolescents with asthma: a randomized, controlled trial

Few clinical trials in asthma have focused on Hispanic populations. To compare the efficacy and safety of budesonide/formoterol (BUD/FM) with BUD in an ethnically diverse group of Hispanic participants with asthma previously treated with inhaled corticosteroids (ICS). This 12-week, randomized, double-blind, active-controlled study (NCT00419757) was designed to enroll Hispanic participants (self-reported) (≥12 years of age) with moderate to severe asthma requiring medium- to high-dose ICS. After a 2-week run-in period (low-dose BUD pressurized metered-dose inhaler [pMDI] 80 μg × 2 inhalations [160 μg] twice daily), participants with a symptom score greater than 0 (scale: 0-3) on 3 or more of 7 run-in days and forced expiratory volume in 1 second (FEV(1)) 45%-85% predicted were randomized to BUD/FM pMDI 160/4.5 μg × 2 inhalations (320/9 μg) twice daily or BUD pMDI 160 μg × 2 inhalations (320 μg) twice daily. Randomized participants (n = 127 BUD/FM; n = 123 BUD) were predominately Mexican (51%) or Puerto Rican (21%). During low-dose ICS run-in, the mean symptom score was 1.0; however, mean predose FEV(1) improved (2.10-2.21 L). During randomized treatment, small, but not statistically significant, improvements favored BUD/FM vs BUD (am peak expiratory flow [PEF; primary efficacy variable] 25.4 vs 19.9 L/min; pm PEF 20.6 vs 15.8 L/min; predose FEV(1) 0.16 vs 0.11 L; rescue medication use -0.7 vs -0.6 inhalations/d). Most adverse events were mild or moderate in intensity. Improvement in clinically relevant control end points occurred in both BUD/FM and BUD groups; both treatments were well tolerated in this Hispanic asthma population but were not significantly differentiated.

Benzodiazepinone Derivatives as CRTH2 Antagonists.

Multiple CRTH2 antagonists are currently evaluated in human clinical trials for asthma and chronic obstructive pulmonary disease (COPD). During our lead optimization for CRTH2 antagonists, an observation of an intramolecular hydrogen bond in ortho-phenylsulfonamido benzophenone derivatives led to the design and synthesis of conformationally constrained benzodiazepinones as potent CRTH2 antagonists. The benzodiazepinones are 2 orders of magnitude more potent than the original flexible bisaryl ethers in our binding assay. Selected benzodiazepinones, such as compound 6, were also potent in the human eosinophil shape change assay. Analysis of the rigid conformations of these benzodiazepinones and ortho-phenylsulfonamido benzophenones provided an explanation for the structure-activity relationship and revealed the possible bound conformations to CRTH2, which may be useful for building a pharmacophore model of CRTH2 antagonists.

Discovery of AMG 853, a CRTH2 and DP Dual Antagonist.

Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2. These efforts led to the discovery of AMG 853 (2-(4-(4-(tert-butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenyl sulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid), which is being evaluated in human clinical trials for asthma.

Daily Symptom Diaries Versus Retrospective Symptom Questionnaires in Clinical Trials: Is This Burden Worth The Effort?

RATIONALE: Diary data are burdensome to gather, often incomplete, susceptible to backfilling or data fabrication and therefore, are of questionable reliability. However, there is also concern that questionnaires administered during study encounters (based on retrospective assessments over the previous 1-4 weeks or more) may be subject to incomplete recall and recall bias. Presently, there is insufficient information to compare the value of daily symptom diaries versus retrospective symptom questionnaires for asthma clinical trials.

Statin drugs, metabolic pathways, and asthma: a therapeutic opportunity needing further research.

The chance discovery of hydroxymethylglutaryl (HMG)-CoA reductase inhibitors has revolutionized the care of patients with cardiovascular disease. The unexpected finding that these cholesterol-lowering drugs (or 'statins') also possess pleiotropic immunomodulatory properties, has opened a new area of research which investigates the anti-inflammatory and anti-proliferative properties of statins. In this brief commentary, we discuss the potential application of these drugs in asthma, where metabolic pathways pertinent to lung inflammation, in addition to the mevalonate cascade, may be targeted. We review mechanisms of action, discuss the potential therapeutic use of statins in asthma, share some preliminary data from our laboratory, discuss results from recent clinical trials in asthma, and propose a new target asthma subpopulation that could potentially benefit. We conclude our essay by highlighting the mevalonate-dependent and -independent pathways that may be modulated by statins, including the emerging area of cholesterol, sphingolipid, and lipid raft biology in lung disease. In this is an opportunity to develop new treatments for asthma, where innovative therapies are urgently needed to prevent acute exacerbations and alter disease progression.

Safety of formoterol in children and adolescents: experience from asthma clinical trials

Safety of formoterol in children and adolescents: experience from asthma clinical trials

Safety of formoterol in children and adolescents: experience from asthma clinical trials

BackgroundThe safety of long-acting β2 agonist (LABA) therapy in asthma remains controversial but no large scale analyses have been published of LABA safety in children.MethodsThe frequency of asthma-related deaths and...

Patient-reported outcomes in clinical trials of inhaled asthma medications: systematic review and research needs

To assess the diversity, application, analysis and interpretation of patient-reported outcomes (PROs) in asthma clinical trials. We critically appraised the use of asthma-specific PROs in 87 randomised controlled trials (RCTs) of inhaled asthma medications published during 1985-2006. A total of 79 RCTs reported PROs, of which 78 (99%) assessed symptom scores and seven (9%) assessed asthma quality of life scores. Only eight (10%) used validated instruments and five (6%) provided clinical interpretation of scores. Due to heterogeneity in the reporting of symptom measures, it is not possible to determine how many discrete symptom assessment instruments have been used. Only 26 (33%) of the RCTs that measured symptom scores reported the scores for follow-up. Limited improvement occurred over time: fewer than 30% of the RCTs used validated PRO measures in any individual year. Numerous validated PRO instruments are available but it is unclear why few are used in asthma clinical trials. Problems include poor reporting, and uncritical analysis and interpretation of PRO scores. Research needs include identifying and recommending a set of PROs for use in asthma clinical research and providing guidance for researchers on the application, analysis and interpretation of PRO measures in clinical trials.

Update in asthma 2009.

The emergence of a novel H1N1 influenza virus in early 2009 dominated the headlines and caused much fear worldwide as the Centers for Disease Control (CDC) proclaimed a pandemic (1). The media's preoccupation with the H1N1 epidemic, however, meant less “on-air” time for debates on the safety of asthma medications, a focus of last year's update (2). Ironically, clinical asthma trials this year also shifted away from the usual asthma medications toward the use of alternative “nonasthma” medications to treat comorbidities (3, 4) or as immunomodulators (5) with the goal of improved asthma control (decreased impairment). The importance of asthma exacerbations as a marker of poor asthma control and as a risk factor for poor long-term outcomes was investigated (6). Other studies examined the prediction of and effective treatment of exacerbations (7, 8). Challenges in the treatment of severe asthma were explored (9) and novel monoclonal antibodies were studied (10–12) as potential treatment options for patients with the most severe disease. Articles published in the American Journal of Respiratory and Critical Care Medicine in 2009 advanced our understanding of the influence of genetics (13–20), gene regulation (19, 21–23), factors in early life (24–28), and the environment (24, 29–33) on the development of asthma or the modification of disease severity. Basic pathobiological studies in humans (22, 23, 30, 34–44) and in animals (21, 29, 36, 45–56) added to our understanding of specific mechanisms in different phenotypes of asthma. Overall, a few areas emerge as particular highlights of the year and we focus your attention to the topics below.