Variability and lack of predictive ability of asthma end-points in clinical trials

Abstract

While a consensus definition of the clinical parameters important in asthma control exists, an adequate objective definition of a response to asthma treatment and parameters for prediction of that response remain undefined. Given that asthma is a complex biological disease and that different parameters may measure dissimilar aspects of the disease status, this study assessed the relationship among several end-points of asthma control, and attempted to select a combination of variables measured before (baseline characteristics) or early in asthma therapy which would be predictive of a long-term clinical response.Data from two previously reported clinical studies which included montelukast, inhaled beclomethasone, and placebo in mild-to-moderate asthmatics (n=1,576) were analysed. The forced expiratory volume in one second (FEV1), daily symptoms score (DSS), b-agonist use, and morning peak expiratory flow (PEFAM) were recorded during the baseline period and throughout the 12-week treatment period.For the long-term response, as measured during the last 9 weeks of treatment, there was a large within-patient variability and no more than a moderate correlation between the changes in FEV1 and PEFAM; DSS and FEV1; and DSS and b-agonist use. The overall predictive values for FEV1 and DSS were 70-80%.The results showed that multiple measurements over a length of time are needed to establish a more complete profile of response, and that demographic and early treatment responses had a small but inadequate ability to predict future response. This study demonstrates the complex relationship among asthma end-points and the difficulty of reliably estimating long-term response using common, surrogate clinical markers of asthma control.

Fluctuation analysis of lung function as a predictor of long-term response to 2-agonists

“…Additionally, airway hyperresponsiveness, lung function and its variability have been proposed to predict treatment response [15]. However, often only a weak relationship exists between these factors and treatment response, suggesting that conventional pathophysiological measurements are inadequate to predict the behaviour of complex diseases such as asthma [16,17]. Therefore, a crucial target for investigation remains: to find new predictors that allow clinicians to identify patients who would or would not benefit from treatment.…”

Domiciliary diurnal variation of exhaled nitric oxide fraction for asthma control

“…The guidelines have also recommended the need for assessing control over a period of time rather than just at one assessment. Hence, home monitoring can be important for this [3,4]. Daily home monitoring of peak expiratory flow (PEF) also provides an additional tool for asthma management [5,6].…”

Guideline-defining asthma clinical trials of the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network and Childhood Asthma Research and Education Network

“…Due to the poor correlation of pulmonary function responses to controller therapy with many nonpulmonary clinical control outcomes 43 , the CARE Network also reported additional CLIC asthma clinical control outcomes in a subsequent manuscript. 44 As expected, improvements in most clinical asthma control measures occurred with both FP and montelukast.…”