Clinical trial design, nasal allergen challenge models, and considerations of relevance to pediatrics, nasal polyposis, and different classes of medication

Abstract

Clinical trials in allergic rhinitis present several specific difficulties. In seasonal pollen-related disease, there are variations between subjects in the extent of pollen sensitization, individual variations in exposure to pollen even within a set area because of lifestyle differences, and variations between different areas in pollen counts and weather patterns. Thus, large patient numbers are needed in multicenter trials to account for such variations when the standard endpoint is symptom reporting. Furthermore, a pollen season may be relatively short (eg, lasting 6-8 weeks), and the pollen count is inconsistent during this period. Crossover study designs are thus inappropriate, and trials are usually conducted with a parallel-group design. This further increases the trial sample size as it reduces statistical power. These large patient numbers must be recruited over a very short period. Perennial house dust mite-sensitive allergic rhinitis presents other problems. Although there is less disease variation, it is appreciated that symptoms may be induced by nonallergic as well as allergic mechanisms because of the nasal hyperresponsiveness. The nonallergic symptoms may not be modified by treatments based on allergic disease mechanisms. Thus, symptom outcomes--although relevant to the patient--may not adequately reflect the pharmacologic efficacy of the specific intervention. To control variability and focus on allergic disease mechanisms, nasal allergen challenge has been used in drug development. Single-dose challenges in the laboratory or in a pollen chamber, which allow many volunteers to be studied at the same time, have proven useful in the evaluation of drugs that afford acute symptom relief. However, such challenges incompletely model naturally occurring disease, in which the repeated daily exposure to allergen modifies the mucosal inflammatory cell profile and in particular promotes the epithelial accumulation of effector cells. This alters the response to allergen exposure. To model this, repeated low-dose daily allergen exposure has been used to generate these mucosal changes artificially, and early studies suggest that this may be a more valid model for the evaluation of anti-inflammatory therapy. However, little has been published with this model. Different disease groups are associated with their own specific issues in clinical trials. The pediatric population, in which allergic rhinitis is common, has different requirements for education, quality of life evaluation, and adverse-event monitoring; nasal polyposis, because of the nature of the disease, requires additional means of assessment, such as nasal endoscopy and imaging (eg, computerized tomography scanning), as well as attention to additional outcome measures (eg, the measurement of sense of smell). Within clinical trial design, there are important questions to be considered in relationship to the therapeutic intervention. Should this be given topically or systemically? What are the appropriate timing and frequency of medication? Does the disease itself modify the treatment efficacy, and does combination therapy afford better clinical outcome than single-modality therapy? These issues are discussed, and the influences of current therapies on objective outcome measures in allergic rhinitis are reviewed.