Master protocols have received a growing interest during the last years. By assigning patients to specific substudies, they aim at targeting and accelerating clinical development. Given their complexity, basket, umbrella, and platform designs have raised challenging regulatory and statistical questions, especially the control of multiplicity in confirmatory trials. In basket trials, regulatory assessment of the benefit/risk in pooled populations and choice of the treatment indication is challenging. We provide here our perspectives on these topics. In master protocols, as long as the statistical hypotheses tested between the different substudies are independent, no supplementary adjustment for multiplicity over the different substudies should be required. Moreover, sharing a control arm within an umbrella or a platform trial investigating different drugs would not require a correction for the type I error rate, whereas the chance of multiple false positive regulatory decisions should be recognized. In basket trials, pooling across substudies requires a rationale supporting the intended indication and should be preplanned. Assessment of the benefit/risk in pooled target populations can be complicated by differences in design or in efficacy/safety signals between the substudies. While trials governed by a master protocol can offer logistic and financial advantages, more experience is needed to gain a deeper insight into this novel framework.
The effects of particulate matter v10 mm in diameter (PM10) and other air pollutants on lung function were assessed in 975 schoolchildren, from eight communities in Lower Austria between 1994-1997. In each community, air pollution data were collected. Spirometry was performed twice a year. PM10 concentration (mean concentration between two subsequent lung-function measures in spring and autumn (summer interval) or between autumn and spring (winter interval)) showed a mean value of 17.36 mg?m-3 in the summer interval and 21.03 mg?m-3 in the winter interval. A slower increase in the forced expiratory volume in one second (FEV1) and midexpiratory flow between 25 and 75% of the forced vital capacity (MEF25-75) with age in children exposed to higher summer PM10 was observed in the 3-yr study period. After adjusting for potential confounders (sex, atopy, passive smoking, initial height, height difference, site, initial lung function) an increase of summer PM10 by 10 mg?m-3 was associated with a decrease in FEV1 growth of 84 mL?yr-1 and 329 mL?s-1 ?yr-1 for MEF25-75. Nitrogen dioxide and ozone also showed a negative effect on lung-function growth, confirming previous work. The authors concluded that long-term exposure to particulate matter v10 mm in diameter had a significant negative effect on lung-function proxy for the development of large (forced expiratory volume in one second) and small (midexpiratory flow between 25 and 75% of the forced vital capacity) airways, respectively, with strong evidence for a further effect of ozone and nitrogen dioxide on the development of forced vital capacity and forced expiratory volume in one second. In recent years numerous studies have observed associations between ambient particulate matter and respiratory health. Effects of particulate air pollution on respiratory symptoms [1-8], hospitalization for respiratory and cardiovascular disease [9, 10], asthma attacks [11-13] asthma-medication use [1, 14], lung function [1-3, 7, 15-17] and mortality [18, 19] have been shown. Several studies observed short-term associations between particulate matter and lung function. HOEK et al. [2] found in a study on Dutch children that an increase of particulate matterv10 mm in diameter (PM10) by 100 mg?m-3 , on the same day, was associated with a decrease in different lung-function parameters (forced vital capacity (FVC), forced expiratory volume in one second (FEV1)) by y2.5%. Investigations of symptomatic and asympto-matic children in the USA [20] showed a decrease in the peak expiratory flow by 1.8% and 1.3% respectively , associated with a 150 mg?m-3 increase in the concurrent days9 PM10. A summer-camp study in the Austrian Alps [21] suggested a cumulative negative short-term effect of acid aerosols and PM10 on FEV1. So far, a susceptible subpopulation has not been identified. A study in the European Union found no consistent association between PM10 and lung function in a sample of children with chronic respiratory symptoms [22]. The six-cities study [23] that observed cross-sectionally th...
Colonization with Aspergillus fumigatus (Af) constitutes a common finding in children with cystic fibrosis (CF). The relationship between sensitization to Af and lung functon (LF) was studied in 118 patients with CF (61 girls and 57 boys; mean age: 14.3 yr; SD: 7 yr). Mean follow up was 2.2 yr. On average, 8.1 (SD: 4.8) LF tests were performed per patient. Measurement of total IgE and specific IgE antibodies to Af, and a skin prick test (SPT) for Af, were done once a year. Thirty-one children (26%) were sensitized to Af. On average, LF parameters were not significantly different in Af-sensitized children than in nonsensitized children. Linear regression analyses were performed, using the repeated measures design. With adjustment for gender, age, height, and weight, sensitization to Af was associated with lower values of FEV1 (beta = -0.209; p < 0.05) and FEF(25-75) (beta = -0.356; p < 0.01). Analysis of different subgroups of sensitization demonstrated the effect on LF only in Af-sensitized patients with elevated total IgE levels, and not in Af-sensitized patients with normal IgE levels. Furthermore, there was evidence for a more rapid decline in LF for Af-sensitized patients with elevated total IgE levels than in those with normal IgE levels. We conclude that sensitization to Af in the presence of increased IgE values is associated with lower LF values in children with CF.
A farming environment has a strong negative effect on the development of allergic sensitization. Furthermore, the study provides evidence that atopic children living on a farm lose their SPT positivity more frequently than children from non-farming environments.
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