DOSE OF INHALED CORTICOSTEROID WITH EQUISYSTEMIC EFFECTS (DICE)--PILOT STUDY

在正式方案开始之前，使用84微克/支的倍氯米松(BDP)和44微克/支的氟替卡松(FP)进行如下初步研究：吸入皮质类固醇的等体效应剂量(DICE)将在6个中心中的每个中心研究大约5名受试者(最终总共27名)，以获得有关轻中度哮喘受试者吸入皮质类固醇(ICS)系统吸收变异性的初步数据，并确保在正式方案启动之前，所有技术在每个中心都能正常工作。此外，对于BDP和FP，我们将首先确定肾上腺抑制的剂量。试点研究的结果将指导正式方案的剂量、样本量和技术。背景和原理吸入型皮质类固醇(ICS)被推荐用于哮喘治疗，其频率和剂量均高于以前)。由于皮质类固醇具有多种潜在的全身不良反应，因此比较不同的吸入类固醇和给药系统对哮喘的全身影响和疗效是至关重要的。虽然目前已有几种吸入型类固醇(具有不同的体外效力和药代动力学特征)和吸入型给药系统可用，其他的预计将在未来几年推出，但缺乏比较这些吸入型类固醇和给药系统的体内全身效应数据。在这项DICE研究中，我们提出了一种实验范式，其中吸入类固醇和给药系统根据全身效应进行表征，以便随后可以在未来的疗效试验中比较“等全身”剂量，包括题为“测量吸入皮质类固醇疗效”的哮喘临床研究网络(ACRN)疗效试验(MICE)。在DICE试验中，肾上腺抑制将被用作全身吸收的主要指标。作为一个网络，我们承认儿童的生长发育和结缔组织参数是全身吸收的重要指标，但由于这些结果指标的变化速度很慢，它们不适合快速评估。因此，我们建议使用血浆皮质醇曲线(随时间测定)，这是基础肾上腺功能的一个敏感和可重复性的指标，作为我们全身类固醇吸收的指标。尿皮质醇排泄将是肾上腺抑制的次要指标。对类固醇，特别是血清骨钙素和尿N-端肽敏感的骨重建标志物，也将被纳入全身吸收和效果的二级指标。

Prior to the initiation of the formal protocol, Dose of Inhaled Corticosteroids with Equisystemic Effect (DICE), a pilot study described below is to be performed employing beclomethasone (BDP) at 84 mcg/puff and fluticasone (FP) at 44 mcg/puff. Approximately five subjects will be studied at each of six centers (final total of 27) to obtain preliminary data on the variability of systemic absorption of inhaled corticosteroids (ICS) among subjects with mild-moderate asthma and to ensure all techniques are working appropriately at each center prior to initiation of the formal protocol. Additionally, for both BDP and FP we will establish at what dose adrenal suppression is first demonstrated. The results of the pilot study will guide dosing, sample size and techniques for the formal protocol. Background and Rationale Inhaled corticosteroids (ICS) are being recommended for use in asthma treatment both more frequently and at higher doses than previously). Since corticosteroids have multiple potential adverse systemic effects, it is essential to be able to compare the different available inhaled steroids and delivery systems with respect to both systemic effects and efficacy as an asthma treatment. While several inhaled steroids (with differing in vitro potencies and pharmacokinetic characteristics) and inhaled delivery systems are presently available, and others expected to be introduced in coming years, in vivo systemic effects data comparing these inhaled steroids and delivery systems are lacking. In this DICE study we propose an experimental paradigm in which inhaled steroids and delivery systems are characterized in terms of systemic effects so that "equi-systemic" doses can be subsequently compared in future efficacy trials, including the Asthma Clinical Research Network (ACRN) efficacy trial entitled "Measuring Inhaled Corticosteroid Efficacy" (MICE). In the DICE trial, adrenal suppression will be used as the primary index of systemic absorption. As a network we acknowledge that growth in children and connective tissue parameters are important indicators of systemic absorption, but due to the slow rate of change in these outcome measures, they do not lend themselves to rapid evaluation. We therefore propose to use plasma cortisol profiles (determined over time) which are a sensitive and reproducible indicator of basal adrenal function as our index of systemic steroid absorption. Urine cortisol excretion will be a secondary measure of adrenal suppression. Markers of bone remodelling which are sensitive to steroids, specifically serum osteocalcin and urinary N-telopeptide, will also be incorporated as secondary indices of systemic absorption and effect.