Skoner D P, Rachelefsky G S, Meltzer E O, Chervinsky P, Morris R M, Seltzer J M, Storms W W, Wood R A
Children's Hospital, Pittsburgh, Pennsylvania 15231, USA.
Pediatrics. 2000 Feb;105(2):E23. doi: 10.1542/peds.105.2.e23.
Intranasal beclomethasone dipropionate (BDP) has generally been considered to have no systemic activity at recommended doses, but the potential for long-term effects on growth has not previously been evaluated. This study was undertaken to assess the effects of 1 year of treatment with intranasal BDP on growth in children.
In this double-blind, randomized, parallel-group study, 100 prepubertal children 6 to 9 years old with perennial allergic rhinitis were treated with aqueous BDP 168 microg twice daily (n = 51) or placebo (n = 49) for 1 year. Subjects' baseline heights were required to be between the 5th and 95th percentile, and skeletal age as determined by left wrist radiograph was required to be within 2 years of chronological age. Washout periods for medications known to affect growth, including other forms of corticosteroids, were established, and these medications were prohibited during the study. However, short courses of oral prednisolone lasting no more than 7 days, and short courses of dermatologic corticosteroids lasting no more than 10 days, were allowed. Height was measured with a stadiometer after 1, 2, 4, 6, 8, 10, and 12 months of treatment. The hypothalamic-pituitary-adrenocortical axis was assessed by measurements of 8 AM basal cortisol concentrations and response to. 25 mg cosyntropin stimulation. The primary safety parameter was the rate of change in standing height. Statistical analyses were based on all randomized subjects who received at least 1 dose of medication (intent-to-treat principle). The rate of change in standing height was analyzed for all subjects who entered the study and for those completing the full 12 months of treatment (n = 80). The rate of change in standing height over the 1-year study was calculated as the slope of a linear regression line fitted to each subject's height measurements over time. Because there was a statistically significant between-group difference in standing height at baseline, an analysis of covariance was performed for all analyses of standing height data.
Of the 100 subjects enrolled, 90 completed the study. The 2 treatment groups were generally comparable at baseline; however, at baseline, mean age and mean height were significantly greater in the BDP treatment group that the in placebo treatment group. In both analyses, overall growth rate was significantly slower in BDP-treated subjects than placebo-treated subjects. The mean change in standing height after 1 year was 5.0 cm in the BDP-treated subjects compared with 5.9 cm in the placebo-treated subjects. The difference in growth rates was evident as early as the 1-month treatment visit, suggesting that the effect on growth occurred initially. The growth-suppressive effect of BDP remained consistent across all age and gender subgroups, and among subjects with and without a previous history of corticosteroid use. Use of additional exogenous corticosteroids during the study was similar in both groups and did not affect the results. Because there was a baseline imbalance in height, a supplemental analysis of the differences in prestudy growth rates was performed. This analysis found no baseline imbalance in prestudy growth rates. To determine whether the difference in growth rates during the study could be attributed to preexisting growth rates, a z score analysis was performed. The heights of both groups were normalized at baseline and at the end of the study using the US National Center for Health Statistics data for mean and standard deviations of height. This analysis confirmed that the difference in growth rates between the 2 groups was primarily attributable to the treatment rather than to any preexisting difference in growth. Additional analyses confirmed that the results were not influenced by outlier values. No significant between-group difference were found in the hypothalamic-pituitary-adrenocortical axis assessments. No unusual adverse events were observed. (ABSTRACT
一般认为，推荐剂量的鼻内丙酸倍氯米松（BDP）无全身活性，但此前尚未评估其对生长的长期影响。本研究旨在评估鼻内BDP治疗1年对儿童生长的影响。
在这项双盲、随机、平行组研究中，100名6至9岁患有常年性变应性鼻炎的青春期前儿童，每天两次接受168微克水性BDP治疗（n = 51）或安慰剂治疗（n = 49），为期1年。受试者的基线身高需在第5至95百分位数之间，通过左手腕X线片确定的骨龄需在实足年龄的2年内。确定了已知会影响生长的药物（包括其他形式的皮质类固醇）的洗脱期，且在研究期间禁止使用这些药物。然而，允许使用疗程不超过7天的口服泼尼松龙短疗程，以及疗程不超过10天的皮肤科用皮质类固醇短疗程。在治疗1、2、4、6、8、10和12个月后，使用身高计测量身高。通过测量上午8点的基础皮质醇浓度和对25毫克促肾上腺皮质激素刺激的反应来评估下丘脑-垂体-肾上腺皮质轴。主要安全参数是站立身高的变化率。统计分析基于所有接受至少1剂药物治疗的随机受试者（意向性治疗原则）。对所有进入研究的受试者以及完成全部12个月治疗的受试者（n = 80）分析站立身高的变化率。1年研究期间站立身高的变化率计算为拟合每个受试者随时间的身高测量值的线性回归线的斜率。由于基线时站立身高存在统计学上的显著组间差异，因此对站立身高数据的所有分析均进行了协方差分析。
100名受试者中，90名完成了研究。两个治疗组在基线时总体相当；然而，基线时，BDP治疗组的平均年龄和平均身高显著高于安慰剂治疗组。在两项分析中，BDP治疗的受试者总体生长速度均显著慢于安慰剂治疗的受试者。BDP治疗的受试者1年后站立身高的平均变化为5.0厘米，而安慰剂治疗的受试者为5.9厘米。生长速度的差异早在1个月治疗访视时就很明显，表明对生长的影响最初就已出现。BDP的生长抑制作用在所有年龄和性别亚组中以及在有和没有皮质类固醇使用史的受试者中均保持一致。研究期间两组额外使用外源性皮质类固醇的情况相似，且未影响结果。由于身高存在基线不平衡，因此对研究前生长速度的差异进行了补充分析。该分析发现研究前生长速度不存在基线不平衡。为了确定研究期间生长速度的差异是否可归因于先前存在的生长速度，进行了z评分分析。使用美国国家卫生统计中心的身高均值和标准差数据，在基线和研究结束时对两组的身高进行了标准化。该分析证实两组之间生长速度的差异主要归因于治疗，而非任何先前存在的生长差异。额外的分析证实结果不受异常值的影响。下丘脑-垂体-肾上腺皮质轴评估中未发现显著的组间差异。未观察到异常不良事件。（摘要）
