重组人生长激素注射液治疗儿童生长激素缺乏症的临床评价

Efficacy and safety of recombinant human growth hormone solution in children with growth hormone deficiency in China： A multicenter trial

目的生长激素缺乏症（GHD）有赖于生长激素替代治疗。生长激素注射液可简化注射过程，提高依从性。进一步评价中国重组人生长激素注射液治疗儿童GHD的疗效和安全性。方法采用多中心、前瞻性、随机开放的研究方法，对31例[男20例，女11例，年龄（10，5±4．1）岁]确诊为完全性GHD的患儿，给予重组人生长激素注射液，0．25mg／（kg·周）[0．107U／（kg·d）]，每晚睡前皮下注射1次，治疗3、6、9、12个月后进行随访，疗程12个月。比较治疗前后的身高增长量（AHT）、年生长速率（growthvelocity，GV）、身高均值标准差积分（HTSDS）、血胰岛素样生长因子I（IGF-1）、胰岛素样生长因子结合蛋白质3（IGFBP-3）、抗生长激素抗体和骨成熟情况的变化，并评估药物治疗的安全性。结果（1）治疗3、6、9、12个月后△HT（cm）分别为4．0±1．3、7．0±2．0、10．3±2．6和12．9±3．3（P〈0．01），显示治疗后呈良好线性生长；GV（cm／年）治疗前为2．7±0．9，治疗后分别升至16．0±5．1、14．1±4．0、13．7±3．5和12．9±3．3，显示治疗后追赶生长明显，治疗前后比较，差异有统计学意义（P〈0．01）；HTSDS治疗前为-4．62±1．46，治疗后分别为-3．80±1．53、-3．28±1．60、-2．86±1．75和-2．47±1．86，显示治疗后身高与同年龄同性别正常儿童差距逐步缩小，与治疗前相比差异有统计学意义（P〈0．01）；（2）血IGF-1（μg/L）治疗前为41±64，治疗后分别为179±155、202±141、156±155和159±167；IGFBP-3（mg／L）治疗前为1540±1325，治疗后分别为3891±1815、4051±1308、3408±1435和3533±1413，显示随着身高增长，IGF-1、IGFBP-3被药物激活到较高水平，治疗前后差异均有统计学意义（P〈0．01）；（3）在治疗6个月、12个月后进行骨龄评估，骨成熟程度（ABA／ACA）分别为1．01±0．57、1．07±0．75，显示骨龄无加速发展；（4）治疗期间未发生严重不良事件，与药物有关的伴随反应主要表现为甲状腺功能减低。结论重组人生长激素注射液是一种安全有效治疗儿童GHD的药物。

Objective Human growth hormone （hGH） is an essential therapeutic drug for the treatment of growth hormone （ GH ） deficiency （ GHD ）. However, the process of dissolving hGH of the powder form is complicated and potentially hazardous. In the present study, we evaluated the efficacy and safety of preparation in the replacement therapy for children with GH deficiency. Methods A 12-month randomized, open-label, multicenter trial was conducted in 31 previously untreated children with growth failure secondary to GH deficiency [20 boys and 11 girls,mean age （10. 5 ±4. 1）years]. An recombined human growth hormone （rhGH） solution （Jintropin AQ） was given via subcutaneous injection daily in every evening at a weekly dose of 0. 25 mg/kg. The patients were followed up at 3, 6, 9, and 12 months of the treatment, and the course of treatment was 12 months. Body height was measured 3-monthly and height velocity （HV） and mean height standard deviation score （HT SDS） were calculated. Serum Insulin-like growth factor I （ IGF-1 ）, Insulin-like growth factor binding protein 3 （ IGFBP-3）, GH antibodies and safety parameters were assessed at the baseline and at 3-month intervals. Bone age （BA） was assessed at the baseline and the rate of skeletal maturation （△BA/△CA） was calculated after 6 and 12 months of rhGH treatment by a central bone age reader. Moreover, the safety of rhGH solution treatment was assessed. Results After 12 months of liquid rhGH therapy, growth parameters were significantly increased over baseline. （ 1 ） The mean （ ± SD） height increment AHT （cm） was 4. 0 ± 1.3, 7. 0 ± 2. 0, 10. 3 ± 2. 6 and 12.9 ± 3.3 after 3, 6, 9, and 12 months of treatment, respectively （P 〈 0. 01 ）, which indicated linear growth after treatment. The GV （cm/years） was 2. 7 ± 0. 9 before treatment and increased to 16. 0 ± 5.1, 14. 1 ±4. 0, 13.7 ± 3.5, and 12. 9 ± 3.3 after treatment, suggesting that catch-up growth was significant after treatment as compared to the pre-treatment status （P 〈 0. 01 ）. Accordingly, post-treatment catch-up growth was obvious, significent differences were observed in HT SDS, which was - 4. 62 ± 1.46 at the onset of therapy and increased significantly after the treatment to - 3.80 ± 1.53, - 3.28 ± 1.60, - 2. 86 ± 1.75 and -2.47 ± 1.86, respectively （P 〈 0. 01 ）. The height difference between GH deficient children and unimpaired children of the same age and gender gradually decreased after treatment, which was significantly different from that seen before treatment （ P 〈 0. 01 ）. （2） The levels of serum IGF-1 and IGFBP-3 were increased comparably for the treatment. IGF-1 level （μg/L） was 41 ± 64 at baseline and increased to 179 ± 155,202 ± 141, 156 ± 155 and 159 ± 167 after 3, 6, 9, 12 months of treatment. IGFBP-3 level （mg/L） was 1540 ± 1325 at baseline, and increased to 3891 ± 1815,4051 ~ 1308,3408 ±1435 and 3533 ± 1413, respectively, suggesting that with the increases in height, IGF-1, and IGFBP-3 were significantly activated to relatively high levels by the medication and reached peak values between 3 and 6 months of treatment. The levels of IGF-1 and IGFBP-3 were significantly different before and after treatment （P 〈0. 01 ）. The IGF-1/ IGFBP-3 molar ratio significantly increased during GH therapy （0. 143 ± O. 013 pre-therapy up to 0. 240 ± 0. 055 post-therapy, P 〈 0. O1 ）. The IGF-1/IGFBP-3 molar ratio tended to stabilize after 3-month GH therapy. （3） The bone age assessment carried out 6 and 12 months after treatment showed that the bone maturity （ABA,/ACA） was 1.01 ±0. 57 and 1.07 ±0. 75, respectively, suggesting that there was no speed- up development in the bone age. No severe adverse events were observed during the trial and the most frequent accompanying event was mild hypothyroidism. Conehtsions rhGH solution （Jintropin AQ） is a safe and effective preparation in the replacement therapy for children with GH deficiency.