Abstract：
BACKGROUND: Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years.
METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 μg/kg for infants aged 0-23 months; 15·0 μg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697.
RESULTS: Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53).
CONCLUSIONS: Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline.
BACKGROUND: BioMarin Pharmaceutical.
METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 μg/kg for infants aged 0-23 months; 15·0 μg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697.
RESULTS: Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53).
CONCLUSIONS: Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline.
BACKGROUND: BioMarin Pharmaceutical.
摘要：
背景：Vosoritide是一种重组C型利钠肽类似物，可提高5-18岁软骨发育不全儿童的年生长速度。我们旨在评估vosoritide在婴儿和5岁以下儿童中的安全性和有效性。
方法：这种双盲，随机化，安慰剂对照,在澳大利亚的16家医院进行了2期试验，Japan,英国,和美国。经基因检测证实临床诊断为软骨发育不全且完成基线生长研究或观察期的小于60个月的儿童根据筛查年龄纳入三个连续队列之一：24-59个月（队列1）;6-23个月（队列2）;和0-5个月（队列3）。每个队列包括接受vosoritide以确定适当的每日药物剂量的哨兵，其余的随机分配(1：1)在每个年龄段(日本除外，其中参与者在每个队列中被随机分配)接受每日皮下注射vosoritide(0~23个月婴儿为30·0μg/kg;24~59个月儿童为15·0μg/kg)或安慰剂,持续52周.参与者,看护者,调查员,和赞助商被掩盖在治疗分配中。第一个主要结果是安全性和耐受性，在接受至少一次研究剂量的所有参与者中进行评估。第二个主要结果是身高Z评分在基线52周时的变化，在所有随机分配的参与者中进行分析。这个试验在EudraCT注册,2016-003826-18，和ClinicalTrials.gov，NCT03583697。
结果：在2018年5月13日至2021年3月1日之间，招募了75名参与者（37名（49％）女性）。11人被分配为哨兵，而32人被随机分配接受vosoritide和32安慰剂。两名参与者停止了治疗和研究：一名在vosoritide组（死亡），一名在安慰剂组（戒断）。不良事件发生在所有75（100％）参与者中（vosoritide组每位患者的年发生率为204·5，安慰剂组每位患者的年发生率为73·6），其中大多数是短暂的注射部位反应和注射部位红斑。严重不良事件发生在vosoritide组的三名（7％）参与者中（氧饱和度降低，呼吸道合胞病毒毛细支气管炎和婴儿猝死综合征，和肺炎）和安慰剂组的六名（19％）参与者（小癫痫，自闭症,胃肠炎,呕吐和副流感病毒感染，呼吸窘迫,以及颅骨骨折和中耳炎）。vosoritide组和安慰剂组之间的身高Z评分从基线变化的最小二乘平均差为0·25（95％CI-0·02至0·53）。
结论：3-59个月接受vosoritide治疗52周的软骨发育不全儿童出现轻度不良事件，身高Z评分从基线开始增加。
背景：BioMarin制药。
方法：这种双盲，随机化，安慰剂对照,在澳大利亚的16家医院进行了2期试验，Japan,英国,和美国。经基因检测证实临床诊断为软骨发育不全且完成基线生长研究或观察期的小于60个月的儿童根据筛查年龄纳入三个连续队列之一：24-59个月（队列1）;6-23个月（队列2）;和0-5个月（队列3）。每个队列包括接受vosoritide以确定适当的每日药物剂量的哨兵，其余的随机分配(1：1)在每个年龄段(日本除外，其中参与者在每个队列中被随机分配)接受每日皮下注射vosoritide(0~23个月婴儿为30·0μg/kg;24~59个月儿童为15·0μg/kg)或安慰剂,持续52周.参与者,看护者,调查员,和赞助商被掩盖在治疗分配中。第一个主要结果是安全性和耐受性，在接受至少一次研究剂量的所有参与者中进行评估。第二个主要结果是身高Z评分在基线52周时的变化，在所有随机分配的参与者中进行分析。这个试验在EudraCT注册,2016-003826-18，和ClinicalTrials.gov，NCT03583697。
结果：在2018年5月13日至2021年3月1日之间，招募了75名参与者（37名（49％）女性）。11人被分配为哨兵，而32人被随机分配接受vosoritide和32安慰剂。两名参与者停止了治疗和研究：一名在vosoritide组（死亡），一名在安慰剂组（戒断）。不良事件发生在所有75（100％）参与者中（vosoritide组每位患者的年发生率为204·5，安慰剂组每位患者的年发生率为73·6），其中大多数是短暂的注射部位反应和注射部位红斑。严重不良事件发生在vosoritide组的三名（7％）参与者中（氧饱和度降低，呼吸道合胞病毒毛细支气管炎和婴儿猝死综合征，和肺炎）和安慰剂组的六名（19％）参与者（小癫痫，自闭症,胃肠炎,呕吐和副流感病毒感染，呼吸窘迫,以及颅骨骨折和中耳炎）。vosoritide组和安慰剂组之间的身高Z评分从基线变化的最小二乘平均差为0·25（95％CI-0·02至0·53）。
结论：3-59个月接受vosoritide治疗52周的软骨发育不全儿童出现轻度不良事件，身高Z评分从基线开始增加。
背景：BioMarin制药。
