AN INTERNATIONAL, MULTICENTER, RANDOMIZED, OPEN-LABEL, SAFETY AND EFFICACY TR

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 摘要 严重成骨不全（OI）儿童的治疗选择有限。 目前还没有批准的药物治疗OI，直到最近，治疗的重点是骨折管理和畸形的手术矫正。 除了针对症状性疼痛缓解的药物治疗外，所有药物治疗（包括氟化物、镁、降钙素和合成代谢类固醇）均无效。 双膦酸盐是焦磷酸盐的合成类似物，已广泛用于治疗患有骨丢失和骨脆性的成人。 最近的研究表明，生物膦酸盐，帕米膦酸盐，在儿童严重的骨生成障碍，骨密度明显增加，早在六个星期后开始治疗。 无一例外，BMD的增加大于健康儿童的预期增加。 在接受生物膦酸盐治疗的几天内，骨痛的症状消失，骨折率显著降低，尽管由于活动性增加而导致受伤的风险更高。 这是CZOL 446 H2202的一项为期一年的扩展研究，CZOL 446 H2202是一项多中心疗效和安全性试验，比较了静脉注射唑来膦酸与静脉注射帕米膦酸盐治疗重度成骨障碍儿童的疗效和安全性。 本研究扩展是一项国际、多中心、随机、开放标签、安全性和有效性试验，评价唑来膦酸两种不同给药方案（每年一次或每年两次）持续治疗的安全性。 将通过监测耐受性、肾脏安全性、一般安全性和不良事件来证明唑来膦酸治疗儿童重度成骨障碍的安全性。 疗效评估将包括骨矿物质密度测量、脊椎和左手的X线检查、评价骨吸收和形成的专门血清试验、骨痛评估和握力测量。 假设 唑来膦酸治疗儿童重度成骨障碍安全有效。 具体目标 本扩展研究的主要目的是在核心CZOL 446 H2202研究中已完成1年唑来膦酸治疗的儿童患者中，检查两种不同剂量方案的唑来膦酸在额外12个月内的长期安全性，重点关注一般安全性和肾脏安全性。 次要目的是评估在随机化时重度成骨障碍儿科患者中的持续安全性和疗效，通过以下指标进行测量： - 按核心治疗分层列出的第18个月和第24个月腰椎骨密度（BMD）较基线（核心研究访视1）的百分比变化。 - 按核心治疗分层列出的第18个月和第24个月腰椎Z评分较基线（核心研究访视1）的变化。 - 12个月扩展期和整个24个月期间（核心和扩展）每例患者的临床骨折数量（所有解剖部位的总和）。 - 通过测量以下骨标志物，测量第15、18、21和24个月时基础吸收和骨形成标志物相对于基线（核心研究访视1）的变化：按核心治疗分层列出的血清骨特异性碱性磷酸酶（形成）、I型胶原蛋白N-末端前肽（P1 NP）（形成）、c-端肽（吸收）。 - 按核心治疗分层列出的第15、18、21和24个月时仰卧位身长（或身高）较基线（核心研究访视1）的变化。 - 使用Wong-Baker FACES疼痛评定量表，按核心治疗分层列出的骨痛较基线（核心研究访视1）的变化。 - 按核心治疗分层列出的第18个月和第24个月全身骨矿物质含量较基线（核心研究访视1）的变化。 - 按核心治疗分层列出的第24个月时皮质骨厚度较基线（核心研究访视1）的变化。 - 按核心治疗分层列出的第24个月时脊椎长度较基线（核心研究访视1）的变化。 - 按核心治疗分层，在第15、18、21和24个月时通过AHND测力法测量的握力相对于基线（核心研究的访视1）的变化。 - 按核心治疗分层列出的扩展期间计划给药访视前需要治疗的患者百分比。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT Treatment options for children with severe osteogenesis imperfecta (OI) are limited. There is no approved drug treatment for OI, and until recently treatment focused on fracture management and surgical correction of deformity. All medical therapies other than those directed at symptomatic pain relief, including fluoride, magnesium, calcitonin and anabolic steroids have been ineffective. Bisphosphonates, the synthetic analogs of pyrophosphate, have been widely used for the treatment of adults suffering from bone loss and bone fragility. Recent studies of the biophosphonate, pamidronate, in children with severe osteogenesis imperfecta show an increase in BMD evident as early as six weeks after the start of treatment. Without exception, this gain in BMD has been greater than the increase expected in healthy children. Signs of bone pain disappear within days of receiving the biophosphonate and a marked decrease in fracture rate is observed despite a higher risk of injury due to increased mobility. This is a one-year study extension to CZOL446H2202, a multicenter efficacy and safety trial which compared intravenous zoledronic acid to intravenous pamidronate in children with severe osteogenesis imperfecta. This study extension is an international, multicenter, randomized, open-label, safety and efficacy trial, evaluating the safety of continued treatment with two different dosing regimens of zoledronic acid: once yearly or twice yearly. The safety of zoledronic acid for the treatment of severe osteogenesis imperfecta in children will be shown through the monitoring of tolerability, renal safety, general safety and adverse events. Efficacy assessments will include bone mineral density measurements, x-rays of vertebral spine and left hand, specialized serum tests to evaluate bone resorption and formation, bone pain assessment, and grip strength measurements. HYPOTHESIS Zoledronic acid is safe and efficacious for the treatment of childrn with severe osteogenesis imperfecta. SPECIFIC AIMS The primary aim of this extension study is to examine the long-term safety of two different dosage regiments of zoledronic acid over an additional 12 months in pediatric patients who have completed one-year of treatment of zoledronic acid in the core CZOL446H2202 study, with focus on general safety and renal safety. Secondary Aims are to assess continued safety and efficacy in pediatric patients with severe osteogenesis imperfecta at the time of randomization in the core as measured by: - the percentage change from baseline (visit 1 of the core study) in lumbar spine bone mineral density (BMD) at month 18 and 24 by core treatment stratum. - the change from baseline (visit 1 of the core study) in Z score of the lumbar spine at month 18 and 24 by core treatment stratum. - the number of clinical fractures per patient (sum of all anatomic sites) over the 12-month extension period and over the entire 24-month period (core and extension). - the change from baseline (visit 1 of core study) in base resorption and bone formation markers at month 15, 18, 21 and 24 by measuring the following bone markers: serum bone-specific alkaline phosphatase (formation), N-terminal propeptide of type I collagen (P1NP) (formation), c-telopeptide (resorption) by core treatment stratum. - the change from baseline (visit 1 of the core study) in supine length (or height) at months 15, 18, 21 and 24 by core treatment stratum. - the change from baseline (visit 1 of the core study) in bone pain, using the Wong-Baker FACES pain rating scale by core treatment stratum. - the change from baseline (visit 1 of the core study) in bone mineral content of the total body at month 18 and 24 by core treatment stratum. - the change from baseline (visit 1 of the core study) in cortical bone thickness at month 24 by core treatment stratum. - the change from baseline (visit 1 of the core study) in vertebral spine length at month 24 by core treatment stratum. - the change from baseline (visit 1 of the core study) in grip strength, measured by ahnd dynamometry relative at month 15, 18, 21 and 24 by core treatment stratum. - the percentage of patients who need treatment before the scheduled dosing visits during the extension by core treatment stratum.