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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 摘要 严重成骨不全(OI)儿童的治疗选择有限。目前还没有批准的治疗OI的药物，直到最近，治疗主要集中在骨折治疗和畸形的外科矫正上。除了针对症状性疼痛缓解之外的所有药物治疗，包括氟化物、镁、降钙素和合成类固醇，都是无效的。 双膦酸盐是焦磷酸盐的合成类似物，已被广泛用于治疗患有骨丢失和骨脆性的成年人。最近对生物磷酸盐帕米磷酸钠治疗严重成骨不全儿童的研究表明，早在治疗开始六周后，骨密度就明显增加。无一例外，骨密度的增加超过了健康儿童的预期。在接受生物磷酸盐治疗的几天内，骨疼痛的迹象消失，尽管由于活动能力增加，受伤的风险更高，但骨折发生率明显下降。 这是对CZOL446H2 202的一项为期一年的研究，该研究是一项多中心有效性和安全性试验，比较了静脉注射唑来膦酸和静脉注射帕米磷酸钠治疗严重成骨不全儿童的疗效和安全性。这项扩展研究是一项国际性、多中心、随机、开放标签、安全性和有效性的试验，评估两种不同剂量的唑来膦酸持续治疗的安全性：一年一次或一年两次。 通过对耐受性、肾脏安全性、一般安全性和不良事件的监测，将显示唑来膦酸治疗儿童严重成骨不全的安全性。疗效评估将包括骨密度测量、脊柱和左手的X光检查、评估骨吸收和形成的专门血清测试、骨骼疼痛评估和握力测量。 假设 唑来膦酸治疗儿童严重成骨不全安全有效。 具体目标 这项扩展研究的主要目的是检验两种不同剂量的唑来膦酸在CZOL446H2 202核心研究中已完成一年唑来膦酸治疗的儿科患者额外12个月的长期安全性，重点是一般安全性和肾脏安全性。 第二个目标是评估在核心随机分组时有严重成骨不全的儿童患者的持续安全性和有效性，其衡量标准为： -核心治疗层在18个月和24个月时腰椎骨密度(BMD)较基线(核心研究访问1)的百分比变化。 -核心治疗层在18个月和24个月时腰椎Z评分较基线(核心研究访问1)的变化。 -在12个月延长期和整个24个月延长期(核心和延伸期)内，每个患者的临床骨折数量(所有解剖部位的总和)。 -在15个月、18个月、21个月和24个月时，通过测定以下骨标志物：血清骨特异性碱性磷酸酶(形成)、I型胶原N末端前肽(形成)、c-端肽(吸收)，观察基础吸收和骨形成标志物的变化(核心研究访问1)。 -核心治疗层在15、18、21和24个月时仰卧位长度(或高度)较基线(核心研究访问1)的变化。 -骨疼痛自基线(核心研究的访问1)的变化，使用Wong-Baker Faces疼痛评定表(按核心治疗层级)。 -核心治疗层在第18个月和第24个月时全身骨矿含量较基线(核心研究访问1)的变化。 -核心治疗层在第24个月时皮质骨厚度较基线(核心研究访问1)的变化。 -核心治疗层在第24个月时脊柱长度较基线(核心研究访问1)的变化。 -核心治疗层在第15、18、21和24个月通过AHND测力测量相对基准(核心研究的访问1)的握力变化。 -按核心治疗层级划分，在延长治疗期间按预定剂量探访之前需要治疗的患者的百分比。

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.