A PHASE 1B MULTIPLE DOSE SAFETY, PHARMAKOKINETIC(PK) ANDPHARMACODYNAMIC(PD)

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。人类生长激素在人类中的使用历史很长，大约在1958年报告了第一次人类剂量。生长抑素是通过重组DNA技术从E.Coli中提取的，由礼来公司以Humtrepe的名称销售，并被批准用于治疗生长激素缺乏症儿童的身材矮小。此外，Humtrepe被批准用于生长激素缺乏的成年人的替代治疗。过去和现在接受治疗的患者大多是儿科患者。吸入性研究的最新进展使开发一种吸入型Humtrepe成为可能，以造福于儿童和成人。这项技术现在已经在健康的成年志愿者身上进行了单剂量和多剂量测试。本研究建议对体重大于或等于18.0公斤至小于或等于52.0公斤的儿童受试者，在通过干粉吸入器给予多次吸入剂量后，评估生长激素吸入粉(SIP)的安全性。这项研究的合理性是基于28天的灵长类毒理学研究的安全性数据，之前三项针对男性志愿者的第一阶段研究，以及一项正在进行的针对多达15名患有哮喘的成年男性和女性的研究。在灵长类动物和人类身上的这一早期经验表明，在受试者中没有组织病理学异常、临床重大不良事件或对肺功能的不良影响。先前的SIP结果表明，吸入剂量是耐受的，并支持拟议的儿科计划。本研究将对呼吸系统疾病研究和儿科内分泌学卓越中心的儿科受试者开始有限的活性药物吸入不超过7天。在那里，他们可以受到仔细的安全监控。计划进行一项随机、安慰剂对照试验，以获得这些安全和疗效相关措施的最高质量数据。这项研究是第一次使用吸入剂量的人类生长激素的儿科研究，旨在评估使用干粉吸入器给药后这一人群的安全反应。在目前设计的基础上，这项研究将能够评估该吸入器在儿科受试者使用过程中的安全性、生物利用度、IGF-1和IGFBP-3标志物的相对反应以及该吸入器的质量性能。此外，比较成人和儿童受试者在以前的多剂量研究中的反应将支持未来的药物开发决策，并允许在第二阶段成人和儿童生长激素缺乏症临床试验中选择适当的剂量。各种证据表明，由于缺乏依从性、避免治疗或过早终止激素替代疗法，肠外给药不足。这些证据包括：1.针刺恐惧症。以过度或不合理地害怕注射或血液为特征。遇到或预期注射经常会导致血管迷走神经低血压反射，这是由针刺引起的。这种疾病通常是家族性的。这种恐惧症的结果是逃避医疗护理，由于依从性差而导致治疗不足，以及过早终止治疗。2.临床试验期间依从性差和提前终止治疗：即使在最好的情况下，在美国国立卫生研究院(NIH)进行的一项儿科临床试验中，礼来公司的数据显示，在继续试验到最终高度的受试者中，有证据表明一些受试者丢失了高达40%的注射。大约50%的受试者在达到最终高度之前停止了研究，主要是由于“患者的决定”(Lilly，2002)。研究护士报告说，许多人辞职是因为“她们厌倦了打针”。3.生长激素商业使用依从性差：在典型的临床情况下，多达50%的生长激素缺乏的儿科患者承认在就诊前一周避免注射(Smith等人。1993年)。此外，来自患者、他们的家人和儿科内分泌学家的大量轶事报告表明，许多患者会避免或抵制注射，成人患者经常选择直接拒绝治疗，儿科患者经常与照顾者发生肢体冲突。礼来公司指出，当有选择时，患者将从针头转向鼻腔或口服治疗，就像醋酸去氨加压素(DDAVP)的情况一样。因此，寻找肠外治疗以外的其他选择对患者和正在给孩子注射的父母来说是一个重要的问题。礼来公司试图通过展示给有需要的患者使用生长激素的替代模式的安全性和有效性来解决这一需求。

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. Human growth hormone has a long history of use in humans, the first human dose being reported in approximately 1958. Somatropin, derived from E. Coli through recombinate DNA technology, is marketed by Eli Lilly and Company as Humatrope, and is approved for human use in the treatment of short stature in children with growth hormone deficiency. In addition, Humatrope is approved for replacement therapy in growth hormone deficient adults. The majority of patients treated in the past and present are pediatric patients. Recent advances in inhalation research make possible the development if an inhaled form of Humatrope for the benefit of children and adults. This technology has now been tested in healthy adult volunteers in single dose and multiple dose testing. The present study proposes to assess the safety of somatropin inhalation powder (SIP) following multiple inhaled doses administered through a dry powder inhaler to pediatric subjects weighing greater that or equal to 18.0 kilograms to less than or equal to 52.0 kilograms. Justification for this study is based on 28-day safety data from toxicology studies in primates, three previous phase 1 studies in male volunteers and an ongoing study with up to 15 male and female adult subjects with asthma. This early experience in primates and humans has demonstrated no histopathological abnormalities, clinical significant adverse events or adverse effects on pulmonary function in subjects tested. The previous SIP results indicate that the inhaled doses were tolerated and support the proposed pediatric plan. The present study will initiate a limited exposure of no more that 7 days inhalation of active drug to pediatric subjects in centers of excellence for respiratory disease research and pediatric endocrinology. There they can be monitored carefully for safety. A randomized, placebo-controlled trial is planned to obtain the highest quality data on these safety- and efficacy- related measures. This study represents the first pediatric investigation using inhaled doses of human growth hormone and is designed to assess the safety responses in this population following drug delivery using a dry powder inhalation device. Based on the current design, this investigation will permit the evaluation of safety, relative bioavailability between SIP and subcutaneous humatrope, the relative response in IGF-1 and IGFBP-3 markers and the qualitative performance of this inhaler during use by pediatric subjects. Further, comparison of the responses between adult and pediatric subjects from the previous multi-dose studies will support future drug development decisions and permit appropriate dose selection in Phase 2 adult and pediatric growth hormone deficiency clinical trials. Various lines of evidence highlight the inadequacy of parenteral administration, due to a lack of compliance, avoidance of therapy or early termination of hormonal replacement therapy. Such evidence includes the following: 1. Needle phobia. Characterized by an excessive or unreasonable fear of injections or blood. Encounters or anticipation of an injection frequently result in a vasovagal, hypotensive reflex triggered by needle puncture. The disorder is often familial. The result of such phobia is avoidance of medical care, inadequate therapy due to poor compliance and premature termination of therapy. 2. Poor compliance and early termination of therapy during clinical trials: Even under the best of circumstances in a pediatric clinical trial conducted at National Institutes of Health (NIH), Lilly data show that among subjects who remained in the trial to final height, there was evidence of some subjects missing as many as 40% of their injections. Approximately 50% of subjects discontinued the study before reaching final height, primarily due to "patient decision" (Lilly, 2002). Study nurses report anecdotally that many quit "because they were tired of the shots". 3. Poor compliance during commercial use of growth hormone: Under typical clinic circumstances, as many as 50% of pediatric patients with growth hormone deficiency admit to avoiding injections during the week prior to clinic visit (Smith et al. 1993). In addition, substantial anecdotal reports from patients, their families and pediatric endocrinologists indicate that many patients will avoid or resist injections, with adult patients frequently opting to reject treatment outright and pediatric patients physically battling caregivers. Lilly notes that when options are available, patients will convert from needles to nasal or oral therapy, as was the case with desmopressin acetate (DDAVP). Therefore, finding other options than parenteral therapy is an important issue to patients and the parents who are injecting their children. Lilly seeks to address this need by demonstrating the safety and efficacy of an alternative mode of administrating somatropin to patients in need.