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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。人类生长激素在人类中使用的历史很长，大约在1958年报道了第一次人类剂量。生长激素来源于E.大肠杆菌通过重组DNA技术，由礼来公司以Humatrope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，Humatrope被批准用于生长激素缺乏症成人的替代疗法。过去和现在接受治疗的大多数患者为儿科患者。 吸入研究的最新进展使开发一种有益于儿童和成人的吸入形式的Humatrope成为可能。这项技术现已在健康成人志愿者中进行了单剂量和多剂量测试。本研究拟评估体重≥ 18.0 kg至≤ 52.0 kg的儿科受试者通过干粉吸入器多次吸入给予重组人生长激素粉吸入剂（SIP）的安全性。本研究的依据是基于灵长类动物毒理学研究的28天安全性数据、之前在男性志愿者中进行的3项I期研究和一项正在进行的多达15例男性和女性成人哮喘受试者研究。在灵长类动物和人类中的这种早期经验已经证明，在测试的受试者中没有组织病理学异常、临床显著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，并支持拟定的儿科计划。本研究将在呼吸系统疾病研究和儿科内分泌学卓越中心对儿科受试者进行不超过7天的活性药物吸入有限暴露。在那里，他们可以仔细监测安全。计划进行一项随机、安慰剂对照试验，以获得有关这些安全性和有效性相关指标的最高质量数据。 本研究代表了首次使用吸入剂量人生长激素的儿科研究，旨在评估使用干粉吸入装置给药后该人群的安全性反应。基于当前设计，本研究将允许评价SIP和皮下Humatrope之间的安全性、相对生物利用度、IGF-1和IGFBP-3标志物的相对反应以及儿科受试者使用期间该吸入器的定性性能。此外，比较既往多次给药研究中成人和儿童受试者的反应将支持未来的药物开发决策，并允许在II期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、避免治疗或提前终止激素替代治疗，胃肠外给药不足。这些证据包括：1。针头恐惧症。对注射或血液有过度或不合理的恐惧。遇到或预期注射经常导致血管迷走神经反射，针刺触发。这种疾病往往是家族性的。这种恐惧症的结果是避免医疗护理，由于依从性差而导致治疗不足和过早终止治疗。2.临床试验期间依从性差和提前终止治疗：即使在美国国立卫生研究院（NIH）进行的儿科临床试验的最佳情况下，礼来公司的数据显示，在仍留在试验中达到最终身高的受试者中，有证据表明一些受试者错过了多达40%的注射。大约50%的受试者在达到最终身高前中止研究，主要是由于“患者决定”（Lilly，2002）。研究护士报告说，许多人退出“因为他们厌倦了注射”。3.生长激素商业使用期间依从性差：在典型的临床情况下，多达50%的生长激素缺乏症儿科患者承认在临床访视前一周内避免注射（Smith et al. 1993）。此外，来自患者、其家属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，成年患者经常选择完全拒绝治疗，而儿科患者则与护理人员进行身体对抗。礼来公司指出，当选择可用时，患者将从针头转换为鼻腔或口服治疗，如醋酸去氨加压素（DDAVP）。因此，寻找除胃肠外治疗之外的其他选择对患者和给孩子注射的父母来说是一个重要的问题。礼来公司试图通过证明向有需要的患者给予重组人生长激素的替代模式的安全性和有效性来满足这一需求。

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.