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.
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