Impact of Daily Growth Hormone Adherence on Height Velocity Among Children With Growth Hormone Deficiency (GHD).

OBJECTIVE: To describe adherence to daily somatropin treatment and impact on height velocity within 1 year of treatment start among patients with pediatric growth hormone deficiency in a real-world US population. METHODS: This retrospective cohort study included pediatric patients aged ≥3 years to <16 years with pediatric growth hormone deficiency prescribed somatropin by a pediatric endocrinologist at a US-based center of excellence between January 1, 2015 and December 31, 2020. Patient data were collected using hospital electronic health records linked to a specialty pharmacy patient prescription records. Adherence, evaluated over 12 months, was measured using the proportion of days covered metric and patients were categorized as adherent if their proportion of days covered ≥80%. Height velocity was annualized to compare across adherent and nonadherent patients. RESULTS: One hundred eighty-one patients were identified and included in this study, of which 70.2% were male,73.5% were white, and mean age (standard deviation [SD]) at index was 12.1 (2.8). In the height velocity analysis, 174 patients were included and the mean (SD) annualized change in height was 10.2 (5.7) cm/y in the adherent group (n = 108) and 9.8 (7.6) in the nonadherent group (n = 66). The difference in height velocity between the groups was not statistically significant. CONCLUSIONS: Minor improvements in average height velocity were observed in the patient group who were adherent to somatropin therapy, although not statistically significant. Lack of observed significance may be due to small sample sizes, short observation period, a likely heterogenous population in terms of growth hormone prescribing, data bias due to single-center origin, or potential patient misclassification.

Fatal overdose from injection of human growth hormone; a case report and review of the literature.

BACKGROUND: Human growth hormone (HGH) is a categorized as a performance-enhancing substance. HGH has been abused by athletes for doping purposes. CASE PRESENTATION: We present a first lethal case of HGH acute toxicity. A young-agitated-athlete with a history of somatropin for the past 2-year, who had hallucinations referred to the emergency department reporting to have abused of 300 mg subcutaneous injections of HGH. He was tachycardic with mild hypertension. Lab data revealed hypernatremia (157 mEq/L), hyperkalemia (5.3 mEq/L), high LDH (1448 U/L), and CPK (2620 U/L), in favor of rhabdomyolysis. Routine drug screening tests were negative for all substances. He was intubated due to low O2 saturation and progressive loss of consciousness. After several episodes of hyperthermia, hypertension, and possibly pulmonary embolism, he died subsequent to somatropin overdose. CONCLUSIONS: Complications of HGH misuse can be life-threatening and athletes should be warned of its deleterious effects.

Association of Daily Growth Hormone Injection Adherence and Height Among Children With Growth Hormone Deficiency.

OBJECTIVE: Recombinant human growth hormone (somatropin) is recommended for children with growth hormone deficiency (GHD) to normalize adult height. Prior research has indicated an association between adherence to somatropin and height velocity. Further research is needed using real-world data to quantify this relationship; hence the objective of this study was to investigate the association between adherence to somatropin and change in height among children with GHD. METHODS: This retrospective cohort study included patients in the IQVIA PharMetrics Plus and Ambulatory Electronic Medical Records databases aged 3 to 15 years, with ≥1 GHD diagnosis code claim and newly initiated on somatropin between January 1, 2007 and November 30, 2019. Adherence was measured over the follow-up using the medication possession ratio (MPR); patients were classified as adherent (MPR ≥ 0.8) or nonadherent (MPR < 0.8). RESULTS: Among 201 patients initiated on somatropin, 74.6% were male, mean age was 11.4 years, and the mean follow-up was 343.3 days. Approximately 76.6% of patients were adherent to somatropin over the follow-up period. Adjusted growth trajectories were similar between adherent and nonadherent patients pre-treatment initiation (P = .15). Growth trajectories post-initiation were significantly different (P = .001). On average, adherent patients gained an additional 1.8 cm over 1 year compared with nonadherent patients, adjusted for covariates. CONCLUSION: Greater adherence to somatropin therapy is associated with improved height velocity. As suboptimal adherence to daily somatropin therapy is an issue for children with GHD, novel strategies to improve adherence may improve growth outcomes.

Long-term efficacy and safety of two doses of Norditropin® (somatropin) in Noonan syndrome: a 4-year randomized, double-blind, multicenter trial in Japanese patients.

This 4-year randomized, double-blind, multicenter trial (NCT01927861) investigated the long-term efficacy and safety of Norditropin® (NN-220; somatropin) in Japanese children with short stature due to Noonan syndrome. Pre-pubertal children with Noonan syndrome were randomized 1:1 to receive 0.033 mg/kg/day (n = 25, mean age 6.57 years) or 0.066 mg/kg/day (n = 26, mean age 6.06 years) GH. Height standard deviation score (SDS) change after 208 weeks from baseline was evaluated using an analysis of covariance model. Height SDS improved from -3.24 at baseline with a significantly greater increase (estimated mean [95% confidence interval]) with 0.066 vs. 0.033 mg/kg/day GH (1.84 [1.58; 2.10] vs. 0.85 [0.59; 1.12]; estimated mean difference 0.99 [0.62; 1.36]; p < 0.0001). The majority of treatment-emergent adverse events (TEAEs) were non-serious, mild and assessed as unlikely treatment-related. TEAE rates and frequencies of serious TEAEs were similar between groups. Three patients receiving 0.066 mg/kg/day were withdrawn; two due to TEAEs at days 1,041 and 1,289. Mean insulin-like growth factor-I SDS increased from -1.71 to -0.75 (0.033 mg/kg/day) and 0.57 (0.066 mg/kg/day) (statistically significant difference). In both groups, there were only minor glycosylated hemoglobin changes, similar oral glucose tolerance test insulin response increases and no clinically relevant changes in oral glucose tolerance test blood glucose, vital signs, electrocardiogram or transthoracic echocardiography. In conclusion, treatment with 0.033 and 0.066 mg/kg/day GH for 208 weeks improved height SDS in Japanese children with short stature due to Noonan syndrome with a significantly greater increase with 0.066 vs. 0.033 mg/kg/day GH and was well tolerated, with no new safety concerns.

Designing a Personalized Digital Patient Support Program for Patients Treated With Growth Hormone: Key Design Considerations.

BACKGROUND: Recombinant human growth hormone treatment can optimize growth potential; however, optimal outcomes are not always achieved for several reasons, including poor adherence. The overall objective of this project was to design a patient support program to maximize the chances of treatment success for people being treated with somatropin injection. An approach known as the behavior change wheel was used to enhance the development of the patient support program. The behavior change wheel provided a comprehensive framework to support the design of interventions. OBJECTIVE: The aim of this paper was to describe how the steps of the behavior change wheel were applied to the development of a patient support program for individuals with growth hormone deficiency undergoing treatment with somatropin. METHODS: We followed a series of steps that align to tenets of the behavior change wheel, namely, a narrative literature review to identify which behaviors needed to change and the potential drivers of and barriers to the behaviors, the selection of an intervention strategy and discrete behavior change techniques, and, finally, intervention specification. RESULTS: A recent systematic review identified a range of potentially modifiable factors found to have an influence on patient adherence to growth hormone treatment. Insights from the systematic review were used to guide the development of a patient support program. The final design of the patient support program consisted of four elements: (1) a personalization questionnaire to tailor support for each individual, (2) tailored reminder and support SMS text messages, (3) nurse-led phone calls, and (4) Easypod connect, an automated electronic autoinjector drug-delivery device with a transmitter and connection platform for Saizen (somatropin) that allows automatic recording, storage, and transmission of drug-usage data, thus providing insight into suboptimal adherence. CONCLUSIONS: The patient support program that was designed is currently being piloted with patients to assess engagement with the program and determine its impact on patient outcomes. Results from the pilot will be used to further refine the program to ensure it meets user needs.

Facilitating the adherence journey of children, adolescents, and adults on long-term growth hormone therapy.

Growth hormone deficiency in children and adolescents is treated with recombinant growth hormone injections, with the aim of helping patients reach a final height that falls within their genetically predicted adult height. While this treatment is very successful, overcoming issues of patient adherence is a challenge at each stage of the treatment journey, from early childhood to adulthood. An advisory board of senior endocrine nurses convened to discuss what strategies and tools work well in achieving adherence, and the best practices they identified-including the key strategies of choice, information, teamwork, and support-were presented at the 2016 meeting of The Endocrine Society. The advisers agreed that key steps to improve adherence include: patient/carer-centric endocrine nursing services, good-quality education and support, patient autonomy (where possible), broader treatment choice (in terms of device and self-injection), optimal follow-up from childhood to adulthood, and sharing of best practices.

COMPLIA: A 12-MONTH PROSPECTIVE, MULTICENTRE, NON-INTERVENTIONAL STUDY TO EVALUATE TREATMENT ADHERENCE AND TREATMENT SATISFACTION IN A GROWTH HORMONE DEFICIENT PAEDIATRIC POPULATION TREATED WITH NUTROPINAQ® A SOMATROPIN ANALOGUE.

BACKGROUND/AIMS: Growth hormone deficiency (GHD) in children and adolescents is managed with growth hormone (GH) therapy and aims to achieve optimal height development. However, treatment adherence can be poor, reducing the likelihood of a successful outcome. Adherence varies between geographic regions. This observational study assessed satisfaction and adherence to NutropinAq (somatropin, recombinant human GH) treatment in Romanian children with GHD. METHODS: Patients ≥3 years of age with GHD for which GH replacement therapy with NutropinAq had been initiated were recruited from 13 centres in Romania (protocol number: A-38-58035-016). The primary variable was patient/caregiver-reported treatment adherence (assessed at 3, 6 and 12 months on a 5-item Likert scale), secondary variables included treatment satisfaction assessed by the treating physician and patient/caregiver on a 5-point scale. RESULTS: Most patients did not miss any treatment injections in any 3-month period between assessments (≥79.8% of patients were 100% compliant). The incidence of missed injections was higher among patients <7 years of age than older children, but no differences between genders was observed. At study end, 94.3% of patients/caregivers and 94.3% of physicians reported complete satisfaction with treatment. CONCLUSIONS: Overall treatment adherence to NutropinAq was high in the Romanian GHD paediatric population, and a high level of treatment satisfaction was reported by patients/caregivers. This suggests reliable treatment outcomes can be anticipated in this population.

Towards preventive pharmacovigilance through medicine misuse identification: an example with recombinant human growth hormone for aesthetic purposes.

PURPOSE: Historically, somatropin has been used for conditions related with ageing, but since the marketing of recombinant human growth hormone (rhGH), increasing promotional pressure has prompted aesthetic uses, despite lack of evidences about its efficacy and safety for those purposes. METHODS: A routine analysis of the Pharmacovigilance Center of São Paulo (Brazil) showed reports of suspected adverse reactions in young adults and mature patients receiving rhGH. After presuming an off-label use of this expensive product, a drug utilisation study within the pharmacovigilance database has been carried out. RESULTS: The analysis showed a bimodal age distribution of the rhGH reports. Up to 17.1% of the 1289 reports (n = 220) involved patients aged ≥ 20 years taking rhGH for off-label uses. CONCLUSIONS: This information was the basis to design interventions in order to reduce inappropriate utilisation of this expensive product. Analyses of how medicines are being used through pharmacovigilance databases are a way to identify its irrational utilisation, thus facilitating preventive actions to improve how medicines are used and reducing avoidable adverse effects.

Efficacy and safety of two doses of Norditropin® (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients.

This randomized double-blind multicenter trial (NCT01927861) evaluated the growth-promoting effect and safety of Norditropin® (NN220; somatropin) in Japanese children with short stature due to Noonan syndrome. Prepubertal children aged 3-<11 years (boys) or 3-<10 years (girls) with Noonan syndrome were randomized to receive GH 0.033 mg/kg/day (n = 25, mean age 6.57 years, 11 females) or 0.066 mg/kg/day (n = 26, mean age 6.06 years, eight females) for 104 weeks. Change in height standard deviation score (HSDS) from baseline was analyzed based on an ANCOVA model. Baseline HSDS was -3.24. Estimated change in HSDS [95% CI] after 104 weeks' treatment was 0.84 [0.66, 1.02] and 1.47 [1.29, 1.64] for the lower and higher doses, respectively; estimated mean difference 0.63 [0.38, 0.88], p < 0.0001. Rates and patterns of adverse events (AEs) were similar between groups. Most were mild and reported as unlikely to be related to Norditropin®. There were no withdrawals due to AEs. Insulin-like growth factor-I SDS increased from -1.71 to -0.64 (0.033 mg/kg/day) and to 0.63 (0.066 mg/kg/day). HbA1c increased slightly (0.033 mg/kg/day: +0.14%; 0.066 mg/kg/day: +0.13%); glucose profiles were almost unchanged; insulin profiles increased in both groups in the oral glucose tolerance test. There were no clinically significant abnormal electrocardiogram or echocardiography findings. We conclude that Norditropin® at doses of 0.033 mg/kg/day or 0.066 mg/kg/day for 104 weeks increases height in Japanese children with short stature due to Noonan syndrome, with a favorable safety profile. The effect was greater with 0.066 mg/kg/day compared with 0.033 mg/kg/day.

Safety and effectiveness of long-term growth hormone therapy in Japanese patients with adult growth hormone deficiency: a postmarketing, multicenter, observational study.

We aimed to evaluate the long-term safety and effectiveness of growth hormone (GH) therapy in Japanese patients with adult growth hormone deficiency (AGHD). In this observational, multicenter study, Norditropin® (Novo Nordisk A/S, Bagsvaerd, Denmark) was administered as injections of 0.021 mg/kg/week as a starting dose divided into 6-7 doses/week. The dose was increased according to clinical response. Patients' data were obtained from medical records. Measurements (lipids, glucose metabolism, and body composition) taken at baseline; 3, 6, and 12 months; and yearly until the end of the study were collected. Adverse drug reactions (ADRs), serious ADRs, and serious adverse events (SAEs) were evaluated. Of 387 registered patients, 334 were eligible for safety. After GH treatment initiation, a marked decrease in total cholesterol was observed earlier in the child-onset group than in the adult-onset group. LDL-cholesterol also decreased, but no significant differences in changes in LDL-cholesterol between adult-onset and child-onset groups were found. A significant increase in HDL-cholesterol starting 1 year after GH treatment initiation was found in the adult-onset group. There was no effect of GH treatment on glucose metabolism. Because of the small number of dual-energy X-ray absorptiometry data, the overall assessment of changes of body composition was difficult. Fifty-six (16.8%), 12 (3.6%), and 35 (10.5%) patients experienced ADRs, serious ADRs, and SAEs, respectively. This study demonstrated a favorable long-term safety and effectiveness profile of GH therapy in AGHD patients in the real-life Japanese clinical practice setting.

Post hoc subgroup analysis of Asian children with paediatric GHD from the global phase 3 efficacy and safety study of once-weekly somatrogon vs. once-daily somatropin.

OBJECTIVES: Somatrogon is a long-acting recombinant human growth hormone used to treat patients with paediatric growth hormone deficiency (pGHD). This global phase 3 study compared the efficacy and safety of once-weekly somatrogon with once-daily somatropin in children with GHD. METHODS: Prepubertal patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. The primary endpoint was height velocity (HV) at month 12; secondary endpoints included HV at month 6 and change in height standard deviation score (SDS) at months 6 and 12 and insulin-like growth factor 1 (IGF-1) SDS. RESULTS: This post hoc subgroup analysis focused specifically on Asian children (somatrogon: n=24 and mean age=7.76 years; somatropin: n=21 and mean age=8.10 years) across eight countries. Mean HV at month 12 was 10.95 cm/year (somatrogon) and 9.58 cm/year (somatropin); the treatment difference of 1.38 cm/year favoured somatrogon. The lower bound of the two-sided 95 % CI of the treatment difference (somatrogon-somatropin) was -0.20, similar to the overall study population (-0.24). Compared with the somatropin group, the somatrogon group had numerically higher HV at month 6 (8.31 vs. 11.23 cm/year); a similar trend was observed for height SDS and IGF-1 SDS at months 6 and 12. Safety and tolerability were similar between treatment groups; adverse events occurred in 83 % of somatrogon-treated children and 76 % of somatropin-treated children. CONCLUSIONS: This subgroup analysis demonstrated that somatrogon efficacy and safety in Asian children were consistent with the overall study population, where once-weekly somatrogon was non-inferior to once-daily somatropin. Clinicaltrials.gov: NCT02968004.

Health-related quality of life in pre-pubertal children with pediatric growth hormone deficiency: 12-month results from a phase 3 clinical trial of once-weekly somatrogon versus once-daily somatropin.

OBJECTIVE: Treatment of pediatric growth hormone deficiency (pGHD) with daily injection of recombinant human growth hormone (somatropin) aims to increase height velocity and improve health-related quality of life (HRQoL). The Quality of Life in Short Stature Youth (QoLISSY) questionnaire was administered in a phase 3 clinical trial that evaluated efficacy and safety of once-weekly somatrogon versus once-daily somatropin in children with pGHD (ClinicalTrials.gov no NCT02968004). METHODS: Treatment-naïve prepubertal children with pGHD received once-weekly somatrogon or once-daily somatropin for 12 months. The QoLISSY core module (physical/social/emotional subscales) was administered at baseline and 12 months after treatment initiation. QoLISSY-Parent was completed by parents/caregivers of children <7 years old and some parents/caregivers of children ≥7 years old; children ≥7 years old self-completed QoLISSY-Child. RESULTS: Baseline characteristics were similar between treatment groups (N = 117). Among children <7 years old, QoLISSY-Parent total and subscale scores showed similarly improved HRQoL at 12 months relative to baseline in both treatment groups. Self-reported QoLISSY-Child total and subscale scores in children ≥7 years old indicated HRQoL improvements at 12 months that were numerically better with somatrogon than somatropin (similar results with QoLISSY-Parent in this age group). At both time points, children reported better HRQoL than perceived by their parents/caregivers. CONCLUSION: Treatment for 12 months with once-weekly somatrogon or once-daily somatropin resulted in comparable improvements in HRQoL among children with pGHD. Lower HRQoL perceived by parents/caregivers possibly reflect children's tendency to emphasize adaptation. These results suggest that evaluation of HRQoL could help support treatment decisions in children with pGHD treated with growth hormone.

Pediatric growth hormone deficiency is a condition that causes slow growth. Children with this condition have height that is lower than normal unless the condition is treated. The slow growth and short height may have bad effects on the emotional and social well-being of these children. Treatment usually consists of a growth hormone that is administered by daily injection under the skin over a period of years. However, children and their parents may not like these daily injections and often stop treatment. A newer treatment is available that can be injected once weekly. This newer treatment increases growth the same as daily injections. We looked at whether 12 months of treatment given once a week has the same positive effects on the physical, social, and emotional health of children as the daily treatment. Children and their parents answered questions that asked how being short affects the physical, social, and emotional parts of their life. These questions were asked before starting treatment and 12 months after starting treatment. In children younger than 7 years old, improvements at 12 months in their physical, social, and emotional health were similar between the treatments. In children 7 years old or older, those who received the once-weekly injections had slightly better improvements than those who received the daily injections. These results can help parents and doctors make decisions about treating children with pediatric growth hormone deficiency.

Separation of somatropin charge variants by multiple-injection CZE with Polybrene/chondroitin sulfate A double-coated capillaries.

The performance of dynamic double-coated fused-silica capillaries with Polybrene and chondroitin sulfate A has been compared with uncoated fused-silica capillaries for the determination of recombinant human growth factor (somatropin) charge variants. The separations were carried out under the same electrophoretic conditions as described in the European Pharmacopoeia, i.e. at pH 6.0 and 30°C. The coating significantly reduced the interactions between the proteins and the surface of the fused-silica capillary. The first five separations performed in a new bare fused-silica capillary were discarded because of very poor separation performance as a result of protein-surface interactions. There was an approximate twofold increase in the interday migration time precision (%RSD ≤ 6.5%) in the double-coated capillaries. The method was successfully transferred to a multiple CZE mode where two samples were analyzed in a single electrophoretic run. The average purity of somatropin certified reference standard was 98.0% (%RSD ≤ 0.3%) determined by using uncoated and coated capillaries.

Optimized Signal Peptide for Secretory Expression of Human Recombinant Somatropin in E. coli.

Purpose: The human somatropin is a single-chain polypeptide with a pivotal role in various biological processes. Although Escherichia coli is considered as a preferred host for the production of human somatropin, the high expression of this protein in E. coli results in the accumulation of protein as inclusion bodies. Periplasmic expression using signal peptides could be used to overcome the formation of inclusion bodies; still, the efficiency of each of the signal peptides in periplasmic transportation is varied and often is protein specific. The present study aimed to use in silico analysis to identify an appropriate signal peptide for the periplasmic expression of human somatropin in E. coli. Methods: A library containing 90 prokaryotic and eukaryotic signal peptides were collected from the signal peptide database, and each signal's characteristics and efficiency in connection with the target protein were analyzed by different software. The prediction of the secretory pathway and the cleavage position was determined by the signalP5 server. Physicochemical properties, including molecular weight, instability index, gravity, and aliphatic index, were investigated by ProtParam software. Results: The results of the present study showed that among all the signal peptides studied, five signal peptides ynfB, sfaS, lolA, glnH, and malE displayed high scores for periplasmic expression of human somatropin in E. coli, respectively. Conclusion: In conclusion, the results indicated that in-silico analysis could be used for the identification of suitable signal peptides for the periplasmic expression of proteins. Further laboratory studies can evaluate the accuracy of the results of in silico analysis.

Investigating significant health trends in growth hormone treatments registry: rationale, aims and design of a nationwide prospective registry (study protocol).

BACKGROUND: Somatropin treatment is indicated in a variety of disorders including growth hormone (GH) deficiency, Prader-Willi and Turner syndrome, chronic renal insufficiency and others. To date, almost all studies have been limited to single GH products, and no independent registry across indications and somatropin products was ever established. AIM: The present investigator-initiated registry named INSIGHTS-GHT aims to provide comprehensive information on various aspects of somatropin treatment in Germany in approved indications within routine clinical practice: drug utilization, effectiveness (including real final height, body composition), tolerability, quality of life, other patient related outcomes (PRO), and health economic variables. METHODS: Registry (prospective observational study) in specialised pediatric and adult endocrinology centres in Germany. Patients of any age are eligible for documentation, if they are on ongoing or newly initiated treatment with any approved somatropin or somatropin-related product within the labelling, available for long term follow-up documentation, and if they provided informed consent. Subjects may switch, discontinue/interrupt or initiate somatropin products at any time. They are followed up for at least 3 years (minimal study duration). Documentation is planned once or twice per year to record somatropin utilisation (product, dosing), other medications, laboratory status (glucose, lipids, GH function including stimulation tests, IGF-I, IGFBP3), if applicable, pubertal development, auxological parameters, body composition and bone age. Patient reported outcome (PRO) measures include, but are not limited to, Short Form 12 in adults and adolescents aged 14 years and over. Safety reporting includes adverse events. CONCLUSIONS: The registry documents children and adults in one joint registry, includes, at present, patients in Germany and allows documentation of patients on all approved somatropin and other growth hormone preparations. It will allow to describe the transition of subjects from adolescence to adulthood (treatment and height), to describe switches between somatotropin preparations, to perform responder analyses, and to analyse differences and similarities of somatropin utilization (by age group, sex, setting, and PRO instrument). INSIGHTS-GHT offers a broad, comprehensive research platform to assess multiple relevant aspects of somatropin treatment and outcomes (including the transition of subjects from adolescence to adulthood), allows the documentation of all GH products including long-acting GH preparations after their introduction, and will evaluate the data independently of funders. Trial registration BfArM Nr. NIS7492, DRKS registry DRKS00027394.

Evaluation of human growth hormone (somatropin) in socket healing: a split-mouth randomized controlled trial.

Techniques for preserving alveolar bone after tooth extraction are becoming a part of the usual clinical practice of clinicians. These techniques aim at minimizing postextraction bony resorption, hence, minimizing subsequent follow-up for implant insertion. This randomized clinical study aimed to measure and compare alveolar bone and soft tissue healing between extraction sockets treated with somatropin to untreated sockets. Methods: The study is designed as a split-mouth randomized clinical trial. The selected patients were indicated for bilateral symmetrical tooth extraction, where each patient had an indication to extract two symmetrical teeth in anatomy and number of roots. Somatropin was applied to the tooth socket of the randomly selected side after tooth extraction by gel foam, and the control side was filled with gel foam only. A clinical follow-up of the soft tissue was done 7 days after tooth extraction to evaluate clinical aspects of the healing process. Radiographic follow-up was performed using a cone-beam computed tomography scan to assess volumetric changes of alveolar bone in the extraction area prior to and 3 months after the surgical procedure. Results: A total of 23 patients (aged 29.1±9.5 years) participated. The results showed a statistically significant association between somatropin application and better preservation of the bony dimensions of the alveolar ridge. Bone loss was -0.691±0.628 mm for the buccal plate on the study side compared to -2.008±1.175 mm on the control side. The level of the lingual/palatal plate bone loss was -1.052±0.855 mm on the study side compared to -2.695±1.878 mm on the control side. The bone loss of alveolar width was -1.626±1.061 mm on the study side compared to -3.247±1.543 mm on the control side. The results also showed better healing of covering soft tissues (P<0.05), as well as bone density in the socket where somatropin was applied, which has been statistically significant. Conclusion: The data from this study demonstrated that the application of somatropin in tooth sockets postextraction showed an effective contribution to reducing alveolar bone resorption and improving bone density following extraction, in addition to better healing of covering soft tissue.

Long-term Effectiveness and Safety of GH Replacement Therapy in Adults ≥60 Years: Data From NordiNet® IOS and ANSWER.

Context: Effectiveness and safety data on GH replacement therapy (GHRT) in older adults with adult GH deficiency (AGHD) are limited. Objective: To compare GHRT safety and clinical outcomes in older (≥60 years and, for some outcomes, ≥75 years) and middle-aged (35-<60 years) patients with AGHD. Design/setting: Ten-year follow-up, real-world data from 2 large noninterventional studies-NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program-were analyzed. Patients: GH-naïve and non-naïve patients with AGHD. Intervention: Norditropin® (somatropin). Main outcome measures: Outcomes included GH exposure, IGF-I standard deviation scores (SDS), body mass index (BMI), glycated hemoglobin (HbA1c), serious and nonserious adverse reactions (SARs and NSARs, respectively), and serious adverse events (SAEs). Adverse reactions were events with possible/probable causal relationship to GHRT. Results: The effectiveness analysis set comprised 545 middle-aged and 214 older patients (19 aged ≥75 years) from NordiNet® IOS. The full analysis set comprised 1696 middle-aged and 652 older patients (59 aged ≥75 years) from both studies. Mean GH doses were higher in middle-aged vs older patients. For both age groups and sexes, mean IGF-I SDS increased following GHRT, while BMI and HbA1c changes were similar and small.Incidence rate ratios (IRRs) did not differ statistically between older and middle-aged patients for NSARs [IRR (mean, 95% confidence interval) 1.05 (.60; 1.83)] or SARs [.40 (.12; 1.32)]. SAEs were more frequent in older than middle-aged patients [IRR 1.84 (1.29; 2.62)]. Conclusion: Clinical outcomes of GHRT in AGHD were similar in middle-aged and older patients, with no significantly increased risk of GHRT-related adverse reactions in older patients.

Physician experience with once-weekly somatrogon versus once-daily rhGH regimen in pediatric patients with growth hormone deficiency: a cross-sectional survey of physicians from the global phase 3 study.

Introduction: The standard of care for pediatric growth hormone deficiency (pGHD) is once-daily recombinant human growth hormone (rhGH). Somatrogon, a long-acting rhGH, requires less frequent, once-weekly, dosing. We describe physicians' preference for, experiences, and satisfaction with once-weekly somatrogon vs once-daily rhGH. Methods: English-speaking investigators from somatrogon's global phase III study (NCT02968004) with prior experience using once-daily rhGH were included. Participants answered an online survey containing 14 closed- and open-ended items. Results: Twenty-four pediatric endocrinologists (41.7% men; 79.2% practiced at public/private hospitals) from 12 countries with 25.8 ± 12.0 years' experience treating pGHD completed the survey. In terms of the time and effort required to explain device instructions, injection regimen, procedure for missed injection, and address patients'/caregivers' concerns, a similar proportion of physicians chose once-weekly somatrogon and once-daily rhGH; 62.5% physicians indicated that once-daily rhGH required greater effort to monitor adherence. Overall, 75% preferred once-weekly somatrogon over once-daily rhGH, 79.2% considered once-weekly somatrogon to be more convenient and less burdensome, and 83.3% were likely to prescribe somatrogon in the future. Overall, 50% felt that once-weekly somatrogon was more beneficial to patients, while 50% chose "No difference". Most physicians (62.5%) felt both regimens were equally likely to support positive long-term growth outcomes and reduce healthcare utilization. More physicians were "very satisfied" with once-weekly somatrogon (62.5%) than with once-daily rhGH (16.7%). Reduced injection frequency, patient and caregiver burden, increased convenience, and improved adherence were reasons for these choices. Conclusion: Physicians had a positive experience with, and perception of, treating pGHD with once-weekly somatrogon.

An open-label extension of a phase 2 dose-finding study of once-weekly somatrogon vs. once-daily Genotropin in children with short stature due to growth hormone deficiency: results following 5 years of treatment.

OBJECTIVES: Somatrogon is a long-acting recombinant human growth hormone (GH) employed as a once-weekly treatment for children with GH deficiency (GHD). A 12-month, phase 2 study of once-weekly somatrogon vs. once-daily GH (Genotropin®) was initiated, after which participants could enroll into an open-label extension (OLE) evaluating the safety and efficacy of long-term somatrogon treatment. METHODS: There were five study periods, Periods I and II were 6 months each while Periods III, IV, and V were 12 months each. In the main study (Periods I and II), 53 prepubertal children with GHD were randomized to once-weekly somatrogon (0.25, 0.48, or 0.66 mg/kg/week) or once-daily Genotropin (0.034 mg/kg/day); 48 continued into the OLE, consisting of Period III (original somatrogon dose; Genotropin recipients randomized to one of three somatrogon doses), Period IV (somatrogon 0.66 mg/kg/week), and Period V (prefilled somatrogon pen [0.66 mg/kg/week]). RESULTS: At the end of Period III, the mean ± SD annual height velocity (HV) for 0.25, 0.48, and 0.66 mg/kg/week somatrogon groups was 7.73 ± 1.89, 7.54 ± 1.28, and 8.81 ± 1.12 cm/year, respectively; HV was sustained during Periods IV/V. Height SD scores (SDS) showed progressive improvement throughout the OLE, regardless of initial cohort assignment, approaching the normal range (-0.69 ± SD 0.87) at the end of Period V Year 1. Mild or moderate treatment-emergent adverse events were reported in 81.3% of participants, most unrelated to study drug. CONCLUSIONS: Up to 5 years of once-weekly somatrogon was well tolerated and resulted in sustained improvement in height SDS and delta height SDS in prepubertal short children with GHD.

Treatment of Isolated Idiopathic Growth Hormone Deficiency in Children and Thyroid Function: Is the Need for LT4 Supplementation a Concern in Long-Term Therapy?

Introduction Recombinant human growth hormone (rhGH) replacement therapy might be able to induce hypothyroidism, but this is a controversial issue. Previous studies evaluated the effects of rhGH replacement therapy on thyroid function, but little information is available in the subset of children with isolated idiopathic growth hormone deficiency (GHD). Our aim was to assess the effects of rhGH replacement therapy on thyroid function in children with isolated idiopathic GHD. Methods Retrospective analysis of the medical files of 64 children with confirmed GHD treated with rhGH. After review, 56 children with isolated idiopathic GHD and treated with rhGH for at least one year were included. Auxological (weight standard deviation score [SDS], height SDS, growth velocity [GV] SDS) and biochemical (free thyroxine [FT4], thyroid-stimulating hormone [TSH], and insulin-like growth factor 1 [IGF-1]) parameters were recorded before, during, and after treatment with rhGH. Results FT4 and TSH levels decreased significantly during rhGH therapy in children with isolated idiopathic GHD. Twenty-one percent (n=12) of the children developed hypothyroidism, on average 47 months after initiation of rhGH. Higher baseline FT4 levels were protective against the need for levothyroxine (LT4) (OR=0.8, CI 0.592-0.983; p=0.036). Hypothyroidism was reversed after interruption of rhGH, except in one patient; FT4 levels returned to baseline in the first year after completing the treatment. Final height SDS of the children who developed hypothyroidism was not different from their counterparts without hypothyroidism (-1.24 [-1.52 to -1.10] vs -1.13 [-1.78 to -0.74], p=1.000). Predicted adult height (PAH) SDS in patients who completed rhGH treatment was similar in both LT4 supplemented (n=7; final Ht SDS -1.16 [-1.31 to -1.10] vs PAH -1.00 [-1.42 to -0.48]; p=0.398) and not supplemented patients (n=25; final Ht SDS -1.46 [-1.83 to -0.78] vs PAH SDS -0.88 [-1.35 to -0.56]; p=0.074). Conclusions Our results show that patients with isolated idiopathic GHD may transiently need LT4 during GH treatment. Properly supplemented patients achieved PAH.