Pediatric growth hormone deficiency: Understanding the patient and caregiver perspectives.

Childhood growth hormone deficiency (GHD) is a rare disorder associated with significant burden on both patients and caregivers. Although previous reports have detailed aspects of the burden experienced by patients and their caregivers, there is a paucity of first-hand information on the patient and caregiver journeys from their respective voices. To address this need, an advisory board meeting was conducted on September 30, 2022, with 4 pediatric patients with GHD and their caregivers to discuss their experiences prior to GHD diagnosis, during the diagnostic process, and during ongoing treatment with recombinant growth hormone. Feedback from patients and caregivers was reviewed by pediatric endocrinologists, who provided their own perspectives on the patient and caregiver journeys based on the information reported. Despite the small sample size, important insights were obtained: patients and caregivers reported remarkable growth benefits achieved with treatment, which provided strong motivation to remain adherent to daily injection regimens. Patient and caregiver accounts reflected wide variability between families in time from suspicion to diagnosis and in treatment challenges faced, ranging from practical issues such as handling and administration of medication to broader concerns about treatment access and continuity, as well as key knowledge gaps among patients, caregivers, and clinicians. Recommendations are provided to enhance the patient and caregiver journeys, including increasing development and availability of educational materials, providing opportunities for patient advocacy by clinicians and health care providers, and encouraging institutional improvements to ensure that patients continue to receive uninterrupted treatment during their critical period of growth.

Medical Costs Associated with High/Moderate/Low Likelihood of Adult Growth Hormone Deficiency: A Healthcare Claims Database Analysis.

Purpose: Adult growth hormone deficiency (AGHD) is often underdiagnosed and undertreated, leading to costly comorbidities. Previously, we developed an algorithm to identify individuals in a commercially insured US population with high, moderate, or low likelihood of having AGHD. Here, we estimate and compare direct medical costs by likelihood level. Patients and Methods: Retrospective, observational analysis using the Truven Health MarketScan database to analyze direct medical costs relating to inpatient and outpatient claims, outpatient prescription claims, medication usage, clinical utilization records, and healthcare expenditures. Patients were categorized into groups based on algorithmically determined likelihoods of AGHD. Likelihood groups were further stratified by age and sex. Trajectories of annual costs (USD) by likelihood level were also investigated. Results: The study cohort comprised 135 million US adults (aged ≥18 years). Individuals ranked as high-likelihood AGHD had a greater burden of comorbid illness, including cardiovascular disease and diabetes, than those ranked moderate- or low-likelihood. Those in the high-likelihood group had greater mean total direct medical monthly costs ($1844.51 [95% confidence interval (CI): 1841.24;1847.78]) than those in the moderate- ($945.65 [95% CI: 945.26;946.04]) and low-likelihood groups ($459.10 [95% CI: 458.95;459.25]). Outpatient visits accounted for the majority of costs overall, although cost per visit was substantially lower than for inpatient services. Costs tended to increase with age and peaked around the time that individuals were assigned a level of AGHD likelihood. Total direct medical costs in individuals with a high likelihood of AGHD exceeded those for individuals with moderate or low likelihood. Conclusion: Understanding the trajectory of healthcare costs in AGHD may help rationalize allocation of healthcare resources.

Growth hormone is an important substance found in the body. Adult growth hormone deficiency (AGHD) is the reduced production of growth hormone unrelated to the normal reduction seen with aging. Untreated AGHD can result in the development of other conditions, known as comorbidities, which can be expensive to manage. Previously, 135 million privately insured people in the US, aged 18­64 years, were categorized into groups by their likelihood (high, medium, or low) of having AGHD. This study compared the estimated direct medical costs (eg hospital care and medication) across the different likelihood levels. People with a high likelihood of AGHD had more comorbidities than people with a medium/low likelihood, and an average total direct medical monthly cost of $1844.51, nearly twice as much as those with a medium likelihood ($945.65), and four times as much as those with a low likelihood ($459.10). These costs tended to increase with age, with the highest costs associated with people aged 50­59 years and 60­64 years. Outpatient costs (for treatments not requiring an overnight hospital stay) accounted for the greatest proportion of total medical costs, ahead of inpatient costs (for treatments requiring an overnight hospital stay) and medication costs. These findings suggest that diagnosing and treating AGHD earlier may help to reduce medical costs over time. Increased testing and treatment will cause an initial increase in the use of healthcare resources, but could improve overall cost effectiveness by reducing the long-term impact of the disease and avoiding unnecessary healthcare use.

Insights from an advisory board: Facilitating transition of care into adulthood in brain cancer survivors with acquired pediatric growth hormone deficiency.

OBJECTIVE: Children with growth hormone deficiency (GHD) face multiple challenges that can negatively impact the transition from pediatric to adult endocrinology care. For children with GHD resulting from brain cancer or its treatment, the involvement of oncology care providers and possible disease-related comorbidities add further complexity to this transition. DESIGN: An advisory board of pediatric and adult endocrinologists was convened to help better understand the unique challenges faced by childhood cancer survivors with GHD, and discuss recommendations to optimize continuity of care as these patients proceed to adulthood. Topics included the benefits and risks of growth hormone (GH) therapy in cancer survivors, the importance of initiating GH replacement therapy early in the patient's journey and continuing into adulthood, and the obstacles that can limit an effective transition to adult care for these patients. RESULTS/CONCLUSIONS: Some identified obstacles included the need to prioritize cancer treatment over treatment for GHD, a lack of patient and oncologist knowledge about the full range of benefits provided by long-term GH administration, concerns about tumor recurrence risk in cancer survivors receiving GH treatment, and suboptimal communication and coordination (e.g., referrals) between care providers, all of which could potentially result in treatment gaps or even complete loss of follow-up during the care transition. Advisors provided recommendations for increasing education for patients and care providers and improving coordination between treatment team members, both of which are intended to help improve continuity of care to maximize the health benefits of GH administration during the critical period when childhood cancer survivors transition into adulthood.

Coverage of education and training of traumatic brain injury-induced growth hormone deficiency in US residency and fellowship programs: a cross-sectional study.

BACKGROUND: Hypopituitarism, including growth hormone deficiency (GHD), is a common sequela of traumatic brain injury (TBI). This study explored the coverage of education and training of TBI-induced hypopituitarism in general and GHD in particular, in postgraduate program curricula to identify knowledge gaps and opportunities. METHODS: An online survey and qualitative interviews (focus groups) were conducted among endocrinology, neurology, and physiatry postgraduate program directors in the United States (US). The study received an IRB exemption. RESULTS: A total of 419 fellowship and residency programs were invited to participate; 60 program directors completed the survey and 11 of these participated in the focus groups. About half of the respondents considered TBI-induced hypopituitarism important or fairly important to include in the curriculum, and nearly two-thirds considered it an appropriate training component. Neurology program directors considered education regarding hypopituitarism following TBI less important and relevant for their curricula compared with endocrinology and physiatry program directors. About half (53%) of the programs responded that they included TBI-induced pituitary disorders in their curricula. About two-thirds (68%) of endocrinology programs, compared with only one-quarter (25%) of neurology programs, covered TBI-induced pituitary disorders. Respondents identified multiple barriers to expanding hypopituitarism following TBI in the curriculum, including the rarity of condition and lack of time/room in the curriculum. Respondents reported that consensus clinical guidelines and the availability of more data on TBI-induced hypopituitarism, including GHD, would greatly impact the development of educational curricula on this topic. CONCLUSIONS: To improve the management of TBI-induced hypopituitarism, education and training should be expanded in US fellowship and residency programs to prepare trainees to effectively screen, diagnose, and treat TBI-induced hypopituitarism, including GHD.

A traumatic brain injury (TBI) can occur with a sudden blow to the head or the body. Most people recover from TBI within weeks, but the injury can cause long-term effects by reducing the body's production of growth hormone (GH), which can interfere with daily activities and impair quality of life. This study explored education and training of doctors in the US to identify gaps in knowledge about GH deficiency and opportunities for improvement. Online survey and interviews (focus groups) were conducted among directors of 3 postgraduate (after medical school) training programs: endocrinology, neurology, and physiatry (the diagnosis, prevention, and treatment of all types of impairment related to the brain, nerves, bones, and muscles).A total of 60 program directors completed the survey and 11 of these participated in the focus groups. About half of the respondents felt education about GH deficiency caused by TBI is important, and nearly two-thirds thought it was appropriate to include in medical training. Half of the programs said that hormone disorders caused by TBI were currently included in their training. Respondents identified multiple barriers to expanding education on this topic in training programs. The main barriers were that the condition is thought to be uncommon and not having time for more training. Respondents thought that clinical guidelines and availability of more information on the condition would greatly impact the development of training about GH deficiency after TBI.To improve the management of GH deficiency caused by TBI, education and training should be expanded to prepare doctors in training to be better able to screen, diagnose, and treat GH deficiency caused by TBI.

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.

Factors Associated With Response to Growth Hormone in Pediatric Growth Disorders: Results of a 5-year Registry Analysis.

Context: Growth hormone (GH) therapy can increase linear growth in patients with growth hormone deficiency (GHD), Turner syndrome (TS), Noonan syndrome (NS), and Prader-Willi syndrome (PWS), although outcomes vary by disease state. Objective: To assess growth and identify factors associated with growth response with long-term GH therapy. Methods: Data from pediatric patients with GHD, TS, NS, and PWS obtained at GH treatment initiation (baseline) and annually for 5 years in the ANSWER Program and NordiNet® IOS were analyzed retrospectively. Height standard deviation score (HSDS) was assessed over time, and multivariate analyses determined variables with significant positive effects on growth outcomes in each patient cohort. Results: Data from patients with GHD (n = 12 683), TS (n = 1307), NS (n = 203), and PWS (n = 102) were analyzed. HSDS increased over time during GH treatment in all cohorts. Factors with significant positive effects on ΔHSDS were younger age at GH initiation and lower HSDS at baseline (all cohorts) and higher GH dose (GHD and TS only); sex had no effect in any cohort. The modeling analysis showed that ΔHSDS was greatest in year 1 and attenuated over consecutive years through year 5. Estimated least-squares mean ΔHSDS values at year 5 by cohort were 1.702 (females) and 1.586 (males) in GHD, 1.033 in TS, 1.153 in NS, and 1.392 in PWS. Conclusion: Long-term GH therapy results in large increases in HSDS in patients with GHD, TS, NS, and PWS. Greater gains in HSDS can be obtained with higher GH doses and earlier initiation of treatment.

Early GH Treatment Is Effective and Well Tolerated in Children With Turner Syndrome: NordiNet® IOS and Answer Program.

CONTEXT: Despite having normal growth hormone (GH) secretion, individuals with Turner syndrome (TS) have short stature. Treatment with recombinant human GH is recommended for TS girls with short stature. OBJECTIVE: This work aimed to evaluate the effectiveness and safety of Norditropin (somatropin, Novo Nordisk) with up to 10 years of follow-up in children with TS. METHODS: Secondary analysis was conducted of Norditropin data from 2 non-interventional studies: NordiNet® IOS (NCT00960128) and the ANSWER program (NCT01009905). RESULTS: A total of 2377 girls with TS were included in the safety analysis set (SAS), with 1513 in the treatment-naive effectiveness analysis set (EAS). At the start of treatment, 1273 (84%) participants were prepubertal (EAS); mean (SD) age was 8.8 (3.9) years. Mean (SD) dose received at the start of GH treatment was 0.045 (0.011) mg/kg/day (EAS). Mean (SD) baseline insulin-like growth factor-1 (IGF-I) SD score (SDS) was -0.86 (1.52), and mean (SD) duration of GH treatment (SAS) was 3.8 (2.8) years.Height SDS (HSDS) increased throughout follow-up, with near-adult HSDS reached by 264 (17%) participants (mean [SD] -1.99 [0.94]; change from baseline +0.90 [0.85]). During the study, 695 (46%) participants (EAS) entered puberty at a mean (SD) age of 12.7 (1.9) years (whether puberty was spontaneous or induced was unknown). Within the SAS, mean IGF-I SDS (SD) at year 10 was 0.91 (1.69); change from baseline +1.48 (1.70). Serious adverse reactions were reported in 10 participants (epiphysiolysis [n = 3]). CONCLUSION: GH-treated participants with TS responded well, without new safety concerns. Our real-world data are in agreement with previous studies.

Early Growth Hormone Initiation Leads to Favorable Long-Term Growth Outcomes in Children Born Small for Gestational Age.

CONTEXT: Early initiation of growth hormone (GH) therapy is recommended for short children born small for gestational age (SGA); however, real-world data indicate that treatment is often delayed. OBJECTIVE: We aimed to assess the impact of patient age at GH therapy initiation on long-term growth outcomes and safety in short children born SGA. METHODS: Analysis of pooled data from NordiNet® International Outcome Study (NCT00960128; 469 European clinics) and the ANSWER Program (NCT01009905; 207 US clinics), two large, complementary observational studies. Patients received GH as prescribed by their treating physician. Enrolled patients born SGA were categorized into three groups based on their age at GH treatment initiation: 2 to <4 years, 4 to <6 years, and ≥6 years. Patient characteristics at birth and GH initiation, auxology, and safety data were evaluated. RESULTS: The effectiveness analysis (treatment-naïve and prepubertal patients at GH initiation) included 3318 patients: 10.7% aged 2 to <4 years at therapy initiation, 31.6% aged 4 to <6 years, and 57.7% aged ≥6 years. Following 8 years of therapy, the mean improvement in height standard deviation score from baseline was significantly greater in the 2 to <4 years group vs the 4 to <6 years (+2.5 vs +2.2; P = 0.0054) and ≥6 years groups (+2.5 vs +1.7; P < 0.0001). No unexpected safety events were reported. CONCLUSION: Early initiation of GH therapy in short children born SGA may be an important contributor to height optimization. The data are reassuring regarding the long-term safety of GH therapy in this population.

Reduced CV risk with long-term GH replacement in AGHD: data from two large observational studies.

Adult growth hormone deficiency (AGHD) is associated with an increased risk of cardiovascular (CV) disease. Long-term growth hormone (GH) treatment could improve CV outcomes. The objective of this study was to evaluate CV disease risk in patients with AGHD who received GH replacement therapy for up to 10 years as part of NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905). The studies were observational, non-interventional and multicentre, monitoring long-term effectiveness and safety of GH treatment. NordiNet® IOS involved 23 countries (469 sites) across Europe and the Middle East. The ANSWER Program was conducted in the USA (207 sites). This analysis included patients aged 18-75 years who were GH naïve at study entry, who had ≤10 years of GH treatment data and who could be assessed for CV risk for at least 1 follow-up year. The main outcome measure was risk of CV disease by age 75 years, as calculated with the Multinational Cardiovascular Risk Consortium model (Brunner score) using non-high-density lipoprotein cholesterol adjusted for age, sex and CV risk factors. The results of this analysis showed that CV risk decreased gradually over the 10-year period for GH-treated patients. The risk was lower for patients treated for 2 and 7 years vs age- and sex-matched control groups (not yet started treatment) (14.51% vs 16.15%; P = 0.0105 and 13.53% vs 16.81%; P = 0.0001, respectively). This suggests that GH treatment in people with AGHD may reduce the risk of CV disease by age 75 years compared with matched controls.

A consensus on optimization of care in patients with growth hormone deficiency and mild traumatic brain injury.

OBJECTIVE/DESIGN: Approximately 2.9 million children and adults in the US experience traumatic brain injuries (TBIs) annually, most of which are considered mild. TBI can induce varying consequences on pituitary function, with growth hormone deficiency (GHD) among the more commonly reported conditions. Panels of pediatric and adult endocrinologists, neurologists, physical medicine and rehabilitation specialists, and neuropsychologists convened in February and October 2020 to discuss ongoing challenges and provide strategies for detection and optimal management of patients with mild TBI and GHD. RESULTS: Difficulties include a low rate of seeking medical attention in the population, suboptimal screening tools, cost and complexity of GHD testing, and a lack of consensus regarding when to test or retest for GHD. Additionally, referrals to endocrinologists from other specialists are uncommon. Recommendations from the panels for managing such patients included multidisciplinary guidelines on the diagnosis and management of post-TBI GHD and additional education on long-term metabolic and probable cognitive benefits of GH replacement therapy. CONCLUSION: As patients of all ages with mild TBI may develop GHD and/or other pituitary deficiencies, a multidisciplinary approach to provide education to endocrinologists, neurologists, neurosurgeons, traumatologists, and other providers and guidelines for the early identification and management of persistent mild TBI-related GHD are urgently needed.

Adult Growth Hormone Deficiency: Diagnostic and Treatment Journeys From the Patients' Perspective.

Adult growth hormone deficiency (AGHD) is a rare and serious condition associated with significant morbidity, including reduced quality of life, and is underdiagnosed and often missed in patients. Although the onset of AGHD can occur in either childhood or adulthood, adult-onset AGHD is more difficult to identify as it lacks the auxologic signs caused by GHD during childhood, includes symptoms that tend to be nonspecific, and lacks reliable, simple biomarker testing options. A panel of 9 patients with AGHD (3 with childhood onset; 6 with adult onset) was assembled to share their first-hand experiences, to help reveal important areas of need, increase health literacy, and to raise awareness about GHD among patients, caregivers, and healthcare practitioners. Interviews with patients yielded valuable insights from the patient perspective to supplement prior knowledge about AGHD symptomatology, biomarker testing, and treatment outcomes. Some patients described a burdensome and ineffective screening process that sometimes included many visits to different specialists, repeated rounds of biomarker testing, and, in some cases, excessive delays in AGHD diagnosis. All patients expressed frustration with insurance companies that often resist and/or delay treatment authorization and reimbursement and frequently require additional testing to verify the diagnosis, often leading to treatment gaps. These findings emphasize the necessity of more efficient identification and screening of patients with possible AGHD, better recognition by clinicians and insurance providers of the importance of sustained GH replacement therapy during adulthood, and better patient support for accessing and maintaining uninterrupted GH replacement therapy for patients with documented AGHD.

Development of a Novel Algorithm to Identify People with High Likelihood of Adult Growth Hormone Deficiency in a US Healthcare Claims Database.

Objective: Adult growth hormone deficiency (AGHD) is an underdiagnosed disease associated with increased morbidity and mortality. Identifying people who may benefit from growth hormone (GH) therapy can be challenging, as many AGHD symptoms resemble those of aging. We developed an algorithm to potentially help providers stratify people by their likelihood of having AGHD. Design: The algorithm was developed with, and applied to, data in the anonymized Truven Health MarketScan® claims database. Patients. A total of 135 million adults in the US aged ≥18 years with ≥6 months of data in the Truven database. Measurements. Proportion of people with high, moderate, or low likelihood of having AGHD, and differences in demographic and clinical characteristics among these groups. Results: Overall, 0.5%, 6.0%, and 93.6% of people were categorized into groups with high, moderate, or low likelihood of having AGHD, respectively. The proportions of females were 59.3%, 71.6%, and 50.4%, respectively. People in the high- and moderate-likelihood groups tended to be older than those in the low-likelihood group, with 58.3%, 49.0%, and 37.6% aged >50 years, respectively. Only 2.2% of people in the high-likelihood group received GH therapy as adults. The high-likelihood group had a higher incidence of comorbidities than the low-likelihood group, notably malignant neoplastic disease (standardized difference -0.42), malignant breast tumor (-0.27), hyperlipidemia (-0.26), hypertensive disorder (-0.25), osteoarthritis (-0.23), and heart disease (-0.22). Conclusions: This algorithm may represent a cost-effective approach to improve AGHD detection rates by identifying appropriate patients for further diagnostic testing and potential GH replacement treatment.

Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status.

Introduction: Mutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated. Methods: This analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naïve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin®, Novo Nordisk A/S). Results: A total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was -1.9 (1.1) and -1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses. Conclusions: GHT resulted in improved growth outcomes over 4 years in GHT-naïve, pre-pubertal NS patients, irrespective of PTPN11 mutation status.

Cardiovascular safety of growth hormone treatment in Noonan syndrome: real-world evidence.

Objective: The study aims to assess the cardiovascular safety of growth hormone (GH) treatment in patients with Noonan syndrome (NS) in clinical practice. Design: The study design involves two observational, multicentre studies (NordiNet® IOS and the ANSWER Program) evaluating the long-term effectiveness and safety of GH in >38,000 paediatric patients, of which 421 had NS. Methods: Serious adverse events, serious adverse reactions (SARs) and non-serious adverse reactions (NSARs) were reported by the treating physicians. Cardiovascular comorbidities at baseline and throughout the studies were also recorded. Results: The safety analysis set comprised 412 children with NS (29.1% females), with a mean (s.d.) baseline age of 9.29 (3.88) years, treated with an average GH dose of 0.047 (0.014) mg/kg/day during childhood. Cardiovascular comorbidities at baseline were reported in 48 (11.7%), most commonly pulmonary valve stenosis (PVS) and atrial septal defects. Overall, 22 (5.3%) patients experienced 34 safety events. The most common were the NSARs: headache (eight events in seven patients) and arthralgia (five events in three patients). Two SARs occurred in one patient (brain neoplasm and metastases to spine). No cardiovascular safety events were recorded in patients with NS. Five cardiovascular comorbidities in five patients were reported after initiation of GH treatment: three cases of unspecified cardiovascular disease, one ruptured abdominal aortic aneurysm and one PVS. Conclusions: GH treatment had a favourable safety profile in patients with NS, including those with cardiovascular comorbidities. Prospective studies are warranted to systematically assess the safety of GH treatment in patients with NS and cardiovascular disease.

Pregnancy outcomes in women receiving growth hormone replacement therapy enrolled in the NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program.

PURPOSE: Data on the safety of growth hormone (GH) replacement therapy during pregnancy are limited. We report a combined analysis of data from pregnant women treated with GH while enrolled in two non-interventional, multicenter studies: NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program. METHODS: Pregnancy data were pooled from NordiNet® IOS and the ANSWER Program. Data were collected during routine clinic visits by participating physicians using a web-based system. Patients exposed to GH replacement therapy during pregnancy were included in the analysis. RESULTS: The study population included 40 female patients with typical causes of adult GH deficiency (GHD). Overall, there were 54 pregnancies. Of these, 47 were exposed to GH between conception and delivery. In 48.9% of pregnancies exposed to GH, the dose was > 0.6 mg/day. GH was continued past conception and then stopped during the first, second, and third trimester, in 27.7%, 17.0%, and 2.1% of pregnancies, respectively. In 29.8%, GH was continued throughout pregnancy, with an unchanged dose in most cases. Of the 47 GH-exposed pregnancies, 37 (78.7%) progressed to normal delivery. There were three adverse events reported in two pregnancies. CONCLUSION: These real-world data suggest that there were no new safety signals related to GH exposure in women with GHD during pregnancy. These results are consistent with findings from previous studies reporting data in pregnancies exposed to GH at conception or throughout pregnancy. This observational study in additional pregnancies provides further evidence that GH exposure does not adversely affect pregnancy outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00960128 (date of registration: August 13, 2009) and NCT01009905 (date of registration: November 5, 2009).

Long-Term Safety of Growth Hormone Treatment in Childhood: Two Large Observational Studies: NordiNet IOS and ANSWER.

CONTEXT: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. OBJECTIVE: This work aims to assess the long-term safety of GH treatment in clinical practice. METHODS: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. RESULTS: The combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively). CONCLUSIONS: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Thorough QT/QTc Study Evaluating the Effect of Macimorelin on Cardiac Safety Parameters in Healthy Participants.

Macimorelin is an orally active growth hormone secretagogue indicated for the diagnosis of adult growth hormone deficiency. The primary objective of this study was to evaluate the effect of macimorelin on the baseline and placebo-corrected mean QT interval using Fridericia's formula (ΔΔQTcF). Secondary objectives were to determine QTcF for moxifloxacin; evaluate the effects of macimorelin on other cardiac intervals (PR, QRS, RR), heart rate, and electrocardiogram morphology parameters; characterize pharmacokinetics; and assess safety of macimorelin. The phase 1 thorough QT/QTc study, designed according to the International Council for Harmonisation E14 guideline, was a randomized, placebo-controlled, double-blind, 3-way complete crossover study comparing the effect of macimorelin 2.0 mg/kg with placebo and moxifloxacin 400 mg (positive control). Data were collected over a 3-month span from male (n=36) and female participants (n=24) aged 18 to 55 years with body mass index between 18.5 and 30.0 kg/m2 . Fifty-six participants received all 3 treatments. The ΔΔQTcF for macimorelin showed a prolongation with a maximum mean value of 9.61 milliseconds (2-sided 90% confidence interval, 7.81 milliseconds and 11.41 milliseconds) at 4 hours after dosing. The 2-sided 90% confidence interval of this value also exceeded the 10 millisecond threshold at 3 hours after dosing. Assay sensitivity was confirmed with moxifloxacin. Other electrocardiogram parameters evaluated were not influenced by macimorelin. Macimorelin did not raise other safety concerns and was well tolerated. In summary, a single supratherapeutic dose of macimorelin prolonged cardiac repolarization according to the regulatory guideline.

Adult growth hormone deficiency: Optimizing transition of care from pediatric to adult services.

OBJECTIVE: Most patients with childhood-onset growth hormone deficiency (CO-GHD) receive treatment with exogenous growth hormone (GH) to facilitate the attainment of their full potential adult height. Recent evidence suggests that continuing GH administration during the transition period between the end of linear growth and full adult maturity is necessary for proper body composition and bone and muscle health, and may also have beneficial effects on metabolic parameters, bone mineral density, and quality of life. The timing of this transition period coincides with the transfer of care from a pediatric to an adult endocrinologist, creating the potential for a care gap as a consequence of losing the patient to follow-up. DESIGN: An advisory board comprising both pediatric and adult endocrinologists was assembled to address current clinical unmet needs and to collaborate on a structured transitional plan for optimal management of patients with CO-GHD. INSIGHTS/CONCLUSION: The advisors suggest collaborative, multidisciplinary approaches to ensure continuity of care; ongoing testing and monitoring of GHD status into adulthood; and a clearly structured protocol that includes practical guidance for clinicians to establish best practices for transitioning older adolescents with persistent CO-GHD to adult care.

Sensitivity and specificity of the macimorelin test for diagnosis of AGHD.

OBJECTIVE: The macimorelin test is approved for the diagnosis of adult growth hormone deficiency (AGHD) based on its efficacy vs the insulin tolerance test (ITT). Macimorelin has a significant advantage over ITT in avoiding hypoglycemia. Analyses were conducted to determine whether macimorelin performance is affected by age, BMI, or sex, and evaluate its performance vs ITT over a range of GH cutpoints. DESIGN: Post hoc analyses of data from a previous randomized phase 3 study included participants aged 18-66 years with BMI <37 kg/m2 and high (Group A), intermediate (Group B), or low (Group C) likelihood for AGHD based on pituitary history, and matched controls (Group D). METHODS: Probability of AGHD was estimated using unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted logistic models. Area under the curve (AUC) of the estimated receiver operating characteristic (ROC) curve (range, 0-1; 1 = perfect) was compared for adjusted vs unadjusted models. Separate analyses evaluated agreement, sensitivity, and specificity for macimorelin and ITT using cutpoints of 2.8, 4.0, 5.1, and 6.5 ng/mL. RESULTS: For participants in Group A (n = 41) and Group D (n = 29), unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted models had ROC AUCs (95% CIs) of 0.9924 (0.9807-1), 0.9924 (0.9807-1), 0.9916 (0.9786-1), and 0.9950 (0.9861-1), respectively. CONCLUSIONS: Macimorelin performance was not meaningfully affected by age, BMI, or sex, indicating robustness for AGHD diagnosis. Of the 4 GH cutpoints evaluated, the cutpoint of 5.1 ng/mL provided maximal specificity (96%) and high sensitivity (92%) and was in good overall agreement with the ITT at the same cutpoint (87%).

Outcomes in children treated with growth hormone for Prader-Willi syndrome: data from the ANSWER Program® and NordiNet® International Outcome Study.

BACKGROUND: Growth hormone (GH) deficiency is common in patients with Prader-Willi syndrome (PWS) and leads to short adult stature. The current study assessed clinical outcomes based on real-world observational data in pediatric patients with PWS who were treated with GH. METHODS: Data from patients previously naïve to treatment with GH who began therapy with somatropin were collected from 2006 to 2016 in the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program® and NordiNet® International Outcome Study. Variables affecting change from baseline in height standard deviation scores (HSDS; n = 129) and body mass index standard deviation scores (BMI SDS; n = 98) were determined. RESULTS: Patients included in both HSDS and BMI SDS analyses were treated with a mean GH dose of 0.03 mg/kg/d (SD, 0.01 mg/kg/d). Results from the HSDS analysis revealed that baseline age and years on treatment had a significant impact on the change in HSDS. In the BMI SDS analysis, longer GH treatment time led to a greater change in BMI SDS from baseline, and patients with a higher BMI at the start of treatment had a greater decrease in BMI over time. CONCLUSIONS: GH is effective in the management of children with PWS. Earlier treatment resulted in a greater gain in height, and a longer treatment period resulted in better outcomes for both height and BMI. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov ( NCT01009905 ) on November 9, 2009.