Insulin-like Growth factor-I Standard Deviation Score Research Articles

Investigating the Bioavailability and Insulin-like Growth Factor-I Release of Two Different Strengths of Somapacitan: A Randomised, Double-Blind Crossover Trial.

Randomised, double-blind, crossover trial to confirm bioequivalence of somapacitan, a long-acting growth hormone (GH), in 5mg/1.5mL and 10mg/1.5mL strengths in equimolar doses. Healthy participants were randomised (1:1:1) to subcutaneous somapacitan treatment in one dosing period with 5mg/1.5mL and two periods with 10mg/1.5mL. Eligibility criteria included age 18-45years and body mass index 18.5-24.9kg/m2. Exclusion criteria included history of GH deficiency, previous GH treatment, weight > 100.0kg and participation in any clinical trial of an investigational medicinal product within 45days or five times the half-life of the previous investigational product before screening. Area under the curve from time 0 until last quantifiable observation (AUC0-t), maximum serum concentration (Cmax), time to Cmax and terminal half-life of somapacitan and safety were assessed. In total, 33 participants were randomised. For AUC0-t, estimated treatment ratio (ETR) (5mg/1.5mL versus 10mg/1.5mL) was 0.95 (90% confidence interval [CI] 0.89-1.01). Point estimate and 90%CIs were within the acceptance range (0.80-1.25). For Cmax, ETR was 0.77 (90%CI 0.68-0.89). Point estimate and 90%CIs were outside the acceptance range (0.80-1.25). Mean insulin-like growth factor-I (IGF-I) and IGF-I standard deviation score concentration-time curves for each strength were almost identical. No new safety issues were identified. Bioequivalence criterion for somapacitan 5mg/1.5mL and 10mg/1.5mL was met for AUC0-t but not for Cmax. The two strengths had equivalent IGF-I responses. ClinicalTrials.gov, NCT03905850 (3 April 2019).

FRI049 Correlation Between Tri-Ponderal Mass Index And Insulin-like Growth Factor-I, Insulin-like Growth Factor Binding Protein-3 In Children And Adolescent

Abstract Disclosure: I.H. Choi: None. M. Kim: None. Purpose: We aimed to investigate relation between Tri-ponderal mass index (TMI) and Insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) which has been known to be associated with growth and development of fat. Methods: 1630 children and adolescent has been selected among patient who has visited Jeonbuk National University children’s hospital and been diagnosed as normal. Patient’s medical chart were reviewed retrospectively about age, sex, height, weight, Body mass index (BMI), TMI, IGF-I, IGFBP-3. Male group and female group were categorized into 4 age groups and weight group such as underweight, normal, overweight, obesity according to BMI and TMI. Correlation between each of BMI, TMI and IGF-I, IGF-I standard deviation score (SDS), IGFBP-3, IGFBP-3 SDS, IGF-I/IGFBP-3 ratio were analyzed. Results: In male group, significant correlation between BMI and IGF-I, IGF-I SDS, IGFBP-3, IGFBP-3 SDS, IGF-I/IGFBP-3 ratio was observed only in normal weight group. But Significant correlation was observed in normal weight group between TMI and IGF-I, IGF-I SDS, IGFBP-3, IGFBP-3 SDS, IGF-I/IGFBP-3 ratio, also in overweight group between TMI and IGF-I, IGFBP-3, IGFBP-3 SDS. In female group, significant correlation for BMI was observed in normal weight group with all variable and in overweight group with IGFBP-3, IGFBP-3 SDS. Significant correlation for TMI was observed in normal weight group with all variable except IGFBP-3 SDS, and in overweight group with all variable, also in obesity group with IGFBP-3 SDS (rho=0.571, p=0.041). Conclusions: TMI may have significant correlation with IGF-I and IGFBP-3 in overweight and obesity group more than BMI. Especially IGFBP-3 SDS with TMI may be more helpful to evaluate overweight and obesity in female adolescent Presentation: Friday, June 16, 2023

OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency

Abstract Disclosure: T. Garner: Grant Recipient; Self; Novo Nordisk. P.E. Clayton: Grant Recipient; Self; Novo Nordisk. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P. Murray: Grant Recipient; Self; Novo Nordisk. A. Stevens: Grant Recipient; Self; Novo Nordisk. Background: Growth hormone (GH) replacement therapy often requires daily subcutaneous injections that can be burdensome for patients and their caregivers. Somapacitan is a long-acting, once-weekly GH derivative in development for treating GH deficiency (GHD) in children. Somapacitan reduces treatment burden and shows a similar efficacy and safety profile as daily GH in children with GHD. Here, we investigate the prediction of first-year growth and insulin-like growth factor-I (IGF-I) response based on baseline blood transcriptome in children with GHD treated with somapacitan or daily GH. Methods: 200 treatment-naïve prepubertal children with GHD were enrolled into REAL4, a randomised, multinational, open-labelled, and active-controlled phase 3 trial. 128 consented to a baseline blood transcriptome profile. Children were treated with once-weekly somapacitan (n=81) or daily GH (n=47) for 52 weeks and categorised based on treatment response: the upper quartile of height velocity (HV; cm/year) was defined as good responders, and the lower quartile as poor responders. We split the somapacitan group into training (70%) and testing (30%) sets for prediction validation of HV and the GH response marker: ΔIGF-I standard deviation score (SDS). Gene expression was assessed between the target quartile and the remaining quartiles for both HV and ΔIGF-I SDS to identify the top 100 differentially expressed genes by adjusted p-value. Classes were balanced using a synthetic minority oversampling technique and Boruta, a feature selection algorithm, was used to refine gene lists. We performed random forest and calculated “out of box” (OOB) area under the curve (AUC) and OOB error rate (ER), measures of predictive accuracy and robustness, respectively. Results: HV prediction from the transcriptome was excellent for both treatments (AUC range: 0.95-0.99). It was more robust for identifying good responders (ER: 7.0-7.5%) than poor responders (ER: 13.2-17.5%). Genes previously identified as predictive of growth response for daily GH (Stevens et al., 2021. The Pharmacogenomics J., 21:594-607) were demonstrated to have high predictive value for once-weekly somapacitan and daily GH treatment in this study (AUC range: 0.84-0.97, ER <22%). Using the somapacitan group for validation, HV prediction (AUC range: 0.78-0.81) was stronger than ΔIGF-I SDS prediction (AUC range: 0.63-0.72). Conclusions: We demonstrate pre-treatment blood transcriptome predicts first-year growth response for somapacitan. This represents an independent validation of earlier observations and shows that genes predictive of growth response for daily GH treatment in children with GHD are also predictive for once-weekly somapacitan. Further, we demonstrate that the pre-treatment blood transcriptome predicts growth response better than it predicts IGF-I SDS response. Presentation: Saturday, June 17, 2023

RF26 | PMON335 Once-Weekly Somapacitan Versus Daily Growth Hormone in Children Born Small for Gestational Age: Results From a Randomized Phase 2 Trial

Abstract Treatment of persistent short stature in children born small for gestational age (SGA) requires daily growth hormone (GH) injections that can be burdensome for patients and caregivers. Once-weekly somapacitan is a long-acting GH currently in phase 3 development for replacement therapy in children with GH deficiency. We report the 26-week results of the first phase 2, multinational, randomized, open-label, controlled, dose-finding trial (NCT03878446) investigating the efficacy and safety of somapacitan as treatment for short stature in children born SGA compared with daily GH (Norditropin®, Novo Nordisk A/S). A total of 62 (35.5% female) GH-treatment-naïve, prepubertal children received 0.16, 0.20 or 0.24 mg/kg/week subcutaneous (s.c.) somapacitan, or 0.035 or 0.067 mg/kg/day s.c. daily GH for 26 weeks (main phase). All children are subsequently included in an extension to this trial. The primary outcome was annualized height velocity (HV). At week 26, the estimated mean HV was: 8.9, 11.0 and 11.3 cm/year for 0.16 mg/kg/week (n=12), 0.20 mg/kg/week (n=13) and 0.24 mg/kg/week (n=12) somapacitan, respectively, versus 10.3 and 11.9 cm/year for 0.035 mg/kg/day (n=12) and 0.067 mg/kg/day (n=13) daily GH, respectively. A dose-dependent response in the estimated mean HV was observed with both somapacitan and daily GH. The effect of somapacitan on HV was not statistically significantly different compared with daily GH. A similar pattern was observed for change from baseline in height standard deviation score (SDS) and change from baseline in HV SDS. Consistent dose-dependent increases were observed in insulin-like growth factor-I (IGF-I) SDS with both somapacitan and daily GH. Exposure-response modeling of somapacitan exposure versus HV and IGF-I SDS vs. HV indicated an exposure-dependent increase in HV for both these parameters. Somapacitan was well tolerated at all doses investigated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to glucose metabolism, and no detection of anti-drug antibodies in any of the dose groups. In conclusion, all investigated doses of weekly somapacitan were efficacious and well tolerated throughout the study period. Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, a somapacitan dose of 0.24 mg/kg/week appears as the most efficacious dose, providing similar efficacy, safety and tolerability to daily GH 0.067 mg/kg/day after 26 weeks of treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.

RF26 | PMON334 Once-Weekly Somapacitan in Growth Hormone Deficiency: 4-Year Efficacy and Safety Results from REAL 3, a Randomised Controlled Phase 2 Trial

Abstract The current treatment for growth hormone deficiency (GHD) requires daily subcutaneous injections, which can be burdensome. Somapacitan is a long-acting growth hormone (GH) derivative in development for once-weekly use in children with GHD. REAL 3 (NCT02616562) is an ongoing, phase 2, multinational, randomised, open-label, controlled trial designed to investigate the efficacy and safety of somapacitan compared with daily GH (Norditropin®). Prepubertal children with GHD who were naïve to GH treatment received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) somapacitan, or daily GH 0.034 mg/kg/day (equivalent to 0.238 mg/kg/week; n=14) for 1 year. This was followed by a 2-year safety extension, in which all patients on somapacitan (n=45) received 0.16 mg/kg/week, while patients receiving daily GH remained on daily GH. In a further, ongoing 4-year long-term safety extension, patients treated with somapacitan remained on somapacitan (somapacitan/somapacitan, n=39) and all patients on daily GH switched to somapacitan 0.16 mg/kg/week (daily GH/somapacitan, n=11). Here, we present efficacy and safety results from the first year of the 4-year long-term safety extension. At year 4, the mean (SD) height velocity (HV) was 7.4 (1.6) cm/year for the somapacitan/somapacitan group and 6.6 (1.6) cm/year for the daily GH/somapacitan group, compared with 8.3 (1.7) and 7.6 (2.0) cm/year for the somapacitan/somapacitan and daily GH groups, respectively, at year 3. The mean (SD) HV standard deviation score (SDS) was 1.55 (1.70) for the somapacitan/somapacitan group and 0.88 (1.61) for the daily GH/somapacitan group, and the mean (SD) change in height SDS from baseline was 2.85 (1.25) and 2.28 (0.97), respectively. The mean (SD) insulin-like growth factor-I SDS at year 4 was 1.29 (1.23) and 0.94 (1.60) for the somapacitan/somapacitan and daily GH/somapacitan groups, respectively. During year 4, 20 patients (51.3%) experienced 84 adverse events (AEs) in the somapacitan/somapacitan group, and eight patients (72.7%) experienced 12 AEs in the daily GH/somapacitan group. The most common AE was nasopharyngitis, occurring in four patients (10.3%) in the somapacitan/somapacitan group and one patient (9.1%) in the daily GH/somapacitan group; all other AEs occurred in <10% of patients in either group. Most AEs were mild or moderate and unlikely related to GH treatment. One severe AE (surgery for elbow fracture) occurred in the somapacitan/somapacitan group. No serious AEs were reported in year 4. Since previously reported in year 3, one patient in the somapacitan/somapacitan group experienced five injection-site reactions; none occurred in the daily GH/somapacitan group. In conclusion, these year 4 data support the efficacy and safety results of somapacitan observed in the previous 3 years of the trial. In year 4, height-related outcomes were similar for patients who continued treatment with somapacitan and those who switched from daily GH to somapacitan. Somapacitan was well tolerated, and no safety signals were identified. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:44 p.m. - 12:49 p.m.

Once-Weekly Somapacitan Versus Daily Growth Hormone in Growth Hormone Deficiency: 2-Year Efficacy Results From REAL 3, a Randomized Phase 2 Trial

Abstract Current treatment for growth hormone (GH) deficiency (GHD) requires daily injections, which can be burdensome for the patients/caregivers. Once-weekly somapacitan is a long-acting GH derivative currently in phase 3 for use in children with GHD and phase 2 for short children born small for gestational age. A phase 2, multinational, randomized, open-label, controlled trial (NCT02616562) investigated the efficacy and safety of somapacitan in children compared with daily GH (Norditropin®). GH-treatment-naïve prepubertal children with GHD received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) subcutaneous (s.c.) somapacitan, or s.c. daily GH 0.034 mg/kg/day (0.24 mg/kg/week; n=14) for 52 weeks, followed by a 104-week safety extension. In the extension phase, all patients on somapacitan received 0.16 mg/kg/week; daily GH dose remained unaltered. The 52-week efficacy and safety results have been reported previously. We report here the efficacy results after 104 weeks of GH treatment. At week 104, mean (standard deviation [SD]) height velocity (HV) in the first year of the safety extension was: 10.6 (1.4), 10.0 (1.6) and 9.2 (1.7) cm/year for 0.04/0.16 mg/kg/week (n=13), 0.08/0.16 mg/kg/week (n=15) and 0.16/0.16 mg/kg/week (n=14) somapacitan, respectively, versus 9.0 (2.3) cm/year for daily GH (n=11). Mean (SD) change from baseline in HV standard deviation score (SDS) was 8.04 (2.52), 6.21 (2.90) and 6.40 (3.04) for somapacitan, respectively, versus 6.58 (3.15) for daily GH. Compared with week 52, mean HV and HV SDS at week 104 were increased in children in the somapacitan 0.04/0.16 mg/kg/week and 0.08/0.16 mg/kg/week treatment groups. Height SDS values improved during the second year of treatment with somapacitan and daily GH, with the greatest change from baseline in the somapacitan 0.16/0.16 mg/kg/week treatment group. The mean (SD) change in height SDS from baseline to week 104 was 1.73 (0.76), 1.87 (0.81) and 2.18 (1.18) for somapacitan, respectively, versus 1.72 (0.65) for daily GH. The observed mean (SD) change in insulin-like growth factor-I (IGF-I) SDS from baseline was similar between the somapacitan 0.08/0.16 and 0.16/0.16 mg/kg/week treatment groups (3.15 [1.17] and 3.21 [1.12], respectively), and slightly higher compared with IGF-I SDS in the 0.04/0.16 mg/kg/week group (2.99 [1.05]) and the daily GH group (3.06 [1.26]). Mean IGF-I SDS values remained below the upper limit (+2) of the normal range for all treatment groups throughout the 104-week trial duration. Somapacitan was well tolerated at all doses investigated, with no new safety or local tolerability issues identified during the 104 weeks of treatment. In conclusion, at week 104, height-based outcomes were similar between somapacitan 0.16/0.16 mg/kg/week and daily GH, with comparable mean change in IGF-I SDS. Furthermore, the key improvements observed in the first year were maintained in the second year of the study.

Population Pharmacokinetics and Pharmacodynamics of Once-Daily Growth Hormone Norditropin® in Children and Adults.

Background and ObjectiveOnce-daily injectable recombinant human growth hormone (GH) formulations (e.g. Norditropin®; Novo Nordisk A/S) are used to treat GH deficiency in children and adults, with much of the therapeutic effect mediated via the insulin-like growth factor-I (IGF-I) response. Despite a long history of use, there are few data on the pharmacokinetics and pharmacodynamics (serum IGF-I response) of this therapy, or of potential differences in the relationship of GH pharmacokinetic/pharmacodynamic (PK/PD) effects between children and adults. This study aimed to characterise the GH pharmacokinetics and IGF-I profile following daily subcutaneous GH in adults and children with GH deficiency.MethodsA model was developed based on a population PK/PD modelling meta-analysis of data from three phase I clinical trials (two using Norditropin® as a comparator with somapacitan, and one as a comparator with a pegylated GH product). Sequential model building was performed, first developing a model that could describe GH pharmacokinetics. A PD model of IGF-I data was then developed using PK and PD data, and where all PK parameters were kept fixed to those estimated in the PK model.ResultsThe model developed accurately describes and predicts GH pharmacokinetics and IGF-I response. Body weight was shown to have an important inversely correlated influence on GH exposure (and IGF-I standard deviation score), and this largely explained differences between adults and children.ConclusionsThe pharmacokinetics/pharmacodynamics developed here can inform expectations about the PD effects of different doses of GH in patients with GH deficiency of different body weights, regardless of their age.Clinical Trial RegistrationPooled modelling analysis of data from ClinicalTrials.gov identifiers NCT01973244, NCT00936403 and NCT01706783.Dates of registrationNCT01973244: 22 October, 2013; NCT00936403: 9 July, 2009; NCT01706783: 11 October, 2012.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01011-3.

Anthropometric, biochemical and hormonal profiles of the partially admixed pygmoid group in Rampasasa (Flores, Indonesia).

We performed a cross-sectional study on anthropometric and laboratory characteristics of inhabitants of Rampasasa (Flores, Indonesia). Adults were categorised according to ancestry into three groups: pygmoid (P/P, offspring of pygmoid parents, n=8), mixed pygmoid (P/N, offspring of pygmoid and non-pygmoid parents, n=12) and non-pygmoid (N/N, n=10). Children (n=28) were P/N. Measurements included height, weight, sitting height, arm span, head circumference, haematological analysis and serum albumin, calcium, vitamin D, insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3). Pubertal stage and bone age was assessed in children. Anthropometric data were expressed as standard deviation score (SDS) for age. IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio were expressed as SDS for age, bone age and pubertal stage. Mean height SDS showed a gradient from P/P (-4.0) via P/N (-3.2) to N/N (-2.3) (-3.4,-3.1 and-2.2 adjusted for age-associated shrinking). Sitting height and head circumference showed similar gradients. Serum IGF-I SDS was similar among groups (approximately-1 SDS). IGFBP-3 SDS tended toward a gradient from P/P (-1.9) via P/N (-1.5) to N/N (-1.1), but IGF-I/IGFBP-3 ratio was normal in all groups. In P/P and P/N, mean head circumference SDS was >2SD greater than mean height SDS. Children showed a progressive growth failure and bone age delay, delayed female pubertal onset and an initial low serum IGF-I, normal IGFBP-3 and low IGF-I/IGFBP-3 ratio. P/P showed proportionate short stature with relative macrocephaly and relatively low IGFBP-3; P/N presented an intermediate pattern. P/N children were progressively short, showed delayed skeletal maturation, delayed puberty in girls and low IGF-I and IGF-I/IGFBP-3.

A Proposal for the Interpretation of Serum IGF-I Concentration as Part of Laboratory Screening in Children with Growth Failure

The serum insulin-like growth factor-I (IGF-I) concentration is commonly used as a screening tool for growth hormone deficiency (GHD), but there is no consensus on the cut-off limit of IGF-I standard deviation score (SDS) to perform GH stimulation tests for confirmation or exclusion of GHD. We argue that the cut-off limit is dependent on the clinical pre-test likelihood of GHD and propose a diagnostic strategy in which the cut-off limit varies between zero to -2 SDS.

SAT-091 First Report of Disease-Specific Patient-Reported Outcomes from a Randomized Phase 2 Trial of Once-Weekly Somapacitan vs Daily GH in Children with GHD

Somapacitan is a long-acting, reversible albumin-binding growth hormone (GH) derivative being developed for once-weekly dosing in adults and children with GH deficiency (GHD). The efficacy, safety and tolerability of somapacitan were compared with daily GH in children with GHD in a multicenter, randomized, controlled, double-blinded to dose, phase 2 trial (REAL 3, NCT02616562). Treatment-naïve, prepubertal children with GHD were randomized 1:1:1:1 to once-weekly sc somapacitan (0.04, 0.08 or 0.16 mg/kg/week [wk]) or daily sc GH (Norditropin®; 0.034 mg/kg/day) during the 26-wk main trial period and 26-wk extension. Efficacy of the 0.16 mg/kg/wk dose was similar to that of daily GH, judged by height standard deviation scores (SDS) and insulin-like growth factor-I SDS, and, at wk 52, height velocity was statistically significantly greater with somapacitan 0.16 mg/kg/wk vs daily GH. Safety and tolerability of somapacitan were consistent with the profile of daily GH. Here, we report the results of a pre-planned analysis of patient-reported outcomes (PROs) collected during REAL 3. This is, to our knowledge, the first report of a disease-specific PRO score from a randomized trial in GHD.PROs were investigated using the Growth Hormone Deficiency - Child Impact Measure observer-report (GHD-CIM ObsRO). This is a new, validated questionnaire, developed according to US FDA guidance, to assess the impact of GHD on physical functioning, and social and emotional wellbeing in children aged 4 to <13 years, to be completed by caregivers. Minimal important differences (MID) in scores were determined based on Patient and Clinician Global Impression of Severity. Changes from baseline to wk 52 in GHD-CIM ObsRO scores were compared between daily GH and each dose of somapacitan, and were analyzed using an analysis of covariance model.A total of 59 patients were randomized (somapacitan n=45; daily GH n=14); the full analysis set included 57 children (somapacitan: 0.04 mg/kg/wk n=14; 0.08 mg/kg/wk n=15; 0.16 mg/kg/wk n=14; daily GH n=14). Mean age was 5.9 years; 60% were male; 11 children were <4 years old at baseline. For the change from baseline in GHD-CIM ObsRO score, the estimated treatment differences (ETDs) between somapacitan 0.16 mg/kg/wk and daily GH at wk 52 exceeded the MID in favor of somapacitan for the emotional wellbeing (ETD -9.34; MID 7) and social wellbeing domains (ETD -10.12; MID 5), as well as total score (ETD -7.43; MID 5). The somapacitan 0.16 mg/kg/wk group showed a numerical improvement over daily GH across all GHD-CIM ObsRO domains and total score, although none of the ETDs reached statistical significance.At 52 wks, the difference in GHD-CIM ObsRO scores between somapacitan 0.16 mg/kg/wk and daily GH exceeded the MID for the total score, and for the emotional and social wellbeing domains, suggesting clinically relevant improvement for these parameters in favor of somapacitan in children with GHD.

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.

Association between hemoglobin levels and diabetic retinopathy risk in type 2 diabetes mellitus

Objective To investigate the independent association of the body mass index(BMI) with serum uric acid among shorter children and adolescent. Methods A cross-sectional study was conducted to collect general clinical data of 922 subjects with shorter statures. In each case, their information about height, weight, insulin-like growth factor-Ⅰ(IGF-Ⅰ), growth hormone peak, uric acid, and blood lipids were collected, and their BMI and BMI standard deviations score(SDS) were calculated. Smooth curve fitting and multiple piecewise linear regression were used to analyze the relationship between BMI SDS and uric acid. Results Univariate analysis found that serum uric acid was positively correlated with age, height standard deviation score, body weight standard deviation score, BMI SDS, IGF-Ⅰ standard deviation score, growth hormone peak, triglyceride, and creatinine(P<0.05), while negatively correlated with high-density lipoprotein-cholesterol(P<0.01). Female had significantly lower serum uric acid levels than male(P=0.003). The serum uric acid level was significantly increased after puberty(P<0.01). After adjusting for potential confounders, the smooth curve fitting revealed a U-shaped relationship between BMI SDS and uric acid, with a BMI SDS inflection point of -0.7. In the population of BMI SDS<-0.7, for every unit increase of BMI SDS, serum uric acid decreased by 11.78 μmol/L(P=0.030). In the population of BMI SDS≥-0.7, uric acid increased by 11.79 μmol/L(P<0.01) for every unit increase of BMI SDS. Conclusion Serum uric acid levels seem to be affected by BMI, and increased in population with thin or obesity. We should pay attention to the measurement of serum uric acid in both thin and obese children. Key words: Body mass index; Uric acid; Children and adolescents; Cross-sectional study

A multi-center clinical study of early predictors and follow-up parameters for girls with rapidly progressive central precocious puberty

Objective To study the early diagnostic predictors and key follow-up parameters for girls with rapidly progressive central precocious puberty(RP-CPP). Methods A total of 260 girls with CPP participated in a prospective, nonrandomized, multi-center, nested case control study. After follow-up six months without any therapy, 114 girls were divided into RP-CPP(n=70)and slowly progressive CPP(SP-CPP)(n=44)groups. Results The basal serum LH and insulin-like growth factor Ⅰstandard deviation score(IGF-ⅠSDS)were the important risk factors of RP-CPP(OR 4.04, 1.578), especially the former. The receiver operating characteristic(ROC)curve revealed that the areas under the ROC curve of basal LH and IGF-ⅠSDS were 0.83 and 0.807, respectively. The levels of basal LH and IGF-ⅠSDS were at 0.52 mIU/ml and 0.35 respectively for the accuracy diagnosis of RP-CPP with the maximum Youden indexs. After follow-up for six months, the change levels of height, breast stages, bone age/chronological age ratio, serum LH, uterine and ovarian volume in RP-CPP group were significantly higher than those in SP-CPP group(all P<0.05). Conclusions The level of basal serum LH and IGF-ⅠSDS may be used as the risk predictors for early diagnosis for girls with RP-CPP. The change levels of basal LH, progress rates of gonad and sex character, height, and impaired growth potential seem to be the key follow-up parameters for CPP progress. (Chin J Endocrinol Metab, 2017, 33: 312-316) Key words: Central precocious puberty; Predictors; Follow-up parameters

IGF-I levels reflect hypopituitarism severity in adults with pituitary dysfunction.

To evaluate the utility of Insulin-like growth factor I (IGF-I) standard deviation score (SDS) as a surrogate marker of severity of hypopituitarism in adults with pituitary pathology. We performed a retrospective data analysis, including 269 consecutive patients with pituitary disease attending a tertiary endocrine clinic in 1990-2015. The medical files were reviewed for the complete pituitary hormone profile, including IGF-I, and clinical data. Age-adjusted assay reference ranges of IGF-I were used to calculate IGF-I SDS for each patient. The main outcome measures were positive and negative predictive values of low and high IGF-I SDS, respectively, for the various pituitary hormone deficiencies. IGF-I SDS correlated negatively with the number of altered pituitary axes (p<0.001). Gonadotropin was affected in 76.6% of cases, followed by thyrotropin (58.4%), corticotropin (49.1%), and prolactin (22.7%). Positive and negative predictive values yielded a clear trend for the probability of low/high IGF-I SDS for all affected pituitary axes. Rates of diabetes insipidus correlated with IGF-I SDS values both for the full study population, and specifically for patients with non-functioning pituitary adenomas. IGF-I SDS can be used to evaluate the somatotroph function, as a valid substitute to absolute IGF-I levels. Moreover, IGF-I SDS predicted the extent of hypopituitarism in adults with pituitary disease, and thus can serve as a marker of hypopituitarism severity.

Management and interpretation of heterogeneous observational data: Using insulin-like growth factor-I data from the NordiNet® International Outcome Study

ObjectiveThe NordiNet® International Outcome Study (IOS), a large-scale, non-interventional, multi-centre, real-world study of Norditropin® treatment, registers insulin-like growth factor-I (IGF-I) values, as measured by different assays. This paper considers the potential biases introduced by using a single IGF-I reference data set in analysing NordiNet® IOS data. DesignTo evaluate possible biases from different IGF-I assays used across NordiNet® IOS, a mixed-effect linear model was fitted to IGF-I data (analyses on log-transformed data). Pre-growth hormone treatment (pre-GHT) IGF-I values were assumed to depend on diagnosis, sex and age. During GHT, a treatment-effect dependent on these factors was added. Differences between assays were assumed multiplicative on the original scale. Individual measurements were scaled to a common level (Nichols Advantage) giving adjusted IGF-I standard deviation score (SDS) values. ResultsIn total, 49 495 IGF-I measurements were available from 9481 paediatric patients. Mixed-effect linear modelling showed a systematic difference between IGF-I levels measured by different assays. Differences were minimised when assessing change in IGF-I SDS from the start of GHT to 1-year follow-up. This applied to values adjusted for actual-assay used and for unadjusted delta IGF-I SDS values. Largest differences between unadjusted change in IGF-I SDS values were: for growth hormone deficiency 0.1 (girls) and 0.3 (boys); for small-for-gestational age 0.1; and for Turner syndrome 0.2. Similar magnitude differences were seen for data with unknown assay. ConclusionsAnalysis and modelling suggest the current approach to IGF-I data collection and analyses in the NordiNet® IOS is sound: in a large cohort without assay-used information, potential bias is minimised by analysing changes in IGF-I SDS.

Comparative evaluation of short-term biomarker response to treatment for growth hormone deficiency in Chinese children with growth hormone deficiency born small for or appropriate for gestational age: a randomized phase IV open-label study

Objectives:To compare the response between Chinese children with growth hormone deficiency (GHD) born either small for gestational age (SGA) or appropriate for gestational age (AGA) after 4 weeks of recombinant human growth hormone (r-hGH) therapy.Methods:This was a phase IV, open-label, multicenter, interventional study (NCT01187550). Prepubertal children with GHD received open-label treatment with daily r-hGH (0.033 mg/kg) for 4 weeks. Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP3), and metabolic markers (including fasting glucose, insulin, total cholesterol, and homeostasis model assessment of insulin resistance) were assessed at baseline and after 4 weeks of treatment, and were analyzed according to patient subgroup (SGA or AGA).Results:A total of 205 children with GHD (mean age 10.4 years; 175 AGA, 30 SGA) were included in the analysis. Mean baseline serum IGF-I and IGFBP3 standard deviation scores (SDS) across the whole patient population were lower than the population norms (mean values: -2.1 SDS for IGF-I and -1.2 SDS for IGFBP3), with no significant differences between the two patient subgroups. After 4 weeks, IGF-I and IGFBP3 levels increased by 1.0 SDS (p < 0.001) and 0.34 SDS (p < 0.001), respectively, but no significant differences were found between the two patient subgroups for growth-related or metabolic markers.Conclusions:For children with GHD born SGA, IGF-I and IGFBP3 are short-term biomarkers of responsiveness to treatment with growth hormone, as for children with GHD born AGA.

An observational study of the effectiveness and safety of growth hormone (Humatrope&lt;sup&gt;®&lt;/sup&gt;) treatment in Japanese children with growth hormone deficiency or Turner syndrome

This study assessed the effectiveness and safety of growth hormone (GH; Humatrope(®)) therapy in Japanese children with GH deficiency (GHD) or Turner syndrome (TS) enrolled in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). GeNeSIS is an open-label, multinational, multicenter, observational study conducted in 30 countries. In this interim report, there were 1129 GH treatment-naïve children with GHD, with a mean chronological age (± standard deviation) of 8.75 (3.32) years, and 90 girls with TS, with a mean chronological age of 8.93 (3.67) years. The mean height standard deviation score (SDS) increased from -2.73 (0.63) SD and -2.71 (0.63) SD at study entry to -2.22 (0.68) SD and -2.20 (0.60) SD after 1 year of treatment in the GHD and TS groups, respectively. In both groups, mean height SDS increased further with each year of treatment to 4 years; however, the magnitude of change in height SDS declined with time. The mean insulin-like growth factor-I SDS increased from below the mean of the reference population at study entry to a level similar to (GHD group) or higher than (TS group) the mean of the reference population during the 4-year treatment period. The incidence of serious adverse events (AEs), treatment-related AEs, and AEs related to glucose intolerance was low in both groups (0.1% to 3.0%). In conclusion, GH treatment in Japanese children with GHD or TS resulted in increased growth over a 4-year treatment period with a favorable safety profile; however, the improvements in growth declined with time.

Metabolic Impact of Growth Hormone Treatment in Short Children Born Small for Gestational Age

Background: Growth hormone (GH) treatment in short children born small for gestational age (SGA) may result in metabolic changes with potential long-term effects. Methods: 149 short SGA children (mean birth weight 2.0 ± 0.6 kg, age 5.5 ± 1.5 years, height standard deviation score (SDS) –3.1 ± 0.6) were randomised to: low-dose GH therapy (0.033 mg/kg/day) for 2 years; high-dose GH therapy (0.100 mg/kg/day) for 1 year, or mid-dose GH therapy (0.067 mg/kg/day) for 1 year. Leptin, ghrelin, insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1), lipids, fasting blood glucose and fasting insulin were assessed at baseline, 12 and 24 months. Results: After 1 year of active treatment, GH significantly reduced serum ghrelin and increased IGF-I SDS and insulin levels. Regression analysis showed an inverse correlation between ghrelin and IGF-I SDS (p < 0.001). Leptin and IGFBP-1 also declined (both p < 0.05). Changes in insulin levels reversed upon discontinuation. Improvements in lipid profile were nonsignificant and fasting blood glucose levels remained within the normal range. Conclusion: In short SGA children, ghrelin and leptin reductions associated with GH treatment may occur through a negative feedback loop of the GH–IGF-I axis. Consequently, via ghrelin and leptin suppression, GH treatment may modify food intake and body composition and potentially improve long-term metabolic outcomes.

A Canadian multi-centre, open-label long-term study of Pegvisomant treatment in refractory acromegaly

Acromegaly is a rarely diagnosed condition with potentially serious complications including accelerated heart disease and reduced survival. After a mean interval of nearly 9 years from onset of disease, a significant proportion of patients are diagnosed with invasive adenomas precluding complete surgical resection. Furthermore, strict normalization of the growth hormone (GH) target insulin-like growth factor I (IGF-I) cannot always be achieved by adjunctive medical therapy with somatostatin analogues. Here we report the results of a Canadian multi-centre study open-label, dose-titrated long-term study examining safety and efficacy outcomes of a growth hormone receptor antagonist, pegvisomant in 19 patients with refractory acromegaly. Previously pegvisomant-treated and treatment-naïve refractory acromegalic patients at least 18 yr of age were eligible (n=19). Patients received open-label daily subcutaneous injections of pegvisomant adjusted according to IGF-I levels. Safety and IGF-I levels were assessed every 4 to 6 wk. Baseline and follow-up visits at 3-month intervals also included administration of the Signs and Symptoms of Acromegaly Questionnaire. This study is registered with ClinicalTrials.gov, NCT00151437. We show that, in escalating doses, pegvisomant results in age-adjusted normalization of IGF-I in nearly all such patients. This IGF-I normalization occurred early on and was maintained throughout the study period of 27 months (IGF-I standard deviation score (SDS), mean +/- SE: 1.66 +/- 0.36, P=0.0003 vs baseline), with a nadir at 18 months (IGF-I SDS, mean +/- SE: 1.50 +/- 0.38, P=0.0010 vs baseline). IGF-I control was also accompanied by measurable improvements in disease-associated symptoms and without radiographic evidence of pituitary tumour progression. Overall, the safety profile of pegvisomant therapy in this patient population was found to be satisfactory and suitable for a long-term treatment. Our findings provide support for the long-term safety and efficacy of the GH receptor antagonist pegvisomant in achieving IGF-I control in patients with refractory acromegaly.

Low insulin‐like growth factor I and leukopenia in anorexia nervosa

Considering that leukopenia and anemia are commonly observed in anorexia nervosa (AN) and that growth hormone (GH) and insulin-like growth factor-I (IGF-I) markedly influence the activation, growth and survival of hemopoietic cells, we sought for possible relationships between hematologic parameters and the GH-IGF-I axis in a group of patients with AN. Twenty patients were studied. Leukocyte and erythrocyte counts, as well as baseline serum GH levels and IGF-I standard deviation score (SDS) values, were determined in each participant and correlations between parameters were searched. Leukocyte and erythrocyte counts, as well as IGF-I SDS values, were significantly lower, conversely GH was significantly higher in AN patients than in normal weight participants. In patients, IGF-I SDS values were positively correlated with leukocyte count and BMI, whereas no correlation was found between IGF-I SDS and hemoglobin or erythrocytes. The demonstration of a positive correlation between leukocyte number and circulating IGF-I in AN suggests a likely pathogenetic role of IGF-I deficiency in this hematologic abnormality.