Effective growth hormone replacement with once-weekly somapacitan in Japanese children with growth hormone deficiency: Results from REAL4, a phase 3 clinical trial.

OBJECTIVE: Somapacitan is a long-acting growth hormone (GH) derivative developed for the treatment of GH deficiency (GHD). This study evaluates the efficacy and tolerability of somapacitan in Japanese children with GHD after 104 weeks of treatment and after switch from daily GH. DESIGN: Subanalysis on Japanese patients from a randomised, open-labelled, controlled parallel-group phase 3 trial (REAL4, NCT03811535). PATIENTS AND MEASUREMENTS: Thirty treatment-naïve patients were randomised 2:1 to somapacitan (0.16 mg/kg/week) or daily GH (0.034 mg/kg/day) up to Week 52, after which all patients received somapacitan. Height velocity (HV; cm/year) at Weeks 52 and 104 were the primary measurements. Additional assessments included HV SD score (SDS), height SDS, bone age, insulin-like growth factor-I (IGF-I) SDS, and observer-reported outcomes. RESULTS: At Week 52, observed mean HV was similar between treatment groups (10.3 vs. 9.8 cm/year for somapacitan and daily GH, respectively). Similar HVs between groups were also observed at Week 104: 7.4 cm/year after continuous somapacitan treatment (soma/soma) and 7.9 cm/year after 1-year somapacitan treatment following switch from daily GH (switch). Other height-related endpoints supported continuous growth. IGF-I SDS increased in both groups with mean IGF-I SDS within -2 and +2 during the study. Somapacitan was well tolerated, one mild injection site reaction was reported, with no reports of injection site pain. Patient preference questionnaires showed that most patients and their caregivers (90.9%) who switched treatment at Week 52 preferred once-weekly somapacitan over daily GH treatment. CONCLUSIONS: Somapacitan showed sustained efficacy in Japanese children with GHD over 104 weeks and for 52 weeks after switching from daily GH. Somapacitan was well tolerated and preferred over daily GH.

Effective GH Replacement With Somapacitan in Children With GHD: REAL4 2-year Results and After Switch From Daily GH.

CONTEXT: Somapacitan is a long-acting GH derivative for treatment of GH deficiency (GHD). OBJECTIVE: Evaluate the efficacy and tolerability of somapacitan in children with GHD after 2 years of treatment and after the switch from daily GH. DESIGN: A randomized, multinational, open-labelled, controlled parallel group phase 3 trial, comprising a 52-week main phase and 3-year safety extension (NCT03811535). SETTING: Eighty-five sites across 20 countries. PATIENTS: A total of 200 treatment-naïve prepubertal patients were randomized and exposed; 194 completed the 2-year period. INTERVENTIONS: Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (0.034 mg/kg/d) during the first year, after which all patients received somapacitan 0.16 mg/kg/wk. MAIN OUTCOME MEASURES: Height velocity (HV; cm/year) at week 104. Additional assessments included HV SD score (SDS), height SDS, IGF-I SDS, and observer-reported outcomes. RESULTS: HV was sustained in both groups between 52 and 104 weeks. At week 104, mean (SD) for HV between weeks 52 and 104 was 8.4 (1.5) cm/year after continuous somapacitan treatment and 8.7 (1.8) cm/year after 1 year of somapacitan treatment following switch from daily GH. Secondary height-related endpoints also supported sustained growth. Mean IGF-I SDS during year 2 was similar between groups and within normal range (-2 to +2). Somapacitan was well tolerated, with no safety or tolerability issues identified. GH patient preference questionnaire results show that most patients and their caregivers (90%) who switched treatment at year 2 preferred once-weekly somapacitan over daily GH treatment. CONCLUSIONS: Somapacitan in children with GHD showed sustained efficacy and tolerability for 2 years, and after switching from daily GH. Patients/caregivers switching from daily GH expressed a preference for somapacitan. CLINICAL TRIAL REGISTRATION: NCT03811535.

Weekly somapacitan had no adverse effects on glucose metabolism in adults with growth hormone deficiency.

PURPOSE: The long-term effects of long-acting growth hormone (LAGH) analogues on glucose metabolism in adult growth hormone deficiency (AGHD) are not known. We investigated the impact of LAGH somapacitan, administered once-weekly, on glucose metabolism in patients with AGHD. METHODS: In post hoc-defined analyses, we compared the effects of somapacitan with daily growth hormone (GH) and placebo on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-ß) in patients with AGHD across a unique data set from three phase 3 randomized controlled trials (REAL 1, REAL 2 and REAL Japan). RESULTS: No new cases of diabetes mellitus were reported with somapacitan. Among GH-naïve patients (n = 120 somapacitan, n = 119 daily GH), higher changes from baseline in FPG, HOMA-IR and fasting insulin levels were observed with daily GH versus somapacitan at 34 weeks, but not at 86 weeks. HbA1c and HOMA-ß did not differ between groups at either timepoint. Among treatment-naïve patients, sex, age, fasting insulin, glucose tolerance status and body mass index did not influence changes in glucose metabolism. In previously treated patients (REAL 1 extension: n = 51 somapacitan, n = 52 daily GH; REAL 2: n = 61 and n = 31, respectively; REAL Japan: n = 46 and n = 16, respectively), the difference in changes from baseline were not statistically significant between somapacitan and daily GH for any glucose metabolism parameters. CONCLUSIONS: Somapacitan, compared with daily GH, did not adversely affect glucose metabolism up to 86 weeks in a large cohort of treatment-naïve or previously treated patients with AGHD. Trial registrations (date of registration): NCT02229851 (2 September 2014), NCT02382939 (3 March 2015), NCT03075644 (7 March 2017).

Psychometric Validation of the Growth Hormone Deficiency-Child Treatment Burden Measure (GHD-CTB) and the Growth Hormone Deficiency-Parent Treatment Burden Measure (GHD-PTB).

PURPOSE: The aim was to evaluate the measurement properties of the Growth Hormone Deficiency-Child Treatment Burden Measure-Child (GHD-CTB-Child), a patient-reported outcome (PRO) for children aged 9 to < 13 years; the Growth Hormone Deficiency-Child Treatment Burden Measure-Observer (GHD-CTB-Observer), an observer-reported outcome (ObsRO) version completed by parents/guardians of children with growth hormone deficiency (GHD) aged 4 to < 9 years; and the Growth Hormone Deficiency-Parent Treatment Burden Measure (GHD-PTB), a PRO that assesses the treatment burden of parents/guardians living with children with GHD aged 4 to < 13 years. METHODS: A non-interventional, multi-center, clinic-based study across 30 private practice and large institutional sites in the United States and the United Kingdom was conducted. The sample consisted of 145 pre-pubertal children aged 9 to < 13 years at enrollment with a physician confirmed GHD diagnosis as well as 98 parents/guardians of pre-pubertal younger children aged 4 to < 9 years at enrollment with a physician confirmed GHD diagnosis. The child sample consisted of 59 treatment-naïve children (no prior exposure to growth hormone [GH] therapy; were starting GH treatment at study start per standard of care) and 184 children already maintained on treatment for at least 6 months. At baseline, all study participants completed a paper validation battery including all measures needed to conduct the validation analyses. Follow-up assessments with children in the maintenance group and their caregiver/parent were conducted approximately 2 weeks post-baseline to evaluate test-retest reproducibility. To evaluate sensitivity to change and meaningful change thresholds, treatment-naïve participants in both child and parent/guardian populations were assessed within 1 week of report of minimal improvement between week 3 and week 11 and at week 12. Psychometric analyses were implemented following an a priori statistical analysis plan. RESULTS: Factor analyses confirmed the a priori conceptual domains and Overall score for each measure (GHD-CTB-Child and GHD-CTB-Observer domains: Physical, Emotional Well-being, and Interference; GHD-PTB domains: Emotional Well-being and Interference). Internal consistency was acceptable for all measures (Cronbach's alpha > 0.70). Test-retest reliability was acceptable for the Physical, Emotional, and Overall domains of the GHD-CTB versions, and the Emotional and Overall domains of the GHD-PTB (intraclass correlation coefficient above 0.70). All but one of the convergent validity hypotheses for the GHD-CTB versions and all hypotheses for the GHD-PTB were proven (r > 0.40). Known-groups validity hypotheses were significant for length of time to administer the injections in the GHD-CTB versions (p < 0.001 for Physical, Emotional, and Overall, and p < 0.01 for Interference) and whether parents/guardians versus child gave the injections more often for the Emotional domain of the GHD-PTB (p < 0.05). Associated effect sizes ranged from -0.27 to -0.57 for GHD-CTB versions and from -0.74 to -0.69 for the GHD-PTB, indicating that the measures are sensitive to change. Anchor-based patient and parent/guardian ratings of severity suggest preliminary meaningful change thresholds (GHD-CTB: 6 points for Physical score, 9 for Emotional, and 6 for Interference; GHD-PTB: 10 points for Emotional and 6 for Interference scores). CONCLUSIONS: The psychometric properties of the GHD-CTB-Child, GHD-CTB-Observer, and GHD-PTB support the validity of their use as PRO and ObsRO measures to capture the experiences associated with treatment burden for children with GHD and their parents/guardians in both clinical and research settings. The Clinicaltrials.gov registration number NCT02580032 was first posted October 20, 2015.

Weekly Somapacitan is Effective and Well Tolerated in Children With GH Deficiency: The Randomized Phase 3 REAL4 Trial.

CONTEXT: Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD). OBJECTIVE: To demonstrate efficacy and safety of somapacitan vs daily GH. METHODS: REAL4 is a randomised, multinational, open-labeled, active-controlled parallel group phase 3 trial, comprising a 52-week main trial and 3-year extension (NCT03811535). SETTING: Eighty-six sites across 20 countries. PATIENTS: 200 treatment-naïve patients were randomized and exposed. INTERVENTIONS: Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (Norditropin; 0.034 mg/kg/d), administered subcutaneously. MAIN OUTCOME MEASURES: The primary endpoint was annualized height velocity (HV; cm/y) at week 52. Additional assessments included HV SD score (SDS), height SDS, bone age, IGF-I SDS, patient-reported outcomes, and safety measures. RESULTS: Estimated mean HV at week 52 was 11.2 and 11.7 cm/y for somapacitan and daily GH, respectively. Noninferiority was confirmed. Changes in HV SDS, height SDS, bone age, and IGF-I SDS from baseline to week 52 were similar between treatment groups. At week 52, mean IGF-I SDS values were similar between treatment groups and within normal range (-2 to +2). Safety of somapacitan was consistent with the well-known daily GH profile. Low proportions of injection-site reactions were reported for somapacitan (5.3%) and daily GH (5.9%). Both treatments similarly reduced disease burden from baseline to week 52, whereas a greater treatment burden reduction was observed for somapacitan. CONCLUSIONS: Similar efficacy for somapacitan compared to daily GH was demonstrated over 52 weeks of treatment with comparable safety and mean IGF-I SDS levels in treatment-naïve children with GHD.

Dose-exposure-IGF-I response of once-weekly somapacitan in adults with GH deficiency.

Objective: Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose-responses among patients. The aim of this study was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose-insulin-like growth factor I (IGF-I) responses in AGHD patients. Design: Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials. Methods: Pharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose-IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing. Results: The analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7-9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3-4 days after somapacitan dosing and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose-exposure-IGF-I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment. Conclusions: This study extends the knowledge of the somapacitan dose-IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.

Absorption, metabolism and excretion of once-weekly somapacitan, a long-acting growth hormone derivative, after single subcutaneous dosing in human subjects.

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative in clinical development for once-weekly administration in patients with adult GH deficiency (AGHD) and children with GH deficiency (GHD). To date, the use of somapacitan in AGHD or severe AGHD has been approved in the USA and Japan, respectively. This study (ClinicalTrials.gov, NCT02962440) investigated the absorption, metabolism and excretion, as well as the pharmacokinetics (PK), of tritium-labelled somapacitan ([3H]-somapacitan). Seven healthy males received a single subcutaneous dose of 6 mg somapacitan containing [3H]-somapacitan 20 MBq. Blood, serum, plasma, urine, faeces, and expired air were collected for radioactivity assessment. Metabolites were identified and quantified in plasma and urine collected. The PK of plasma components were determined, and the radioactive peaks of the most abundant plasma metabolites and urine metabolites were selected for analysis. Twenty-eight days after dosing, 94.0% of the administered dose was recovered as [3H]-somapacitan-related material, most of which was excreted in urine (80.9%); 12.9% was excreted in faeces, and an insignificant amount (0.2%) was exhaled in expired air. PK properties of [3H]-somapacitan-related material appeared to be consistent across plasma, serum and blood. Three abundant plasma metabolites (P1, M1 and M1B) and two abundant urine metabolites (M4 and M5) were identified. The total exposure of intact somapacitan accounted for 59% of the total exposure of all somapacitan-related material, P1 accounted for 21% and M1 plus M1B accounted for 12%. M4 and M5 were the most abundant urine metabolites and accounted for 37% and 8% of the dosed [3H]-somapacitan radioactivity, respectively. No intact somapacitan was found in excreta. Two subjects had six adverse events (AEs); all were mild in severity and unlikely to be related to trial product. The majority of dosed [3H]-somapacitan (94%) was recovered as excreted metabolites. Urine was the major route for excretion of somapacitan metabolites, followed by faeces, and exhalation in expired air was negligible. The low molecular weights of identified urine metabolites demonstrate that somapacitan was extensively degraded to small residual fragments that were excreted (fully biodegradable). The extensive metabolic degradation and full elimination of metabolites in excreta were the major clearance pathways of somapacitan and the key elements in its biological fate. A single dose of 6 mg somapacitan (containing [3H]-somapacitan) in healthy male subjects was well tolerated with no unexpected safety issues identified.

Pharmacokinetics and Pharmacodynamics of Once-Weekly Somapacitan in Children and Adults: Supporting Dosing Rationales with a Model-Based Analysis of Three Phase I Trials.

BACKGROUND: Somapacitan, a long-acting growth hormone (GH) derivative, has been well-tolerated in children with GH deficiency (GHD) and adults (healthy and adult GHD), in phase I, single- and multiple-dose trials, respectively, and has pharmacokinetic and pharmacodynamic properties supporting a once-weekly dosing regimen. OBJECTIVE: In the absence of a multiple-dose phase I trial in children with GHD, the aim was to develop a pharmacokinetic/pharmacodynamic model to predict somapacitan exposure and insulin-like growth factor-I (IGF-I) response after once-weekly multiple doses in both children and adults with GHD. METHODS: Pharmacokinetic/pharmacodynamic models were developed from pharmacokinetic and IGF-I profiles in three phase I trials of somapacitan (doses: healthy adults, 0.01-0.32 mg/kg; adult with GHD, 0.02-0.12 mg/kg; children with GHD, 0.02-0.16 mg/kg) using non-linear mixed-effects modeling. Pharmacokinetics were described using a non-linear one-compartment model with dual first- and zero-order absorption through a transit compartment, with saturable elimination. IGF-I profiles were described using an indirect response pharmacokinetic/pharmacodynamic model, with sigmoidal-effect relationship. RESULTS: The non-linear pharmacokinetic and IGF-I data were well-described in order to confidently predict pharmacokinetic/pharmacodynamic profiles after multiple doses in adults and children with GHD. Body weight was found to be a significant covariate, predictive of the differences observed in the pharmacokinetics and pharmacodynamics between children and adults. Weekly dosing of somapacitan provided elevated IGF-I levels throughout the week, despite little or no accumulation of somapacitan, in both adults and children with GHD. CONCLUSION: This analysis of somapacitan pharmacokinetic/pharmacodynamic data supports once-weekly dosing in adults and children with GHD. TRIAL REGISTRATION: ClinicalTrials.gov identifier numbers NCT01514500, NCT01706783, NCT01973244.

Assessing the Impact of Growth Hormone Deficiency (GHD) in Adults: Interpreting Change of the Treatment-Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD).

BACKGROUND: This study's purpose was to assess the minimal important difference (MID) for the Treatment-Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD), a patient-reported outcome measure assessing growth hormone deficiency (GHD) impacts. The measure was demonstrated to have adequate psychometric measurement properties, and be reliable and valid. For scores to be interpretable, the TRIM-AGHD must be responsive to treatment benefit and the MID in scores quantified. METHODS: A prospective, non-interventional, observational, clinic-based survey study of naïve-to-treatment adult GHD patients (N = 98) was conducted. Key assessments were at baseline and follow-up (between 4 and approximately 8 weeks), with weekly telephone monitoring post-baseline (last n = 34 patients). Responsiveness was evaluated using the effect size of change scores from baseline to follow-up. MID estimates were derived from distribution-based (half standard deviation [0.5 SD], standard error of measurement [SEm]) and anchor-based methods (patient global rating of change [PGRC]) using change scores from baseline to initial report of minimal improvement in GHD severity. Findings from each method were converged to establish an acceptable MID. RESULTS: Patients were mean age 49.7 years, 65.6% female, and 76.0% Caucasian. The TRIM-AGHD was highly responsive to treatment with the total score effect size being 1.38. For the total score, the 0.5 SD was 8.09 and the SEm was 2.66. The difference found using the PGRC was 20.43. The converged MID value for the total score was 10 points. CONCLUSIONS: The TRIM-AGHD is a highly responsive measure assessing AGHD treatment impacts. A 10-point change score is considered a clinically meaningful improvement.

Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial.

OBJECTIVE: Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin®. Local tolerability and treatment satisfaction were also assessed. DESIGN: 26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). METHODS: Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan (n = 61) or once-daily Norditropin (n = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). RESULTS: Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin (P = 0.0171). CONCLUSIONS: In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin.

Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial.

OBJECTIVE: To evaluate the safety, local tolerability, pharmacodynamics and pharmacokinetics of escalating single doses of once-weekly somapacitan, a reversible, albumin-binding GH derivative, vs once-daily GH in children with GH deficiency (GHD). DESIGN: Phase 1, randomized, open-label, active-controlled, dose-escalation trial (NCT01973244). PATIENTS: Thirty-two prepubertal GH-treated children with GHD were sequentially randomized 3:1 within each of four cohorts to a single dose of somapacitan (0.02, 0.04, 0.08 and 0.16 mg/kg; n=6 each), or once-daily Norditropin® SimpleXx® (0.03 mg/kg; n=2 each) for 7 days. MEASUREMENTS: Pharmacokinetic and pharmacodynamic profiles were assessed. RESULTS: Adverse events were all mild, and there were no apparent treatment-dependent patterns in type or frequency. Four mild transient injection site reactions were reported in three of 24 children treated with somapacitan. No antisomapacitan/anti-human growth hormone (hGH) antibodies were detected. Mean serum concentrations of somapacitan increased in a dose-dependent but nonlinear manner: maximum concentration ranged from 21.8 ng/mL (0.02 mg/kg dose) to 458.4 ng/mL (0.16 mg/kg dose). IGF-I and IGFBP-3, and change from baseline in IGF-I standard deviation score (SDS) and IGFBP-3 SDS, increased dose dependently; greatest changes in SDS values were seen for 0.16 mg/kg. IGF-I SDS values were between -2 and +2 SDS, except for peak IGF-I SDS with 0.08 mg/kg somapacitan. Postdosing, IGF-I SDS remained above baseline levels for at least 1 week. CONCLUSIONS: Single doses of once-weekly somapacitan (0.02-0.16 mg/kg) were well tolerated in children with GHD, with IGF-I profiles supporting a once-weekly treatment profile. No clinically significant safety/tolerability signals or immunogenicity concerns were identified.

Understanding Treatment Burden for Children Treated for Growth Hormone Deficiency.

OBJECTIVE: Growth hormone deficiency (GHD) treatment for children requires growth hormone injections, typically administered daily until the child reaches adult height. Child GHD treatment burden is not well understood and no disease-specific measures exist to assess this burden. The purpose of the study was to explore GHD treatment burden for children and their parents by conducting concept elicitation interviews supporting a theoretical model of the impact of GHD treatment. METHODS: Four focus groups (in Germany) and 52 telephone interviews (in the UK and USA) were conducted with children/adolescents with GHD aged 8 to <13 years and parents of children with GHD aged ≥4 to <13 years. The purpose of the interviews was to understand the experience of GHD treatment from the child's perspective, and for parents, the impact of their child's treatment on themselves. Interview transcripts were analyzed thematically based on modified grounded theory principles. RESULTS: Interviews with 70 respondents who produced descriptions (n = 73) of patients experiences with GHD treatment (three parents spoke for two children each) were conducted. Analysis identified three major areas of GHD treatment burden for children: physical; emotional well-being; and interference. Parent burdens identified were: emotional well-being and interference. Modifiers such as treatment efficacy and duration, which may impact the degree of treatment burden severity, were identified. CONCLUSIONS: Overall treatment burden of child GHD is considerable for children and their parents. The concept elicitation and theoretical model can be used to develop a disease-specific outcome measure, which adequately reflects the burden of GHD treatment for children and their parents.

Understanding burden of illness for child growth hormone deficiency.

PURPOSE: Research demonstrates that children and adolescents with growth hormone deficiency (GHD) are impacted in multiple ways beyond their short stature; however, there are no disease-specific measures to assess these impacts. The purpose of this study was to examine the burden of GHD on children and adolescents, and to conduct concept elicitation to develop a model of the impact of GHD to support a disease-specific outcome measure. METHODS: Four focus groups and 52 telephone interviews were conducted with children with GHD and parents/guardians of children with GHD to understand the experience and impacts from the child's perspective, reported by children or parent-observers about the impact on the child. The interviews and focus groups were conducted in Germany, the United Kingdom, and the United States. Interview transcripts were analyzed thematically based on modified grounded theory principles. RESULTS: There were 73 descriptions of patient's experiences elicited from 70 respondents, as three respondents spoke for two children each. A majority of GHD descriptive narratives refer to boy children (n = 51, 69.9%) and a majority of children had taken GHD treatment (n = 64, 89%). Analysis identified four major areas of GHD impact: Signs and Symptoms (beyond short stature), Physical Aspects of Daily Life, Social Well-Being, and Emotional Well-Being. CONCLUSIONS: The burden of GHD in children and adolescents is considerable and not limited to short stature. The severity of GHD impact on children and adolescents appears to be variable and individualized, but these data indicate that early identification and growth hormone treatment may lead to fewer impacts.

Reversible Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult Growth Hormone Deficiency.

CONTEXT: NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration. OBJECTIVES: The objective of the study was to evaluate safety, local tolerability, pharmacodynamics, and pharmacokinetics of multiple, once-weekly doses of NNC0195-0092, compared with daily GH. DESIGN AND SETTING: This was a phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial. PATIENTS: Thirty-four GH-treated adult subjects (male, n = 25) with GH deficiency participated in the study. INTERVENTIONS AND MAIN OUTCOME MEASURES: Subjects were sequentially assigned into four cohorts of eight subjects, randomized within each cohort (3:1) to once-weekly NNC0195-0092 (n = 6) for 4 weeks (0.02, 0.04, 0.08, and 0.12 mg/kg) or daily injections of Norditropin NordiFlex (n = 2) for 4 weeks with a dose replicating the pretrial dose of somatropin. A safety assessment was performed prior to initiating treatment at the next dose level of NNC0195-0092. Daily GH treatment was discontinued 14 days before the trial start. Blood samples were drawn for assessment of safety, pharmacokinetics, pharmacodynamics (IGF-1 and IGF-binding protein-3) profiles, and immunogenicity studies. RESULTS: Numbers of adverse events were similar at the dose levels of 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 vs daily injections of Norditropin NordiFlex, whereas the number of adverse events was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (area under the curve[0-168h]) and peak plasma concentration) increased in a dose-dependent manner, and a dose-dependent increase in IGF-1 levels was observed. IGF-1 profiles were elevated for at least 1 week, and for the 0.02-mg/kg and 0.04-mg/kg NNC0195-0092 doses, the observed IGF-1 levels were similar to the levels for the active control group. CONCLUSION: Four once-weekly doses of NNC0195-0092 (dose range 0.02-0.12 mg/kg) administered to adult patients with GH deficiency were well tolerated, and IGF-1 profiles were consistent with a once-weekly treatment profile. No clinically significant safety and tolerability signals causally related to NNC0195-0092 were identified, nor were any immunogenicity concerns revealed.

Impact of adult growth hormone deficiency on daily functioning and well-being.

BACKGROUND: Adult Growth Hormone Deficiency (AGHD) is a debilitating condition resulting from tumors, pituitary surgery, radiation of the head, head injury, or hypothalamic-pituitary disease. This qualitative study was conducted to better understand the multi-faceted impacts and treatment effects of GHD on adult patients' daily lives.Seven focus groups and four telephone interviews were conducted in three countries. Eligible AGHD patients were age 22 or older who had started and stopped growth hormone treatment at least once as an adult. Transcripts were analyzed thematically. RESULTS: Thirty-nine patients were interviewed; majority etiology was pituitary disease or tumor (62%). Thirty-four patients (87%) were currently on growth hormone replacement therapy; therapy initiation mean age was 43 years. Analysis identified five domains of disease impact: 1) Psychological Health--changed body or self-image and negative emotional impacts; 2) Physical Health--problems with sleep/fatigue, sex drive, weight gain, hair, skin, muscle/bone loss; 3) Cognition--concentration or memory trouble; 4) Energy Loss and its negative impacts (productivity, exercise, chores, socialization, or motivation); and 5) Treatment Effect--treatment enhances quality of life, enabling patients to increase effort (exercise, chores, or work improvements). Energy and sleep are improved. Saturation of themes was reached after the sixth focus group. A conceptual model of GHD disease impacts was developed. CONCLUSIONS: Untreated AGHD has significant negative impacts for patients, which treatment often improves. It is important for clinicians and researchers to understand these multiple impacts so that they can address them in individualized treatment plans and incorporate them when assessing treatment outcomes.

A reversible albumin-binding growth hormone derivative is well tolerated and possesses a potential once-weekly treatment profile.

CONTEXT: Human growth hormone (hGH) replacement therapy currently requires daily sc injections for years/lifetime, which may be both inconvenient and distressing for patients. NNC0195-0092 is a novel hGH derivative intended for once-weekly treatment of GH deficiency. A noncovalent albumin binding moiety is attached to the hGH backbone. Clearance is reduced as a consequence of a reversible binding to circulating serum albumin, which prolongs the pharmacodynamic (PD) effect. OBJECTIVE: To evaluate safety, local tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose (SD) and multiple doses (MD) of NNC0195-0092. SETTING AND DESIGN: Randomized, single-center, placebo-controlled, double-blind, SD/MD, dose-escalation trial of 105 healthy male subjects. NNC0195-0092 sc administration: Five cohorts of eight subjects received one dose of NNC0195-0092 (0.01-0.32 mg/kg) (n = 6) or placebo (n = 2). Sixteen subjects (equal numbers of Japanese and non-Asian) received once-weekly doses of NNC0195-0092 (0.02-0.24 mg/kg; n=12) or placebo (n=4) for 4 weeks. Blood samples were drawn for assessment of safety, PK, IGF-1, and IGF binding protein 3 profiles and anti-drug antibodies. RESULTS: SD and MD of NNC0195-0092 were well tolerated at all dose levels. No safety concerns or local tolerability issues were identified. A dose-dependent IGF-1 response was observed. IGF-1 profiles suggest that NNC0195-0092 may be suitable for once-weekly dosing, with a clinically relevant dose ≤0.08 mg/kg/week. No differences in PK and PD were observed between Japanese and non-Asian subjects. CONCLUSIONS: SD and MD of NNC0195-0092 administered to healthy Japanese and non-Asian male subjects were well tolerated at all doses. The present trial suggests that NNC0195-0092 has the potential for an efficacious, well-tolerated, once-weekly GH treatment.

Assessing the impact of growth hormone deficiency and treatment in adults: development of a new disease-specific measure.

CONTEXT: Approximately 50 000 adults in the United States are diagnosed with GH deficiency, which has negative impacts on cognitive functioning, psychological well-being, and quality of life. OBJECTIVE: This paper presents development and validation of a patient-reported outcome measure (PRO), the Treatment-Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD). The TRIM-AGHD was developed to measure the impact of GH deficiency and its treatment. DESIGN AND SETTINGS: The development and validation of the TRIM-AGHD was conducted according to the Food and Drug Administration guidance on the development of PROs. Concept elicitation, conducted in three countries included interviews with patients, clinical experts, and literature review. Qualitative data were analyzed based on grounded theory principles, and draft items were cognitively debriefed. The measure underwent psychometric validation in a US clinic-based population. An a priori statistical analysis plan included assessment of the measurement model, reliability, and validity. Item functioning was reviewed using item response theory analyses. PATIENTS OR OTHER PARTICIPANTS: Forty-eight patients and six clinical experts participated in concept elicitation and 169 patients completed the validation study. MAIN OUTCOME MEASURE: TRIM-AGHD was measured. RESULTS: Factor analysis resulted in four domains: energy level, physical health, emotional health, and cognitive ability. The item response theory confirmed adequate item fit and placement within their domain. Internal consistency ranged from 0.82 to 0.95 and test-retest ranged from 0.80 to 0.92. All prespecified hypotheses for convergent validity and all but two for discriminant validity were met. CONCLUSIONS: The final 26-item TRIM-AGHD can be considered a reliable and valid PRO of the impact of disease and treatment for adult GH deficiency.

Biochemical markers of bone turnover in tibia fracture patients randomly assigned to growth hormone (GH) or placebo injections: Implications for detection of GH abuse.

CONTEXT: It has been argued that increased levels of bone remodelling markers are not suitable indicators of GH abuse, as bone injuries per se increase the expression levels of these markers. OBJECTIVE: To investigate the impact of a recovering tibia fracture on circulating bone markers in subjects receiving placebo or GH treatment. DESIGN AND SETTING: A randomised, double-blind, placebo-controlled trial of up to 16weeks GH treatment, followed by a 16-week washout. PARTICIPANTS AND INTERVENTION: Subjects (406 adult males and females) with a tibia fracture were randomly allocated within three days after surgery, to either placebo or GH treatment (15, 30 or 60µg/kg daily) until fracture healing or 16weeks after treatment initiation. MAIN OUTCOME MEASURES: IGF-I, serum C-terminal telopeptide of type I collagen (CTX), osteocalcin (OST) and bone-specific alkaline phosphatase (BAP) were measured during and after treatment. RESULTS: Dose-dependent increases were observed in groups receiving GH, and mean levels in the highest GH dose group peaked at eight (IGF-I, CTX) or 12weeks (OST) after treatment initiation. Statistically significant differences between GH treatment and placebo were seen for IGF-I, CTX and OST in all GH dose groups throughout the treatment period, and persisted until eight (CTX) or 12 (OST) weeks after cessation of treatment. CONCLUSION: IGF-I, CTX and OST are suitable candidate markers of prolonged, illicit administration of GH. Furthermore, CTX and OST have potentials to serve as markers also after cessation of GH administration.

Normal sweat secretion despite impaired growth hormone-insulin-like growth factor-I axis in obese subjects.

Adults with GH deficiency are known to exhibit reduced sweating. Whether sweating capacity is impacted in obese subjects with impaired GH secretion have not previously been investigated. The main objective was to investigate sweat secretion rate and the GH-IGF-I axis in obese subjects before and after weight loss. Sixteen severely obese women (BMI, 40.6 ± 1.1 kg/m(2)) were investigated before and after a diet-induced weight loss. Sixteen age-matched nonobese women served as controls. The obese subjects presented the characteristic decreased GH release, hyperinsulinaemia, increased FFA levels, and impaired insulin sensitivity, which all were normalised after diet-induced weight loss of 30 ± 5 kg. Sweat secretion rates were similar comparing obese and nonobese subjects (78 ± 10 versus 82 ± 9 mg/30 minutes) and sweat secretion did not change after a diet-induced weight loss in obese subjects. We conclude that although obese subjects have markedly reduced GH release and impaired IGF-I levels, sweat secretion rate is found to be normal.