Efficacy and Safety of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Phase 3 Study.

CONTEXT: Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). OBJECTIVE: We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. METHODS: In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12. RESULTS: HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the 2-sided 95% CI was higher than the prespecified noninferiority margin (-1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon: 78.9%, somatropin: 79.1%). CONCLUSION: The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).

A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness.

CONTEXT: Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. OBJECTIVE: To identify genetic variants associated with GH responsiveness. DESIGN: Genome-wide association study (GWAS). SETTING: Cohorts from multiple academic centers and a clinical trial. PATIENTS: A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. INTERVENTION: Association of more than 2 million variants was tested. MAIN OUTCOME MEASURES: Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness. RESULTS: No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score. CONCLUSIONS: We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height.

Treatment with high doses of pegvisomant in 56 patients with acromegaly: experience from ACROSTUDY.

OBJECTIVE: To investigate the characteristics of patients who need more or less pegvisomant (PEGV) to normalize serum IGF-I. DESIGN: ACROSTUDY is a global noninterventional safety surveillance study of long-term treatment outcomes in patients treated with PEGV. As of June, 2014, ACROSTUDY included data on 2016 patients. All patients treated for at least 6weeks at a dose above 30mg/day and who had two consecutive normal serum IGF-I values were included in the 'high'-dose group (H; n=56; mean daily dose 44±12.5; median dose 40, 35-60 (10-90%)). Patients with two consecutive normal IGF-I values and who never received a PEGV dose above 10mg/day were included in the 'low'-dose group (L; n=368; mean daily dose 7.5±2.5; median dose 8.6, 4.3-10 (10-90%)). RESULTS: Patients in the H group were significantly younger (median 47 vs 52years) and had a significantly higher BMI (median 31.8 vs 26.5kg/m(2)). They had more diabetes (55% vs 21%), sleep apnea (25% vs 14 %) and more hypertension (61% vs 43%). The incidence of (serious) adverse events was low and was not different between the groups. CONCLUSIONS: Patients who need more PEGV to normalize IGF-I have more aggressive disease, as they are younger, have higher baseline IGF-I levels, more hypertension, more sleep apnea and diabetes and are more overweight. A better understanding of this dose-efficacy relationship of PEGV might avoid inappropriate dosing and prevent serum IGF-I levels from remaining unnecessarily uncontrolled.

Weight gain in Turner Syndrome: association to puberty induction? - longitudinal analysis of KIGS data.

CONTEXT: Girls with Turner Syndrome (TS) treated or not treated with growth hormone (GH) are prone to overweight. Therefore, we hypothesize that puberty induction in TS is associated with weight gain. METHODS: We analyzed weight changes (BMI-SDS) between onset of GH treatment and near adult height (NAH) in 887 girls with TS enrolled in KIGS (Pfizer International Growth Database). Puberty was induced with estrogens in 646 (72·8%) girls with TS. RESULTS: Weight status did not change significantly between GH treatment start and 1 year later (mean difference -0·02 BMI-SDS), but increased significantly (P < 0·001) until NAH (+0·40 BMI-SDS). The BMI-SDS increased +0·21 until start of puberty (P < 0·001). Girls with spontaneous and induced puberty showed similar BMI-SDS changes. Puberty induction at ≥12 years was associated with a significant (P < 0·001) less increase of BMI-SDS (+0·7 BMI-SDS) between baseline and NAH compared to puberty induction at <12 year (+1·0 BMI-SDS). In multiple linear regression analyses changes of BMI-SDS between baseline and NAH were negatively associated with baseline BMI-SDS (P < 0·001), GH doses (P = 0·015), and age at puberty induction (P < 0·001), positively with years on GH treatment (P = 0·004), while duration and dose of estrogens, its route of administration (transdermal/oral), changes of height-SDS, thyroxin and oxandrolone treatment, and karyotype did not correlate significantly to changes of BMI-SDS in this time period. CONCLUSIONS: Puberty does not seem to play a major role in weight gain in girls with TS since the majority of the increases in BMI-SDS occurred before puberty. However, late puberty induction seems to decrease the risk of weight gain.

Overall and cause-specific mortality in GH-deficient adults on GH replacement.

OBJECTIVE: Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients. DESIGN: In KIMS (Pfizer International Metabolic Database) 13,983 GH-deficient patients with 69,056 patient-years of follow-up were available. METHODS: This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05. RESULTS: All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04-1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044). CONCLUSIONS: GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.

Ease of use and preference for a new disposable self-injection pen compared with a reusable pen for administering recombinant human growth hormone: A multicenter, 2-month, single-arm, open-label clinical trial in patient-caregiver dyads.

BACKGROUND: Improved ease of use of drug-delivery devices may enhance compliance. Development of an easier-to-use device for administration of recombinant human growth hormone (rhGH) may thus be beneficial for patients and their caregivers. OBJECTIVE: This study compared ease of use and preference for a new disposable rhGH injection pen relative to previous experience with the currently available reusable pen in standard practice. Both pens deliver the same formulation of rhGH. METHODS: This multicenter, single-arm, open-label study assessed ease of use and preference for the 2 injection pens in patient-caregiver dyads. Eligible children were aged 8 through 18 years, were currently being treated with rhGH, and had been compliant with use of the current reusable pen for ≥ 3 months before study entry. A validated self-reported Injection Pen Assessment Questionnaire was administered twice during the study-at baseline (to assess perceptions of the reusable pen) and after 2 months of use of the new disposable pen-to assess ease of use of the individual pens (rated on a 5-point Likert-type scale), the comparative ease of use of the 2 pens, and pen preference. The primary end point was the proportion of dyads who rated the new pen as no different or easier to use than the current pen. Regardless of treatment or suspected causal relationship to the investigational product, all observed or volunteered adverse events (AEs) were recorded and rated as mild, moderate, or severe. RESULTS: Of 137 screened dyads, 136 (91 boys, 45 girls) were included in the safety population and 133 were included in the efficacy population. The children had a mean age of 12.3 years, a mean weight of 42.2 kg, a mean height of 145.9 cm, and a mean body mass index of 19.3 kg/m(2); 84.6% of the children were white. The majority (82.4%) of adult dyad members were subjects' mothers. The adult dyad members were more likely than the child members to be responsible for preparing the injection (82.0%) and administering the injection (72.9%). Overall, 73.7% of dyads rated the new disposable pen no different or easier to use than the reusable pen (95% CI, 66.2%-81.2%), and 65.2% rated the disposable pen no different or preferable to the reusable pen (95% CI, 57.0%-73.3%). Overall, 60 all-causality AEs occurred in 28 subjects (20.6%), most of them (93.3%) either mild or moderate in intensity. Eight device-related AEs occurred in 7 subjects (5.1%) (injection-site hematoma in 3 and injection-site pain in 5). The most common AEs were headache (7 events), injection-site pain (5), upper respiratory tract infection (4), and pyrexia (4). No deaths or serious AEs were reported. CONCLUSIONS: Nearly three quarters of patients and caregivers reported that the new disposable pen was no different or easier to use than the reusable pen, and nearly two thirds preferred the disposable pen. No safety concerns were identified. The findings suggest that the improvements in the new pen were recognized by patients and caregivers.

Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study.

OBJECTIVE: To compare the efficacy and safety of glimepiride versus metformin in pediatric subjects with type 2 diabetes inadequately controlled with diet and exercise alone or oral monotherapy. RESEARCH DESIGN AND METHODS: This 26-week, single-blind, active-controlled, multinational study randomized 285 subjects to receive glimepiride (1-8 mg once daily) or metformin (500-1000 mg twice daily) for 24 weeks. The primary end point was mean change in A1C from baseline to week 24. Safety was assessed by incidence of hypoglycemia and other adverse events. RESULTS: Significant reductions from baseline A1C were seen in both the glimepiride (-0.54%, P = 0.001) and metformin (-0.71%, P = 0.0002) groups. A total of 42.4% (56 of 132) and 48.1% (63 of 131) of subjects in the glimepiride and metformin groups, respectively, in the intent-to-treat population achieved A1C <7.0% at week 24. No significant differences were observed between groups in reductions in A1C and self-monitored blood glucose levels, changes in serum lipid concentrations, or hypoglycemia incidence. Significant differences were observed in mean changes from baseline in BMI between groups (0.26 kg/m(2) for glimepiride and -0.33 kg/m(2) for metformin; P = 0.003). The adjusted mean body weight increase was 1.97 kg for glimepiride and 0.55 kg for metformin (P = 0.005). A hypoglycemic episode with blood glucose <50 mg/dl (<2.8 mmol/l) was experienced by 4.9 and 4.2% of glimepiride- and metformin-treated subjects, respectively. A single severe hypoglycemic event occurred in each group. CONCLUSIONS: Glimepiride reduced A1C similarly to metformin with greater weight gain, and there was comparable safety over 24 weeks in the treatment of pediatric subjects with type 2 diabetes.

Type 2 diabetes and the metabolic syndrome in children and adolescents.

The prevalence rates of obesity, metabolic syndrome, and type 2 diabetes in children are increasing at an alarming rate. The potential impact of these conditions on the individual, the family, and society, especially in regard to the costs and utilization of health care resources, are very serious. Strategies aimed at reducing caloric intake, increasing caloric expenditure through regular exercise, and treating cardiovascular risk factors and type 2 diabetes early and aggressively are necessary to meet the challenges they impose.