Average IGF-1 Prediction for Once-Weekly Lonapegsomatropin in Children With Growth Hormone Deficiency.

CONTEXT: Serum insulin-like growth factor 1 (IGF-1) levels are relatively constant in somatropin-treated children with growth hormone deficiency (GHD), and guide dose adjustments for clinical efficacy and long-term safety. IGF-1 levels following treatment with long-acting growth hormones such as lonapegsomatropin (lonapegsomatropin-tcgd, TransCon hGH), a once-weekly somatropin prodrug, exhibit a characteristic profile over the dosing interval. OBJECTIVE: This study aimed to develop a method to predict average IGF-1 in lonapegsomatropin-treated GHD children to interpret IGF-1 data based on a single sample obtained any time at steady state. METHODS: A population nonlinear mixed-effect pharmacodynamic model for IGF-1 was developed based on 2 randomized, open-label trials of TransCon hGh in GHD children and used to develop a linear mixed model with Taylor series to fit simulated IGF-1 profiles of lonapegsomatropin-treated children. A TOTAL OF: 49 896 IGF-1 sample data simulated from 105 lonapegsomatropin-treated GHD children were utilized for the final prediction model. The dosage range of TransCon hGh was 0.14 to 0.30 hGH mg/kg/week, and weekly average IGF-1 was calculated using IGF-1 profiles simulated from the nonlinear pharmacodynamic model. Predicted average IGF-1 was obtained by linear mixed model with Taylor series. RESULTS: The nonlinear mixed-effect model provided satisfactory model fit. The linear mixed model with Taylor series fit simulated IGF-1 data well, with a relatively straightforward prediction formula. IGF-1 values sampled at ~4.5 days post-dose coincided with weekly average IGF-1 at steady state. CONCLUSION: A formula to predict average IGF-1 from a single sample of IGF-1 at steady state was established to aid clinicians in interpreting IGF-1 levels in GHD children administered lonapegsomatropin.

Evaluation of Potentially Prolactin-Related Adverse Events and Sexual Maturation in Adolescents with Schizophrenia Treated with Paliperidone Extended-Release (ER) for 2 Years: A Post Hoc Analysis of an Open-Label Multicenter Study.

BACKGROUND: Elevated prolactin levels (hyperprolactinemia) are a frequent adverse effect of antipsychotic medications, especially in young populations. Prolonged hyperprolactinemia may affect sexual functioning and the onset and progression of puberty. OBJECTIVE: This study assessed potentially prolactin-related treatment-emergent adverse events (PPRL-TEAEs) and sexual maturation during long-term treatment of adolescents with paliperidone extended-release (ER). METHODS: This post hoc analysis of a 2-year open-label multicenter study (NCT00488319) included patients of either sex aged 12-17 years at study enrollment, diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]) for ≥1 year, who had received one or more adequate antipsychotic treatment prior to enrollment but had not responded sufficiently. Patients were initially treated with 6 mg/day paliperidone ER and further titrated between 1.5 and 12 mg/day based on clinical response and tolerability. The primary objective was to determine the relationship between characteristics (including sex, age at study entry, ethnicity, geographic region, age at diagnosis, duration of illness, number of prior hospitalizations, serum prolactin, and baseline Tanner stages) and onset or risk of PPRL-TEAEs. The secondary objective was to assess sexual maturation during long-term treatment with paliperidone ER. RESULTS: In total, 400 patients were enrolled in the study and 184 patients completed the 2-year study; the majority were boys (61%), White (66%), and aged >14 years at study enrolment (73%) with mean (standard deviation [SD]) body mass index (BMI) of 21.96 (4.375) kg/m2 at baseline. Girls (18.5%) had a higher incidence of PPRL-TEAEs than did boys (3.3%). Most of these events were mild to moderate in severity, and none were serious; four patients discontinued the study due to PPRL-TEAEs. Mean prolactin levels in the total population of boys and girls increased early during treatment then stabilized with time. Mean ± SD maximum changes in prolactin levels from baseline were higher in girls and boys with PPRL-TEAEs than in those without (Girls: 74.7 ± 32.3 ng/ml [n = 28] vs. 50.5 ± 44.9 ng/ml [n = 114]; p = 0.008. Boys: 33.6 ± 23.7 ng/ml [n = 8] vs. 31.0 ± 24.5 ng/ml [n = 205]; p = 0.77). No clinically significant mean changes from baseline in growth-adjusted z-score for weight, height, or BMI were observed. Overall, ~90% of the patients who completed the 2-year study achieved Tanner stages 4-5 by study endpoint. Female sex, age at diagnosis (13-14 years), girls of Hispanic ethnicity, and region (EU and North America) were associated with a greater risk for PPRL-TEAEs; higher baseline Tanner stages for pubic hair (boys and girls) and breast development (stage 3 vs. 4 or 5) also seemed to be associated with a higher incidence of PPRL-TEAEs. CONCLUSIONS: Female sex appeared to be associated with an increased risk for PPRL-TEAEs. Other potential predictors, such as ethnicity, region, age at diagnosis, and Tanner stage 4 or 5, all seemed to be related to sex. Evidence from this study was insufficient to definitively conclude that prolactin values at baseline and change during treatment were predictive of PPRL-TEAEs, although there is a signal that this may be the case in girls. These results are exploratory in nature, and confirmatory studies are needed to confirm these observations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00488319.

Dissecting the workforce and workplace for clinical endocrinology, and the work of endocrinologists early in their careers.

CONTEXT: The United States lacks timely reliable mechanisms for assessing the professional work of subspecialty physicians. OBJECTIVE: The aim was to use early-career members of The Endocrine Society as a model to estimate subspecialty physician involvement in patient care, teaching, research, and administration among clinical, academic, federal, and pharmaceutical/biotech workplaces and to assess the workforce for research within individual workplaces. METHODS: Physicians joining The Endocrine Society from 1991-2005 and residing in North America were invited to complete a Web-based survey. This report relies on 817 early-career endocrinologists or 29.6% of eligible respondents. RESULTS: Respondents from all types of workplaces engaged in patient care, teaching, research, and administration. The time committed to the four tasks, however, differed significantly among workplaces. Research (basic, translational, disease, patient, population, and prevention) was accomplished within all workplaces, but the scope and scale of investigative work was employer dependent. Recipients of National Institutes of Health K08/23 awards succeeded in receiving federal research project grants (P < 0.001). Respondents associated research with lowered incomes, a perception validated by an estimated drop in annual earnings of 2.8% per half-day spent on research (P < 0.001). Women in academic settings earned less than men (P < 0.01) and were less likely to occupy tenure-eligible positions (P < 0.01). CONCLUSIONS: Web-based surveys offer a simple tool for estimating the work of subspecialty physicians and provide a framework for improving biomedical investigation. Several interventions should be considered for endocrinology: recruit physicians from underrepresented demographic groups, increase K08/23 awards, incentivize investigative careers, and improve the national infrastructure for biomedical research.

Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial.

BACKGROUND: Growth hormone secretion and muscle mass decline from midpuberty throughout life, culminating in sarcopenia, frailty, decreased function, and loss of independence. The decline of growth hormone in the development of sarcopenia is one of many factors, and its etiologic role needs to be demonstrated. OBJECTIVE: To determine whether MK-677, an oral ghrelin mimetic, increases growth hormone secretion into the young-adult range without serious adverse effects, prevents the decline of fat-free mass, and decreases abdominal visceral fat in healthy older adults. DESIGN: 2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial. SETTING: General clinical research center study performed at a university hospital. PARTICIPANTS: 65 healthy adults (men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy) ranging from 60 to 81 years of age. INTERVENTION: Oral administration of MK-677, 25 mg, or placebo once daily. MEASUREMENTS: Growth hormone and insulin-like growth factor I levels. Fat-free mass and abdominal visceral fat were the primary end points after 1 year of treatment. Other end points were body weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function, and quality of life. All end points were assessed at baseline and every 6 months. RESULTS: Daily administration of MK-677 significantly increased growth hormone and insulin-like growth factor I levels to those of healthy young adults without serious adverse effects. Mean fat-free mass decreased in the placebo group but increased in the MK-677 group (change, -0.5 kg [95% CI, -1.1 to 0.2 kg] vs. 1.1 kg [CI, 0.7 to 1.5 kg], respectively; P < 0.001), as did body cell mass, as reflected by intracellular water (change, -1.0 kg [CI, -2.1 to 0.2 kg] vs. 0.8 kg [CI, -0.1 to 1.6 kg], respectively; P = 0.021). No significant differences were observed in abdominal visceral fat or total fat mass; however, the average increase in limb fat was greater in the MK-677 group than the placebo group (1.1 kg vs. 0.24 kg; P = 0.001). Body weight increased 0.8 kg (CI, -0.3 to 1.8 kg) in the placebo group and 2.7 kg (CI, 2.0 to 3.5 kg) in the MK-677 group (P = 0.003). Fasting blood glucose level increased an average of 0.3 mmol/L (5 mg/dL) in the MK-677 group (P = 0.015), and insulin sensitivity decreased. The most frequent side effects were an increase in appetite that subsided in a few months and transient, mild lower-extremity edema and muscle pain. Low-density lipoprotein cholesterol levels decreased in the MK-677 group relative to baseline values (change, -0.14 mmol/L [CI, -0.27 to -0.01 mmol/L]; -5.4 mg/dL [CI, -10.4 to -0.4 mg/dL]; P = 0.026); no differences between groups were observed in total or high-density lipoprotein cholesterol levels. Cortisol levels increased 47 nmol/L (CI, 28 to 71 nmol/L (1.7 microg/dL [CI, 1.0 to 2.6 microg/dL]) in MK-677 recipients (P = 0.020). Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677 recipients. Increased fat-free mass did not result in changes in strength or function. Two-year exploratory analyses confirmed the 1-year results. LIMITATION: Study power (duration and participant number) was insufficient to evaluate functional end points in healthy elderly persons. CONCLUSION: Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated. Long-term functional and, ultimately, pharmacoeconomic, studies in elderly persons are indicated.

The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture.

OBJECTIVES: To evaluate the effects of MK-0677, an orally active growth hormone (GH) secretagogue, on functional recovery from hip fracture in previously mobile older individuals. DESIGN: Placebo-controlled, randomized, double-blind trial. SETTING: Thirteen medical centers in England, Sweden, Denmark, Belgium, Switzerland, Canada, and the United States. Patients were recruited between 3 and 14 days postoperatively, or no more than 18 days postfracture, at acute care hospitals and rehabilitation centers. PARTICIPANTS: One hundred sixty-one hip-fracture patients were enrolled. Entry criteria included consenting hip-fracture patients who were aged 65 and older and who were ambulatory before their fracture, medically stable postoperatively, and mentally competent. Patients were excluded if they had multiple fractures or severe trauma, diabetes mellitus, cancer, uncontrolled hypertension, congestive heart failure, or total hip replacement in the involved extremity. INTERVENTION: Random assignment to 6 months of daily treatment with MK-0677 or placebo. Patients were followed for an additional 6 months after completion of therapy. MEASUREMENTS: Change from Week 6 to Week 26 in a panel of functional performance measures. Additional outcome measures included change in the Sickness Impact Profile for Nursing Homes (SIP-NH), the ability to live independently, and insulin-like growth factor I (IGF-I) levels. RESULTS: MK-0677 treatment increased serum IGF-I levels by 84% (95% confidence interval (CI)=63-107), compared with an increase of 17% (95% CI=8-28) on placebo. There were no significant differences between MK-0677 and placebo in improvement in functional performance measures or in the overall SIP-NH score. Although MK-0677 patients showed greater improvement relative to placebo in three of four lower extremity functional performance measures, in the physical domain of the SIP, and in the ability to live independently, these differences were not statistically significant. CONCLUSION: Although MK-0677 treatment increased serum IGF-I, it is uncertain whether clinically significant effects on physical function were achieved. Measuring function in clinical trials in hip-fracture patients is difficult because of the lack of validated outcome measures, high variability, and the lack of a baseline assessment. Present functional performance measures may not be sufficiently responsive for use as the primary endpoint of small intervention studies; alternatively, stimulation of GH may not result in significant functional improvement.

A randomized, placebo controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis.

PURPOSE: We determine the effects of treatment with rofecoxib and placebo in patients with chronic prostatitis. MATERIALS AND METHODS: Patients diagnosed with chronic nonbacterial prostatitis were randomized to 6 weeks of 25 or 50 mg., rofecoxib or placebo in a double-blind multicenter study with a 1-week run in of placebo. End points included the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (average pain score item 4 primary end point), and patient global assessment questions of pain, disease activity and response to therapy. RESULTS: A total of 161 patients were randomized in the study. The NIH-CPSI total, domain and pain scores significantly decreased from baseline in all groups and, although the mean scores numerically favored the rofecoxib groups, the difference was not significantly different among groups. There was a trend for the percentage of patients with a 25% (or 6 point) improvement in total score being superior on rofecoxib versus placebo with the difference being significantly different (p <0.05) for the 50 mg. rofecoxib group. Patient global assessment of pain, response to therapy and disease activity also favored rofecoxib over placebo (p <0.05, p = 0.07, p = 0.06, respectively). Of the patients 79% on 50 mg. rofecoxib versus 59% on placebo reported no or mild pain, and 56% of patients on 50 mg. rofecoxib versus 27% on placebo experienced significant improvement in quality of life (p <0.005). Rofecoxib was generally well tolerated. CONCLUSIONS: To our knowledge this study is the first to evaluate rofecoxib versus placebo in patients with prostatitis and the first large multicenter treatment study to use the NIH-CPSI. Subjective assessment with patient global questions may be more sensitive to change than the NIH-CPSI and, therefore, may be a better tool to use in future therapeutic trials. Although 6 weeks of rofecoxib treatment appear to benefit many men diagnosed with chronic prostatitis/chronic pelvic pain syndrome further studies are needed.

Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia.

OBJECTIVES: To evaluate the incidence and resolution of sexual adverse experiences (AEs) in men with benign prostatic hyperplasia treated with finasteride 5 mg compared with placebo. METHODS: The Proscar Long-term Efficacy and Safety Study (PLESS) was a 4-year, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of finasteride 5 mg in 3040 men, aged 45 to 78 years, with symptomatic benign prostatic hyperplasia, enlarged prostates, and no evidence of prostate cancer. Patients completed a questionnaire at screening regarding their history of sexual dysfunction. During treatment, spontaneously self-reported sexual AEs were recorded. RESULTS: At screening, 46% of patients in each treatment group reported some history of sexual dysfunction. During year 1 of the study, 15% of finasteride-treated patients and 7% of placebo-treated patients had sexual AEs that were considered drug related by the investigator (P <0.001). During years 2 to 4, no between-group difference was noted in the incidence of new sexual AEs (7% in each group). The drug-related sexual AE profile for finasteride was similar for men with or without a history of sexual dysfunction. Sexual AEs resolved while continuing therapy in 12% of finasteride patients and 19% of placebo patients. Only 4% of finasteride and 2% of placebo patients discontinued the study because of sexual AEs. In men who discontinued with a sexual AE, 50% and 41% experienced resolution of their sexual AE after discontinuing finasteride or placebo therapy, respectively. CONCLUSIONS: Compared with placebo, men treated with finasteride experienced new drug-related sexual AEs with an increased incidence only during the first year of therapy.