A method to determine the likelihood of transition to puberty in a heterogeneous prepubertal age group.

A model based on pubertal status and age in normal healthy children that can be used to estimate the probability that a given child will enter or progress through puberty in a given period is presented. This model could also be used to estimate the proportion of children who would be expected to have changes in their pubertal status over a given period, for example, in an interventional trial of growth promoting agents.

A GH Secretagogue Receptor Agonist (LUM-201) Elicits Greater GH Responses than Standard GH Secretagogues in Subjects of a Pediatric GH Deficiency Trial.

INTRODUCTION: LUM-201 (ibutamoren, formerly MK-0677) is an orally administered GH secretagogue receptor agonist under development for treatment of pediatric growth hormone deficiency (PGHD). METHODS: The GH response to a single dose of LUM-201 and to other GH secretagogues used for diagnosis of PGHD were compared in 68 pediatric subjects participating in a trial for growth hormone deficiency. RESULTS: LUM-201 elicited greater GH responses than observed in GHD diagnostic tests with arginine, glucagon, clonidine, L-dopa, and insulin-induced hypoglycemia [median and interquartile ranges 15.0 ng/mL (3.5, 49) vs. 5.5 ng/mL (1.8, 7.6) (p < 0.0001)]. The difference between responses was greatest in subjects with higher baseline IGF-I concentrations and higher GH responses to standard GH stimuli. CONCLUSION: LUM-201 elicits greater GH responses than standard stimuli in subjects with higher peak GH in response to conventional testing and is potentially an orally administered treatment alternative to injectable rhGH in a subset of patients with adequate responses to an acute dose of LUM-201.

When Is a Positive Test for Pediatric Growth Hormone Deficiency a True-Positive Test?

BACKGROUND: In most cases, the growth hormone stimulation test is a necessary component for the diagnosis of growth hormone deficiency (GHD) in children. Diagnostic testing can lead to unnecessary treatment of children with false-positive test results and omission of treatment in children with false-negative results. False-positive results are suggested by the absence of typical growth responses in treated children and false-negative results are suggested by continued growth failure in those left untreated. SUMMARY: The probability that a positive test result indicates the presence of the condition (true positive) depends on the prevalence of that condition in the test population and the false positive rate of the test. This probability has been estimated using published data on the prevalence of GHD in children and the false positive rates estimated from performance of stimulation tests in normally growing children and from repeated testing in short children. Because of the low prevalence of GHD and the substantial false positive rate of the test, the probability of a true-positive result in a child with short stature is 0.028, or about 1 in 36 cases. Key Messages: In children with short stature, most positive growth hormone stimulation test results will be false-positive results, resulting in growth hormone treatment of children misdiagnosed as growth hormone deficient. Additional information is required for accurate diagnosis and prediction of successful treatment outcomes in children. Improvements in diagnostic accuracy and treatment outcome predictions can be anticipated from the use of additional predictive enrichment markers identified and evaluated in broadly based studies of growth hormone treatment in children.

Corroboration of Height Velocity Prediction Markers for rhGH With an Oral GH Secretagogue Treatment in Children With GHD.

CONTEXT: Recombinant human growth hormone (rhGH) is approved for treatment of pediatric growth hormone deficiency (GHD), with greatest growth responses observed in those with severe GHD. Orally administered GH secretagogues (GHS) may be useful treatment in patients with moderate GHD. Distinguishing children with severe vs moderate GHD could identify children who would be better treated with rhGH or GHS. OBJECTIVES: Evaluate baseline insulin-like growth factor-I (IGF-I) and stimulated peak GH response as predictors of 12-month height velocity (HV) in children with GHD. DESIGN: Data on children with GHD were analyzed in a legacy data base (GeNeSIS data). PARTICIPANTS: 514 naïve to rhGH-treatment, prepubertal children with idiopathic isolated GHD for whom stimulated GH, baseline serum IGF-I, and first-year HV during rhGH treatment data are available. OUTCOME MEASURES: Children with severe or moderate GHD were categorized based on GH and IGF-I data and evaluated based on baseline auxologic and hormone profiles and first-year growth response to rhGH. RESULTS: Cohorts of severe and moderate GHD were 81/514 (15.8%) and 433/514 (84.2%). Cohorts differed significantly with regard to indicators of GHD [eg, baseline height SD score (SDS), height SDS minus target height SDS, HV, HV SDS, and change in height SDS during rhGH treatment]. Multiple regression analysis showed IGF-I and stimulated GH were significant predictors of HV independent of other known variables. Expected first-year HV in moderate GHD was 8.3 cm/y. CONCLUSIONS: The combination of peak GH to GH stimulation testing and baseline IGF-I concentration are predictive enrichment markers for annualized HV responses to rhGH therapy.

Development of a Predictive Enrichment Marker for the Oral GH Secretagogue LUM-201 in Pediatric Growth Hormone Deficiency.

CONTEXT: We hypothesize, based on the degree of residual hypothalamic-pituitary function, that some, but not all, children with growth hormone deficiency (GHD) may have beneficial growth responses to the orally administered growth hormone (GH) secretagogue LUM-201. OBJECTIVE: To determine if pretreatment testing can identify predictive enrichment markers (PEM) for subjects with adequate residual function who are responsive to LUM-201. METHODS: We performed an analysis of a completed, randomized, placebo-controlled trial of LUM-201, a GH secretagogue receptor agonist, in which all randomized subjects had pretreatment testing. This international multicenter study conducted in pediatric endocrinology clinics included 68 naïve-to-treatment, prepubertal children with established diagnoses of GHD. Outcome measures included the sensitivity, specificity, and predictive accuracy of potential markers to predict 6-month growth responses to oral LUM-201 and daily rhGH. RESULTS: Two PEM were identified for use in defining PEM-positive status: (1) baseline insulin-like growth factor I (IGF-I) concentration >30 ng/mL and (2) peak GH response of ≥5 ng/mL upon administration of single-dose LUM-201. PEM-positive status enriches a population for better growth responses to LUM-201. PEM-negative status enriches a population for better growth responses to rhGH. CONCLUSION: Combined, the peak GH response to single-dose LUM-201 and the baseline IGF-I concentration are effective PEMs for 6-month growth responses to LUM-201 and rhGH in prepubertal children with GHD.

A rationale for the treatment of short stature in children with the combination of recombinant human growth hormone (rhGH) and recombinant human insulin-like growth factor-I (rhIGF-I).

Both rhGH and rhIGF-I are signaling molecules with the capacity to restore the rate of growth in certain subsets of slowly growing children. In some instances, heights attained at or near the time of cessation of linear growth are indistinguishable from the height distribution of the community as a whole or from the height distribution expected based on the heights of biological parents. The GH: IGF-I signaling system is sequential, forming a continuous loop wherein GH will stimulate production of IGF-I and IGF-I will inhibit production of GH. This feature suggests that a deficiency of GH will be accompanied by a deficiency of IGF-I and that treatment of GH deficiency with rhGH will restore IGF-I and the subnormal growth of combined GH: IGF-I deficiency. Although logical, this proposition is not always true. rhGH and rhIGF-I are distinct polypeptides, with distinct cell surface receptors and distinct intracellular signaling pathways both capable of amplifying distinct, yet overlapping, patterns of gene replication, protein synthesis and metabolic activities. These features suggest that neither treatment with rhGH nor rhIGF-I alone will invariably recapitulate the combined activities of the GH: IGF-I system, At the present time, this proposition appears both logical and true. The possibility that combined rhGH and rhIGF-I treatment can accomplish that which neither monotherapy can has been examined in gene knock-out experiments in animals and direct comparisons of GH, IGF-I and combined GH: IGF- treatments in animals and in children with short stature, normal GH and low IGF-I (primary IGF-I deficiency). In these experimental models, the growth rates with combined rhGH and rhIGF-I treatment exceed those of either monotherapy. The extent to which this proposition can be generalized to various short stature populations remains to be determined.

Insulin growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study.

CONTEXT: Weight-based dosing of GH is the standard of care for short children, although IGF-I is thought to be the main mediator of GH actions on growth. OBJECTIVE: The objective of the study was to test whether IGF-I levels achieved during GH therapy are determinants of the growth responses to GH treatment. DESIGN: This was a 2-yr, open-label, randomized, IGF-I concentration-controlled trial. Prepubertal short children [n = 172, mean age 7.53 yr, mean height sd score (HT-SDS) -2.64] with low IGF-I levels (mean IGF-I SDS -3.56) were randomized to receive one of two GH dose-titration arms in which GH dosage was titrated to achieve an IGF-I SDS at the mean [IGF((low)) group, n = 70] or the upper limit of the normal range [+2 SDS, IGF((high)) group, n = 68] or to a comparison group of conventional GH dose of 40 microg/kg/d (n = 34). SETTING: The study was conducted in a multicenter, outpatient setting. PRIMARY OUTCOME MEASURE: Change in HT-SDS over 2 yr was measured. RESULTS: One hundred forty-seven patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6-9 months. The changes in HT-SDS were +1.0, +1.1, and +1.6 for conventional, IGF((low)), and IGF((high)), respectively, with IGF((high)) showing significantly greater linear growth response (P < 0.001, compared with the other two groups). The IGF((high)) arm required higher doses (>2.5 times) than the IGF((low)) arm, and these GH doses were highly variable (20-346 microg/kg/d). Multivariate analyses suggested that the rise in the IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. CONCLUSION: IGF-I-based GH dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher IGF-I targets results in improved growth responses, although at higher average GH doses.

Recombinant IGF-I: Past, present and future.

Normal linear growth in humans requires GH and IGF-I. Diminished GH action resulting in reduced availability of IGF-I and IGF-binding proteins is the hallmarks of GH Insensitivity Syndromes (GHIS). The deficiencies are the perceived mechanisms for the growth failure of affected patients and the therapeutic targets for the restoration of normal growth. Early treatment attempts with pituitary-derived GH had limited effects in GHIS patients. Recombinant human insulin-like growth factor-I (rhIGF-I) treatment initially provides accelerated growth to GHIS children and provides substantial benefit. But, in general, catch up growth is less substantial with rhIGF-I treatment of GHIS than with rhGH treatment of GH Deficiency. Few classic GHIS patients have reached heights in the normal range (height SD score between -2.0 SD and +2.0 SD) with rhIGF-I monotherapy. A potential explanation is that while rhIGF-I treatment increases circulating concentrations of IGF-1 and IGFBP-3, such treatment reduces endogenous GH levels by negative feedback inhibition of pituitary GH release. In as much as both GH and IGF-I are required for good catch up growth, the loss of any residual GH signaling during IGF-I monotherapy in GHIS patients may attenuate possible catch up growth. Consistent with this explanation is the finding that, as predicted by the preclinical studies by Ross Clark, combination of rhGH & rhIGF-1 provides better growth responses than rhIGF-1 monotherapy in prepubertal children with short stature and low IGF-I levels despite normal stimulated GH responses. In the future, rhGH and rhIGF-I combination therapy can potentially improve growth outcomes over that seen with rhIGF-I monotherapy in all GHIS patients except in those with a total lack of functional GH signaling. Future alternative treatments for GHIS subjects may also include the use of post-growth hormone receptor signaling agonists which restore both GH signaling and IGF-I exposures or the addition of long-acting rhGH species to rhIGF-I. Additional etiologic factors for the growth failure in GHIS should be considered if the growth deficits of GHIS do not resolve with treatment.

A Randomized Safety and Efficacy Study of Somavaratan (VRS-317), a Long-Acting rhGH, in Pediatric Growth Hormone Deficiency.

CONTEXT: Somavaratan (VRS-317) is a long-acting form of recombinant human GH under development for children and adults with GH deficiency (GHD). OBJECTIVES: To determine the optimal somavaratan dose regimen to normalize IGF-1 in pediatric GHD and to evaluate safety and efficacy of somavaratan over 6 months. DESIGN: Open-label, multicenter, single ascending dose study followed by 6-month randomized comparison of 3 dosing regimens. SETTING: Twenty-five United States pediatric endocrinology centers. PATIENTS: Naive-to-treatment, prepubertal children with GHD (n = 68). INTERVENTION(S): Patients received single sc doses of somavaratan (0.8, 1.2, 1.8, 2.7, 4.0, or 6.0 mg/kg) during the 30-day dose-finding phase, then were randomized to somavaratan 1.15 mg/kg weekly, 2.5 mg/kg twice monthly, or 5.0 mg/kg monthly for 6 months. MAIN OUTCOME MEASURES: Safety, pharmacokinetics, pharmacodynamics, 6-month height velocity (HV). RESULTS: Somavaratan pharmacokinetics was linearly proportional to dose; dose-dependent increases in the magnitude and duration of IGF-1 responses enabled weekly, twice-monthly or monthly dosing. A single dose of somavaratan sustained IGF-1 responses for up to 1 month. No somavaratan or IGF-1 accumulation occurred with repeat dosing. Mean annualized HVs for somavaratan administered monthly, twice monthly, or weekly (7.86 ± 2.5, 8.61 ± 2.7, and 7.58 ± 2.5 cm/y, respectively) were similar between groups. Adverse events were mostly mild and transient. CONCLUSIONS: Somavaratan demonstrated clinically meaningful improvements in HV and IGF-1 in prepubertal children with GHD, with no significant differences between monthly, twice-monthly, or weekly dosing.

Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety.

We evaluated the dose-response effects of GH on the growth and growth factor levels of GH-deficient patients. One hundred eleven short (-3.0 +/- 0.9 height SD score), prepubertal GH-deficient children were randomized to receive low- (L; 0.025 mg/kg per day), medium- (M; 0.05 mg/kg per day), or high- (H; 0.1 mg/kg per day) dose GH. One hundred four children completed the 2-yr study. At 2 yr, the three groups displayed increases in height SD scores of 1.4 +/- 0.1 for L, 2.2 +/- 0.1 for M, and 2.3 +/- 0.1 for H (P < 0.001 relative to L, P = NS relative to M). The serum levels of IGF-I and IGF binding protein-3 during treatment also demonstrated dependency on the GH dose and were independently correlated with the increase in height SD scores attained. Bone age advancement, the occurrence of puberty, fasting glucose, and hemoglobin A1c did not change during therapy, but fasting insulin levels rose in a dose-dependent manner. Surprisingly, the GH dose-response curve for both auxological and biochemical parameters differed between prepubertal females (n = 33) and males (n = 71). Males had a linear GH dose response, whereas females had an apparent plateau of both linear growth and IGF-I SD score responses at 0.05 mg/kg per day. In this large, randomized, 2-yr study, we observed a dose-response effect of GH on growth and serum growth factor levels and a prepubertal gender difference in GH sensitivity. These results suggest that the efficacy and theoretical safety of GH therapy can be optimized by modulating the GH dose in a gender-specific manner, based on the growth response and serum growth factor levels.

Age of thelarche and menarche in contemporary US females: a cross-sectional analysis.

AIM: A recent secular trend towards earlier thelarche has been suggested. The aim of this study is to examine normative ages of thelarche and menarche in contemporary US females. METHODS: Trained physicians documented Tanner breast stage by observation in a cross-sectional cohort. Age of menarche was self-reported. The subjects were healthy female children and adolescents. The mean age of thelarche was determined by probit analysis and the mean age of menarche was determined by using a normal time-to-event model. RESULTS: Mean age of thelarche was 9.7 years among 610 females aged 3.0-17.9 years (70% non-Hispanic Caucasian (NHC), 14% African-Americans, 7% Hispanic, 9% "other"). The mean age of menarche was 12.8 years for NHC, with African-Americans having menarche 0.6 years earlier. CONCLUSIONS: Thelarche occurred earlier than recently reported, while age of menarche remained unchanged, this supported a persistent secular trend towards earlier thelarche but stable age of menarche. This suggests that the observed thelarche is gonadotropin-independent or the tempo of pubertal advancement has slowed.

A long-acting human growth hormone with delayed clearance (VRS-317): results of a double-blind, placebo-controlled, single ascending dose study in growth hormone-deficient adults.

BACKGROUND: Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes. OBJECTIVES: This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317. DESIGN: This was a randomized, double-blind, placebo-controlled, single ascending dose study. PATIENTS: Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo). SETTING: The study was conducted in 17 adult endocrinology centers in North America and Europe. MAIN OUTCOME MEASURES: Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed. RESULTS: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3-5.0 µg/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between -1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed. CONCLUSIONS: The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing.

Recombinant insulin-like growth factor (IGF)-I treatment in short children with low IGF-I levels: first-year results from a randomized clinical trial.

CONTEXT: Short stature in children may be associated with low IGF-I despite normal stimulated GH levels and without other causes. OBJECTIVE: Our objective was to assess the safety and efficacy of recombinant human IGF-I (rhIGF-I) in short children with low IGF-I levels. DESIGN: This was a 1-yr, randomized, open-label trial (MS301). SETTING: The study was conducted at 30 U.S. pediatric endocrinology clinics. SUBJECTS: A total of 136 short, prepubertal subjects with low IGF-I (height and IGF-I sd scores <-2, stimulated GH > or =7 ng/ml); 124 completed the study, and six withdrew for adverse events and six for other reasons. INTERVENTION: rhIGF-I was administered sc, twice daily using weight-based dosing (40, 80, or 120 microg/kg; n = 111) or subjects were observed (n = 25). MAIN OUTCOME MEASURES: First-year height velocity (centimeters per year, cm/yr), height sd score, IGF-I, and adverse events were prespecified outcomes. RESULTS: First-year height velocities for subjects completing the trial were increased for the 80- and 120-microg/kg twice-daily vs. the untreated group (7.0 +/- 1.0, 7.9 +/- 1.4, and 5.2 +/- 1.0 cm/yr, respectively; all P < 0.0001) and for the 120- vs. 80-microg/kg group (P = 0.0002) and were inversely related to age. They were not predicted by GH stimulation or IGF-I generation test results and were not correlated with IGF-I antibody status. The most commonly reported adverse events of special interest during treatment were headache (38% of subjects), vomiting (25%), and hypoglycemia (14%). CONCLUSIONS: rhIGF-I treatment was associated with age- and dose-dependent increases in first-year height velocity. Adverse events during treatment were less common than in previous studies and were generally transient, easily managed, and without known sequelae.

Recombinant human insulin-like growth factor-1 treatment: ready for primetime.

The combination of targeted gene knockout studies in animals and human mutational analysis has demonstrated the key role of the IGF system in mammalian growth, both in utero and postnatally. The concept of IGF deficiency as a diagnostic category for children with growth failure first was proposed in the mid 1990s, and has gained support through the demonstration of patients with mutations in key components of the growth hormone (GH)-IGF axis, as well as the widespread use of IGF-I assays for evaluating short stature. The US Food and Drug Administration has approved IGF-I therapy for treating children who have severe primary IGF deficiency, defined as a height SD score < or =-3 and a serum IGF-1 SD score < or =-3, normal serum GH. Recent studies have demonstrated the efficacy and safety of IGF-I therapy in such patients, and investigations are in progress to determine optimal dosing. The availability of IGF-I therapy thus has expanded the therapeutic tool chest available to endocrinologists caring for children who have growth failure.

Abuse of medications employed for the treatment of ADHD: results from a large-scale community survey.

OBJECTIVE: The objective is to assess abuse of prescription and illicit stimulants among individuals being treated for attention-deficit/hyperactivity disorder (ADHD). METHODS: A survey was distributed to patients enrolled in an ADHD treatment center. It included questions designed to gain information about demographics; ADHD treatment history; illicit drug use; and misuse of prescribed stimulant medications, including type of stimulant medication most frequently misused or abused, and how the stimulant was prepared and administered. RESULTS: A total of 545 subjects (89.2% with ADHD) were included in the survey. Results indicated that 14.3% of respondents abused prescription stimulants. Of these, 79.8% abused short-acting agents; 17.2% abused long-acting stimulants; 2.0% abused both short- and long-acting agents; and 1.0% abused other agents. The specific medications abused most often were mixed amphetamine salts (Adderall; 40.0%), mixed amphetamine salts extended release (Adderall XR; 14.2%), and methylphenidate (Ritalin; 15.0%), and the most common manner of stimulant abuse was crushing pills and snorting (75.0%). Survey results also showed that 39.1% of respondents used nonprescription stimulants, most often cocaine (62.2%), methamphetamine (4.8%), and both cocaine and amphetamine (31.1%). Choice of illicit drug was based on rapidity of high onset (43.5%), ease of acquisition (40.7%), ease of use (10.2%), and cost (5.5%). CONCLUSIONS: The risks for abuse of prescription and illicit stimulants are elevated among individuals being treated in an ADHD clinic. Prescription agents used most often are those with pharmacologic and pharmacokinetic characteristics that provide a rapid high. This suggests that long-acting stimulant preparations that have been developed for the treatment of ADHD may have lower abuse potential than short-acting formulations.