The PARADIGHM (physicians advancing disease knowledge in hypoparathyroidism) registry for patients with chronic hypoparathyroidism: study protocol and interim baseline patient characteristics.

BACKGROUND: The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. METHODS: An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. RESULTS: As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. CONCLUSIONS: At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. TRIAL REGISTRATION: EUPAS16927, NCT01922440.

Burden of illness in not adequately controlled chronic hypoparathyroidism: Findings from a 13-country patient and caregiver survey.

OBJECTIVE: To address knowledge gaps regarding burdens associated with not adequately controlled chronic hypoparathyroidism. DESIGN: Global patient and caregiver survey. STUDY POPULATIONS: Patients with chronic hypoparathyroidism not adequately controlled on conventional therapy and their caregivers. MEASUREMENTS: Health-related quality of life (HRQoL) and health status were evaluated using the 36-item Short Form version 2 (SF-36 v2.0) and Five-Level EuroQoL 5 Dimensions (EQ-5D-5L) instruments, respectively. Hypoparathyroidism-associated symptoms were assessed by a disease-specific Hypoparathyroidism Symptom Diary and caregiver burden via the Modified Caregiver Strain Index (MCSI). RESULTS: Data were obtained from 398 patients and 207 caregivers. Patients' self-rated hypoparathyroidism-related symptom severity was none (3%), mild (32%), moderate (53%) or severe (12%). Per the Hypoparathyroidism Symptom Diary, patients reported moderate, severe or very severe symptoms of physical fatigue (73%), muscle cramps (55%), heaviness in limbs (55%) and tingling (51%) over a 7-day recall period. Impacts (rated 'somewhat' or 'very much') were reported by 84% of patients for ability to exercise, 78% for sleep, 75% for ability to work and 63% for family relationships. Inverse relationships were observed between patient self-rated overall symptom severity and HRQoL and health status assessment scores-the greater the symptom severity, the lower the SF-36 and EQ-5D-5L scores. Caregiver burden increased with patient self-rated symptom severity: none, 1.7 MCSI; mild, 5.4 MCSI; moderate, 9.5 MCSI; and severe, 12.5 MCSI. CONCLUSION: Patients with not adequately controlled hypoparathyroidism reported substantial symptoms and impacts. Greater patient symptom severity was associated with decreased patient HRQoL and health status assessments and increased caregiver burden.

TRENDS IN GROWTH HORMONE STIMULATION TESTING AND GROWTH HORMONE DOSING IN ADULT GROWTH HORMONE DEFICIENCY PATIENTS: RESULTS FROM THE ANSWER PROGRAM.

OBJECTIVE: Adult growth hormone deficiency (AGHD) results in physiologic impairments that may reduce quality of life and negatively impact body composition. AGHD can be treated with recombinant human growth hormone (GH). This study analyzes AGHD patients enrolled in the American Norditropin(®) STUDIES: Web-Enabled-Research (ANSWER) Program/NovoNet, a U.S. observational noninterventional study of patients treated with Norditropin(®) (somatropin [recombinant DNA origin] injection) at the discretion of their physicians. METHODS: Data were evaluated for GH stimulation test (GHST) usage and Norditropin(®) doses over 4 years. RESULTS: Adults (N = 468) with isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) were evaluated. The most commonly used GHSTs were arginine + L-dopa (27%; mostly a single center) and glucagon (25%; most frequent test after 2009). The percent of patients meeting recommended test-specific cut points varied from 32 to 100%, depending on the GHST used. Mean baseline GH doses were higher for MPHD patients and for younger patients in both IGHD and MPHD groups. CONCLUSION: MPHD was more common than IGHD. Mean GH doses were higher in younger patients, consistent with a transition from higher pediatric to lower adult dosing. Over time, glucagon became the most popular GHST. The use, in some patients, of other GHSTs with cut points, as well as starting doses not consistent with current recommendations, highlights the need for continued education regarding treatment guidelines for AGHD.

Attention-Deficit/Hyperactivity Disorder Medication Treatment Impact on Response to Growth Hormone Therapy: Results from the ANSWER Program, a Non-Interventional Study.

OBJECTIVE: To examine whether attention-deficit/hyperactivity disorder (ADHD) stimulant medication modified the linear growth response to growth hormone (GH) treatment in children enrolled in the American Norditropin Studies: Web-Enabled Research Program. STUDY DESIGN: Short, GH treatment-naive children with or without GH deficiency (GHD) received GH therapy. A subset also received ADHD stimulant medication (n = 1190), and others did not (n = 7230). Linear mixed models (adjusted means) examined height SDS (HSDS) and body mass index (BMI) SDS from baseline through year 4. Analyses were repeated with ADHD groups matched for baseline age, height, weight, BMI, and sex. Groups with and without GHD were compared between ADHD groups. RESULTS: Adjusted change in HSDS for the group receiving ADHD stimulant medication was slightly lower than that for patients not receiving stimulant medication at years 1 to 4 (P < .05). However, adjusted change in HSDS was similar between children receiving and not receiving ADHD stimulant medication when matched for baseline measurements. At year 4, 86.7% of patients receiving ADHD stimulant medication, 86.8% of total patients not receiving ADHD stimulant medication, and 84.6% of matched group patients not receiving ADHD stimulant medication achieved HSDS >-2. Year 4 adjusted change in BMI SDS was greater in the patients receiving ADHD stimulant medication compared with both groups not receiving ADHD stimulant medication (P < .05). Patients with GHD showed comparable differences in adjusted change in BMI SDS among the ADHD groups at year 4, whereas patients without GHD showed no significant differences. CONCLUSIONS: ADHD medication did not affect the linear growth response of children treated with GH when those receiving or not receiving ADHD stimulant medication were matched for baseline measurements. Underlying reasons for the observed greater increase in BMI in patients with GHD concomitantly treated with ADHD medication remain to be elucidated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01009905.

Dose-sparing and safety-enhancing effects of an IGF-I-based dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations.

CONTEXT AND OBJECTIVE: Titrating the dosage of growth hormone (GH) to serum levels of insulin-like growth factor-I (IGF-I) is a feasible treatment strategy in children with GH deficiency (GHD) and idiopathic short stature (ISS). The objective was to assess the dose-sparing effect and theoretical safety of IGF-I-based GH therapy. DESIGN, SETTING AND PATIENTS: This was a post hoc analysis of a previously described 2-year, multicenter, open-label, randomized, outpatient, controlled clinical trial in 172 prepubertal short children [age 7·5 ± 2·4 years; height standard deviation score (HSDS) -2·64 ± 0·61] classified by baseline peak GH levels as GHD (<7 ng/ml) or ISS (≥7 ng/ml). INTERVENTION: Conventional weight-based dosing of GH (0·04 mg/kg/day) (n = 34) or GH dosing titrated to an IGF-I target of 0 SDS (IGF0T; n = 70) or an IGF-I target of +2 SDS (IGF2T; n = 68). MAIN OUTCOME MEASURES: Change in HSDS per GH mg/kg/day dose (∆HSDS/GH dose ratio) and proportion of IGF-I levels above +2 SDS at the end of 2 years. RESULTS: GH dosing titrated to an IGF-I target of 0 SDS was the most dose-sparing treatment regimen for GHD or ISS children (mean±SE ∆HSDS/GH dose ratios 48·1 ± 4·4 and 32·5 ± 2·8, respectively) compared with conventional dosing (30·3 ± 6·6 and 21·3 ± 3·5, respectively; P = 0·02, P = 0·005) and IGF2T (32·7 ± 4·8 and 16·3 ± 2·8, respectively; P = 0·02, P < 0·0001). IGF0T also resulted in the fewest IGF-I excursions above +2 SDS (6·8% vs 30·0% for conventional dosing; P < 0·01). CONCLUSIONS: IGF-I-based GH dosing, targeted to age- and gender-adjusted means, may offer a more dose-sparing and potentially safer mode of therapy than traditional weight-based dosing.

Efficacy of IGF-based growth hormone (GH) dosing in nonGH-deficient (nonGHD) short stature children with low IGF-I is not related to basal IGF-I levels.

OBJECTIVE: Weight-based GH dosing is the standard for treating children with short stature. The current study validates the usefulness of IGF-based GH dosing for GH therapy in nonGH-deficient (nonGHD) children and its relationship with pretreatment serum IGF-I concentration. DESIGN AND PATIENTS: In this twelve-month, open-label, randomized controlled study, 151 nonGHD (based on GH-stimulation tests), prepubertal children with short stature and IGF-I levels ≤ 33rd percentile [-0.44 standard deviation score (SDS)] were randomly assigned to receive GH (dose based on IGF-I titration algorithm; n = 114) or to observation (n = 37). GH dose (initially 40 µg/kg/d) was adjusted every 3 months to achieve an IGF-I SDS in the upper normal range (66-99 th percentile). MEASUREMENTS AND RESULTS: In treated children, mean height SDS (HSDS) increased from -2.5 at baseline to -1.7 at 12 months and mean IGF-I SDS increased from -1.7 to 0.1. These parameters remained unchanged in untreated children. There was no relationship between change in HSDS (ΔHSDS) and degree of IGF-I deficiency at baseline. No safety problems were observed. Both groups had a similar advance in bone age. At the end of study, ΔHSDS in treated children showed a positive correlation with IGF-I SDS, but not with GH dose [mean 59 µg/kg/d (range 29-92)], basal IGF-I SDS or 1-month IGF parameters. CONCLUSIONS: In nonGHD subjects with short stature and serum IGF-I concentrations within and below the lower third of normal, adjusting GH dose to achieve an IGF-I level in the upper normal range resulted in a significant increase in HSDS, regardless of basal IGF-I levels.

Administration burden associated with recombinant human growth hormone treatment: perspectives of patients and caregivers.

Patients treated with recombinant human growth hormone (rhGH) for growth hormone disorders follow a challenging treatment schedule. This study assessed patient and caregiver experiences with rhGH therapy treatment regimens. Patients 13 years or older with growth hormone deficiency and caregivers completed Web-based surveys. A total of 61 patients and 239 caregivers participated. Storage of rhGH was considered burdensome by more than a third. More than 51% considered storage "somewhat more" to "much more of a burden" relative to the burden while not traveling. "Away from home or traveling" was the most frequently endorsed reason for missing a dose. rhGH treatment while traveling is challenging because of rhGH storage burden.

Comparison of human growth hormone products' cost in pediatric and adult patients. A budgetary impact model.

We assessed the economic impact to the United States payer of recombinant human growth hormone (rhGH) utilization, comparing the relative dosage efficiency of marketed pen-based and vial-based products in a pediatric and in an adult population. A budgetary impact model calculated drug costs based on product waste and cost. Waste was the difference between prescribed dose, based on patient weight, and actual delivered dose, based on dosing increments and maximum deliverable dose for pens and a fixed-percent waste as derived from the literature for vials. Annual wholesale acquisition costs were calculated based upon total milligrams delivered, using a daily dose of 0.03 mg/kg for pediatric patients and 0.016 mg/kg for adults. Total annual drug costs were compared for two scenarios: 1) a product mix based on national market share and 2) restricting use to the product with lowest waste. Based on the literature, waste for each vial product was 23 percent. Among individual pens, waste was highest for Humatrope 24 mg (19.5 percent pediatric, 14.3 percent adult) and lowest for Norditropin Nordi-Flex 5 mg (1.1 percent pediatric, 1 percent adult). Restricting use to the brand with least waste (Norditropin), compared to national product share mix, resulted in a 10.2 percent reduction in annual pediatric patient cost from $19,026 to $17,089 and an 8 percent reduction in annual adult patient cost from $24,099 to $22,161. We concluded that pen delivery systems result in less waste than vial and syringe. Considering all approved delivery systems, Norditropin resulted in the least product waste and lower annual patient cost for both pediatric and adult populations.

Efficacy and safety of hypoglycemic drugs in children with type 2 diabetes mellitus.

STUDY OBJECTIVES: To assess the characteristics of children with type 2 diabetes mellitus and to determine the efficacy and safety of drug therapies for this disease in this population. DESIGN: Retrospective review of medical records. SETTING: Endocrinology specialty clinic at a tertiary teaching children's hospital. PATIENTS: Forty-two children and adolescents with type 2 diabetes examined between January 1996 and December 2001. MEASUREMENTS AND MAIN RESULTS: Demographic information, presenting signs and symptoms, drug history, and laboratory values were obtained in all patients. Presenting signs and symptoms were similar to those seen in adults. Patients were initially treated with metformin (14.3%), sulfonylureas (14.3%), insulin (31.0%), or combination therapy (14.3%). Most drug regimens decreased hemoglobin A 1c (A1C) levels. Overall, patients treated with drugs had a significant decrease in A1C values, from 10.6% +/- 2.7% (mean +/- SD) before treatment to 8.0% +/- 2.0% at 3.2-52.9 months of treatment (p<0.001). Adverse reactions attributed to drugs included hypoglycemia and gastrointestinal distress. CONCLUSION: Drug therapy appears to be effective in lowering A1C values in pediatric patients, although further prospective trials are necessary to determine optimal drug therapy in this population.

Attaining genetic height potential: Analysis of height outcomes from the ANSWER Program in children treated with growth hormone over 5 years.

OBJECTIVE: This study aimed to assess attainment of genetic height potential after long-term growth hormone (GH) treatment in GH-naïve children diagnosed with isolated growth hormone deficiency (IGHD), multiple pituitary hormone deficiency (MPHD), born small for gestational age (SGA), or idiopathic short stature (ISS) enrolled in the American Norditropin® STUDIES: Web-enabled Research (ANSWER) Program. DESIGN: Children with IGHD (n=2884), MPHD (n=200), SGA (n=481), or ISS (n=733) with baseline height standard deviation score (HSDS)≤-2 were assessed over 5 years of GH treatment for mean HSDS, change in HSDS (ΔHSDS), and corrected HSDS (HSDS-target HSDS). RESULTS: Mean HSDS and corrected HSDS significantly increased to close to target height across all diagnostic groups after 5 years of GH treatment (P<0.0001). ∆HSDS at year 5 increased for all groups (IGHD: 1.8; MPHD: 2.1; SGA: 1.8; ISS: 1.6). Among patients who continued GH for 5 years, mean insulin-like growth factor-I (IGF-I) SDS increased to within normal range across all groups. Body mass index (BMI) SDS remained relatively stable in all diagnostic groups. Bone age (BA) increased, and the mean BA to chronological age (BA/CA) ratio reached or approached 1 across diagnostic groups over 5 years of GH treatment. CONCLUSIONS: Long-term GH therapy resulted in a significant increase in mean HSDS and corrected HSDS from baseline values in all diagnostic groups. The observed increase in mean corrected HSDS is consistent with growth that approached the patients' genetic height potential, although complete height gains will be evaluated at the attainment of final height.

Increased height standard deviation scores in response to growth hormone therapy to near-adult height in older children with delayed skeletal maturation: results from the ANSWER Program.

BACKGROUND: A primary goal of recombinant human growth hormone therapy (GHT) in children is attaining normal adult height. In this study, children with growth hormone deficiency (GHD) (including isolated idiopathic growth hormone deficiency [IGHD] and multiple pituitary hormone deficiency [MPHD]), idiopathic short stature (ISS), and Turner syndrome (TS) were evaluated for near-adult height (NAH) and percent achieving NAH within the normal range after approximately 4 years of GHT. METHODS: Data from the American Norditropin® STUDIES: Web-Enabled Research (ANSWER) Program were analyzed for NAH from age at treatment start (ATS) (i.e., referral age as defined by age at enrollment in the study) to last clinic visit using one of the following two criteria: 1) age ≥18 years, or 2) if male: ≥16 years and height velocity (HV) <2 cm/year; if female: ≥15 years and HV <2 cm/year. All patients had a baseline height standard deviation score (HSDS) ≤ -2, and either GHD (n = 201), ISS (n = 19), or TS (n = 41). The main outcome measures included HSDS and corrected HSDS (HSDS-target HSDS) in response to GH treatment, and correlation of ATS with NAH HSDS. RESULTS: Mean (± SD) chronological and bone ages at baseline were 14.0 ± 2.1 years and 11.7 ± 2.0 years, respectively, and mean GHT duration was 4.0 ± 1.6 years. Mean HSDS (baseline to NAH; GHD: -2.7 to -1.0; ISS: -2.8 to -1.4; TS: -3.0 to -1.8) and mean corrected HSDS (baseline to NAH; GHD: -2.1 to -0.3; ISS: -2.1 to -0.6; TS: -1.8 to -0.6) increased across diagnostic indications. Percentages of patients reaching near-adult HSDS > -2 were GHD: 87.6%; ISS: 78.9%; TS: 65.8%. Significant negative correlations were found between ATS and NAH HSDS when analyzed by sex. CONCLUSIONS: Despite a relatively advanced childhood age, the majority of GH-treated patients attained mean near-adult HSDS within the normal range (HSDS > -2). Negative correlations of ATS with near-adult HSDS indicate that an earlier age at treatment start would likely have resulted in greater adult height achieved in both male and female patients.

Noonan syndrome and Turner syndrome patients respond similarly to 4 years' growth-hormone therapy: longitudinal analysis of growth-hormone-naïve patients enrolled in the NordiNet® International Outcome Study and the ANSWER Program.

BACKGROUND: Turner syndrome (TS) and Noonan syndrome (NS) are distinct syndromes associated with short stature and other similar phenotypic features. We compared the responses to growth hormone (GH) therapy of TS and NS patients enrolled in the NordiNet® International Outcome Study (IOS) or the American Norditropin Studies: Web-Enabled Research (ANSWER) Program, which collect information on GH therapy in clinical practice. METHODS: Repeated-measures regression analysis was performed on change in height standard deviation score (HSDS) and target-height-corrected HSDS, based on national normal references and treatment-naïve disease-specific references. Models were adjusted for baseline age and HSDS, and average GH dose. The study population was paediatric patients with TS and NS in the NordiNet® IOS and ANSWER Program. Longitudinal growth responses over 4 years were evaluated. RESULTS: In 30 NS patients (24 males; baseline age 8.39 ± 3.45 years) and 294 TS patients (7.81 ± 3.22 years), 4-year adjusted ΔHSDS were +1.14 ± 0.13 and +1.03 ± 0.04, respectively (national references). Based on untreated, disease-specific references, 4-year adjusted ΔHSDS for NS and TS were +1.48 ± 0.10 and +1.79 ± 0.04. The analyses showed a significant increase in HSDS over time for both NS and TS (P < 0.0001). ΔHSDS in NS was higher with younger baseline age; ΔHSDS in TS was higher for patients with younger baseline age and higher GH dose. CONCLUSIONS: NS and TS patients responded well and similarly over 4 years of GH treatment.

Prepubertal children with growth hormone deficiency treated for four years with growth hormone experience dose-dependent increase in height, but not in the rate of puberty initiation.

BACKGROUND/AIMS: Limited data exist on long-term dose response to recombinant human growth hormone (rhGH) in prepubertal GH-deficient (GHD) children. The effect of low, intermediate, and high-dose rhGH (25, 50, and 100 µg/kg/day, respectively) on growth and puberty in children with GHD was investigated for 48 months. METHODS: A prospective, dose-response study in 111 patients (aged 3-16 years) evaluated growth velocity (cm/year), height standard deviation score (HSDS), corrected HSDS, bone age/chronologic age ratio, body mass index SDS, and the percentage starting puberty. RESULTS: Dose-related increases were observed in growth velocity (p < 0.001), HSDS (p < 0.001), and corrected HSDS (p < 0.001) from baseline to 48 months. Increases in the bone age/chronologic age ratio (p = 0.043) and body mass index SDS (p = 0.018) occurred up to 36 months at intermediate and high doses versus low-dose rhGH; increases at 48 months were not significant. No significant differences in growth were found between intermediate and high doses of rhGH. Percentages of rhGH-treated patients starting puberty at each dose were equivalent (p = 0.607). CONCLUSIONS: rhGH, 50 and 100 µg/kg/day, induced greater growth than 25 µg/kg/day without altering the proportion of children starting puberty. The maximum approved dose for pubertal patients (100 µg/kg/day) is not required or recommended for prepubertal children with GHD.

The NordiNet® International Outcome Study and NovoNet® ANSWER Program®: rationale, design, and methodology of two international pharmacoepidemiological registry-based studies monitoring long-term clinical and safety outcomes of growth hormone therapy (Norditropin®).

OBJECTIVE: Randomized controlled trials have shown that growth hormone (GH) therapy has effects on growth, metabolism, and body composition. GH therapy is prescribed for children with growth failure and adults with GH deficiency. Carefully conducted observational study of GH treatment affords the opportunity to assess long-term treatment outcomes and the clinical factors and variables affecting those outcomes, in patients receiving GH therapy in routine clinical practice. DESIGN: The NordiNet® International Outcome Study (IOS) and the American Norditropin® STUDIES: Web Enabled Research (ANSWER Program®) are two complementary, non-interventional, observational studies that adhere to current guidelines for pharmacoepidemiological data. PATIENTS: The studies include pediatric and adult patients receiving Norditropin®, as prescribed by their physicians. MEASUREMENTS: The studies gather long-term data on the safety and effectiveness of reallife treatment with the recombinant human GH, Norditropin®. We describe the origins, aims, objectives, and design methodology of the studies, as well as their governance and validity, strengths, and limitations. CONCLUSION: The NordiNet® IOS and ANSWER Program® studies will provide valid insights into the effectiveness and safety of GH treatment across a diverse and large patient population treated in accordance with real-world clinical practice and following the Good Pharmacoepidemiological Practice and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.

Effect of 4 years of growth hormone therapy in children with Noonan syndrome in the American Norditropin Studies: Web-Enabled Research (ANSWER) Program® registry.

BACKGROUND: Noonan syndrome (NS) is a genetic disorder characterized by phenotypic features, including facial dysmorphology, cardiovascular anomalies, and short stature. Growth hormone (GH) has been approved by the United States Food and Drug Administration for short stature in children with NS. The objective of this analysis was to assess the height standard deviation score (HSDS) and change in HSDS (ΔHSDS) for up to 4 years (Y4) of GH therapy in children with NS. METHODS: The American Norditropin Studies: Web-Enabled Research (ANSWER) Program®, a US-based registry, collects long-term efficacy and safety information on patients treated with Norditropin® (somatropin rDNA origin, Novo Nordisk A/S) at the discretion of participating physicians. A total of 120 children (90 boys, 30 girls) with NS, naïve to previous GH treatment, were included in this analysis. RESULTS: The mean (SD) baseline age of subjects (n = 120) was 9.2 (3.8) years. Mean (SD) HSDS increased from -2.65 (0.73) at baseline to -1.32 (1.11) at Y4 (n = 17). Subjects showed continued increase in HSDS from baseline to Y4 without significant differences between genders at Y1 or Y2. The mean (SD) GH dose was 47 (11) mcg/kg/day at baseline and 59 (16) mcg/kg/day at Y4. There was a negative correlation between baseline age and ΔHSDS at Y1 (R = -0.3156; P = 0.0055) and Y2 (R = -0.3394; P = 0.017). ΔHSDS at Y1 was significantly correlated with ΔHSDS at Y2 (n = 37; R = 0.8527, P < 0.0001) and Y3 (n = 20; R = 0.5145; P = 0.0203), but not Y4 (n = 12; R = 0.4066, P = 0.1896). CONCLUSIONS: GH treatment-naïve patients with NS showed continued increases in HSDS during 4 years of treatment with GH with no significant differences between genders up to 2 years. Baseline age was negatively correlated with ΔHSDS at Y1 and Y2. Whether long-term therapy in NS results in continued increase in HSDS to adult height remains to be investigated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01009905.

Impact of age and duration of growth hormone therapy in children with Turner syndrome.

BACKGROUND/AIMS: To assess height standard deviation scores (HSDS) in patients with Turner syndrome (TS) by age at treatment initiation and varying durations of treatment with growth hormone (GH). METHODS: GH treatment-naïve patients with TS from the American Norditropin Studies: Web-enabled Research (ANSWER) Program® Registry were analyzed at baseline, 4 months, and annually. RESULTS: Three hundred and eighty-two patients with TS had a baseline mean (±SD) HSDS of -2.6 ± 0.9. Patients received short-term (1 year), long-term (<3 years), and extended GH treatment (≥3 years, mean = 4.54 years), resulting in 40.2% (n = 99/246), 60.5% (n = 69/114), and 62.3% (n = 86/138) of the patients achieving HSDS >-2. Patients starting GH at a younger age experienced better growth response, regardless of treatment duration. Change in HSDS from baseline (ΔHSDS) at 4 months correlated positively with ΔHSDS at 1 and 3 years, and ΔHSDS at 1 year with ΔHSDS at 3 years (p values from 0.0017 to<0.0001). CONCLUSIONS: Height gains in patients with TS during short-term treatment were found to be highly predictive of longer-term results. Continuation of GH treatment (≥3 years) resulted in 62.3% of the patients achieving an HSDS within the normal population range, indicating the clinical importance of early initiation and continuation of GH treatment in patients with TS.

Identification of factors associated with good response to growth hormone therapy in children with short stature: results from the ANSWER Program®.

OBJECTIVE: To identify factors associated with growth in children on growth hormone (GH) therapy using data from the American Norditropin Studies: Web-enabled Research (ANSWER) Program® registry. METHODS: GH-naïve children with GH deficiency, multiple pituitary hormone deficiency, idiopathic short stature, Turner syndrome, or a history of small for gestational age were eligible (N = 1,002). Using a longitudinal statistical approach, predictive factors were identified in patients with GHD for change from baseline in height standard deviation score (ΔHSDS) following 2 years of treatment. RESULTS: Gradual increases in ΔHSDS over time were observed for all diagnostic categories. Significant predictive factors of ΔHSDS, ranked by significance were: height velocity (HV) at 4 months > baseline age > baseline HSDS > baseline body mass index (BMI) SDS > baseline insulin-like growth factor I (IGF-I) SDS; gender was not significant. HV at 4 months and baseline BMI SDS were positively correlated, whereas baseline age, HSDS, and IGF-I SDS were negatively correlated with ΔHSDS. CONCLUSIONS: These results may help guide GH therapy based on pretreatment characteristics and early growth response.

Factors influencing the one- and two-year growth response in children treated with growth hormone: analysis from an observational study.

To assess gender-, pubertal-, age-related differences in change from baseline height standard deviation score (ΔHSDS), data from 5,797 growth hormone (GH) naïve pediatric patients (<18 years) with growth hormone deficiency (GHD), multiple pituitary hormone deficiency (MPHD), Turner syndrome (TS), small for gestational age (SGA), Noonan syndrome (NS), and idiopathic short stature (ISS) were obtained from the ANSWER (American Norditropin Studies: Web-enabled Research) Program registry. For patients with SGA, ΔHSDS at year 1 was significantly greater for males versus females (P = .016), but no other gender differences were observed. For patients with GHD, ΔHSDS was greater in prepubertal than in pubertal patients. Younger patients for both genders (<11 years for boys; <10 years for girls) showed a greater ΔHSDS (P < .05 for GHD, MPHD, and ISS). Overall, positive ΔHSDSs were observed in all patients, with greater growth responses in younger prepubertal children, emphasizing the importance of starting GH treatment early.

Variable degree of growth hormone (GH) and insulin-like growth factor (IGF) sensitivity in children with idiopathic short stature compared with GH-deficient patients: evidence from an IGF-based dosing study of short children.

CONTEXT: We recently showed that, in IGF-based GH therapy, the IGF-I target chosen affects GH dose requirements, and higher IGF-I targets are associated with more robust growth parameters. OBJECTIVE: The objective of the study was to compare the response of GH-deficient (GHD) vs. idiopathic short-stature (ISS) children to IGF-based GH therapy. DESIGN: This was a 2-yr, open-label, randomized trial. SETTING: The setting was multicenter and outpatient. PATIENTS: Prepubertal short children [height sd score (SDS) < -2] with low IGF-I levels (or= 7 ng/ml). INTERVENTIONS: Patients were randomized 2:2:1 to three treatment groups: IGF-I target of 0 SDS (IGF0T), 2 SDS (IGF2T), or a conventional weight-based GH dosing of 40 microg/kg x d (Conv). MAIN OUTCOME MEASURES: Change in (Delta) height SDS, IGF-I SDS, and GH dose was measured. RESULTS: ISS subjects required higher GH doses than GHD patients in the IGF2T (but not IGF0T) arm (medians 119 and 65 microg/kg x d, respectively), indicating that ISS represents a partial GH-insensitive state that manifests during treatment with higher doses of GH. GHD children grew more than those with ISS in both IGF-targeted dosage groups despite similar IGF-I levels (suggesting a degree of IGF insensitivity in ISS subjects): Delta height SDS of 2.04 +/- 0.17 for GHD and 1.33 +/- 0.09 for ISS groups in IGF2T, 1.41 +/- 0.13 for children with GHD, and 0.84 +/- 0.07 for those with ISS in IGF0T. CONCLUSION: IGF-based GH dosing is clinically feasible in both GHD and ISS patients, although GH dose requirements and auxological outcomes are distinct between these groups. This suggests a degree of both GH and IGF insensitivity in subjects with ISS that requires specific management strategies to optimize growth during GH therapy.