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.

Early recognition of growth abnormalities permitting early intervention.

UNLABELLED: Normal growth is a sign of good health. Monitoring for growth disturbances is fundamental to children's health care. Early detection and diagnosis of the causes of short stature allows management of underlying medical conditions, optimizing attainment of good health and normal adult height. CONCLUSION: This review summarizes currently available information on monitoring for short stature in children and conditions usually associated with short stature and summarizes the authors' conclusions on the early recognition of growth disorders.

Children and adolescent acceptability of a new device system to administer human growth hormone--a pilot study.

BACKGROUND: Growth hormone (GH) is used to treat growth failure in children and metabolic impairments in adults with GH deficiency (GHD). Treatment requires daily subcutaneous injections that may affect treatment outcomes, and subsequently efficacy outcomes. To enhance potential adherence, improved GH delivery device systems are being developed. OBJECTIVE: To compare patient acceptability and usability of Norditropin FlexPro/FlexPro PenMate with Norditropin NordiFlex/NordiFlex PenMate for GH administration in children/adolescents with GHD. METHODS: A multinational, open-label, uncontrolled study. Patients (n = 50; 4-18 years) currently on GH therapy injected test medium into a foam pad. Ease-of-use and patient device preference were recorded by questionnaire. RESULTS: The majority (80%) of patients preferred FlexPro PenMate over NordiFlex PenMate with 96% and 84%, respectively, reporting that they found the FlexPro PenMate system user-friendly and that they were highly confident using it. CONCLUSION: The FlexPro system was well accepted by patients. This may facilitate greater adherence to treatment and improve patient outcomes.

Patient preference for a new growth hormone injection device: results of an open-label study in Japanese pediatric patients.

BACKGROUND: Growth hormone deficiency (GHD) in children is treated with daily subcutaneous injections of GH. Poor adherence, resulting in suboptimal treatment outcomes, is common due to long-term treatment. Injection devices that are considered easy to use by patients or guardians could improve adherence. OBJECTIVE: This study assessed the usability of the Norditropin FlexPro pen injector and NovoTwist needles (both Novo Nordisk A/S, Bagsvaerd, Denmark) in Japanese children and adolescents with GHD. METHODS: This open-label, uncontrolled usability test included patients aged 6 to < or = 18 years with GHD currently receiving daily injections of GH with pen injectors. Patients performed repeated injections of test medium into a foam cushion. Patients or guardians completed a questionnaire on pen handling. RESULTS: A total of 73/74 patients (99%) rated Norditropin FlexPro easy to handle, reporting no technical complaints. In total, 60 (81%) preferred Norditropin FlexPro over their current device, with 12% preferring their current device and 7% not sure. CONCLUSIONS: Norditropin FlexPro was perceived as easy to use and reliable, and was well accepted and preferred over the current device for the administration of GH in children and adolescents. Patients were more confident that Norditropin FlexPro delivered the right dose compared with their current device.

Growth hormone stimulates the collagen synthesis in human tendon and skeletal muscle without affecting myofibrillar protein synthesis.

In skeletal muscle and tendon the extracellular matrix confers important tensile properties and is crucially important for tissue regeneration after injury. Musculoskeletal tissue adaptation is influenced by mechanical loading, which modulates the availability of growth factors, including growth hormone (GH) and insulin-like growth factor-I (IGF-I), which may be of key importance. To test the hypothesis that GH promotes matrix collagen synthesis in musculotendinous tissue, we investigated the effects of 14 day administration of 33-50 microg kg(-1) day(-1) recombinant human GH (rhGH) in healthy young individuals. rhGH administration caused an increase in serum GH, serum IGF-I, and IGF-I mRNA expression in tendon and muscle. Tendon collagen I mRNA expression and tendon collagen protein synthesis increased by 3.9-fold and 1.3-fold, respectively (P < 0.01 and P = 0.02), and muscle collagen I mRNA expression and muscle collagen protein synthesis increased by 2.3-fold and 5.8-fold, respectively (P < 0.01 and P = 0.06). Myofibrillar protein synthesis was unaffected by elevation of GH and IGF-I. Moderate exercise did not enhance the effects of GH manipulation. Thus, increased GH availability stimulates matrix collagen synthesis in skeletal muscle and tendon, but without any effect upon myofibrillar protein synthesis. The results suggest that GH is more important in strengthening the matrix tissue than for muscle cell hypertrophy in adult human musculotendinous tissue.

Cardiovascular effects of growth hormone in adult hemodialysis patients: results from a randomized controlled trial.

BACKGROUND/AIMS: The high morbidity and mortality rates in hemodialysis (HD) patients are due, at least in part, to their increased risk for cardiovascular diseases (CVD). This prospective study evaluated the effect of growth hormone (GH) on a number of CVD risk markers in adult patients on HD. METHODS: 139 HD patients were randomized to one of three GH doses or to placebo. Change from baseline in lean body mass (LBM), CVD risk markers (e.g. lipid profile, plasma homocysteine, inflammatory markers, blood pressure, IGF-I, IGFBP-3 and echocardiography) and correlations with serum IGF-I levels and body mass index were evaluated. RESULTS: LBM increased in GH-treated groups compared with placebo (p < 0.001 pooled GH groups vs. placebo). IGF-I (p = 0.0027) and serum high-density-lipoprotein cholesterol levels (p = 0.038) increased with GH treatment. Serum low-density-lipoprotein cholesterol showed a trend to reduction. IGF-I was negatively correlated with plasma homocysteine levels (p = 0.01) and systolic blood pressure (p < 0.0001). Logistic regression analysis showed that interleukin-6, ghrelin and hematocrit values were significant determinants of all-cause mortality. Left ventricular mass was unchanged from baseline in GH-treated groups. CONCLUSION: In adult HD patients, GH treatment had a predominantly beneficial effect on CVD risk markers.

What is the evidence for beneficial effects of growth hormone treatment beyond height in short children born small for gestational age? A review of published literature.

Background An increasing body of evidence supports the view that both an adverse intrauterine milieu and rapid postnatal weight gain in children born small for gestational age (SGA) contribute towards the risk for the development of chronic diseases in adult life. Content The aim of this review was to identify and summarize the published evidence on metabolic and cardiovascular risk, as well as risk of impaired cardiac function, intellectual capacity, quality of life, pubertal development and bone strength among children born SGA. The review will then address whether growth hormone (GH) therapy, commonly prescribed to reduce the height deficit in children born SGA who do not catch up in height, increases or decreases these risks over time. Summary Overall, there are limited data in support of a modest beneficial effect of GH therapy on the adverse metabolic and cardiovascular risk observed in short children born SGA. Evidence to support a positive effect of GH on bone strength and psychosocial outcomes is less convincing. Outlook Further evaluation into the clinical relevance of any potential long-term benefits of GH therapy on metabolic and cardiovascular endpoints is warranted.

European multicentre study in children born small for gestational age with persistent short stature: comparison of continuous and discontinuous growth hormone treatment regimens.

BACKGROUND: The most effective growth hormone (GH) treatment regimen for increasing height in short children born small for gestational age (SGA) has not been well defined. METHODS: Short SGA children (n = 151, age 3-8 years, height less than -2.5 standard deviation scores) were randomised to receive low-dose GH for 2 years (0.033/0.033 mg/kg/day, n = 51), high-dose GH for 1 year and then no treatment for 1 year (0.100/0 mg/kg/day, n = 51) or were untreated for 1 year then received mid-dose GH for 1 year (0/0.067 mg/kg/day, n = 47). Height, bone age and adverse events were determined at check-ups every 3 months. RESULTS: The mean +/- SD additional height gain with GH after 1 year, relative to untreated controls, was higher with discontinuous high-dose than with continuous low-dose GH (6.5 +/- 0.2 vs. 3.3 +/- 0.2 cm). After 2 years, the additional height gain was similar between high- and low-dose GH groups (between-group treatment difference = 0.2, 95% CI = -0.8 to 1.2 cm, p = 0.702). Patients treated exclusively in the last year had a similar height gain to those in the other treatment groups (p = 0.604). CONCLUSIONS: In short SGA children, continuous low-dose and discontinuous high-dose GH regimens were associated with similar height gain. Treatment with mid-dose GH for 1 year also led to a similar improvement in growth.

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.

Growth hormone delivery devices: current features and potential for enhanced treatment adherence.

INTRODUCTION: Adherence to daily growth hormone (GH) injections optimizes treatment benefit; however, adherence rates are sometimes poor. Reasons for poor adherence and persistence are multifaceted. GH injection devices are undergoing continual improvement to enhance adherence. Areas covered: This review evaluates published data on the evolution of GH injection devices to meet patients' needs and preferences, patients' perception of new devices and the projected impact of device developments on adherence. Published studies were identified through literature database searches including EMBASE and PubMed (January 1985-November 2015). Expert opinion: Patient needs and preferences trend towards convenient, easy-to-use devices that enable self-injection, minimize injection preparation steps by reducing the medication reconstitution and storage requirements, and reduce injection pain. In comparative studies, devices that patients considered easier to use than comparator devices were associated with reduced handling errors, fear of injection (needle anxiety/needle phobia) and pain upon needle insertion, and were thus preferred. A combination of the following items are expected to increase patient motivation to better adhere to therapy and improve treatment outcomes: advances in GH injection devices, educating patients regarding injection device and injection technique, and ongoing support from healthcare professionals, including comprehensive education about their condition, medication and expected outcomes.

The efficacy and safety of growth hormone therapy in children with noonan syndrome: a review of the evidence.

Noonan syndrome is a genetic disorder associated with short stature. We reviewed 15 studies in which growth hormone (GH) therapy was used in children with Noonan syndrome. Data show consistent increases in mean height standard deviation score (SDS), with first-year changes of up to 1.26 SDS. Among studies reporting adult or near-adult height, GH therapy over 5-7 years resulted in adult height SDS from -0.6 to -2.1, with up to 60% of subjects in some studies achieving adult height within 1 SDS of mid-parental height. GH treatment results in an acceleration of bone age, likely reflecting normalization from the retarded bone age common in Noonan syndrome patients at the start of therapy. BMI is not affected by GH treatment, but favorable changes in fat mass and body composition are achievable. Longer-term studies and observational studies suggest a waning of the effect of GH therapy over time, as is seen in other GH-treated conditions, and early initiation of therapy and prepubertal status are important predictors of response. GH treatment does not appear to be associated with adverse cardiac or metabolic effects, and data on malignancy during GH treatment give no cause for concern, although they are limited.

A web-based survey assessing the impact of storage flexibility on the daily life of patients and caregivers administering growth hormone.

Many growth hormone (GH) products require refrigeration after first use or reconstitution. This may reduce adherence by affecting patients' daily activities. Persistent treatment adherence is essential for effective GH therapy. A web-based survey was used to compare the impact of storage-flexible GH products (stable at room temperature [<25°C] for up to 21 days after first use) with refrigeration-only GH products on patients' and caregivers' daily lives. Compared with refrigeration-only GH products, storage-flexible GH products were associated with shorter injection times, greater adherence, less GH wastage and fewer missed activities due to difficulties with injection, and were the preferred type of GH product. When offered a choice of GH product, the majority of patients chose a storage-flexible product.

An analysis of product wastage arising from dosing increment granularity in four modern growth hormone administration devices.

OBJECTIVE: Human growth hormone (hGH) delivery systems differ in the size of the dose increments that can be set by the patient, affecting proximity to the target (i.e., prescribed) dose which can be attained. We investigated differences in dosing increment granularity in NordiFlex®, FlexPro®, NordiPen® (all multiple dose devices) and MiniQuick® (single dose) delivery systems. METHODS: A simulation model was developed to project hGH dosing in pediatric patients with growth hormone deficiency, small for gestational age or Turner syndrome, calculating the nearest dose above the target dose administrable by each device in typical EU and US cohorts and projecting the excess dose (hGH wastage) over 1 year of typical use. RESULTS: The device with the smallest dosing increment (FlexPro 5 mg; 0.025 mg dosing increment) was projected to administer doses < 1% above the target across all indications. MiniQuick (0.2 mg dosing increment) was projected to deliver between 5 and 6% above the target dose. None of the sensitivity analyses changed the conclusion that larger dosing increments result in more hGH wastage. CONCLUSIONS: In addition to increasing dosing accuracy, finer dosing increments may result in reductions in unnecessary hGH usage, which may in turn result in reductions in the cost of hGH treatment borne by the health-care payer.

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.

The impact of long-term growth hormone treatment on metabolic parameters in Japanese patients with short stature born small for gestational age.

BACKGROUND/AIMS: An examination of the effects of up to 260 weeks of growth hormone (GH) therapy on metabolic parameters in Japanese children born small for gestational age (SGA). METHODS: Data were analysed from a 156-week extension of a 104-week multicentre, randomised, double-blind, parallel-group trial. Sixty-five children born SGA (age 3-<8 years) received 33 µg/kg/day (n = 31, 64.5% male) or 67 µg/kg/day (n = 34, 58.8% male) GH for 260 weeks. Changes in metabolic parameters - glucose, insulin, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol - were recorded. Alterations in weight, body mass index standard deviation score (BMI SDS) and vital signs were also evaluated. RESULTS: Over 260 weeks of GH treatment, a positive correlation between Δheight SDS and Δinsulin-like growth factor-I SDS was observed. Insulin and glucose levels were generally unaffected. Favourable changes in lipid profiles were recorded, which were maintained for the study duration. No adverse alterations in weight, BMI SDS or vital signs were noted. CONCLUSION: Long-term, continuous GH treatment in children born SGA appears to be efficacious, associated with potential benefits for several metabolic parameters and associated with no long-term safety concerns.

Parent preference in Switzerland for easy-to-use attributes of growth hormone injection devices quantified by willingness to pay.

Sustained treatment adherence, usually over long periods of time, is critical to the success of growth hormone (GH) therapy. However, adherence rates are often poor which may result in suboptimal clinical outcomes. The type of device used by patients to administer their GH can influence adherence. Offering patients a choice of device maximizes the chance of adherence to treatment. Multiple factors will influence a patient's choice of device, depending on individual priorities. This study evaluated the most preferred features of GH injection devices by parents using a web-based questionnaire and as assessed by their willingness to pay for specific device features. The results show that parents are willing to pay for device features facilitating ease of use.

Comparison of injection dose force, accuracy and precision among three growth hormone injection devices.

Successful growth hormone (GH) therapy requires sustained treatment adherence, usually over long periods of time. However, adherence rates are often poor and this can lead to suboptimal clinical outcomes. Developments in GH injection devices aim to help improve adherence by making daily injections easier. Injection force is an important practical aspect for patients receiving daily GH injections, particularly for patients with small hands or reduced hand strength due to muscle weakness. Norditropin FlexPro (Novo Nordisk A/S, Bagsværd, Denmark) is an easy-to-use GH injection pen device, shown here to have reduced injection force, similar dose accuracy and greater dose precision compared with Norditropin NordiFlex (Novo Nordisk A/S) and Genotropin GoQuick (Pfizer Inc., NY, USA). Easier injections may enable patients to self-administer GH more readily and therefore potentially may help improve adherence and clinical outcome.