Anne-Marie Kappelgaard

Liquid Growth Hormone: Preservatives and Buffers

Growth hormone (GH) treatment is a successful medical therapy for children and adults with GH deficiency as well as for growth retardation due to chronic renal disease, Turner syndrome and in children born small for gestational age. For all of these conditions, treatment is long term and patients receive daily subcutaneous injections of GH for many years. Patient compliance is therefore of critical importance to ensure treatment benefit. One of the major factors influencing compliance is injection pain. Besides the injection device used, pain perception and local tissue reaction following injection are dependent on the preservative used in the formulation and the concentration of GH. Injection pain may also be related to the buffer substance and injection volume. A liquid formulation of GH, Norditropin® SimpleXx®, has been developed that dispenses with the need for reconstitution before administration. The formulation uses phenol (3 mg/ml) as a preservative (to protect product from microbial degradation or contamination) and histidine as a buffer. Alternative preservatives used in other GH formulations include m-cresol (9 mg/ml) and benzyl alcohol (3–9 mg/ml). Buffering agents include citrate and phosphate. Phenol has been successfully used as a preservative in drug formulations for more than 50 years and is considered a safe and effective agent which complies with strict international requirements for preservatives in drug formulations. In toxicological studies, no or only mild local reactions have been observed following subcutaneous administration of phenol (7.5 mg/ml), m-cresol (3–4 mg/ml) and benzyl alcohol (9 mg/ml). No general toxicity reactions were observed after subcutaneous administration of these agents. Clinical evaluation of the preservatives and buffers used in Norditropin® SimpleXx® showed that pain perception was similar between formulations containing phenol and benzyl alcohol, whereas m-cresol was associated with more painful injections than benzyl alcohol. Furthermore, patients reported more pain following injection of a citrate-buffered solution than after a histidine-buffered solution. More pain was also reported following large volume injections and following injections with solutions containing high protein concentrations. In summary, optimization of the preservative and buffer content of a liquid GH formulation may reduce injection pain and lead to improved patient compliance.

The benefits of growth hormone therapy in patients with Turner syndrome, Noonan syndrome and children born small for gestational age

This review will summarize the effects of growth hormone (GH) on height, body composition, bone and psychosocial parameters in children with Turner syndrome or Noonan syndrome and those born small for gestational age. The safety of GH treatment in children with these diagnoses is also reported. Despite the reported efficacy and safety of GH in these indications, however, not all children achieve their target height potential, due in some part to poor adherence to GH therapy regimens; indeed up to 50% of children are less than fully compliant with treatment. With this in mind the present and future administration of GH therapy is discussed with respect to advances being made in the presentation of GH for injection and advances in GH injection devices. It is hoped that such progress, aimed at making the administration of GH easier and less painful for the patient will improve treatment adherence and outcome benefits.

Intuitiveness, ease of use, and preference of a prefilled growth hormone injection pen: a noninterventional, randomized, open-label, crossover, comparative usability study of three delivery devices in growth hormone-treated pediatric patients.

BACKGROUND Growth hormone (GH) is used to treat pediatric and adult GH deficiency (GHD) and growth failure in, among others, patients with Turner syndrome or children born small for gestational age. To improve treatment adherence, self-injection devices should be easy to learn, easy to use, and well accepted, especially in pediatric patients. Several GH pen devices are available, each with distinct features designed for specific patient needs. OBJECTIVES This study compared injection time and intuitiveness of a prefilled test injection device (Norditropin FlexPro, Novo Nordisk A/S, Bagsværd, Denmark) with those of 2 commercially available durable injection devices (easypod, Merck Serono SA, Geneva, Switzerland; and Genotropin, Pfizer Inc, New York, New York) in GH-treated pediatric patients. Dose accuracy, application errors, intuitiveness, usability, device features, ease of learning, ease of use, and overall preference were also assessed. METHODS This noninterventional, randomized, open-label, crossover study enrolled patients aged ≥10 to <18 years who were diagnosed with GHD or Turner syndrome or were born small for gestational age. Patients were allocated to an intuitiveness group (without instruction) or an instruction group and assigned to 1 of 3 sequences of device testing. For each device, time taken to deliver a mock injection of test medium (FlexPro) or GH (easypod and Genotropin) into an Eppendorf tube and the delivered dose were measured. Dose accuracy and application errors were assessed by a health care professional. Patients assessed the intuitiveness (intuitiveness group only), device features, ease of learning, ease of use, and overall preference of the devices using questionnaires. RESULTS Included in the study were 56 patients (mean [SD] age, 13.6 [2.1] years; 63% male; GHD, 44 patients; Turner syndrome, 3; born small for gestational age, 9): 30 in the intuitiveness group and 26 in the instruction group. In the intuitiveness group, the mean (SD) mock injection time was significantly shorter with FlexPro (47.0 [49.0] seconds) than with the easypod (219.2 [72.6] seconds; P < 0.001) or the Genotropin pen (95.1 [78.4] seconds; P < 0.01). In the instruction group, injection time was also shortest with FlexPro (30.7 [10.8] seconds vs 59.6 [13.1] with easypod and 40.7 [18.6] with the Genotropin pen; both, P < 0.001). Most patients (70%) ranked FlexPro as the most intuitive device (easypod, 0%; Genotropin, 30%). In both the intuitiveness and instruction groups, a significantly greater proportion of patients considered FlexPro easiest to learn compared with the easypod and Genotropin devices (both, P < 0.001), although more patients preferred the easypod or Genotropin devices than FlexPro with regard to appearance (intuitiveness group: FlexPro, 8 patients; easypod, 9; and Genotropin, 13; instruction group: FlexPro, 4; easypod, 10; and Genotropin, 12) and quality (intuitiveness group: FlexPro, 6 patients; easypod, 10; and Genotropin, 14; instruction group: FlexPro, 8; easypod, 12; and Genotropin, 6), and easy- pods delivery feedback feature was preferred by more patients (intuitiveness group: FlexPro, 8 patients; easypod, 14; Genotropin, 8; instruction group: FlexPro, 8; easypod, 14; and Genotropin, 4). Dose accuracies (as assessed by weighing the delivered dose and calculating variation in the delivered dose by device) were 4.6% with FlexPro, 14.6% with easypod, and 20.6% with the Genotropin pen in the intuitiveness group, and 2.7% with FlexPro, 5.8% with easypod, and 24.4% with the Genotropin pen in the instruction group. CONCLUSION In this study, Norditropin FlexPro was associated with shorter injection times, higher dose accuracy, and greater intuitiveness, and was rated as easier to learn compared with the easypod and Genotropin devices.

Metabolic Impact of Growth Hormone Treatment in Short Children Born Small for Gestational Age

Background: Growth hormone (GH) treatment in short children born small for gestational age (SGA) may result in metabolic changes with potential long-term effects. Methods: 149 short SGA children (mean birth weight 2.0 ± 0.6 kg, age 5.5 ± 1.5 years, height standard deviation score (SDS) –3.1 ± 0.6) were randomised to: low-dose GH therapy (0.033 mg/kg/day) for 2 years; high-dose GH therapy (0.100 mg/kg/day) for 1 year, or mid-dose GH therapy (0.067 mg/kg/day) for 1 year. Leptin, ghrelin, insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1), lipids, fasting blood glucose and fasting insulin were assessed at baseline, 12 and 24 months. Results: After 1 year of active treatment, GH significantly reduced serum ghrelin and increased IGF-I SDS and insulin levels. Regression analysis showed an inverse correlation between ghrelin and IGF-I SDS (p < 0.001). Leptin and IGFBP-1 also declined (both p < 0.05). Changes in insulin levels reversed upon discontinuation. Improvements in lipid profile were nonsignificant and fasting blood glucose levels remained within the normal range. Conclusion: In short SGA children, ghrelin and leptin reductions associated with GH treatment may occur through a negative feedback loop of the GH–IGF-I axis. Consequently, via ghrelin and leptin suppression, GH treatment may modify food intake and body composition and potentially improve long-term metabolic outcomes.

Early recognition of growth abnormalities permitting early intervention

Normal growth is a sign of good health. Monitoring for growth disturbances is fundamental to childrens 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.

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.

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.

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.

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

Abstract 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 ≤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.

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

Abstract 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.