A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency Long-Acting C-Terminal Peptide–Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children A Long-Acting Human Growth Hormone (Nutropin Depot®): Efficacy and Safety Following Two Years of Treatment in Children with Growth Hormone Deficiency MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults A longitudinal study of craniofacial growth in idiopathic short stature and growth hormone-deficient boys treated with growth hormone. The Basis for Optimising Growth with Growth Hormone Usage in Children with Idiopathic Short Stature: Analysis of Data from KIGS (Pfizer International Growth Study Database) Once versus twice daily injections of growth hormone in children with idiopathic short stature One‐year results of growth hormone treatment of short stature in Prader—Willi syndrome Absence of growth hormone effects on cognitive function in girls with Turner syndrome. Early, discontinuous, high dose growth hormone treatment to normalize height and weight of short children born small for gestational age: results over 6 years. Effects of growth hormone therapy in prepubertal children with short stature secondary to intrauterine growth retardation Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency.
Context TransCon Growth Hormone ( GH ) ( Ascendis Pharma ) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency ( GHD ) . Objective To compare the pharmacokinetics , pharmacodynamics , safety , and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD . Design R and omized , open-label , active-controlled study of three doses of weekly TransCon GH versus daily Genotropin ( Pfizer ) . Setting Thirty-eight centers in 14 European countries and Egypt . Patients Prepubertal male and female treatment-naïve children with GHD ( n = 53 ) . Interventions Subjects received one of three TransCon GH doses ( 0.14 , 0.21 , or 0.30 mg GH/kg/wk ) or Genotropin 0.03 mg GH/kg/d for 26 weeks . Main Outcome Measures GH and insulinlike growth factor-1 ( IGF-1 ) levels , growth , adverse events , and immunogenicity . Results Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses . A dose response was observed , with IGF-1 st and ard deviation scores increasing into the normal range for all three TransCon GH doses . Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm , which was not statistically different from 11.6 cm for Genotropin . Adverse events were mild to moderate , and most were unrelated to the study drug . Injection site tolerance was good . One TransCon GH subject developed a low-titer , nonneutralizing antibody response to GH . Conclusions The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH ( pharmacokinetics ) and IGF-1 ( pharmacodynamics ) levels , safety , and efficacy and support advancement into phase 3 development Context Daily injections are required for growth hormone ( GH ) replacement therapy , which may cause low compliance as a result of inconvenience and distress in patients . Objective C-terminal peptide-modified human GH ( MOD-4023 ) is developed for once-a-week dosing regimen in GH-deficient ( GHD ) adults and children . The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children . Design A multicenter , open-label , r and omized , controlled phase 2 study in children with GHD , evaluating the safety , tolerability , pharmacokinetics/pharmacodynamics , and efficacy of three different weekly MOD-4023 doses , compared with daily recombinant human GH ( r-hGH ) . Setting The trial was conducted in 14 endocrinology centers in Europe . Patients Fifty-three prepubertal children with GHD completed 12 months of treatment with either MOD-4023 ( N = 42 ) or r-hGH ( N = 11 ) . Interventions C-terminal peptide-modified hGH ( MOD-4023 ) was administered weekly at a dose of either 0.25 , 0.48 , or 0.66 mg/kg/wk and compared with daily hGH at a dose of 0.24 mg/kg/wk . Results MOD-4023 showed an estimated half-life approximately fivefold to 10-fold longer when compared with daily r-hGH . Insulin-like growth factor (IGF)-I and IGF-binding peptide 3 showed a dose-dependent increase during MOD-4023 treatment . IGF-I st and ard deviation score for MOD-4023 did not exceed + 2 . All MOD-4023 cohorts demonstrated adequate catch-up growth . The 0.66 mg/kg/wk dose demonstrated efficacy closest to daily r-hGH . No serious adverse events were observed during MOD-4023 treatment , and its tolerability was consistent with known properties of r-hGH . Conclusions This study confirms the long-acting properties of MOD-4023 and shows a promising safety and tolerability profile . This provides support for initiation of a phase 3 study in GHD children using a single weekly injection of MOD-4023 BACKGROUND Nutropin Depots [ somatropin ( rDNA origin ) for injectable suspension ] is a long-acting form of human growth hormone ( GH ) to be administered by subcutaneous ( s.c . ) injection . The availability of this formulation offers the opportunity for greater convenience and compliance by decreasing the number of injections and frequency of administration required . OBJECTIVE To determine the efficacy and safety of a long-acting formulation of GH administered in children with GH deficiency ( GHD ) once or twice monthly for 2 years . PATIENTS Fifty-six previously untreated , prepubertal children with GHD received Nutropin Depot 1.5 mg/kg once monthly ( 1x/mo ) , or 0.75 mg/kg twice monthly ( 2x/mo ) for 24 months . The mean pretreatment growth rate was 5.0 + /- 2.4 cm/yr . RESULTS The 0 - 12 mo growth rate ( mean + /- SD ) was 8.3 + /- 1.5 cm/yr in the 1x/mo group and 8.2 + /- 2.0 cm/yr in the 2x/mo group . The 12 - 24 month growth rate was 7.2 + /- 1.5 cm/yr in the 1x/mo group and 6.9 + /- 1.5 cm/yr in the 2x/mo group . During the 24 months of treatment , height st and ard deviation score ( SDS ) increased by 1.0 + /- 0.5 SD in the two groups combined ( p < 0.0001 ) . The corresponding advancement in bone age was 2.2 + /- 0.7 yr , result ing in a gain in Bayley-Pinneau predicted adult height ( PAH ) SDS of 0.6 + /- 0.9 SD in the 1x/mo group and 0.6 + /- 1.0 SD in the 2x/mo group . No serious adverse events attributable to the study drug were reported . Injection site reactions were common , but resolved without intervention . Pre-dose fasting and postpr and ial glucose and insulin levels , as well as hemoglobin A1c levels , were unchanged from baseline values . CONCLUSIONS Treatment with Nutropin Depot is associated with catch-up growth and normal skeletal maturation and is a viable alternative to daily injections of GH in children with GHD Objective Growth hormone ( GH ) replacement therapy currently requires daily injections , which may cause distress and low compliance . C-terminal peptide (CTP)-modified growth hormone ( MOD-4023 ) is being developed as a once-weekly dosing regimen in patients with GH deficiency ( GHD ) . This study ’s objective is to evaluate the safety , pharmacokinetics ( PK ) , pharmacodynamics ( PD ) and efficacy of MOD-4023 administered once-weekly in GHD adults . Design 54 adults with GHD currently treated with daily GH were normalized and r and omized into 4 weekly dosing cohorts of MOD-4023 at 18.5 % , 37 % , 55.5 % or 123.4 % of individual cumulative weekly molar hGH dose . The study included 2 stages : Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023 . Stage B was an extension period of once-weekly MOD-4023 administration ( 61.7 % molar hGH content ) to collect further safety data and confirm the results from Stage A. Results Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment . Insulin-like growth factor I ( IGF-I ) SDS levels were maintained within normal range . The 18.5 % cohort was discontinued due to low efficacy . MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts . The reported adverse events were consistent with known GH-related side effects . Conclusions Once-weekly MOD-4023 administration in GHD adults was found to be clinical ly effective while maintaining a favorable safety profile and may obviate the need for daily injections . Weekly GH injections may improve compliance and overall outcome . The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial , which is currently ongoing The aim of this prospect i ve , longitudinal , controlled study is to describe the long-term safety and efficacy of growth hormone ( GH ) administration on craniofacial morphology in boys with short stature . Forty-six boys , who started GH treatment at the Department of Paediatrics Göteborg Paediatric Growth Research Centre , were consecutively included in the study . Twenty-five boys were classified as growth hormone-deficient ( GHD ) and 21 as idiopathic short stature ( ISS ) . The patients were injected with 33 ( n=31 ) or 67 ( n=15 ) microg GH/kg body weight/day . The mean age at the start of treatment was 11.8 years [ st and ard deviation ( SD ) 1.7 ] . To assess craniofacial growth , st and ard lateral cephalometric radiographs were obtained at the start of GH treatment , annually during 4 years , and at the end of GH treatment or when growth was less than 1 cm/year . The mean follow-up period was 6.4 years ( SD 1.4 ) . Growth changes were compared with boys from a semi-longitudinal reference group of 130 healthy subjects , 7 - 21 years of age . t-tests for independent and paired sample s and multiple regression analysis were applied . Age- and gender-specific st and ard deviation scores for the cephalometric variables were calculated . Repeated measures analysis of variance was used to identify significant covariates over time , such as low/high GH dose and GHD/ISS and orthodontic treatment . During the study period , eight ( out of 40 ) boys were treated with fixed orthodontic appliances , three with functional appliances ( activators ) , and three with other appliances ( plates and lingual arches ) . During GH treatment period , an overall enhancement in growth of the facial skeleton was observed in boys with short stature . The changes induced by GH yielded a more prognathic growth pattern , a more anterior position of the jaws in relation to the cranial base , and increased anterior rotation of the m and ible . The m and ibular corpus length and anterior face height of the GH-treated boys were greater at the end of the study compared with the boys in the reference group . No differences in growth response were noted either between the GHD and ISS boys or between those treated with either 33 ( low dose ) or 67 ( high dose ) microg GH/kg body weight/day . The only change that remained significantly correlated with orthodontic treatment was the alteration in m and ibular ramus height , showing a larger change in the boys who had not undergone orthodontic therapy . The findings of this study demonstrate that GH treatment has a favourable influence on the craniofacial growth pattern of boys with short stature without acromegalic features Many children with idiopathic short stature ( ISS ) remain short as adults . Height can be improved permanently by growth hormone ( GH ) treatment , as in children with Turner syndrome or born small for gestational age . Although GH treatment for ISS is an approved indication in the United States , there is ongoing controversy in Europe about approving GH treatment for this indication as well as determining the optimal mode of treatment . In addition to data from r and omized controlled trials , data from pharmacoepidemiological surveys such as the Pfizer International Growth Study Data base ( KIGS ) have provided substantial information about the short-term and long-term effects of GH on growth and adult height in children with ISS . Based on published articles and a recent survey from KIGS on 454 patients who have reached adult height , we attempted to categorize those children with ISS who have the greatest chances of achieving a normal adult height , or at least gain the most height following GH treatment . This analysis provides a rational basis for discussion about the most efficacious and cost-effective uses of GH treatment in children with ISS The aim of this study was to compare the growth response of 22 short pre‐pubertal children without growth hormone deficiency , treated with a single daily growth hormone injection ( group A ) , to the growth response of 27 similar children , treated with the same daily dose divided into 2 subcutaneous injections per day ( group B ) , for 1 y , in a r and omized study . GH treatment significantly promoted growth parameters , height st and ard deviation score and height velocity st and ard deviation score in both groups . Serum insulin‐like growth factor I was also increased . There were no significant differences in growth response , serum IGF‐I levels , or the advance in bone age between the two study groups after 1 y of GH therapy . We conclude that twice daily s.c . growth hormone injections provide no advantages over once daily injection of the same dose in promoting the linear growth of short children without growth hormone deficiency At least part of the short stature in Prader — Willi syndrome may be explained by a decreased growth hormone ( GH ) secretory capacity , which occurs in most patients . To study the effects of exogenous GH on growth and body composition , 17 prepubertal children with Prader — Willi syndrome , with a short projected final height , were r and omized to a control group ( n = 9 ) or a treatment group ( n = 8) . Children in the treatment group received GH ( 0.15 IU/kg/day s.c . ) for 1 year . One patient in the treatment group developed pseudotumor cerebri , which resolved after discontinuation of GH ; this patient was omitted from further analysis . After 1 year , height velocity in the GH‐treated group was significantly increased ( + 5.5 SD ) compared with reference values for normal healthy children , whereas there was a decrease in the control group ( –2.3 SD ) . The difference in height velocity between the treated and control groups was significant ( p = 0.0012 ) . Concentrations of both insulin‐like growth factor I ( IGF‐I ) and IGF‐binding protein‐3 increased significantly in the GH‐treated group ( p < 0.008 ) . A gain in height was noted for chronological age ( + 1.07 SD ) after 1 year of GH treatment . Height gain ( + 1.02 SD ) remained unchanged when analysed in relation to bone age . No differences between the groups were found for parameters of weight and body composition . In conclusion , although GH appears to have beneficial effects on height , long‐term studies are necessary before recommendations can be made concerning GH treatment in children with Prader — Willi syndrome . □ Body composition , growth , growth hormone treatment , height velocity , insulin‐like growth factor‐binding protein‐3 , insulin‐like growth factor I , Prader — Willi syndrome , Turner syndrome ( TS ) is a genetic disorder characterized by short stature , gonadal dysgenesis , and a particular neurocognitive profile of normally developed language abilities ( particularly verbal IQ ) and impaired visual-spatial and /or visual-perceptual abilities . We have followed a large sample of girls with Turner syndrome who were enrolled in a long-term , double-blind , placebo-controlled trial of the effects of growth hormone ( GH ) treatment on final adult height . This study provides a unique opportunity to prospect ively evaluate the effects of GH treatment on neurocognitive function in this population of girls with Turner syndrome . The GH- and placebo-treated Turner syndrome subjects were well matched for age , treatment duration , race , karyotype , and socioeconomic status . Treatment ( GH or placebo ) duration s ranged from 1 - 7 yr . Whether GH deficiency and /or treatment in childhood and adolescence influences cognitive outcome in short children or GH-children is controversial . The major result of this study was the absence of GH treatment effects on cognitive function in girls with Turner syndrome . Our findings are in agreement with most of the previous studies that found no apparent growth hormone treatment effects on cognitive function in growth-hormone deficient children . We conclude that this study does not support a role for growth hormone in influencing childhood brain development in girls with Turner syndrome . Their characteristic nonverbal neurocognitive deficits were not altered with GH treatment into early adolescence Most children born small for gestational age ( SGA ) normalize their size through spontaneous catch-up growth within the first 2 yr after birth . Some SGA children fail to do so and maintain an abnormally short stature throughout childhood . We have previously reported that high dose GH treatment ( 66 or 100 microg/kg x day s.c . over 2 yr ; age at start , 2 - 8 yr ; n = 38 ) induces pronounced catch-up growth in short children born SGA , thereby normalizing their height and weight in childhood . Here , we report on the further prepubertal growth course of these children over the first 4 yr after withdrawal of early , high dose GH treatment . Of the 38 treated children , none developed precocious puberty , and 22 remained prepubertal . Mean age of the latter at start of GH was 4.4 yr , height was -3.7 SD score , and height after adjustment for midparental height was -2.9 SD score . Height increased by an average of 2.5 SD during the 2 yr of GH treatment and decreased by 0.4 and 0.3 SD , respectively , during the first and second year after GH withdrawal . Subsequently , when stature was not extremely short at the start ( mean adjusted height SD score , -2.7 ; n = 13 ) , no further GH treatment was given , and the adjusted height was stabilized around -1.0 SD score ; when stature was very short at the start ( mean adjusted height , -3.3 SD score ; n = 9 ) , a second course of GH treatment ( 66 microg/kg x day s.c . ) was initiated either 2 yr ( n = 5 ) or 3 yr ( n = 4 ) after initial GH withdrawal . This second course was associated with renewed catch-up growth and also result ed in a mean adjusted height of -1.0 SD score . In each subgroup , the pattern of the weight course paralleled that of the height course ; GH treatment was well tolerated . In conclusion , early , discontinuous , high dose GH treatment appears to be a safe and efficient option to normalize prepubertal height and weight in the majority of short SGA children . It remains to be examined whether the normalized stature will be maintained during pubertal development , either with or without further GH treatment A total of 130 short children were included in a French multicentre study and r and omized between a control group ( group A ) and two groups treated with daily subcutaneous injections of GH at doses of 0.7 IU/kg/week ( group B ) and 1.4 IU/kg/week ( group C ) for 2 years . Height velocity was significantly increased ( p<0.0005 ) in groups B and C , with a greater increase in group C than in group B ( p < 0.001 ) . The benefit after 2 years compared with controls was 4.3 cm in group B and 5.9 cm in group C. The rate of bone maturation was not affected by GH therapy . These results led to the conclusion that 2 years of treatment with GH improves final height prognosis in children with short stature secondary to IUGR , and that this effect is dose dependent . The effect on final height has still to be demonstrated CONTEXT The effect of GH therapy in short non-GH-deficient children , especially those with idiopathic short stature ( ISS ) , has not been clearly established owing to the lack of controlled trials continuing until final height ( FH ) . OBJECTIVE The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children , mainly with ISS , compared with untreated controls . DESIGN AND SETTING A r and omized , controlled , long-term multicenter trial was conducted in Sweden . INTERVENTION Two doses of GH ( Genotropin ) were administered , 33 or 67 microg/kg.d ; control subjects were untreated . SUBJECTS A total of 177 subjects with short stature were enrolled . Of these , 151 were included in the intent to treat ( AllITT ) population , and 108 in the per protocol ( AllPP ) population . Analysis of ISS subjects included 126 children in the ITT ( ISSITT ) population and 68 subjects in the PP ( ISSPP ) population . MAIN OUTCOME MEASURES We measured FH sd score ( SDS ) , difference in SDS to midparenteral height ( diff MPHSDS ) , and gain in heightSDS . RESULTS After 5.9+/-1.1 yr on GH therapy , the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 ( 33 microg/kg.d , -1.7+/-0.70 ; and 67 microg/kg.d , -1.4+/-0.86 ; P<0.032 ) , vs. -2.4+/-0.85 ( P<0.001 ) ; the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 ( P<0.001 ) ; and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 ( P<0.001 ) . GH therapy was safe and had no impact on time to onset of puberty . A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four population s. CONCLUSION GH treatment significantly increased FH in ISS children in a dose-dependent manner , with a mean gain of 1.3 SDS ( 8 cm ) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls
Conclusions There is no evidence to support differences in the effects of long-acting GH compared with those of daily GH .
Purpose Long-acting growth hormone ( GH ) has been developed to address the noncompliance and decreased efficacy associated with daily GH injections .
We aim ed to evaluate the efficacy and safety of long-acting GH replacement therapy in children with short stature .