Effects of growth hormone therapy in prepubertal children with short stature secondary to intrauterine growth retardation Once versus twice daily injections of growth hormone in children with idiopathic short stature MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults Long-Acting C-Terminal Peptide–Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children Once-Weekly Administration of Sustained-Release Growth Hormone in Korean Prepubertal Children with Idiopathic Short Stature: A Randomized, Controlled Phase II Study Safety of Growth Hormone Treatment of Children with Idiopathic Short Stature: The US Experience The growth and cardiovascular effects of high dose growth hormone therapy in idiopathic short stature Long‐term cardiovascular effects of growth hormone treatment in GH‐deficient adults Preliminary data in a small group of patients 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) Patient preference for a new growth hormone injection device: results of an open-label study in Japanese pediatric patients Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. A longitudinal study of craniofacial growth in idiopathic short stature and growth hormone-deficient boys treated with growth hormone. Efficacy and Safety of Growth Hormone Treatment in Children Born Small for Gestational Age in Japan Body composition and quality of life in adults with growth hormone deficiency; effects of low‐dose growth hormone replacement Growth Hormone Treatment in Non‐Growth Hormone‐Deficient Children: Effects of Stopping Treatment Growth parameters and predictors of growth in short children with and without growth hormone (GH) deficiency treated with human GH: a randomized controlled study. A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency
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 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 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 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 / Aims : To determine the optimal dose of LB03002 , a sustained-release , once-weekly formulation of recombinant human growth hormone ( rhGH ) , and to compare its efficacy and safety with daily rhGH in children with idiopathic short stature ( ISS ) . Methods : This multicenter , r and omized , open-label , phase II study included GH-naïve , prepubertal children with ISS , r and omized to receive daily rhGH 0.37 mg/kg/week ( control , n = 16 ) , LB03002 0.5 mg/kg/week ( n = 14 ) , or LB03002 0.7 mg/kg/week ( n = 16 ) . The primary endpoint was height velocity ( HV ) change at week 26 . Results : At week 26 , the least square ( LS ) means for HV change ( cm/year ) with control , LB03002 0.5 mg/kg/week , and LB03002 0.7 mg/kg/week were 5.08 , 3.65 , and 4.38 , and the LS means for the change in height st and ard deviation score were 0.65 , 0.49 , and 0.58 , respectively . The lower bound of the 90 % confidence interval for the difference between LB03002 0.7 mg/kg/week and the control in the LS mean for HV change ( –1.72 ) satisfied the noninferiority margin ( –1.75 ) . Adverse events were generally mild and short-lived . Conclusion : A once-weekly regimen of LB03002 0.7 mg/kg demonstrated noninferiority to the daily regimen of rhGH 0.37 mg/kg/week in terms of HV increments . LB03002 was well tolerated and its safety profile was comparable with that of daily rhGH Recombinant human growth hormone ( rhGH ) is approved in the United States for treatment of idiopathic short stature ( ISS ) . The occurrence of adverse events ( AEs ) and the long-term safety of rhGH treatment in this patient population are review ed . Data were analyzed from postmarketing surveillance studies that included ISS patients , prospect i ve ISS treatment trials and studies of specific AEs in smaller groups of rhGH-treated children . Frequency rates of targeted AEs ( i.e. , scoliosis , slipped capital femoral epiphysis , intracranial hypertension , pancreatitis ) in patients with ISS are similar to or lower than the rates observed in other rhGH-treated conditions . At dosages of 0.24–0.37 mg/kg/week , rhGH treatment in children with ISS does not adversely affect blood glucose levels . At dosages ≧0.3 mg/kg/week , a dose-dependent increase in mean fasting and stimulated insulin levels is observed . Current evidence derived from ‘ on-treatment ’ surveillance studies suggests that rhGH does not increase the risk for new malignancies in children with ISS.The  safety profile  of rhGH at doses ≤0.37 mg/kg/week for the treatment of children with ISS is similar to or better than the profile seen in other rhGH-treated conditions and is not associated with any predictable AEs . Due to a continuing trend toward dose escalation to achieve greater height-promoting effects and the possibility of delayed post-treatment effects of hyperinsulinemia and /or heightened GH and insulin-like growth factor I exposure on cancer risk , caution and ongoing scrutiny of risks versus benefits are warranted OBJECTIVE It Is possible that high dose GH treatment may have beneficial effects on growth but important adverse effects on cardiac function . We have therefore Investigated the efficacy and cardiovascular effects of high dose biosynthetic human GH ( r‐hGH ) treatment in children with idiopathic short stature and a normal pretreatment height velocity OBJECTIVE The long‐term cardiovascular effects of GH administration in adults are of major clinical importance , given the increasing use of such treatment . We have evaluated long‐term cardiovascular effects of recombinant human GH ( rhGH ) substitution in GH deficient men 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 Abstract Background : Growth hormone deficiency ( GHD ) in children is treated with daily subcutaneous injections of GH . Poor adherence , result ing 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 question naire on pen h and ling . Results : A total of 73/74 patients ( 99 % ) rated Norditropin ® FlexPro  ® easy to h and le , 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 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 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 Growth-promoting effects and safety of growth hormone ( GH ) treatment in prepubertal short-statured children born small for gestational age ( SGA ) were evaluated in a multicenter , open-label , r and omized parallel-group comparison study . Patients were r and omized to two dose groups ; 34 and 33 patients received GH at 0.033 and 0.067 mg/kg/day for one year , respectively . The increase of the mean height velocity st and ard deviation score ( SDS ) was significantly ( p < 0.0001 ) higher in the 0.067-mg group ( from -1.4 to 4.7 ) than that in the 0.033-mg group ( -1.9 to 2.6 ) . A significant ( p < 0.0001 ) increase in the mean height SDS was established in the 0.067-mg group ; increases of -3.1 to -2.5 vs -3.1 to -2.2 in the 0.033- and 0.067-mg groups , respectively . The trial was non-eventful . Oral glucose tolerance tests indicated a mostly normal pattern of plasma glucose before and after 12-month GH treatment . The growth-promoting effect was significantly higher with GH treatment at 0.067 mg/kg/day OBJECTIVE Adult growth hormone deficiency ( AGHD ) is characterized by abnormalities in body composition and a poor perceived quality of life ( QoL ) . Weight‐based high‐dose growth hormone replacement ( GHR ) results in improvements in body composition and QoL in AGHD . However , a high patient percentage reported side‐effects on high‐dose GHR result ing in a high rate of patient withdrawal from growth hormone ( GH ) treatment . High‐dose GH therapy also leads to supraphysiological serum insulin‐like growth factor‐I ( IGF‐I ) concentrations that have been associated with breast and prostate cancer , raising major concerns over the use of such high‐dose GH regimen in AGHD . The aim of this study was to assess the effects of low‐dose growth hormone replacement ( GHR ) on body composition and QoL as early as 1 and 3 months ABSTRACT . Overnight physiological  growth hormone ( GH ) secretion was evaluated in 95 short , prepubertal children ( 73 boys , 22 girls ) . All the children were below the 3rd centile for height and achieved CH levels greater than 15 mU/1 following pharmacological stimulation . The mean average GH level was 7.1 mU/l and the mean sum of pulse amplitudes 80.4 mU/l . No relationship was found between age , height or height velocity and any of the parameters of GH secretion . The group was r and omized to receive placebo , GH or remain under observation for the first 6 months and then all patients received GH treatment for a further 6 months . Those treated with GH , 0.27 IU/kg ( 0.1 mg/kg ) three times weekly , in the first phase . demonstrated a mean increase in height velocity SDS of 3.24 . There was no difference in growth response between the placebo or observation groups . In the second 6‐month period . all children received GH according to the same dose regimen : they were then observed for a further 6 months following its discontinuation . In the 6 months following withdrawal of GH , all groups showed a significant fall in height velocity SDS , which returned to pretreatment levels , without demonstrating‘catch‐down’growth . Repeat sampling of overnight GH secretion within 3 days of discontinuing GH showed normal secretory patterns with a small reduction in mean peak amplitude . These results suggest that short children without classic GH insufficiency respond well to exogenous GH in the short term and return to pretreatment height velocities afterwards . Consequently , it may be possible to increase final adult height in such children by GH treatment Seventy-seven prepubertal short children with heights below the third centile for age and gender were divided into three groups according to their peak GH response to clonidine and insulin provocation .  Group ( I ) included 30 children with peak GH response < 7 micrograms/l , group ( II ) included 19 children , with GH peak response between 7 and 10 micrograms/l , and group ( III ) included 24 children with GH peak > 10 micrograms/l . Each group was divided into two subgroups , a and b. Subgroups (I)b , (II)a and (III)b were treated daily for 1 year with subcutaneous recombinant human growth hormone ( GH ) 15 U/m2/week , and group (I)a was treated with GH ( 30 U/m2/week ) . Before initiation of treatment , the chronological age , the height st and ard deviation score ( HtSDS ) , and the bone age delay did not differ among the study subgroups . The height growth velocity ( GV ) and insulin-like growth factor-I concentrations were significantly higher in group ( III ) , with normal GH response to provocation , compared to those for group ( I ) with GH deficiency . All the children had normal thyroid function and normal glucose tolerance . CT examination of the hypothalamic-pituitary area revealed a picture of empty sella ( either partial or complete ) in 35 per cent of the children in group ( I ) and 21 per cent of children in group ( II ) . After 1 year of GH therapy , the HtSDS , GV , and IGF-I concentrations increased significantly in the four subgroups treated with GH compared to their pretreatment values and to their controls . All the children in group ( I ) were responders ( increment in GV of 2 cm2/year above the pretreatment GV ) , of the nine subjects treated in group (II)a , one child was a non-responder and of the 12 children in group (III)a three children were non-responders . GV was non-significantly higher in group (I)a ( 30 U/m2/week ) v. group (I)b ( 15 U/m2/week ) . GV of children in groups (I)b , with abnormal GH response to provocation , was significantly higher than GV of children in group (III)a . Bone age advanced by less than 1 year in the treated groups ( 0.84 + /- 0.14 years ) v. the untreated groups ( 0.73 + /- 0.3 years ) . None of the children had impaired glucose tolerance or abnormal thyroid function after 1 year of GH therapy . In all the treated children , GV after 1 year of GH treatment was correlated significantly with the pretreatment GV ( r = -0.63 , P < 0.01 ) , peak GH response to provocation ( r = -0.59 , P < 0.01 ) , IGF-I concentration ( r = -0.54 , P < 0.01 ) , and positively with the GH dose ( r = 0.589 , P < 0.01 ) . In group ( III ) children , with normal GH reserve , GV correlated significantly with the pretreatment GV ( r = -0.48 , P < 0.01 ) and negatively with the GH peak response to provocation ( r = -0.25 , P < 0.05 ) . In conclusion , GH therapy improved GV of children growing along or parallel to the 3rd centile , irrespective of their GH response to provocation , without untoward effect on skeletal maturation , thyroid function or glucose tolerance 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
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 .