Recombinant growth hormone therapy in children with Turner Syndrome in Korea: a phase III Randomized Trial

Abstract Background Short stature is the most consistent characteristic feature of Turner syndrome (TS). To improve final heights of children with TS effectively, it is important to provide them with early and appropriate treatment using growth hormone (GH). The objective of this study was to assess the efficacy and safety of a new recombinant human GH, Growtropin®-II (DA-3002, Dong-A ST Co., Ltd) versus a comparator (Genotropin®, Pfizer Inc.) for Korean children with TS. Methods This open-label, active-controlled, parallel-group, randomized controlled phase III trial was conducted at 11 hospitals in Korea. Eligible patients (n = 58) were randomized to two groups: 1) DA-3002 group (administrated with DA-3002 at 0.14 IU [0.0450–0.050 mg] /kg/day); and 2) comparator group (administrated with the comparator at 0.14 IU [0.0450–0.050 mg] /kg/day). Results The change from baseline in annualized height velocity (HV) after a 52-week treatment period was 4.15 ± 0.30 cm/year in the DA-3002 group and 4.34 ± 0.29 cm/year in the comparator group. The lower bound of 95% two-sided confidence interval for group difference in the change of annualized HV (− 1.02) satisfied the non-inferiority margin (− 1.5). The change in height standard deviation score (HtSDS) at 52-week was 0.70 ± 0.23 for the DA-3002 group and 0.66 ± 0.39 for the comparator group, showing no significant (p = 0.685) difference between the two groups. The change of skeletal maturity defined as change in bone age/change in chronological age between the two groups was not significantly different (1.25 ± 0.58 for the DA-3002 group and 1.47 ± 0.45 for the comparator group, p = 0.134). Changes from baseline in serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after 52 weeks of treatment did not differ significantly between the two groups (p = 0.565 and p = 0.388, respectively) either. The occurrence of adverse events was not statistically different between groups. Conclusions This study demonstrates that the efficacy and safety of GH treatment with DA-3002 in children with TS are comparable with those of the comparator. It is expected to analysis the long-term effect of DA-3002 on the increase of final adult height in children with TS and possible late-onset complications in the future. Trial registration The study was registered at ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT01813630 (19/03/2013).

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Recombinant Growth Hormone Therapy in Children With Turner’s Syndrome in Korea: A Phase III Randomized Trial

10.21203/rs.3.rs-768818/v1 ◽

2021 ◽

Author(s):

Jinsup Kim ◽

Min-Sun Kim ◽

Byung-Kyu Suh ◽

Cheol Woo Ko ◽

Kee-Hyoung Lee ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Serum Insulin ◽

Standard Deviation Score ◽

Phase Iii ◽

Height Velocity ◽

Insulin Like Growth Factor ◽

Efficacy And Safety ◽

Korean Children ◽

Comparator Group

Abstract Background Short stature is the most consistent characteristic feature of Turner syndrome (TS). To improve final heights of children with TS effectively, it is important to provide them with early and appropriate treatment using growth hormone (GH). The objective of this study was to assess the efficacy and safety of a new recombinant human GH, Growtropin®-II (DA-3002, Dong-A ST Co., Ltd) in comparison with a comparator (Genotropin®, Pfizer Inc.) for Korean children with TS. Methods This open-label, active-controlled, parallel-group, randomized controlled phase III trial was conducted at 11 hospitals in Korea. Eligible patients (n = 58) were randomized to two groups: 1) DA-3002 group (administrated with DA-3002 at 0.14 IU /kg/day); and 2) comparator group (administrated with the comparator at 0.14 IU /kg/day). Results The change from baseline in annualized height velocity (HV) after a 52-week treatment was 4.15 ± 0.30 cm/year in the DA-3002 group and 4.34 ± 0.29 cm/year in the comparator group. The lower bound of 95% two-sided confidence interval for group difference in the change of annualized HV (-1.02) satisfied the non-inferiority margin (-1.5). The change in height standard deviation score (HtSDS) at 52-week was 0.70 ± 0.23 for the DA-3002 group and 0.66 ± 0.39 for the comparator group, showing no significant (p = 0.685) difference between the two groups. Skeletal maturity defined as a change in bone age or a change in chronological age between the two groups was not significantly different (1.25 ± 0.58 for the DA-3002 group and 1.47 ± 0.45 for the comparator group, p = 0.134). Changes of serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after 52 weeks of treatment did not differ significantly between the two groups (p = 0.565 and p = 0.388, respectively) either. Adverse events were not significant in either group. Conclusions This study demonstrates that the efficacy and safety of GH treatment with DA-3002 in children with TS are comparable with those of the comparator. Thus, treatment with DA-3002 can be used to improve their growth. DA-3002 is also well tolerated in children with TS. Trial registration: The study was registered at ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT01813630 (19/03/2013)

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Insulin-like growth factor-1 level is a poor diagnostic indicator of growth hormone deficiency

Scientific Reports ◽

10.1038/s41598-021-95632-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hideyuki Iwayama ◽

Sachiko Kitagawa ◽

Jyun Sada ◽

Ryosuke Miyamoto ◽

Tomohito Hayakawa ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Diagnostic Accuracy ◽

Growth Hormone Deficiency ◽

Screening Test ◽

Characteristic Curve ◽

Hormone Deficiency ◽

Height Velocity ◽

Insulin Like Growth Factor ◽

Predictive Values

AbstractWe evaluated the diagnostic accuracy of insulin-like growth factor-1 (IGF-1) for screening growth hormone deficiency (GHD) to determine the usefulness of IGF-1 as a screening test. Among 298 consecutive children who had short stature or decreased height velocity, we measured IGF-1 levels and performed growth hormone (GH) secretion test using clonidine, arginine, and, in cases with different results of the two tests, L-dopa. Patients with congenital abnormalities were excluded. GHD was defined as peak GH ≤ 6.0 ng/mL in the two tests. We identified 60 and 238 patients with and without GHD, respectively. The mean IGF-1 standard deviation (SD) was not significantly different between the GHD and non-GHD groups (p = 0.23). Receiver operating characteristic curve analysis demonstrated the best diagnostic accuracy at an IGF-1 cutoff of − 1.493 SD, with 0.685 sensitivity, 0.417 specificity, 0.25 positive and 0.823 negative predictive values, and 0.517 area under the curve. Correlation analysis revealed that none of the items of patients’ characteristics increased the diagnostic power of IGF-1. IGF-1 level had poor diagnostic accuracy as a screening test for GHD. Therefore, IGF-1 should not be used alone for GHD screening. A predictive biomarker for GHD should be developed in the future.

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Basal characteristics and first year responses to human growth hormone (GH) vary according to diagnostic criteria in children with non-acquired GH deficiency (naGHD): observations from a single center over a period of five decades

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0025 ◽

2018 ◽

Vol 0 (0) ◽

Author(s):

Michael B. Ranke ◽

Roland Schweizer ◽

Gerhard Binder

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Diagnostic Criteria ◽

Human Growth Hormone ◽

Human Growth ◽

Height Velocity ◽

First Year ◽

Insulin Like Growth Factor ◽

Igf I ◽

Igfbp 3

Abstract Background Children with non-acquired (na) growth hormone deficiency (GHD) diagnosed over decades in one center may provide perspective insight. Methods naGHD is divided into idiopathic GHD (IGHD), GHD of known cause (cGHD) and GHD neurosecretory dysfunction (NSD); time periods: <1988 (I); 1988–1997 (II); 1998–2007 (III); 2008–2015 (IV). Descriptive analyses were performed at diagnosis and during first year GH treatment. Results Patients (periods, N): I, 87; II, 141; III, 356; IV, 51. In cGHD (all), age, maximum GH, insulin-like growth factor-I (IGF-I), and insulin-like growth factor-binding protein-3 (IGFBP-3) (5.1 years, 3.6 μg/L, −5.3 standard deviation score [SDS], −3.7 SDS) were lower than in IGHD (all) (6.8 years 5.8 μg/L, −2.5 SDS, −1.0 SDS), but not height (−3.1 vs. −3.2 SDS). Characteristics of NSD were similar to that of IGHD. Patients with IGHD – not cGHD – diagnosed during 2008–2015 (IV) were the youngest with most severe GHD (maxGH, IGF-I, IGFBP-3), and first year height velocity (HV) and ∆ IGF-I (10.5 cm/year, 4.0 SDS) but not ∆ height SDS were the highest on recombinant human growth hormone (rhGH) (27 μg/kg/day). Conclusions Although during 1988–2007 patient characteristics were similar, the recently (>2008) stipulated more stringent diagnostic criteria – HV before testing, sex steroid priming, lower GH cut-off – have restricted diagnoses to more severe cases as they were observed before the rhGH era.

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Free dissociable insulin-like growth factor I (IGF-I), total IGF-I and their binding proteins in girls with Turner syndrome during long-term growth hormone treatment

Clinical Endocrinology ◽

10.1111/j.1365-2265.2006.02594.x ◽

2006 ◽

Vol 65 (3) ◽

pp. 310-319 ◽

Cited By ~ 9

Author(s):

Ellen M. N. Bannink ◽

Jaap van Doorn ◽

Theo Stijnen ◽

Stenvert L. S. Drop ◽

Sabine M. P. F. de Muinck Keizer-Schrama

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Turner Syndrome ◽

Binding Proteins ◽

Growth Hormone Treatment ◽

Hormone Treatment ◽

Insulin Like Growth Factor ◽

Factor I ◽

Igf I

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Diagnostic accuracy of insulin-like growth factor-1 for screening growth hormone deficiency: a prospective, single-center, diagnostic accuracy study

10.21203/rs.3.rs-547842/v1 ◽

2021 ◽

Author(s):

Hideyuki Iwayama ◽

Sachiko Kitagawa ◽

Jyun Sada ◽

Ryosuke Miyamoto ◽

Tomohito Hayakawa ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Diagnostic Accuracy ◽

Growth Hormone Deficiency ◽

Screening Test ◽

Characteristic Curve ◽

Hormone Deficiency ◽

Height Velocity ◽

Insulin Like Growth Factor ◽

Predictive Values

Abstract Purpose We evaluated the diagnostic accuracy of insulin-like growth factor-1 (IGF-1) for screening growth hormone deficiency (GHD) to determine the usefulness of IGF-1 as a screening test. Methods Among 298 consecutive children who had short stature or decreased height velocity, we measured IGF-1 levels and performed growth hormone (GH) secretion test using clonidine, arginine, and, in cases with different results of the two tests, L-dopa. Patients with congenital abnormalities were excluded. GHD was defined as peak GH ≤ 6.0 ng/mL in the two tests. Results We identified 60 and 238 patients with and without GHD, respectively. The mean IGF-1 (SD) was not significantly different between the GHD and non-GHD groups (p = 0.23). Receiver operating characteristic curve analysis demonstrated the best diagnostic accuracy at an IGF-1 cutoff of −1.493 SD, with 0.685 sensitivity, 0.417 specificity, 0.25 positive and 0.823 negative predictive values, and 0.517 area under the curve. Correlation analysis revealed that none of the items of patients’ characteristics increased the diagnostic power of IGF-1. Conclusion IGF-1 level had poor diagnostic accuracy as a screening test for GHD. Therefore, IGF-1 should not be used alone in the screening of GHD. A predictive biomarker for GHD should be developed in the future.

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Effect of Growth Hormone Therapy on Height Velocity in Korean Children with Idiopathic Short Stature: A Phase III Randomised Controlled Trial

Hormone Research in Paediatrics ◽

10.1159/000491016 ◽

2018 ◽

Vol 90 (1) ◽

pp. 44-53 ◽

Cited By ~ 1

Author(s):

Woo Yeong Chung ◽

Han-Wook Yoo ◽

Jin Soon Hwang ◽

Cheol Woo Ko ◽

Ho-Seong Kim ◽

...

Keyword(s):

Growth Hormone ◽

South Korea ◽

Short Stature ◽

Controlled Trial ◽

Recombinant Human Growth Hormone ◽

Idiopathic Short Stature ◽

Phase Iii ◽

Height Velocity ◽

Control Group ◽

Korean Children

Background/Aims: The SYNERGY (Saizen® for Your New Life and Brighter Tomorrow without Growth Deficiency) study is the first randomised multi-centre, open-label study to assess the short-term efficacy and safety of this recombinant human growth hormone (r-hGH) preparation for prepubertal children with idiopathic short stature in South Korea. Methods: The SYNERGY study (ClinicalTrials.gov NCT01746862) was conducted at 9 centres throughout South Korea between December 2012 and March 2015. The primary endpoint was difference in height velocity from baseline to 6 months in the treatment and control arms. Results: 97 children were screened; 90 were randomly assigned: 60 children to 0.067 mg/kg/day r-hGH for 12 months (treatment) and 30 children to 6 months of no treatment followed by 0.067 mg/kg/day r-hGH for 6 months (control). The 6-month mean height velocity in the treatment group increased from 5.63 cm/year (SD 1.62) to 10.08 cm/year (SD 1.92) (p < 0.0001) and from 4.94 cm/year (SD 1.91) to 5.92 cm/year (SD 2.01) (p = 0.0938) in the control group (between-group difference 3.47 cm/year, 95% CI 2.17–4.78; p < 0.0001). Adherence was > 90% throughout the study. The safety profile was consistent with that already known for r-hGH. Conclusion: Treatment with r-hGH in the SYNERGY study demonstrated a statistically significant increase in height velocity at 6 months.

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Safety and Effectiveness of Recombinant Human Growth Hormone in Children with Turner Syndrome: Data from the PATRO Children Study

Hormone Research in Paediatrics ◽

10.1159/000515875 ◽

2021 ◽

pp. 1-11

Author(s):

Philippe Backeljauw ◽

Shankar Kanumakala ◽

Sandro Loche ◽

Karl Otfried Schwab ◽

Roland Werner Pfäffle ◽

...

Keyword(s):

Growth Hormone ◽

Clinical Practice ◽

Turner Syndrome ◽

Human Growth Hormone ◽

Recombinant Human Growth Hormone ◽

Standard Deviation Score ◽

Human Growth ◽

Height Velocity ◽

Treatment Naïve ◽

Rhgh Treatment

Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). Methods: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7–18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was −2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of −2.02 (0.9). Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.

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Growth response to growth hormone (GH) treatment in children with GH deficiency (GHD) and those with idiopathic short stature (ISS) based on their pretreatment insulin-like growth factor 1 (IGFI) levels and at diagnosis and IGFI increment on treatment

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2021-0389 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Ashraf Soliman ◽

Alan D. Rogol ◽

Sohair Elsiddig ◽

Ahmed Khalil ◽

Nada Alaaraj ◽

...

Keyword(s):

Growth Hormone ◽

Standard Deviation ◽

Growth Factor ◽

Short Stature ◽

Linear Growth ◽

Standard Deviation Score ◽

Idiopathic Short Stature ◽

Insulin Like Growth Factor ◽

Gh Therapy ◽

Deviation Score

Abstract Objectives Some idiopathic short stature (ISS) patients may have varying degrees of insulin-like growth factor 1 (IGFI) deficiency. Others with growth hormone deficiency (GHD) (peak GH < 7 ng/dL after provocation) have normal IGFI levels. Do children with ISS or those with GHD with variable pretreatment IGFI standard deviation score (IGFISDS) have different IGFI and growth responses to recombinant human growth hormone (rhGH) therapy? Methods We studied the effect of GH therapy (0.035–0.06 mg/kg/day) on linear growth and weight gain per day (WGPD) in children with ISS (n=13) and those with GHD (n=10) who have low pretreatment IGFISDS (IGF SDS < −1.5) and compared them with age-matched prepubertal children with ISS (n=10) and GHD (n=17) who had normal pretreatment IGFISDS. An untreated group of children with ISS (n=12) served as a control group. Results At presentation, the height standard deviation score (HtSDS) of children with ISS who had low pretreatment IGFISDS was significantly lower compared to the normal IGFI group. The age, body mass index (BMI), BMISDS, peak GH response to clonidine provocation and bone age did not differ between the two study groups. After 1 year of treatment with rhGH (0.035–0.06 mg/kg/day) IGFISDS increased significantly in both groups (p<0.05). Both had significantly increased HtSDS (catch-up growth). The increase in the HtSDS and WGPD were significantly greater in the lower pretreatment IGFISDS group. The IGFSDS, BMISDS, HtSDS and difference between HtSDS and mid-parental HtSDS were significantly greater in the rhGH treated groups vs. the not treated group. In the GHD groups (normal and low IGFISDS), after 1 year of GH therapy (0.03–0.05 mg/kg/day), the HtSDS increased significantly in both, (p<0.01). The WGPD and increment in BMI were significantly greater in children who had low pretreatment IGFISDS. There was a significant increase in the IGFSDS in the two treated groups (p<0.05), however, the WGPD was greater in the pretreatment low IGFISDS. Conclusions IGFI deficiency represents a low anabolic state. Correction of IGFI level (through rhGH and/or improved nutrition) in short children (ISS and GHD) was associated with increased linear growth and WGPD denoting significant effect on bone growth and muscle protein accretion.

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Design of, and first data from, PATRO Children, a multicentre, noninterventional study of the long-term efficacy and safety of Omnitrope® in children requiring growth hormone treatment

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018813479644 ◽

2013 ◽

Vol 4 (1) ◽

pp. 3-11 ◽

Cited By ~ 14

Author(s):

Roland Pfäffle ◽

Karl Otfried Schwab ◽

Otilia Marginean ◽

Mieczyslaw Walczak ◽

Mieczyslaw Szalecki ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Growth Hormone Treatment ◽

Hormone Treatment ◽

Insulin Like Growth Factor ◽

Efficacy And Safety ◽

Safety Issues ◽

Term Efficacy ◽

Noninterventional Study

Objective: To describe the rationale, design and first data from PATRO Children, a postmarketing surveillance of the long-term efficacy and safety of somatropin (Omnitrope®) for the treatment of children requiring growth hormone treatment. Methods: PATRO Children is a multicentre, open, longitudinal, noninterventional study being conducted in children’s hospitals and specialised endocrinology clinics. The primary objective is to assess the long-term safety of Omnitrope® in routine clinical practice. Eligible patients are infants, children and adolescents (male or female) who are receiving treatment with Omnitrope® and who have provided informed consent. Patients who have been treated with another recombinant human growth hormone (rhGH) product before starting Omnitrope® are eligible for inclusion. All adverse events (AEs) are monitored and recorded, with particular emphasis on: long-term safety; the recording of malignancies; the occurrence and clinical impact of anti-hGH antibodies; the development of diabetes during Omnitrope® treatment in children short for gestational age (SGA); safety issues in patients with Prader–Willi syndrome (PWS). Efficacy assessments include auxological parameters, plus insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Results: As of September 2012, 1837 patients were enrolled in the study from 184 sites in 10 European countries. To date, efficacy data are reassuring and consistent with previous studies. In addition, there have been no confirmed cases of diabetes occurring under Omnitrope® treatment, no reports of malignancy and no safety issues in PWS patients. Conclusions: The efficacy and safety profile of Omnitrope® in the PATRO Children study so far are as expected. The ongoing study will extend the safety database for Omnitrope®, and rhGH products more generally, in paediatric indications. Of particular interest, PATRO Children will add important information on the diabetogenic potential of rhGH in children born SGA, the risk of malignancies in children receiving rhGH, and AEs with a possible causal relationship to rhGH treatment in children with PWS.

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