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

Jinsup Kim, Min-Sun Kim, Byung-Kyu Suh, Cheol Woo Ko, Kee-Hyoung Lee, Han-Wook Yoo, Choong Ho Shin, Jin Soon Hwang, Ho-Seong Kim, Woo Yeong Chung, Chan Jong Kim, Heon-Seok Han, Dong-Kyu Jin, Jinsup Kim, Min-Sun Kim, Byung-Kyu Suh, Cheol Woo Ko, Kee-Hyoung Lee, Han-Wook Yoo, Choong Ho Shin, Jin Soon Hwang, Ho-Seong Kim, Woo Yeong Chung, Chan Jong Kim, Heon-Seok Han, Dong-Kyu Jin

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).

Keywords: Growth hormone; Short stature; Turner syndrome.

Conflict of interest statement

The authors declare no financial competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design and disposition. a study design; b study disposition. SF: Screening failure, PD: Premature discontinuation
Fig. 2
Fig. 2
Annualized HV at baseline, 13, 26, 39, and 52-week (cm/year) and change in annualized HV from baseline at 52-week. a: Annualized HV at baseline, 13, 26, 39 and 52-week; b: Change in annualized HV from baseline at 52-week. HV: height velocity; SE: Standard Error; * LS mean difference for between-treatment groups using ANCOVA model with treatment group as a factor and CA at baseline as a covariate
Fig. 3
Fig. 3
Height standard deviation scores at baseline, 13, 26, 39, and 52 weeks and change in height standard deviation score for annualized height velocity from baseline at 52-week. a Height standard deviation scores at baseline, 13, 26, 39, and 52 weeks; b Change in height standard deviation score of annualized height velocity from baseline at 52-week
Fig. 4
Fig. 4
Comparison of skeletal maturity and changes in IGF-1 and IGFBP-3 levels from baseline. a Skeletal maturity (ratio of change in bone age/chronological age), b Change in IGF-1 level from baseline, c: Change in IGFBP-3 level from baseline. IGF-1: Insulin-like Growth Factor-1; IGFBP-3: Insulin-like Growth Factor Binding Protein-3. * Two sample t-test between treatment groups; **: Wilcoxon rank sum test between treatment groups

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