Short-term efficacy and safety of a lower dose of polyethylene glycol recombinant human growth hormone in children with growth hormone deficiency: A randomized, dose-comparison study

Zhouhong Jiang, Xuefeng Chen, Guanping Dong, Yin Lou, Jianping Zhang, Xinran Cheng, Jiayan Pan, Wei Liao, Jinzhun Wu, Xiaodong Huang, Xianjiang Jin, Deyun Liu, Ting Zeng, Shunye Zhu, Qin Dong, Xiaoming Luo, Dan Lan, Lizhi Cao, Xingxing Zhang, Jing Liu, Mingjuan Dai, Manyan Zhang, Li Liu, Junhua Dong, Dongmei Zhao, Shaoqing Ni, Junfen Fu, Zhouhong Jiang, Xuefeng Chen, Guanping Dong, Yin Lou, Jianping Zhang, Xinran Cheng, Jiayan Pan, Wei Liao, Jinzhun Wu, Xiaodong Huang, Xianjiang Jin, Deyun Liu, Ting Zeng, Shunye Zhu, Qin Dong, Xiaoming Luo, Dan Lan, Lizhi Cao, Xingxing Zhang, Jing Liu, Mingjuan Dai, Manyan Zhang, Li Liu, Junhua Dong, Dongmei Zhao, Shaoqing Ni, Junfen Fu

Abstract

Objective: Polyethylene glycol recombinant human growth hormone (PEG-rhGH, Jintrolong®) is the first long-acting rhGH preparation that is approved to treat children with growth hormone deficiency (GHD) in China. Clinical experience with dose selections of PEG-rhGH is scarce. The present study compared the efficacy and safety of a lower dose to increase dosing regimens of PEG-rhGH treatment. Methods: A multicenter, randomized, open-label, dose-comparison clinical study was conducted to compare the improvements in the height standard deviation score (Ht SDS), height velocity (HV), insulin-like growth factor-1 (IGF-1) SDS, and safety profiles of children with GHD who are treated with 0.2 mg/kg/week of PEG-rhGH dose or 0.14 mg/kg/week for 26 weeks. Results: Ht SDS, HV, and IGF-1 SDS increased significantly after PEG-rhGH treatment in the two dose groups (p < 0.05). The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). Ht SDS improvement in low-dose group was not non-inferiority to that in the high-dose group (p = 0.2987). The incidences of adverse events were comparable between the two groups. Conclusion: The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). PEG-rhGH at the dose of 0.14 mg/kg/week was effective and safe for children with GHD. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02908958.

Keywords: GHD; IGF-1; PEG-rhGH; children; dose.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Jiang, Chen, Dong, Lou, Zhang, Cheng, Pan, Liao, Wu, Huang, Jin, Liu, Zeng, Zhu, Dong, Luo, Lan, Cao, Zhang, Liu, Dai, Zhang, Liu, Dong, Zhao, Ni and Fu.

Figures

FIGURE 1
FIGURE 1
Patient flow diagram.
FIGURE 2
FIGURE 2
Height SDS (A), Height velocity (B) and IGF-1 SDS (C) at baseline and week 4, 13 and 26 with a PEG-rhGH dose of 0.14 mg/kg/week or 0.2 mg/kg/week.

References

    1. Backeljauw P., Miller B. S., Levy R., Mccormick K., Zouater H., Zabransky M., et al. (2021). PATRO children, a multi-center, non-interventional study of the safety and effectiveness of Omnitrope(®) (somatropin) treatment in children: Update on the United States cohort. J. Pediatr. Endocrinol. Metab. 34 (4), 431–440. 10.1515/jpem-2020-0360
    1. Balhara B., Misra M., Levitsky L. L. (2012). Recombinant human IGF-1 (insulin-like growth factor) therapy: Where do we stand today? Indian J. Pediatr. 79 (2), 244–249. 10.1007/s12098-011-0608-5
    1. Cecconi E., Gasperi M., Bogazzi F., Grasso L., Genovesi M., Marcocci C., et al. (2004). Improvement of growth hormone deficiency in patients with primary hyperparathyroidism after parathyroidectomy: Results of a prospective study. J. Clin. Endocrinol. Metab. 89 (3), 1213–1216. 10.1210/jc.2003-031595
    1. Ciresi A., Amato M. C., Criscimanna A., Mattina A., Vetro C., Galluzzo A., et al. (2007). Metabolic parameters and adipokine profile during GH replacement therapy in children with GH deficiency. Eur. J. Endocrinol. 156 (3), 353–360. 10.1530/eje.1.02343
    1. Cohen P., Rogol A. D., Howard C. P., Bright G. M., Kappelgaard A., Rosenfeld R. G., et al. (2007). Insulin growth factor-based dosing of growth hormone therapy in children: A randomized, controlled study. J. Clin. Endocrinol. Metab. 92 (7), 2480–2486. 10.1210/jc.2007-0204
    1. Collett-Solberg P. F., Jorge A., Boguszewski M., Miller B. S., Choong C., Cohen P., et al. (2019). Growth hormone therapy in children; research and practice - a review. Growth Horm. IGF Res. 44, 20–32. 10.1016/j.ghir.2018.12.004
    1. Coutant R., Bosch Muñoz J., Dumitrescu C. P., Schnabel D., Sert C., Perrot V., et al. (2021). Effectiveness and overall safety of NutropinAq® for growth hormone deficiency and other paediatric growth hormone disorders: Completion of the international cooperative growth study, NutropinAq® European registry (iNCGS). Front. Endocrinol. 12, 676083. 10.3389/fendo.2021.676083
    1. Czepielewski M. A., Garret Q., Vencio S., Rassi N., Felicio J. S., Faria M. S., et al. (2019). Efficacy and safety of a biosimilar recombinant human growth hormone (r-hGH cristalia) compared with reference r-hGH in children with growth hormone deficiency (ceres study): A randomized, multicentric, investigator-blind, phase 3 trial. Growth Horm. IGF Res. 48-49, 29–35. 10.1016/j.ghir.2019.07.003
    1. Deal C., Kirsch S., Chanoine J. P., Lawrence S., Cummings E., Rosolowsky E. T., et al. (2018). Growth hormone treatment of Canadian children: Results from the Genesis phase IV prospective observational study. CMAJ Open 6 (3), E372–E383. 10.9778/cmajo.20180020
    1. Du H., Wu D., Yi P., Bai X., Luo Y., Yang H., et al. (2022). Evaluation of efficacy and safety of long-acting PEGylated recombinant human growth hormone (Jintrolong) for patients with growth hormone deficiency. J. Pediatr. Endocrinol. Metab. 35 (4), 511–517. 10.1515/jpem-2021-0735
    1. Graham S., Weinman J., Auyeung V. (2018). Identifying potentially modifiable factors associated with treatment non-adherence in paediatric growth hormone deficiency: A systematic review. Horm. Res. Paediatr. 90 (4), 221–227. 10.1159/000493211
    1. Hou L., Chen Z. H., Liu D., Cheng Y. G., Luo X. P. (2016). Comparative pharmacokinetics and pharmacodynamics of a PEGylated recombinant human growth hormone and daily recombinant human growth hormone in growth hormone-deficient children. Drug Des. devel. Ther. 10, 13–21. 10.2147/DDDT.S93183
    1. Hui L., Cheng J., Xin Z., Zhang Y. Q. (2009). Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years. Chin. J. PED 47 (7), 487–492.
    1. Kubo T., Furujo M., Takahashi K., Hyodo Y., Tsuchiya H., Hattori M., et al. (2017). Effects of growth hormone treatment on lipid profiles. Indian J. Pediatr. 85 (4), 261–265. 10.1007/s12098-017-2509-8
    1. Lal R. A., Hoffman A. R. (2018). Long-acting growth hormone preparations in the treatment of children. Pediatr. Endocrinol. Rev. 16, 162–167. 10.17458/per.vol16.2018.lh.longactingghpreparation
    1. Li J., Pan W., Qian J., Ni Y., Fu J., Ni S. (2022). Metabolomic differential compounds reflecting the clinical efficacy of polyethylene glycol recombinant human growth hormone in the treatment of childhood growth hormone deficiency. Front. Pharmacol. 13, 864058. 10.3389/fphar.2022.864058
    1. Liu H. J., Wang L. H., Chen L. (2019). Evaluation of safety and efficacy of growth hormone therapy by IGF-1 Z score in children with short stature. Adv. Ther. 36 (9), 2374–2383. 10.1007/s12325-019-01021-5
    1. Luo X., Hou L., Liang L., Dong G., Shen S., Zhao Z., et al. (2017). Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: Phase II and phase III multicenter, randomized studies. Eur. J. Endocrinol. 177 (2), 195–205. 10.1530/EJE-16-0905
    1. Miller B. S., Velazquez E., Yuen K. (2020). Long-acting growth hormone preparations - current status and future considerations. J. Clin. Endocrinol. Metab. 105 (6), e2121–e2133. 10.1210/clinem/dgz149
    1. Papathanasiou T., Agersø H., Damholt B. B., Højby R. M., Kildemoes R. J. (2021). Population pharmacokinetics and pharmacodynamics of once-daily growth hormone Norditropin(®) in children and adults. Clin. Pharmacokinet. 60, 1217–1226. 10.1007/s40262-021-01011-3
    1. Pellegrin M. C., Michelon D., Faleschini E., Germani C., Barbi E., Tornese G. (2019). Glucose metabolism evaluated by glycated hemoglobin and insulin sensitivity indices in children treated with recombinant human growth hormone. J. Clin. Res. Pediatr. Endocrinol. 11 (4), 350–357. 10.4274/jcrpe.galenos.2019.2019.0281
    1. Peterkova V., Arslanoglu I., Bolshova-Zubkovskaya E., Romer T., Zdravkovic D., Kratzsch J., et al. (2007). A randomized, double-blind study to assess the efficacy and safety of valtropin, a biosimilar growth hormone, in children with growth hormone deficiency. Horm. Res. 68 (6), 288–293. 10.1159/000105494
    1. Pfäffle R., Bidlingmaier M., Kreitschmann-Andermahr I., Land C., Partsch C. J., Schwab K. O., et al. (2020). Safety and effectiveness of Omnitrope®, a biosimilar recombinant human growth hormone: More than 10 Years' experience from the PATRO children study. Horm. Res. Paediatr. 93 (3), 154–163. 10.1159/000508190
    1. Pfäffle R. (2015). Hormone replacement therapy in children: The use of growth hormone and IGF-I. Best. Pract. Res. Clin. Endocrinol. Metab. 29 (3), 339–352. 10.1016/j.beem.2015.04.009
    1. Qiao Y., Wang Z., Han J., Li G. (2019). Use of PEGylated recombinant human growth hormone in Chinese children with growth hormone deficiency: A 24-month follow-up study. Int. J. Endocrinol. 2019, 1–7. 10.1155/2019/1438723
    1. Renehan A. G., Zwahlen M., Minder C., O'Dwyer S. T., Shalet S. M., Egger M. (2004). Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: Systematic review and meta-regression analysis. Lancet 363 (9418), 1346–1353. 10.1016/S0140-6736(04)16044-3
    1. Rhie Y. J., Yoo J. H., Choi J. H., Chae H. W., Kim J. H., Chung S., et al. (2019). Long-term safety and effectiveness of growth hormone therapy in Korean children with growth disorders: 5-year results of LG growth study. PLoS One 14 (5), e0216927. 10.1371/journal.pone.0216927
    1. Richmond E., Rogol A. D. (2016). Treatment of growth hormone deficiency in children, adolescents and at the transitional age. Best. Pract. Res. Clin. Endocrinol. Metab. 30 (6), 749–755. 10.1016/j.beem.2016.11.005
    1. Saenger P. H., Mejia-Corletto J. (2016). Long-acting growth hormone: An update. Endocr. Dev. 30, 79–97. 10.1159/000439333
    1. Shih K. C., Ho L. T., Kuo H. F., Chang T. C., Liu P. C., Chen C. K., et al. (1994). Linear growth response to recombinant human growth hormone in children with growth hormone deficiency. Zhonghua Yi Xue Za Zhi (Taipei) 54(1), 7–13.
    1. Slattery M., Bredella M. A., Stanley T., Torriani M., Misra M. (2014). Effects of recombinant human growth hormone (rhGH) administration on body composition and cardiovascular risk factors in obese adolescent girls. Int. J. Pediatr. Endocrinol. 2014 (1), 22. 10.1186/1687-9856-2014-22
    1. Sun C., Lu B., Liu Y., Zhang Y., Wei H., Hu X., et al. (2021). Reduced effectiveness and comparable safety in biweekly vs. Weekly PEGylated recombinant human growth hormone for children with growth hormone deficiency: A phase IV non-inferiority threshold targeted trial. Front. Endocrinol. 12, 779365. 10.3389/fendo.2021.779365
    1. Swerdlow A. J., Cooke R., Albertsson-Wikland K., Borgstrom B., Butler G., Cianfarani S., et al. (2015). Description of the SAGhE cohort: A large European study of mortality and cancer incidence risks after childhood treatment with recombinant growth hormone. Horm. Res. Paediatr. 84 (3), 172–183. 10.1159/000435856
    1. Wang C., Huang H., Zhao C., Zhao J., Xiong R., Jin R., et al. (2021). The impact of pegylated recombinant human growth hormone replacement therapy on glucose and lipid metabolism in children with growth hormone deficiency. Ann. Palliat. Med. 10 (2), 1809–1814. 10.21037/apm-20-871
    1. Weber M. M., Biller B. M., Pedersen B. T., Pournara E., Christiansen J. S., Hoybye C., et al. (2017). The effect of growth hormone (GH) replacement on blood glucose homeostasis in adult nondiabetic patients with GH deficiency: Real-life data from the NordiNet® international outcome study. Clin. Endocrinol. 86 (2), 192–198. 10.1111/cen.13256
    1. Witkowska-Sędek E., Rumińska M., Majcher A., Pyrżak B. (2019). Gender-dependent growth and insulin-like growth factor-1 responses to growth hormone therapy in prepubertal growth hormone-deficient children. Adv. Exp. Med. Biol. 1133, 65–73. 10.1007/5584_2018_284
    1. Wu S., Yang W., De Luca F. (2015). Insulin-like growth factor-independent effects of growth hormone on growth plate chondrogenesis and longitudinal bone growth. Endocrinology 156 (7), 2541–2551. 10.1210/en.2014-1983
    1. Xue Y., Gao Y., Wang S., Wang P. (2016). An examination of the effects of different doses of recombinant human growth hormone on children with growth hormone deficiency. Exp. Ther. Med. 11 (5), 1647–1652. 10.3892/etm.2016.3091
    1. Yuan Y., Zhou B., Liu S., Wang Y., Wang K., Zhang Z., et al. (2021). Meta-analysis of metabolic changes in children with idiopathic growth hormone deficiency after recombinant human growth hormone replacement therapy. Endocrine 71 (1), 35–46. 10.1007/s12020-020-02435-w
    1. Yuen K., Miller B. S., Boguszewski C. L., Hoffman A. R. (2021). Usefulness and potential pitfalls of long-acting growth hormone analogs. Front. Endocrinol. 12, 637209. 10.3389/fendo.2021.637209
    1. Zhang Z. X., Liu Y. K., Pan H., Pan L., Zhang Q., Su H. M., et al. (2012). The effect of polyethylene glycol recombinant human growth hormone on growth and glucose metabolism in hypophysectomized rats. Growth Horm. IGF Res. 22 (1), 30–35. 10.1016/j.ghir.2011.12.002

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