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

Chengjun Sun, Biao Lu, Yu Liu, Yaqin Zhang, Haiyan Wei, Xu Hu, Pei Hu, Qian Zhao, Yanling Liu, Kan Ye, Kan Wang, Zaiyan Gu, Zheng Liu, Jin Ye, Hongxiao Zhang, Hong Zhu, Zhihong Jiang, Yanjie Liu, Naijun Wan, Chengming Yan, Jianying Yin, Lirong Ying, Feng Huang, Qingjin Yin, Li Xi, Feihong Luo, Ruoqian Cheng, Chengjun Sun, Biao Lu, Yu Liu, Yaqin Zhang, Haiyan Wei, Xu Hu, Pei Hu, Qian Zhao, Yanling Liu, Kan Ye, Kan Wang, Zaiyan Gu, Zheng Liu, Jin Ye, Hongxiao Zhang, Hong Zhu, Zhihong Jiang, Yanjie Liu, Naijun Wan, Chengming Yan, Jianying Yin, Lirong Ying, Feng Huang, Qingjin Yin, Li Xi, Feihong Luo, Ruoqian Cheng

Abstract

Context: Long-acting recombinant human growth hormone (rhGH) has transformed growth hormone deficiency (GHD) treatment. However, the possibility and rationality for flexible time regimen are pending.

Objective: We studied the efficacy of biweekly versus weekly PEGylated rhGH (PEG-rhGH) therapy in GHD children.

Design setting and patients: This multicenter, phase IV trial with a non-inferiority threshold ≥20% enrolled 585 Tanner stage I GHD children.

Intervention: Subjects randomly received 0.20 mg/kg once-weekly or biweekly PEG-rhGH, or 0.25 mg/kg.w rhGH once daily for 26 weeks.

Main outcome measure: The primary outcome was height SD scores for chronological age (HtSDSCA) at week 26 and safety measurements including adverse events (AEs), IGF-2, and IGFBP-2 changes.

Results: At week 26, the median HtSDSCA changed from -2.75, -2.82, and -2.78 to -2.31, -2.43, and -2.28 with weekly and biweekly PEG-rhGH, and daily rhGH, respectively. The difference in HtSDSCA was 0.17 ± 0.28 between weekly and biweekly PEG-rhGH, and 0.17 ± 0.27 between daily rhGH and biweekly PEG-rhGH, failing the non-inferiority threshold. Nevertheless, the height velocity of children receiving biweekly PEG-rhGH reached 76.42%-90.34% and 76.08%-90.60% that of children receiving weekly PEG-rhGH and daily rhGH, respectively. The rate of AEs was comparable among the groups. No statistical difference was observed in IGF-2 and IGFBP-2 levels among the groups. IGFBP-2 levels decreased over time in all groups, with no notable difference in IGF-2 and IGFBP-2 changes among the three treatment groups.

Conclusions: Although notably promoted height velocity, biweekly PEG-rhGH failed the non-inferiority threshold as compared with either weekly PEG-rhGH or daily rhGH. Compared with short-term rhGH, long-acting PEG-rhGH did not significantly increase tumor-associated IGF-2 and IGFBP-2 expressions.

Clinical trial registration: clinicaltrials.gov, identifier NCT02976675.

Keywords: IGF-2; PEG-rhGH; PEGylated recombinant human growth hormone; children; growth hormone deficiency.

Conflict of interest statement

CS, RC, and FL received lecture fees from GeneScience Pharmaceuticals. The remaining 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 © 2021 Sun, Lu, Liu, Zhang, Wei, Hu, Hu, Zhao, Liu, Ye, Wang, Gu, Liu, Ye, Zhang, Zhu, Jiang, Liu, Wan, Yan, Yin, Ying, Huang, Yin, Xi, Luo and Cheng.

Figures

Figure 1
Figure 1
The study flowchart. Note: A subject may be excluded from the per-protocol set (PPS) due to more than one cause. *Participant’s age > 18 years. **Incomplete height record at baseline.
Figure 2
Figure 2
(A) Height SD scores for chronological age (HtSDSCA) for PEGylated recombinant human growth hormone (PEG-rhGH) every other week (QOW), weekly PEG-rhGH (QW), and daily rhGH (QD) at baseline and weeks 4, 12, and 26. (B) HtSDSCA change at weeks 4, 12, and 26 from baseline for PEG-rhGH QOW, PEG-rhGH QW, and rhGH QD.
Figure 3
Figure 3
Annualized height velocity (HV) (A) and IGF-1 SD scores (SDS) (B) for PEGylated recombinant human growth hormone (PEG-rhGH) every other week (QOW), weekly PEG-rhGH (QW), and daily rhGH (QD) at baseline and weeks 4, 12, and 26. IGF-1 SDS change (C) at weeks 4, 12, and 26 from baseline for PEG-rhGH QOW, PEG-rhGH QW, and rhGH QD.
Figure 4
Figure 4
(A) IGF-2, (B) IGF-2 change, (C) IGFBP-2, and (D) IGFBP-2 change for the PEGylated recombinant human growth hormone (PEG-rhGH) every other week (QOW), weekly PEG-rhGH (QW), and daily rhGH (QD) groups at baseline and weeks 4, 12, and 26.

References

    1. Bao XL, Shi YF, Du YC, Liu R, Deng JY, Gao SM. Prevalence of Growth Hormone Deficiency of Children in Beijing. Chin Med J (Engl) (1992) 105:401–5.
    1. Webster R, Xie R, Didier E, Finn R, Finnessy J, Edgington A, et al. . PEGylation of Somatropin (Recombinant Human Growth Hormone): Impact on Its Clearance in Humans. Xenobiotica (2008) 38:1340–51. doi: 10.1080/00498250802413856
    1. Guan Y, He F, Wu J, Zhao L, Wang X, Huang L, et al. . A Long-Acting Pegylated Recombinant Human Growth Hormone (Jintrolong®) in Healthy Adult Subjects: Two Single-Dose Trials Evaluating Safety, Tolerability and Pharmacokinetics. J Clin Pharm Ther (2018) 43:640–6. doi: 10.1111/jcpt.12732
    1. Salvatori R. Growth Hormone and IGF-1. Rev Endocr Metab Disord (2004) 5:15–23. doi: 10.1023/B:REMD.0000016121.58762.6d
    1. Hou L, Chen ZH, Liu D, Cheng YG, Luo XP. 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 (2015) 10:13–21. doi: 10.2147/DDDT.S93183
    1. Luo X, Hou L, Liang L, Dong G, Shen S, Zhao Z, et al. . 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 (2017) 177:195–205. doi: 10.1530/EJE-16-0905
    1. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. . SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials. Ann Intern Med (2013) 158:200–7. doi: 10.7326/0003-4819-158-3-201302050-00583
    1. Schulz KF, Altman DG, Moher D, CONSORT Group . CONSORT 2010 Statement: Updated Guidelines for Reporting Parallel Group Randomised Trials. BMJ (2010) 340:c332. doi: 10.1136/bmj.c332
    1. Benyi E, Sävendahl L. The Physiology of Childhood Growth: Hormonal Regulation. Horm Res Paediatr (2017) 88:6–14. doi: 10.1159/000471876
    1. Péter F, Bidlingmaier M, Savoy C, Ji HJ, Saenger PH. Three-Year Efficacy and Safety of LB03002, a Once-Weekly Sustained-Release Growth Hormone (GH) Preparation, in Prepubertal Children With GH Deficiency (GHD). J Clin Endocrinol Metab (2012) 97:400–7. doi: 10.1210/jc.2011-2234
    1. Khadilkar V, Radjuk KA, Bolshova E, Khadgawat R, El Kholy M, Desai M, et al. . 24-Month Use of Once-Weekly GH, LB03002, in Prepubertal Children With GH Deficiency. J Clin Endocrinol Metab (2014) 99:126–32. doi: 10.1210/jc.2013-2502
    1. Hoffman AR, Biller BM, Cook D, Baptista J, Silverman BL, Dao L, et al. . Efficacy of a Long-Acting Growth Hormone (GH) Preparation in Patients With Adult GH Deficiency. J Clin Endocrinol Metab (2005) 90:6431–40. doi: 10.1210/jc.2005-0928
    1. Biller BM, Ji HJ, Ahn H, Savoy C, Siepl EC, Popovic V, et al. . Effects of Once-Weekly Sustained-Release Growth Hormone: A Double-Blind, Placebo-Controlled Study in Adult Growth Hormone Deficiency. J Clin Endocrinol Metab (2011) 96:1718–26. doi: 10.1210/jc.2010-2819
    1. Sävendahl L, Cooke R, Tidblad A, Beckers D, Butler G, Cianfarani S, et al. . Long-Term Mortality After Childhood Growth Hormone Treatment: The SAGhE Cohort Study. Lancet Diabetes Endocrinol (2020) 8:683–92. doi: 10.1016/S2213-8587(20)30163-7
    1. Baxter RC. IGF Binding Proteins in Cancer: Mechanistic and Clinical Insights. Nat Rev Cancer (2014) 14:329–41. doi: 10.1038/nrc3720
    1. Dynkevich Y, Rother KI, Whitford I, Qureshi S, Galiveeti S, Szulc AL, et al. . Tumors, IGF-2, and Hypoglycemia: Insights From the Clinic, the Laboratory, and the Historical Archive. Endocr Rev (2013) 34:798–826. doi: 10.1210/er.2012-1033
    1. Livingstone C. IGF2 and Cancer. Endocr Relat Cancer (2013) 20:R321–39. doi: 10.1530/ERC-13-0231
    1. Png KJ, Halberg N, Yoshida M, Tavazoie SF. A microRNA Regulon That Mediates Endothelial Recruitment and Metastasis by Cancer Cells. Nature (2011) 481:190–4. doi: 10.1038/nature10661
    1. Russo VC, Azar WJ, Yau SW, Sabin MA, Werther GA. IGFBP-2: The Dark Horse in Metabolism and Cancer. Cytokine Growth Factor Rev (2015) 26):329–46. doi: 10.1016/j.cytogfr.2014.12.001
    1. Li T, Forbes ME, Fuller GN, Li J, Yang X, Zhang W. IGFBP2: Integrative Hub of Developmental and Oncogenic Signaling Network. Oncogene (2020) 39:2243–57. doi: 10.1038/s41388-020-1154-2
    1. Subspecialty Group of Endocrinologic. Hereditary and Metabolic Diseases. Society of Pediatrics. Chinese Medical Association . Recommendations for the Clinical Use of Recombinant Human Growth Hormone in Children. Zhonghua Er Ke Za Zhi (2013) 51(6):426–32. doi: 10.3760/cma.j.issn.0578-1310.2013.06.007
    1. Guzzetti C, Ibba A, Pilia S, Beltrami N, Di Iorgi N, Rollo A, et al. . Cut-Off Limits of the Peak GH Response to Stimulation Tests for the Diagnosis of GH Deficiency in Children and Adolescents: Study in Patients With Organic GHD. Eur J Endocrinol (2016) 175(1):41–7. doi: 10.1530/EJE-16-0105
    1. Juul A, Skakkebaek NE. Prediction of the Outcome of Growth Hormone Provocative Testing in Short Children by Measurement of Serum Levels of Insulin-Like Growth Factor I and Insulin-Like Growth Factor Binding Protein 3. J Pediatr (1997) 130(2):197–204. doi: 10.1016/s0022-3476(97)70343-3
    1. Loche S, Bizzarri C, Maghnie M, Faedda A, Tzialla C, Autelli M, et al. . Results of Early Reevaluation of Growth Hormone Secretion in Short Children With Apparent Growth Hormone Deficiency. J Pediatr (2002) 140(4):445–9. doi: 10.1067/mpd.2002.122729

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