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

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 (HtSDS CA ) at week 26 and safety measurements including adverse events (AEs), IGF-2, and IGFBP-2 changes. Results At week 26, the median HtSDS CA 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 HtSDS CA 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.