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

Abstract

ContextLong-acting recombinant human growth hormone (rhGH) has transformed growth hormone deficiency (GHD) treatment. However, the possibility and rationality for flexible time regimen are pending.ObjectiveWe studied the efficacy of biweekly versus weekly PEGylated rhGH (PEG-rhGH) therapy in GHD children.Design, Setting, and PatientsThis multicenter, phase IV trial with a non-inferiority threshold ≥20% enrolled 585 Tanner stage I GHD children.InterventionSubjects 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 MeasureThe 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.ResultsAt 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.ConclusionsAlthough 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 Registrationclinicaltrials.gov, identifier NCT02976675.

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

“…After 26 weeks of PEG-rhGH treatment, significant increases in Ht SDS and HV were observed in both dose groups, as expected. The incremental changes in Ht SDS and HV in the high-dose group at week 26 yielded similar results as were reported in a Phase IV clinical trial and another single-center, nonrandomized cohort study of Jintrolong ® at the same dose of 0.2 mg/kg/week ( Qiao et al, 2019 ; Sun et al, 2021 ), but were less than the results from the Phase III clinical trial of Jintrolong ® ( Luo et al, 2017 ). Changes in Ht SDS were negatively correlate with age, baseline IGF-1, and peak GH levels ( Sun et al, 2021 ).…”

“…The incremental changes in Ht SDS and HV in the high-dose group at week 26 yielded similar results as were reported in a Phase IV clinical trial and another single-center, nonrandomized cohort study of Jintrolong ® at the same dose of 0.2 mg/kg/week ( Qiao et al, 2019 ; Sun et al, 2021 ), but were less than the results from the Phase III clinical trial of Jintrolong ® ( Luo et al, 2017 ). Changes in Ht SDS were negatively correlate with age, baseline IGF-1, and peak GH levels ( Sun et al, 2021 ). The mean peak GH level and mean value of IGF-1 SDS were lower in the Phase III clinical trial, which may explain the differences in growth responses in different clinical trials.…”

“…A sample size of at least 191 per group was needed to achieve a power of 90% with an α level of 0.025 for a non-inferiority margin of −20% in Ht SDS change ( Sun et al, 2021 ). We assumed a dropout rate of 20% and to guarantee the robustness of the results, a total of 900 patients were planned to recruit.…”

“…Compared to daily rhGH, PEG-rhGH has a longer T max and t 1/2 and slower plasma clearance, which allows for weekly injection ( Hou et al, 2016 ). Clinical studies have demonstrated the non-inferior efficacy and safety of PEG-rhGH compared to daily rhGH at an equivalent dose for the treatment of GHD ( Luo et al, 2017 ; Qiao et al, 2019 ; Sun et al, 2021 ; Wang et al, 2021 ; Du et al, 2022 ). Notably, in a Phase III trial, PEG-rhGH treatment at 0.2 mg/kg/week was associated with greater increases in most of the efficacy endpoints, including height velocity (HV), height (Ht) standard deviation score (SDS), and insulin-like growth factor-1 (IGF-1) SDS, compared to daily rhGH dosing of 0.25 mg/kg/week ( Luo et al, 2017 ).…”

First Clinical Study on Long-Acting Growth Hormone Therapy in Children with Turner Sydrome

“…No injection-site lipoatrophy was observed, but 1 patient from high-dose LAGH group had injection site nodules, when the patient changed the injection site the nodules disappeared. In the long-acting PEGylated rhGH phase III and phase IV randomized controlled trails, there is no injection-site lipoatrophy reported 24 25 , but some clinical study showed that at 13 weeks after GH treatment, injection-site lipoatrophy occurred, when the injection-site was changed and to avoid repeated injections on the same site, injection-site lipoatrophy recovered after 3–6 months. The other two events occurred in daily rhGH group, two patients had hyperinsulinemia, no type 2 diabetes mellitus occurred.…”