This study was a prospective, multicenter and single-arm study (ChiCTR2100048579). It was conducted in accordance with the research protocol and approved by the Ethics Committee of The Children's Hospital, Zhejiang University School of Medicine (approval No. 2021-IEC-019), with written informed consent obtained from all participants' parents/legal guardians. Eligible participants were given diet and exercise-guided PEG-rhGH (Jintrolong) for a duration of 64 weeks. The overall study period was 66 weeks, comprising a trial screening phase of 2 weeks, a dose-adjustment period of 12 weeks, and a trial drug treatment phase of 52 weeks (Fig. 1). A total of 10 visits were conducted during the study.

Eligible patients had transitional GHD and met the following criteria: (1) patients diagnosed with childhood-onset growth GHD; (2) growth rate less than 2 cm per year; (3) bone age at least 14.5 years for females and 16.5 years for males; (4) chronological age no more than 24 years for females and 26 years for males; (5) interruption of GH replacement therapy for at least 1 year; (6) peak serum GH level less than 5 ng/mL during the insulin tolerance test; (7) In cases of additional hormonal deficiencies, patients must have received appropriate replacement therapy and stabilized therapeutic doses for at least 6 months prior to enrollment; (8) no significant changes in exercise or dietary habits throughout the study period; (9) The participant must be willing and able to comply with all visit schedules, treatment plans, and laboratory trial procedures, and provide written informed consent.

Exclusion criteria included (1) abnormal renal function (Cr [Please spell out. creatine?]> upper limit of normal); (2) abnormal liver function due to hepatophilus or other inherited metabolic liver diseases (except for abnormal liver function due to fatty liver); (3) chronic diseases that chronically affect bone metabolism and body composition (including, but not limited to, renal rickets, abnormal parathyroid function, or Cushing syndrome); (4) diabetic patients; (5) body mass index (BMI) ≥ 28 kg/m2; (6) female patients who are pregnant or breastfeeding, or who have a positive baseline pregnancy test; (7) known to be highly allergic or hypersensitive to the study medication; (8) participants who have participated in a clinical trial of another drug within 3 months; (9) other conditions that the investigator considers inappropriate for enrollment in this clinical trial.

Patients were trained by site staff to self-administer the trial medication via subcutaneous injection, with instructions to alternate injection sites between the abdomen and thighs. Patients received Jintrolong on a once-weekly basis, following a treatment schedule spanning 64 weeks. The initial dose of the drug was 1 mg/wk. The dose-adjustment period occurred during weeks 0-12 of administration and adjustments were made based on subjects' insulin-like growth factor-1 (IGF-1) levels (Supplementary Table 1).

The primary end point for this study was the change in percentage of total body fat mass after 64 weeks of treatment (using dual-energy x-ray absorptiometry). Key secondary end points were changes in lumbar BMD (L1–4) and LBM after 38 and 64 weeks of treatment.

Safety was assessed by adverse events, laboratory findings (IGF-1, routine screening of blood and urine, blood biochemistry, thyroid function tests, thyroid antibodies, fasting glucose, glucose tolerance test, lipids, adrenocorticotropic hormone, follicular fluid, luteinizing hormone, follicle-stimulating hormone, estradiol, testosterone).

Normally distributed variables were described with mean±standard deviation (SD), and indicators before and after treatment were examined using paired t-tests. Variables with skewed distributions were described using median and interquartile range and tested with the signed rank sum test. Categorical variables are described with frequencies and percentages. The value of change from baseline (screening period) for the outcome metrics in this study was calculated as: followup value - baseline value. The IGF-1 SDS was calculated as SDS=((Y_(IGF-1)⁄M)^L-1)/(L×S), where L was 0.4568 for males and 0.4595 for females [19]. The subjects' compliance was calculated as compliance=(actual number of doses administered/prescribed number of treatment courses) × 100%. The computation of SDS was performed with reference to reports on East Asian populations, calculated as (value — mean of the reference population)/SD of the reference population. The fat mass index (FMI) SDS was calculated as follows: SDS=(FMI–mean FMI)/SD, mean FMI=4.31 (male)/5.96 (female), SD=2.03 (male)/1.89 (female). The whole-body Fat% SDS was calculated as: SDS=(Fat%–mean Fat%)/SD, mean Fat%=21.2 % (male)/32.3 % (female), SD=6.9 % (male)/5.9 % (female) [20].

Furthermore, subgroup analyses by sex or etiology (developed the disease after pituitary surgery, continuation from childhood GHD, and other etiologies) are performed to assess the efficacy of PEG-rhGH in different populations of GHD during the transition period. All statistical analyses in this study were analyzed with R 4.3.0 (R Foundation for Statistical Computing, Austria).

Baseline characteristics of the participants are shown in Table 1. This study commenced on September 24, 2021, and end time for patient enrollment was June 30, 2023. The follow-up phase was completed in August 2024. A total of 31 subjects were included, including 23 males (74.2%) and 8 females (25.8%), with a mean age of 20.46 years, ranging from 14.8~25.8 years. All subjects reported stable disease, most had received alternative treatments, and the mean duration of disease was 7.79 years. Most of the subjects did not have a history of smoking and alcohol consumption, and a few had a family history of diabetes, hypertension and cardiovascular disease. Nine patients (29.0%) developed the disease after pituitary surgery, 13 patients (42.0%) had pituitary stalk interruption syndrome, and 9 (29.0%) had other etiologies, such as hypopituitarism of the anterior pituitary gland, idiopathic hypogonadotropic hypogonadism, or combined hypopituitarism.

Patients were given an initial dose of 1 mg/wk, a mean dose of 1.64 mg/wk during the dose-adjustment period, and 3.40 mg/wk during the dose-stabilization period. Participants in the dose-stabilization phase had significantly higher doses of drug exposure compared to the dose-adjustment phase. Subject compliance was 98.85% and 97.69%, respectively, for the 2 phases, which is close to 100% (Supplementary Table 2).

IGF-1 is commonly utilized as a biomarker for monitoring the response to GH therapy. Longitudinal analysis revealed significant improvements in IGF-1 parameters throughout the 64-week study period. The IGF-1 SDS scores demonstrated progressive elevation from baseline (-3.07) to 38 weeks (-1.24) (P<0.001), maintaining therapeutic efficacy at 64 weeks with -1.38 (P<0.001) (Supplementary Table 3; Fig. 2). Furthermore, subgroup analysis by sex indicated that the IGF-1 SDS significantly increased from baseline (-3.07) to 64 weeks (-1.21) (P<0.001) in male subjects, and, similarly, significantly increased from baseline (-3.05) to 64 weeks (-1.80; P=0.014) in female subjects (Supplementary Table 4). Subgroup analysis by etiology (Supplementary Table 5) exhibited some differences: for the subjects who developed GHD after pituitary surgery, the IGF-1 SDS significantly increased from baseline (-3.02) to 64 weeks (-1.35) (P=0.031 for both); for the subjects with continuation from childhood GHD, the IGF-1 SDS from baseline to 64 weeks was -2.66 to -0.87 (P=0.002); for the subjects with GHD caused by other etiologies, the IGF-1 SDS from baseline to 64 weeks was -3.15 to -1.90 (P=0.024). As such, the IGF-1 SDS in all subgroups was significantly elevated.

Significant alterations in body composition parameters were observed throughout the study period. Body weight demonstrated a clinically meaningful elevation of 3.96 kg (P<0.001), while, paradoxically, whole-body adiposity exhibited a nonsignificant downward trend (-0.54 kg; P=0.413) (Table 2). The body weight SDS exhibited significant elevation from baseline (0.67) to 64 weeks (1.14) (P=0.005), and BMI SDS also showed significant elevation from baseline (0.74) to 64 weeks (1.03) (P=0.011). Of particular physiological significance was the robust 4.54 kg augmentation in LBM (P<0.001) (Table 2; Fig. 3B). Notably, there was a statistically significant reduction in whole-body Fat% from 37.40% to 33.94% (Δ2.70%, P=0.008) and Fat% SDS from 1.91 to 1.47 (P=0.009), demonstrating clinically meaningful improvements in body composition parameters (Table 2; Fig. 3A). Subgroup analysis by sex indicated some differences: in male subjects, body weight increased 4.10 kg (P=0.030), body weight SDS increased 0.42 (P=0.038), LBM increased 5.52 kg (P=0.003), and Fat% decreased 9.71% (P=0.004); in female subjects, body weight increased 3.62 kg (P=0.026), body weight SDS increased 0.48 (P=0.039), LBM increased 2.07 kg (P=0.060), and Fat% increased 0.14% (P=0.950), demonstrating that the effects of PEG-rhGH on the changes of LBM and Fat% may be different between male and female GHD patients. Subgroup analysis by etiology exhibited some differences: for the subjects who developed GHD after pituitary surgery, there was no significant change in body composition parameters; however, for the subjects with continuation from childhood GHD, body weight increased 4.44 kg (P=0.027), body weight SDS increased 0.50 (P=0.039), LBM increased 6.04 kg (P=0.004), and Fat% decreased 12.86% (P=0.027). For the subjects with GHD caused by other etiologies, there were significant changes in body weight, body weight SDS, and LBM, but no significant change in Fat%.

While the lumbar BMD z-score change did not reach statistical significance (P>0.05), an absolute increase of 0.43 points was demonstrated, with values improving from -1.54 at baseline to -1.12 postintervention (Table 2; Fig. 4).

TG levels of the subjects decreased significantly from a baseline level of 1.50 mmol/L to 1.14 mmol/L at week 64 (P=0.018) (Supplementary Table 6). Meanwhile, there were no statistically significant differences in the changes in LDL-C, high-density lipoprotein cholesterol (HDL-C), or total cholesterol (TC), but there was a tendency for HDL-C to increase. Subgroup analysis by sex showed a decrease in TG levels, but this was not statistically significant in either males or females (P=0.066 for male subjects; P=0.172 for female subjects). Subgroup analysis by etiology indicated that the lipid profile changes were similar, and there was no statistically significant difference in the changes in TG, LDL-C, HDL-C, and TC in the diverse GHD populations.

In this study, no adverse events attributable to direct drug-related causes were identified. The serious adverse events experienced by 2 patients were both related to accidental falls and injuries, which were not attributable to drug-induced causes. Infection was the adverse reaction with the highest incidence, occurring in 6 patients. One patient discontinued the medication owing to a preexisting history of diabetes mellitus. This 20.7-year-old male participant had a history of type 2 diabetes for about 2 years (baseline fasting plasma glucose, 5.3 mmol/L; glycated hemoglobin [HbA1c], 5.7%), with no family history of diabetes. He initiated GH replacement at 1 mg/wk, with subsequent gradual dose escalation to 2.5 mg/wk at week 8. The patient's HbA1c levels increased at the 12th week following medication initiation. Although there was a temporary decrease during subsequent follow-ups, the levels continued to rise thereafter. Following a comprehensive clinical evaluation, it was determined that the patient should be withdrawn from the clinical trial (Supplementary Table 1).