Long-term Pegylated GH for Children With GH Deficiency: A Large, Prospective, Real-world Study

Abstract

Context

The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited.

Objective

This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in the real world, as well as to examine the effects of dose on patient outcomes.

Design

A prospective, observational, posttrial study (NCT03290235).

Setting, participants and intervention

Children with GHD were enrolled from 81 centers in China in 4 individual clinical trials and received weekly 0.2 mg/kg/wk (high-dose) or 0.1 to <0.2 mg/kg/wk (low-dose) PEG-rhGH for 30 months.

Main outcomes measures

Height SD score (Ht SDS) at 12, 24, and 36 months.

Results

A total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup. The Ht SDS improved significantly after treatment in the total population (P < 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. In addition, the changes in Ht SDS from baseline were significantly improved in the high-dose subgroup compared with the low-dose subgroup at 6, 12, 24, and 36 months after treatment (all P < 0.05). A total of 12 (1.03%) patients developed serious adverse events. There was no serious adverse event related to the treatment, and no AEs leading to treatment discontinuation or death occurred.

Conclusions

PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.

GH deficiency (GHD) is characterized by the impaired production of GH by the pituitary gland in childhood and adolescents (1). The prevalence of isolated GHD is estimated to be 1:4000 to 1:10 000 live births (2, 3). In a cross-sectional study conducted in China, the incidence of GHD was 1:8646 in children aged between 9 and 16 years (4). A child with GHD experiences physical differences and psychological trauma, which affects their personality, emotions, physical health, and mental health, resulting in poor quality of life in adulthood if not adequately treated (5). Hence, it is essential to provide effective and safe treatment regimens as to improve the prognosis of pediatric patients with GHD.

Daily subcutaneous injections of recombinant human GH (rhGH) have been the main treatment options for GHD since 1987 and can be discontinued at or near the completion of skeletal maturation (6, 7). Because of the short-acting nature of current rhGH administration and its limited half-life, long-term use is painful for children, resulting in poor compliance (8, 9). Currently, prolonging half-life rhGH, including long-acting polyethylene glycol conjugated with rhGH (PEG-rhGH) with long-term pharmacological effect in the body, will result in better efficacy with less risk of injection frequency and with better adherence (5, 8, 10-12). A phase 2 study showed that, compared with 0.1 mg/kg/wk, 0.2 mg/kg/wk of PEG-rhGH produced numerically higher height velocity (HV) increases. In the phase 3 study, patients receiving 0.2 mg/kg/wk PEG-rhGH showed significantly higher HV increases than those receiving daily rhGH after 25 weeks of treatment (12). Hence, some manufacturers use PEG-rhGH with an improved long-acting half-life preparation that can be injected once per week to increase adherence to GH therapy to improve growth, metabolic outcomes, and efficacy (8, 11). PEG-rhGH injection (Jintrolong) was approved in January 2014 (drug approval number: S20140001) for use in children with slowed growth resulting from endogenous GHD. PEG-rhGH at 0.2 mg/kg/wk has shown improved efficacy, safety, and tolerability with few serious adverse events (AEs) in several clinical trials (10, 12-15). In the real world, however, there are still limited postmarketing studies of effectiveness and safety of PEG-rhGH, particularly on dose selection, long-term efficacy evaluations, and safety monitoring (16).

In this regard, four phase 4 clinical trials in several cities throughout China in 2014 were conducted to evaluate the effectiveness and safety of PEG-rhGH in treating children with GHD with a large sample size and 26 weeks’ follow-up (17-19). This multicenter, prospective, observational, posttrial study enrolled children with GHD from these four phase 4 trials and aimed to examine the effectiveness and safety of PEG-rhGH in children with GHD following a 30-month extension treatment, as well as to examine the effects of dose on patient outcomes.

Materials and Methods

Study Design and Participants

This multicenter, prospective, observational, posttrial, real-world study was the extension study of four phase IV clinical trials of PEG-rhGH for treatment of children with GHD (NCT02380235 [not published], NCT02908958 (19), NCT02976675 (18), and NCT03249480 (17)), comprising 81 centers in China. GHD was diagnosed using the following criteria: (1) height below −2 SD or the third percentile of the normal growth curve for children of the same chronological age (CA) and sex in China (20); (2) HV ≤ 5 cm/y; 3) serum GH peak <10 μg/L in 2 different GH stimulation tests (stimulation with insulin, L-dopa, glucagon, arginine, or clonidine); and (4) bone age (BA) below 10 years for boys and 9 years for girls, with a minimum of a 1-year delay compared with the CA. Inclusion and exclusion criteria of the 4 clinical trials were identical: children with diagnosed GHD (21) who were prepubertal (Tanner stage I), aged 3 years and older, with bone ages of ≤9 years for girls or ≤10 years for boys and delayed for at least 1 year compared with the patient's chronological age, and have not received GH therapy within 6 months were included in four phase IV clinical trials; children with abnormal liver and kidney function, positive hepatitis B virus test, or complicated severe infection were excluded. The supplementary materials provide details about the hospitals and inclusion and exclusion for the four phase IV clinical trials (Supplementary File 1 (22) and Supplementary Table S1 (22)).

The key inclusion criteria of this posttrial study were patients were treated with PEG-rhGH according to each study protocol for 6 months during the clinical trial phase and patients who completed 6 months of PEG-rhGH injections for GHD according to the protocol and might benefit from continued treatment with no additional safety concern by investigators. The time between the end of the phase 4 clinical trial and the screening of this posttrial study was no more 8 weeks, during which no other GH products would have been received.

This posttrial study was approved by the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology (No. 2017-16), and the ethics committee of each study center participated. Written informed consents were obtained from all the patients. This study has been registered on clinicaltrials.gov (NCT03290235).

Treatment

All eligible patients received PEG-rhGH (Jintrolong, GeneScience Pharmaceuticals, Changchun, China) for another 30 months, which summed up to be a 36-month treatment of PEG-rhGH. Patients receiving 0.2 mg/kg/wk PEG-rhGH during the phase 4 clinical trial maintained their doses in this posttrial study. A dose of 0.1 to 0.2 mg/kg/wk PEG-rhGH was given to patients receiving other doses of PEG-rhGH during the phase 4 clinical trial; the dose of this group was adjusted according to the effectiveness and tolerability evaluated based on the physicians’ experience.

The treatment was suspended for 2 months if the prepubertal subjects had an IGF-1 level ≥2.5 SD of same-sex and same-age children at 2 consecutive assessments (≥3 SD for adolescent patients), and the treatment was discontinued for prepubertal subjects who remained IGF-1 level ≥2.5 SD (≥3 SD for adolescent patients) (23).

Follow-up and Outcomes

The first visit of this posttrial study was conducted on the same day as the final visit for the phase 4 clinical trial; follow-up was conducted every 3 months thereafter. The clinical symptoms and signs, thyroid function, glucose metabolism (fasting blood glucose and fasting insulin), IGF-1, IGFBP-3, and eye fundus, if necessary, were examined every 3 months. A radiograph examination of bone age, routine blood and urine tests (eg, liver and kidney function), hemoglobin A1c, and blood lipids was performed every 6 months. The BA was evaluated using the TW3 method or the G-P method assigned by designated personnel at each clinical center. After the study, the radiographs was sent to a designated person for accurate analysis using the TW3 method. There was no strict control over the dates of each patient's visits, so blood was drawn at each assessment between 2 days before and 2 days after the last injection. IGF1 serum concentrations for patients can be either peaks or troughs (12).

The primary effectiveness outcome was the height standard deviation score (Ht SDS) after 12, 24, and 36 months from baseline (entry to the original trials). The Ht SDS was determined as (height at evaluation time point – average height of children of same age and sex)/(SD of height of children of same age and sex). The secondary effectiveness outcomes included annualized HV, serum IGF-1 SD score (IGF-1 SDS), bone maturity, and IGF-1/IGFBP-3 molar ratio. Annualized HV at 12, 24, and 36 months was calculated from linear regression of height against time using all available height measurements from the previous 12 months. IGF-1 SDS was defined as (actual IGF-1 concentration – median IGF-1 concentration of normal children of same age and sex)/(SD of IGF-1 concentration of normal children of same age and sex). Bone maturity was calculated as BA/CA. In addition, safety was examined to assess any possible AEs associated with GH treatment.

Statistical Analysis

All statistical analyses were performed using SAS 9.4 (SAS Institute, Inc., Cary, NC, USA). For categorical variables, the number of cases and frequency were statistically described. A paired t test or signed-rank test was used for quantitative data comparison before and after the treatment, and a χ² test (including Cochran-Mantel-Haenszel χ² test) or Fisher exact probability test was used for subgroups comparison. The multiple linear regression analysis was used to investigate the associated factor of changes in Ht SDS from baseline (ΔHt SDS), which included the indicators with significant differences in the 1-way ANOVA. All statistical tests used 2-sided tests, and P < 0.05 was considered statistically significant.

Subgroup analysis of interest was performed by average dose of PEG-rhGH. The average dose of 36 months (including the trial period and the expansion period) was calculated. Patients were subgrouped into the high-dose subgroup (0.20 mg/kg/wk) and the low-dose subgroup (0.10-<0.20 mg/kg/wk). Other subgroup analysis was performed by age (aged < 6, 6-8, and ≥8 years), bone age (aged < 5, 5-7, and ≥7 years), GH peak value (<5, 5-7, and ≥7 ng/mL), and IGF-1 SDS (<–2, −2-0, and ≥0).

Results

Baseline Characteristics

A total of 2768 patients were included in four phase 4 clinical trials, and 1598 were excluded due to a >8-week time between the end of phase 4 clinical trial and the screening of this study or received other GH products during this period. Thus, a total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup (Fig. 1). The characteristics at entry to the original trial who continued in this posttrial observation are shown in Table 1. The average age of all patients was 7.26 ± 2.55 years, and 756 (64.62%) were male.

Figure 1.

Flow chart of the post-trial study. PEG-rhGH, polyethylene glycol recombinant human GH.

Table 1.

Baseline characteristics of patients

Variable	Total (N = 1170)	High-dose group (N = 642)	Low-dose group (N = 528)	P value
Age, y	7.26 ± 2.55	7.32 ± 2.56	7.17 ± 2.54	0.363
Sex, n (%)				0.886
Male	756 (64.62%)	416 (64.80%)	340 (64.39%)
Female	414 (35.38%)	226 (35.20%)	188 (35.61%)
Previous GH therapy, n (%)				0.276
No	1144 (97.78%)	625 (97.35%)	519 (98.30%)
Yes	26 (2.22%)	17 (2.65%)	9 (1.70%)
Baseline height, cm	110.44 ± 13.32	110.92 ± 13.37	109.85 ± 13.25	0.265
Baseline weight, kg	19.45 ± 6.09	19.49 ± 6.10	19.40 ± 6.07	0.829
Baseline BMI, kg/m2	15.59 ± 2.01	15.47 ± 1.91	15.73 ± 2.13	0.053
Baseline GH peak value, ng/mL	5.85 ± 2.55	6.00 ± 2.47	5.66 ± 2.62	0.041
Baseline growth rate, cm/y	3.07 ± 1.56	3.21 ± 1.52	2.91 ± 1.59	0.026
Baseline BA, y	5.67 ± 2.28	5.86 ± 2.26	5.45 ± 2.28	0.006
BMI-SDS	−0.24 ± 1.13	−0.33 ± 1.10	−0.14 ± 1.16	0.004
Ht SDS	−2.38 ± 0.92	−2.36 ± 0.90	−2.40 ± 0.95	0.552
IGF-1 SDS	−0.75 ± 1.15	−0.77 ± 1.17	−0.72 ± 1.14	0.338
BA/CA	0.78 ± 0.15	0.79 ± 0.15	0.77 ± 0.15	0.006
HV, cm/y	3.07 ± 1.56	3.21 ± 1.52	2.91 ± 1.59	0.026

Data are presented as mean ± SD or as n (%).

Abbreviations: BA, bone age; BMI, body mass index; CA, chronological age; Ht, height; HV, height velocity; SDS, SD score.

There were no significant differences in baseline height, weight, body mass index (BMI), Ht SDS, and IGF-1 SDS between the 2 dose subgroups (all P > 0.05). Nevertheless, the baseline of GH peak value (P = 0.041), growth rate (P = 0.026), and BA (P = 0.006), BMI-SDS (P = 0.004), BA/CA (P = 0.006), and HV (P = 0.026) demonstrated statistically significant differences between the 2 dose subgroups (Table 1). The average doses were 0.15 ± 0.03 at month 6, 0.16 ± 0.02 at month 12, 0.17 ± 0.02 at month 24, and 0.17 ± 0.02 mg/kg/wk at month 36 in the low-dose subgroup (Fig. 2).

Figure 2.

The average dose of PEG-rhGH in the 2 dose subgroups. PEG-rhGH, polyethylene glycol recombinant human GH.

Effectiveness of Long-term PEG-rhGH

The Ht SDS improved significantly after treatment in the total population (P < 0.0001). The ΔHt SDS at 6 months, 12 months, 24 months, and 36 months was 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, and 1.63 ± 0.75, respectively (Fig. 3A).

Figure 3.

Changes in Ht SDS from baseline in the total population (A) and between the 2 dose subgroups (B). Data are presented as mean ± SEM (*P < 0.05; **P < 0.01; ***P < 0.01). Ht SDS, height SD score; SEM, standard error of mean.

After 6 months, 12 months, 24 months, and 36 months, ΔHV was 7.47 ± 3.16, 6.79 ± 2.66, 4.93 ± 2.37, and 4.13 ± 2.28, respectively (Fig. 4A). The mean IGF1 SDS at 6 months, 12 months, 24 months, and 36 months was 0.96 ± 1.96, 1.13 ± 2.07, 1.47 ± 2.02, 1.53 ± 1.82, respectively (Fig. 5A). Regarding bone maturity, the mean BA/CA ratio was increased numerically, with values of 0.78 ± 0.15, 0.80 ± 0.15, 0.81 ± 0.15, 0.86 ± 0.14, and 0.89 ± 0.14 at baseline, 6 months, 12 months, 24 months, and 36 months, respectively. The mean IGF-1/IGFBP-3 molar ratio at baseline, 6 months, 12 months, 24 months, and 36 months was 0.10 ± 0.04, 0.16 ± 0.06, 0.17 ± 0.07, 0.19 ± 0.09, and 0.19 ± 0.06, respectively.

Figure 4.

Changes in HV from baseline in the total population (A) and between the 2 dose subgroups (B). Data are presented as mean ± SEM (*P < 0.05). HV, height velocity; SEM, standard error of mean.

Figure 5.

Mean IGF1 SDS over time in the total population (A) and between the 2 dose subgroups (B). Data are presented as mean ± SEM (**P < 0.01). SDS, SD score; SEM, standard error of mean.

Subgroup Analysis of Effectiveness by Dose

The ΔHt SDS was significantly improved in the high-dose subgroup than in the low-dose subgroup at 6 months (0.57 ± 0.31 vs 0.48 ± 0.30; P < 0.001), 12 months (0.93 ± 0.49 vs 0.82 ± 0.45; P = 0.001), 24 months (1.40 ± 0.63 vs 1.27 ± 0.62; P = 0.006) and 36 months (1.70 ± 0.76 vs 1.55 ± 0.73; P = 0.025) after treatment (Fig. 3B).

At 6 months, the ΔHV of the high-dose subgroup was significantly higher than that of the low-dose subgroup (7.68 ± 3.09 vs 7.22 ± 3.23, P = 0.018), whereas at 24 months, it was significantly lower (4.79 ± 2.39 vs 5.18 ± 2.33; P = 0.016). There was no significance of ΔHV between 2 subgroups at 12 months and 36 months (both P > 0.05; Fig. 4B). The mean IGF1 SDS between the 2 dose subgroups was significantly different only at 6 months (1.20 ± 1.96 vs 0.71 ± 1.93; P = 0.016; Fig. 5B). The mean BA/CA ratio was significantly higher in the high-dose subgroup than in the low-dose subgroup at baseline, 6 months, and 36 months (all P < 0.05). Moreover, the mean IGF-1/IGFBP-3 molar ratio was significantly different between 2 dose subgroups at baseline and 6 months (all P < 0.05).

Other Subgroup Analyses of Effectiveness

The improvement of ΔHt SDS in the group aged <6 years was greater than that of the 6- to 8-year-old group and the group aged ≥8 years (all P < 0.05), and the 6- to 8-year-old group demonstrated more pronounced improvement than the group aged ≥8 years during the treatment (all P < 0.05; Supplementary Fig. S1 (22)). Besides, the ΔHt SDS of the bone age the group aged <5 years after treatment was significantly greater than that of the 5- to 7-year-old group and the group aged ≥7 years (all P < 0.05; Supplementary Fig. S2 (22)). After 12, 24, and 36 months of treatment, the ΔHt SDS of the GH peak value <5 ng/mL group was significantly greater than that of the 5 to 7 ng/mL group and that of ≥7 ng/mL group (all P < 0.05), and there is no significant difference between the 5 to 7 ng/mL group and the ≥7 ng/mL group (all P > 0.05; Supplementary Fig. S3 (22)). Moreover, the ΔHt SDS of the IGF-1 SDS <−2 group was significantly greater than that of the −2-0 group and ≥0 group (all P < 0.05; Supplementary Fig. S4 (22)).

A multivariate regression analysis revealed that only the age at treatment initiation and baseline BMI SDS was independently associated with the Ht SDS throughout the treatment period (Supplementary Table S2 (22)).

Safety Profiles

A total of 627 (53.59%) and 12 (1.03%) patients developed AEs and serious AEs (Supplementary Table S3 (22)). There was no serious AE related to the treatment, and no AEs leading to treatment discontinuation or death occurred. The most common AEs were upper respiratory tract infection (18.72%), upper respiratory tract viral infection (10.00%), fever (9.83%), and cough (6.32%). The most common AEs of interest was hypothyroidism (2.56%), followed by transient edema (1.88%) and elevated IGF (1.54%).

About one-half of the edema (14/31) occurred within a week of starting the treatment; the latest case occurred 6 months after the treatment, and all the edema disappeared within a week. A total of 15 subjects reported mild scoliosis, with an average onset time of 8 months after treatment (13 cases occurred 6 months after the treatment, 2 cases occurred 18 months after the treatment). After scoliosis onset, the subjects continued taking the medication for 6 to 30 months, with 8 cases remaining on the medication for 36 months. No mild scoliosis was aggravated. There were 6 subjects who had allergic reactions, 3 who developed skin rashes, and 3 who experienced abdominal pain, all of which were mild and resolved within 1 week. There were 2 cases of microscopic hematuria reported 6 months after administration of the medication, but neither subject showed symptoms (the renal Doppler ultrasound was normal in 1 case, and the other had a history of kidney stones before treatment). Both cases continued the treatment for 36 months. One patient experienced mild lipoatrophy at the injection site after receiving the drug for 5 months. However, after 2 weeks of suspension, the patient recovered and continued treatment for 36 months.

A total of 21 patients experienced hypothyroidism. The total T4, T3, and TSH changes between the 2 subgroups did not differ significantly during the 36 months of treatment (all P > 0.05). The average TSH levels of the 2 subgroups were within the normal range. No patient reported diabetes; and no abnormalities in insulin, glycosylated hemoglobin, blood or urine routine, and liver function were observed.

The incidence of AEs was 51.87% in the high-dose subgroup and 55.68% in the low-dose subgroup (P = 0.193). Moreover, there was no difference in the incidence of serious AEs between the 2 dose subgroups (high-dose subgroup: 6 [0.93%] vs low-dose subgroup: 6 [1.14%], P = 0.733).

Discussion

The evidence of long-term, real-world effectiveness and safety of PEG-rhGH in treating children with GHD was limited. This study enrolled children with GHD from four phase 4 trials and examined safety and efficacy of PEG-rhGH following a 30-month extension period. Our results demonstrated that PEG-rhGH showed long-term effectiveness in GHD regarding Ht SDS, HV, and bone maturity. Besides, both the high dose and low dose of PEG-rhGH improved patients’ clinical outcomes, whereas the high-dose subgroup might show additional benefit than the low-dose subgroup. The PEG-rhGH was well tolerated, with few serious AEs during the long-term treatment. To the best of our knowledge, this study was the long-acting GH study with the largest number of participants and the longest follow-up time in China. In addition, all regions of China were represented in this study, which might reflect the Chinese treatment status of children with GHD.

The efficacy and safety of long-acting GH preparations have been widely confirmed in the clinical trial, and some of them have been approved for the treatment of GHD (24, 25). As the first approved long-acting GH available in China, PEG-rhGH (Jintrolong) in previous trials demonstrated its efficacy and safety in treating children with GHD regarding HV and Ht SDS. Thornton et al (26) reported that Ht SDS significantly increased from baseline to week 52 in the weekly long-acting rhGH group. Luo et al (12) reported significantly greater improvement in the Ht SDS associated with Jintrolong throughout treatment. Moreover, PEG-rhGH was studied in four phase 4 clinical trials in several Chinese cities in 2014 with a large sample size to evaluate its effectiveness and safety as a treatment for children with GHD (17-19). In this study, we evaluated the long-term efficacy and safety of PEG-rhGH. The overall curative effect observed in the present extension study is comparable with the long-term observed curative effect of other rhGH treatment of GHD in terms of overall height improvement, and HV (12, 26-29).

Jiang et al (19) also found Ht SDS, HV, and IGF-1 SDS improved more significantly with high-dose PEG-rhGH. Chen et al (17) demonstrated that PEG-rhGH in the 0.1 to 0.2 mg/kg/wk group was effective for patients with GHD, whereas the 0.2 mg/kg/wk group showed preferred outcomes. Comparable findings were founded in the study of Moore et al, who stated that HV and ΔHt SDS have a direct relationship to dose (30). Consistently, though there was improvement in the overall height in both dose subgroups compared with the baseline, the improvement is significantly greater in the 0.2 mg/kg/wk than the 0.1 to <0.2 mg/kg/wk group in this study. In addition to dose, the frequency of PEG-rhGH preparations has also been investigated. Sun et al compared the outcomes of patients with GHD treated with weekly or biweekly PEG-rhGH. The study failed to demonstrate the noninferiority of biweekly PEG-rhGH to weekly PEG-rhGH (18).

In this study, we found that the younger the initial treatment age, the more pronounced the improvement of Ht SDS, which agrees with a previous study that reported significant height improvement occurring in all age groups after 1 year of GH treatment, but final adult height was more significant when the treatment was initiated <8 years of age (27). Our findings indicate that the Ht SDS after treatment is permanently affected by baseline age and follow-up period. Therefore, the longer the follow-up period, the greater the influence of these 2 factors.

PEG-rhGH was also shown to be safe and tolerable with few AEs or local injection responses in this study, which agrees with the study findings of Guan et al and other studies (13, 31-33). None of our patients developed serious AEs related to the treatment, such as diabetes, glycosylated hemoglobin, blood or urine changes, and liver function abnormalities, and no AEs leading to treatment discontinuation or death occurred. Similarly, Wang et al reported no significant impact of PEG-rhGH on glucose and lipid metabolism in children with GHD (5). On the contrary, Pellegrin et al reported that conventional replacement therapy could increase glycated hemoglobin A1c and insulin resistance after 1 year of therapy, regardless of the rhGH dosage, although they neither worsened significantly in the following 2 years nor were associated with overt diabetes (34). Although almost half of the edema developed within a week (14/31), and the last occurred 6 months after medication was started, all of the edema cleared within a week. In addition, only 6 subjects developed allergic reactions, 3 developed skin rashes, and 3 developed abdominal pain, all of which were mild and fully recovered within a week. Hypothyroidism was the most common AE developed in 21 cases. Yao et al also reported that GH therapy might affect thyroid hormone metabolism in patients with GHD. Therefore, they recommend regularly monitoring thyroid function in patients GHD to identify any abnormal thyroid function at an early stage (35). In spite of this, the average TSH levels in the present study were within normal limits, and the influence of GH on thyroid hormone metabolism should be further investigated.

This study has some limitations. Confounding factors cannot be avoided in prospective real-world studies; thus, they were corrected by multivariate analysis. Specifically, the measurement timing of IGF-1 was not prespecified, leading to a possible bias when interpreting the results of IGF-1 comparison between low- and high-dose groups. However, consistent with previous phase 2 and 3 trials (12), we assumed the distribution of troughs or peaks concentration of IGF-1 was random, which could be verified in future studies. Besides, the possible influence of puberty was not analyzed because of not having enough available data. Nonetheless, this is a reasonably lengthy phase 4 clinical trial with at least 36 months of follow-up.

In conclusion, this study further confirmed the long-term effectiveness and safety of PEG-rhGH treatment in children with GHD in a real-world setting. Besides, both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.

Abbreviations

AE

adverse event

BA

bone age

BMI

body mass index

CA

chronological age

GHD

GH deficiency

Ht SDS

height SD score

HV

height velocity

PEG

polyethylene glycol

rhGH

recombinant human GH

Funding

This study was supported by The National Key Research and Development Program of China is funded by Ministry of Science and Technology of the People's Republic of China (2018YFC1002400) and The Special Science and Technology Major Project of Hubei Province is funded by Hubei Provincial Science and Technology Department (ZDZX2020000020).

Author Contributions

X.L. had full access to all of the data in the study and take responsibility for the integrity and accuracy of the data. Concept and design: X.L. and J.F. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: L.H., K.H., and X.L. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: P.Y., L.H., and X.L. Obtained funding: X.L. Administrative, technical, or material support: X.L., J.F., C.G., and F.L. Supervision: X.L., J.F., C.G., and F.L.

Conflict of Interest

The corresponding author obtained the relevant information from all co-authors. The authors declare that there is no conflict of interest.

Data Availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Clinical Trial Information

NCT03290235.