Safety and Effectiveness of Recombinant Human Growth Hormone in Children with Turner Syndrome: Data from the PATRO Children Study.
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ABSTRACT: Introduction
PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS).Methods
The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness.Results
As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7-18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was -2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of -2.02 (0.9).Conclusion
These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.
SUBMITTER: Backeljauw P
PROVIDER: S-EPMC8491505 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Single-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations.Children with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification.The children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes - SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 ?g/L on GH stimulation test), however, in severe GHD (?4 ?g/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR).The PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use.
| S-EPMC5097129 | biostudies-literature
Project description:BackgroundShort stature is the most consistent characteristic feature of Turner syndrome (TS). To improve final heights of children with TS effectively, it is important to provide them with early and appropriate treatment using growth hormone (GH). The objective of this study was to assess the efficacy and safety of a new recombinant human GH, Growtropin®-II (DA-3002, Dong-A ST Co., Ltd) versus a comparator (Genotropin®, Pfizer Inc.) for Korean children with TS.MethodsThis open-label, active-controlled, parallel-group, randomized controlled phase III trial was conducted at 11 hospitals in Korea. Eligible patients (n = 58) were randomized to two groups: 1) DA-3002 group (administrated with DA-3002 at 0.14 IU [0.0450-0.050 mg] /kg/day); and 2) comparator group (administrated with the comparator at 0.14 IU [0.0450-0.050 mg] /kg/day).ResultsThe change from baseline in annualized height velocity (HV) after a 52-week treatment period was 4.15 ± 0.30 cm/year in the DA-3002 group and 4.34 ± 0.29 cm/year in the comparator group. The lower bound of 95% two-sided confidence interval for group difference in the change of annualized HV (- 1.02) satisfied the non-inferiority margin (- 1.5). The change in height standard deviation score (HtSDS) at 52-week was 0.70 ± 0.23 for the DA-3002 group and 0.66 ± 0.39 for the comparator group, showing no significant (p = 0.685) difference between the two groups. The change of skeletal maturity defined as change in bone age/change in chronological age between the two groups was not significantly different (1.25 ± 0.58 for the DA-3002 group and 1.47 ± 0.45 for the comparator group, p = 0.134). Changes from baseline in serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after 52 weeks of treatment did not differ significantly between the two groups (p = 0.565 and p = 0.388, respectively) either. The occurrence of adverse events was not statistically different between groups.ConclusionsThis study demonstrates that the efficacy and safety of GH treatment with DA-3002 in children with TS are comparable with those of the comparator. It is expected to analysis the long-term effect of DA-3002 on the increase of final adult height in children with TS and possible late-onset complications in the future.Trial registrationThe study was registered at ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT01813630 (19/03/2013).
| S-EPMC8662840 | biostudies-literature
Project description:BackgroundPhelan-McDermid syndrome (PMS), also known as the 22q13. 3 deletion syndrome, is a rare neurodevelopmental syndrome with approximately 2,800 patients reported worldwide. Previous pilot study demonstrated that IGF-1 could significantly improve in both social impairment and restrictive behaviors of the patients. However, most of the patients in the developing countries like China cannot afford the high cost of using IGF-1. Our research team speculated that rhGH might serve as a low-cost and more accessible treatment for PMS. Therefore, the purpose of this open-label, cross-over, pilot study was to further investigate the safety and efficiency of rhGH in patients with PMS.MethodsA total of six children with PMS were enrolled in in this open-label, cross-over, pilot study. The children were randomly divided into two different groups. Group A received placebo followed by rhGH, while group B was treated with rhGH first. Neuropsychological and behavior assessments of the patients were performed before the stage I of study and 3 months after the intervention of stage I. After a 4-week period of washout, these assessments were conducted again before the stage II of study and 3 months after the intervention of stage II. Serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding-protein (IGFBP)-3 were also evaluated monthly during the intervention phases of the pilot study.ResultsCompared with the placebo, rhGH treatment significantly decreased subscale scores of GDS (P < 0.0085) and trended to improve the total scores of GDS (P < 0.05), while the total scores and subscale scores of SC-ABC significantly decreased (P < 0.0085) following 3-months rhGH treatment. The similar results were also observed in comparison with baseline. Compared with the baseline, the level of serum IGF-1 and IGFBP-3 increased significantly (P < 0.05) following 3-months rhGH treatment, while the placebo group had no significant impact on serum IGF-1 and IGFBP-3 (P > 0.05). One child developed skin allergy the day after the first rhGH treatment, which were resolved later.ConclusionsIn summary, this pilot study involving six PMS children patients reveals that rhGH has a positive treatment effect on PMS. These results encourage the undertaking of a large, randomized placebo-controlled trial to conclusively prove rhGH efficacy and tolerability in PMS, thereby promoting it as a low-cost, more accessible treatment for PMS, as compared to IGF-1.
| S-EPMC8888442 | biostudies-literature
Project description: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.
| S-EPMC8655095 | biostudies-literature
Project description:There are limited long-term randomized controlled trials of growth hormone (GH) supplementation to adult height and few published reports of the health-related quality of life (HRQOL) following treatment. The present follow-up study of young adults from a long-term controlled trial of GH treatment in patients with Turner syndrome (TS) yielded data to examine whether GH supplementation resulted in a higher HRQOL (either due to taller stature or from the knowledge that active treatment and not placebo had been received) or alternatively a lower HRQOL (due to medicalization from years of injections).The original trial randomized 154 Canadian girls with TS aged 7-13 years from 13 centres to receive either long-term GH injections at the pharmacologic dose of 0.3 mg/kg/week or to receive no injections; estrogen prescription for induction of puberty was standardized. Patients were eligible for the follow-up study if they were at least 16 years old at the time of follow-up. The instrument used to study HRQOL was the SF-36, summarized into physical and mental component scales (PCS and MCS); higher scores indicate better HRQOL.Thirty-four of the 48 eligible participants (71%) consented to participate; data were missing for one patient. Both groups (GH and no treatment) had normal HRQOL at this post-treatment assessment. The GH group had a (mean ± SD) PCS score of 56 ± 5; the untreated group 58 ± 4; mean score for 16-24 year old females in the general population 53.5 ± 6.9. The GH group had a mean MCS score of 52 ± 6; the untreated group 49 ± 13; mean score for 16-24 year old females in the general population 49.6 ± 9.8. Secondary analyses showed no relationship between HRQOL and height.We found no benefit or adverse effect on HRQOL either from receiving or not receiving growth hormone injections in a long-term randomized controlled trial, confirming larger observational studies. We suggest that it remains ethically acceptable as well as necessary to maintain a long-term untreated control group to estimate the effects of pharmacological agents to manipulate adult height. Young adult women with TS have normal HRQOL suggesting that they adjust well to their challenges in life.ClinicalTrials.gov Identifier NCT00191113.
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Project description:Objective: Polyethylene glycol recombinant human growth hormone (PEG-rhGH, Jintrolong®) is the first long-acting rhGH preparation that is approved to treat children with growth hormone deficiency (GHD) in China. Clinical experience with dose selections of PEG-rhGH is scarce. The present study compared the efficacy and safety of a lower dose to increase dosing regimens of PEG-rhGH treatment. Methods: A multicenter, randomized, open-label, dose-comparison clinical study was conducted to compare the improvements in the height standard deviation score (Ht SDS), height velocity (HV), insulin-like growth factor-1 (IGF-1) SDS, and safety profiles of children with GHD who are treated with 0.2 mg/kg/week of PEG-rhGH dose or 0.14 mg/kg/week for 26 weeks. Results: Ht SDS, HV, and IGF-1 SDS increased significantly after PEG-rhGH treatment in the two dose groups (p < 0.05). The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). Ht SDS improvement in low-dose group was not non-inferiority to that in the high-dose group (p = 0.2987). The incidences of adverse events were comparable between the two groups. Conclusion: The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). PEG-rhGH at the dose of 0.14 mg/kg/week was effective and safe for children with GHD. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02908958.
| S-EPMC9402941 | biostudies-literature
Project description:Study on long-acting growth hormone (LAGH) therapy in Turner syndrome (TS) is a 2-year retrospective study including patients diagnosed with TS from 2018-2021. Patients were divided into four groups: Group 1 to 4 were low dose (0.1 mg/kg/ w), high-dose (0.2 mg/kg/w) LAGH, daily GH (0.38 mg/kg/w), and untreated control. The efficacy and safety data were analyzed. Seventy-five TS cases with the age 7.9±2.9 years and the bone age 6.8±2.8 years were recruited. In year 1: The change of height standard deviation score (ΔHtSDS) and height velocity (HV) in Group 2 were comparable to Group 3, both two groups were higher than Group 1. ΔHtSDS and HV in all GH treatment group were higher than untreated group. IGF1 increased in all treatment groups, only 4 cases had IGF1>3 SD. In year 2: ΔHtSDS and HV in Group 2 and 3 were comparable. Five cases had IGF1>3 SD. Correlation analysis for LAGH efficacy at year 1 indicated that baseline variables correlated with ΔHtSDS include: GH dose, CA (chronological age), and bone age (BA). The HV was positively correlated with baseline GH dose, HtSDS, IGF-1SDS and negatively correlated with baseline CA, BA, and BMI. No GH-related serious adverse effects were observed. The high-dose LAGH treatment in TS patients is effective and safe as daily GH for 2 years. The favorable prognosis factors include sufficient GH dose and early treatment. IGF1 monitoring and weight control are important.
| S-EPMC9192150 | biostudies-literature
Project description:BackgroundThe final adult height of untreated girls aged up to 18 years with Turner syndrome (TS) is approximately 20 cm shorter compared with healthy females. Treatment with growth hormone (GH) increases the adult height of people with TS. The effects of adding the androgen, oxandrolone, in addition to GH are unclear. Therefore, we conducted this systematic review to investigate the benefits and harms of oxandrolone as an adjuvant therapy for people with TS treated with GH.ObjectivesTo assess the effects of oxandrolone on growth hormone-treated girls aged up to 18 years with Turner syndrome.Search methodsWe searched CENTRAL, MEDLINE, Embase, the ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was October 2018. We applied no language restrictions.Selection criteriaWe included randomised controlled clinical trials (RCTs) that enrolled girls aged up to 18 years with TS who were treated with GH and oxandrolone compared with GH only treatment.Data collection and analysisThree review authors independently screened titles and abstracts for relevance, selected trials, extracted data and assessed risk of bias. We resolved disagreements by consensus, or by consultation with a fourth review author. We assessed trials for overall certainty of the evidence using the GRADE instrument.Main resultsWe included six trials with 498 participants with TS, 267 participants were randomised to oxandrolone plus GH treatment and 231 participants were randomised to GH only treatment. The individual trial sample size ranged between 22 and 133 participants. The included trials were conducted in 65 different paediatric endocrinology healthcare facilities including clinics, centres, hospitals and academia in the USA and Europe. The duration of interventions ranged between 3 and 7.6 years. The mean age of participants at start of therapy ranged from 9 to 12 years. Overall, we judged only one trial at low risk of bias in all domains and another trial at high risk of bias in most domains. We downgraded the level of evidence mainly because of imprecision (low number of trials, low number of participants or both). Comparing oxandrolone plus GH with GH only for final adult height showed a mean difference (MD) of 2.7 cm in favour of oxandrolone plus GH treatment (95% confidence interval (CI) 1.3 to 4.1; P < 0.001; 5 trials, 270 participants; moderate-quality evidence). The 95% prediction interval ranged between 0.3 cm and 5.1 cm. For adverse events, we based our main analysis on reliable date from two trials with overall low risk of bias. There was no evidence of a difference between oxandrolone plus GH and GH for adverse events (RR 1.81, 95% CI 0.83 to 3.96; P = 0.14; 2 trials, 170 participants; low-quality evidence). Six out of 86 (18.6%) participants receiving oxandrolone plus GH compared with 8/84 (9.5%) participants receiving GH only reported adverse events, mainly signs of virilisation (e.g. deepening of the voice). One trial each investigated the effects of treatments on speech (voice frequency; 88 participants), cognition (51 participants) and psychological status (106 participants). The overall results for these comparisons were inconclusive (very low-quality evidence). No trial reported on health-related quality of life or all-cause mortality.Authors' conclusionsAddition of oxandrolone to the GH therapy led to a modest increase in the final adult height of girls aged up to 18 years with TS. Adverse effects identified included virilising effects such as deepening of the voice, but reporting was inadequate in some trials.
| S-EPMC6820693 | biostudies-literature
Project description:The aim of this study is to investigate the frequency distribution of exon 3 deleted (d3-GHR) genetic polymorphism of growth hormone receptor (GHR) in growth hormone deficient (GHD) Chinese children and to explore the correlation between the growth promoting effects of recombinant human growth hormone (rhGH) and exon 3 genetic polymorphism of GHR in GHD children. In this study, 111 GHD (excluded small for gestational age) children were treated with rhGH (0.20 mg/kg/week) for six months. The body height (Ht), body weight, bone age (BA) and growth velocity (GV) were measured before and after six months of treatment. The d3-GHR and full length GHR (fl-GHR) were analyzed to detect the frequency distribution of two isoforms and their influence on growth promoting effect of rhGH. The results indicated that the frequencies of fl/fl, fl/d3 and d3/d3 GHR genotypes were 67.6%, 18.9% and 13.5%. After six months of GH therapy, there were significant differences of ?GV (?GV: 10.77±3.40 cm/year vs 12.18±3.08 cm/year) (P<0.05) and ?Ht (?Ht: 5.38±1.70 cm vs 6.09±1.54 cm) (P<0.05) were found among GHD children with different genotypes (fl/fl vs fl/d3 and d3/d3). In conclusion, the frequency distribution of three GHR genotypes in 111 Chinese GHD children was different from that reported in Caucasian, indicating the existence of ethnic difference of exon 3 GHR polymorphism. There was a closely relationship between GHR genotypes and growth-promoting effect of rhGH in Chinese GHD children.
| S-EPMC4509300 | biostudies-literature
Project description:Jintrolong® is a long-acting PEGylated recombinant human growth hormone (PEG-rhGH) developed for weekly injection in patients with pediatric growth hormone deficiency (PGHD). Although PEG modification of therapeutic proteins is generally considered safe, concerns persist about the potential for adverse vacuolation in tissues with long-term exposure to PEG-included therapies, particularly in children. We assessed the safety of Jintrolong® in cynomolgus monkeys with an examination of vacuolation in the brain choroid plexus (CP) and reported long-term clinical safety data obtained from children with PGHD. The toxicity of Jintrolong® was assessed following the 52-week administration with doses at 0.3, 1, or 3 mg/kg/week. The levels of vacuolation of CP in animals were dose-dependent and at least partially reversible after a 104- or 157-week recovery period. Vacuolation in the CP epithelium did not lead to obvious subcellular structural or cell functional abnormalities. Compared with the clinical dose of 0.2 mg/kg/week Jintrolong® in PGHD patients, exposure in monkeys under NOAEL 3 mg/kg/week exhibited safety margins greater than 120.5, the predicted minimum dose to induce vacuolation in monkeys is equivalent to 1.29 mg/kg/week in humans, which is 6.45-fold higher than the clinical dose. The safety data acquired in clinical trials for Jintrolong® were also analyzed, which included phase III (360 patients), phase IV (3,000 patients) of 26-week treatment, and a follow-up study with treatment lasting for 3 years. There was no statistically significant difference in the incidence of adverse reactions between the Jintrolong® group and the daily rhGH control group (no PEG), and no new adverse effects (AE) were observed in the Jintrolong® group at the clinical therapeutic dose of 0.2 mg/kg/week.
| S-EPMC9336684 | biostudies-literature