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Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study.

ABSTRACT: 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.

SUBMITTER: Stevens A

PROVIDER: S-EPMC5097129 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study.

Stevens Adam A Murray Philip P Wojcik Jerome J Raelson John J Koledova Ekaterina E Chatelain Pierre P Clayton Peter P

European journal of endocrinology 20160920 6

<h4>Objective</h4>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.<h4>Design and methods</h4>Children with GHD (n = 293) or TS (n = 132) were recruited ret ...[more]

PMID: 27651465

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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).

Project description:ObjectiveThe aim of this study was to perform psychometric testing of the Growth Hormone Deficiency-Child Impact Measure (GHD-CIM): a patient-reported outcome (PRO) for children with GHD aged 9 to < 13 years and an observer-reported outcome (ObsRO) for parents/guardians of children who are unable to answer for themselves.MethodsA non-interventional, multicenter, clinic-based study was conducted in 30 private-practice and large institutional sites in the US and the UK. Psychometric analyses were conducted following an a priori validation statistical analysis plan.ResultsA preliminary examination of the data determined a PRO version for children aged 9 to < 13 years was not psychometrically sound and therefore the decision was made to have only an ObsRO measure of the GHD-CIM, which would be suitable for children aged 4 to < 13 years. The GHD-CIM ObsRO validity analyses included 98 parents/guardians. Factor analyses identified three domains: Physical Functioning (PHYS), Social Well-Being (SWB), and Emotional Well-Being (EWB). Internal consistency reliability was acceptable for all domains and for the overall score (Cronbach's alpha > 0.70), as was test-retest reliability for the SWB, EWB and overall (above 0.70). At least one convergent validity hypotheses for each domain and overall was proven (r > 0.40). Known-groups validity hypotheses for the EWB and SWB domains were significant (p < 0.05). Associated effect sizes ranged from - 0.40 to - 0.58, indicating that the GHD-CIM is sensitive to change. Anchor-based patient and clinician ratings of severity of disease suggest a preliminary minimally important difference of 5 points for the overall score, and 5 for PHYS, 7 for EWB, and 5 for SWB.ConclusionsThe GHD-CIM ObsRO was found to be a reliable and valid measure to assess disease-specific functioning, which will provide a more complete patient-centric picture to the growth hormone therapy experience in children.Trial registrationClinicalTrials.gov NCT02580032, first posted 20 October 2015.

Project description:BackgroundQuantifying the association between adherence and the growth response to growth hormone (GH) treatment is hampered by suboptimal methods of measuring adherence, confounders associated with the growth response, and restriction of the outcome parameters to yearly growth velocities.AimTo investigate the effect of adherence on the two-year growth response to GH treatment in prepubertal children with idiopathic isolated growth hormone deficiency (GHD) participating in the easypod connect observational study (ECOS), a 5-year, Phase IV open-label study to continuously assess real-world adherence via the easypod electronic drug-delivery device.Patients and methodsOutcome measures were change in height standard deviation score (?HSDS), index of responsiveness (IoR), and parameters of two catch-up growth (CUG) curve functions (monomolecular growth curve and second degree polynomial) with adj-HSDS (HSDS minus Target height (TH) SDS) as dependent variable. Inclusion criteria were GHD, naïve to GH treatment, known TH, age <10y in girls and <12y in boys, ?3 measurements, HSDS <-2 at start, complete data on growth and adherence in the first and second year. Linear regression analyses were performed to test the association between adherence (continuous and high vs. low) and the outcome measures, also adjusted for potential clinical confounders (age at start, adj-HSDS at start, birth weight SDS, gestational age (<37 weeks vs ?37 weeks), GH dose, GH max (n = 58)). The formula of IoR already adjusts for confounders.ResultsIn total, 95 patients complied with the inclusion criteria. The strongest associations were found between high adherence in the second year (?91% as cut-off value) and IoR 2y (+0.62), and average adherence and high adherence (?78%) in the first two years and ?HSDS 0-2y (+0.11 SD per 1 injection/week, and +0.34 SD for high vs. low adherence).ConclusionSuboptimal adherence negatively affected the growth response in the first two years of GH treatment.

Project description:BACKGROUND:Cystic fibrosis is an inherited condition causing disease most noticeably in the lungs, digestive tract and pancreas. People with cystic fibrosis often have malnutrition and growth delay. Adequate nutritional supplementation does not improve growth optimally and hence an anabolic agent, recombinant growth hormone, has been proposed as a potential intervention. OBJECTIVES:To evaluate the effectiveness and safety of recombinant human growth hormone therapy in improving lung function, quality of life and clinical status of children and young adults with cystic fibrosis. SEARCH METHODS:We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 15 May 2013.We conducted a search of relevant endocrine journals and proceedings of the Endocrinology Society meetings using Scopus and Proceedings First. Date of latest search: 15 March 2012. SELECTION CRITERIA:Randomised and quasi-randomised controlled trials of all preparations of recombinant growth hormone compared to either no treatment, or placebo, or each other at any dose (high-dose and low-dose) or route and for any duration, in children or young adults aged up to 25 years diagnosed with cystic fibrosis (by sweat test or genetic testing). DATA COLLECTION AND ANALYSIS:Two authors independently screened papers, extracted trial details and assessed their risk of bias. MAIN RESULTS:Four controlled trials were included in this review (with 161 participants in total), each with an unclear risk of bias. Analysis of data obtained from these trials shows improvement in height for all comparisons, but improvements in weight and lean tissue mass were only reported in the comparison of standard dose recombinant growth hormone versus no treatment. There is moderate improvement in one parameter of pulmonary function tests, functional vital capacity (per cent predicted) when comparing standard dose recombinant growth hormone and no treatment. Little evidence was found for improvement in quality of life. An improvement in fasting blood glucose levels was reported when comparing rhGH to placebo only. Exercise capacity improved in participants receiving standard dose recombinant growth hormone versus no treatment, but not for any other comparison. There is insufficient evidence to conclude any changes in hospitalisations, antibiotic use or significant adverse effects. AUTHORS' CONCLUSIONS:Recombinant growth hormone therapy is effective in improving the intermediate outcomes in height, weight and lean tissue mass when compared with no treatment. One measure of pulmonary function test showed moderate improvement. No significant changes in quality of life, clinical status or side-effects were observed in this review. Long-term, well-designed randomised controlled trials of recombinant growth hormone therapy in patients with cystic fibrosis are required prior to evaluation of human growth hormone treatment for routine use in patients.

Dataset Information

Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study.

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Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study.

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