Dataset Information

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD-a non-inferiority Randomised Controlled Trial (RCT).

ABSTRACT:

Background

Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64-82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved.

Methods/design

Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario.

Discussion

If this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8-4.6 million (€2.05-5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects.

Trial registration

EudraCT number: 2020-001006-39.

SUBMITTER: Brettell E

PROVIDER: S-EPMC10440873 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD-a non-inferiority Randomised Controlled Trial (RCT).

Brettell Elizabeth E Högler Wolfgang W Woolley Rebecca R Cummins Carole C Mathers Jonathan J Oppong Raymond R Roy Laura L Khan Adam A Hunt Charmaine C Dattani Mehul M

Trials 20230821 1

<h4>Background</h4>Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I ...[more]

PMID: 37605233

Similar Datasets

Project description:PurposeThe aim was to evaluate the measurement properties of the Growth Hormone Deficiency-Child Treatment Burden Measure-Child (GHD-CTB-Child), a patient-reported outcome (PRO) for children aged 9 to < 13 years; the Growth Hormone Deficiency-Child Treatment Burden Measure-Observer (GHD-CTB-Observer), an observer-reported outcome (ObsRO) version completed by parents/guardians of children with growth hormone deficiency (GHD) aged 4 to < 9 years; and the Growth Hormone Deficiency-Parent Treatment Burden Measure (GHD-PTB), a PRO that assesses the treatment burden of parents/guardians living with children with GHD aged 4 to < 13 years.MethodsA non-interventional, multi-center, clinic-based study across 30 private practice and large institutional sites in the United States and the United Kingdom was conducted. The sample consisted of 145 pre-pubertal children aged 9 to < 13 years at enrollment with a physician confirmed GHD diagnosis as well as 98 parents/guardians of pre-pubertal younger children aged 4 to < 9 years at enrollment with a physician confirmed GHD diagnosis. The child sample consisted of 59 treatment-naïve children (no prior exposure to growth hormone [GH] therapy; were starting GH treatment at study start per standard of care) and 184 children already maintained on treatment for at least 6 months. At baseline, all study participants completed a paper validation battery including all measures needed to conduct the validation analyses. Follow-up assessments with children in the maintenance group and their caregiver/parent were conducted approximately 2 weeks post-baseline to evaluate test-retest reproducibility. To evaluate sensitivity to change and meaningful change thresholds, treatment-naïve participants in both child and parent/guardian populations were assessed within 1 week of report of minimal improvement between week 3 and week 11 and at week 12. Psychometric analyses were implemented following an a priori statistical analysis plan.ResultsFactor analyses confirmed the a priori conceptual domains and Overall score for each measure (GHD-CTB-Child and GHD-CTB-Observer domains: Physical, Emotional Well-being, and Interference; GHD-PTB domains: Emotional Well-being and Interference). Internal consistency was acceptable for all measures (Cronbach's alpha > 0.70). Test-retest reliability was acceptable for the Physical, Emotional, and Overall domains of the GHD-CTB versions, and the Emotional and Overall domains of the GHD-PTB (intraclass correlation coefficient above 0.70). All but one of the convergent validity hypotheses for the GHD-CTB versions and all hypotheses for the GHD-PTB were proven (r > 0.40). Known-groups validity hypotheses were significant for length of time to administer the injections in the GHD-CTB versions (p < 0.001 for Physical, Emotional, and Overall, and p < 0.01 for Interference) and whether parents/guardians versus child gave the injections more often for the Emotional domain of the GHD-PTB (p < 0.05). Associated effect sizes ranged from -0.27 to -0.57 for GHD-CTB versions and from -0.74 to -0.69 for the GHD-PTB, indicating that the measures are sensitive to change. Anchor-based patient and parent/guardian ratings of severity suggest preliminary meaningful change thresholds (GHD-CTB: 6 points for Physical score, 9 for Emotional, and 6 for Interference; GHD-PTB: 10 points for Emotional and 6 for Interference scores).ConclusionsThe psychometric properties of the GHD-CTB-Child, GHD-CTB-Observer, and GHD-PTB support the validity of their use as PRO and ObsRO measures to capture the experiences associated with treatment burden for children with GHD and their parents/guardians in both clinical and research settings. The Clinicaltrials.gov registration number NCT02580032 was first posted October 20, 2015.

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:Background and aimsHaemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin-angiotensin system (RAS) inhibitors (angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers). Whether stopping RAS inhibitors to minimise hypotension, or continuing RAS inhibitors to avoid hypertension, reduces peri-operative myocardial injury remains unclear.MethodsFrom 31 July 2017 to 1 October 2021, patients aged ≥60 years undergoing elective non-cardiac surgery were randomly assigned to either discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. Renin-angiotensin system inhibitors were withheld for different durations (2-3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury [plasma high-sensitivity troponin-T (hs-TnT) ≥ 15 ng/L within 48 h after surgery, or ≥5 ng/L increase when pre-operative hs-TnT ≥15 ng/L]. Pre-specified adverse haemodynamic events occurring within 48 h of surgery included acute hypertension (>180 mmHg) and hypotension requiring vasoactive therapy.ResultsTwo hundred and sixty-two participants were randomized to continue (n = 132) or stop (n = 130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomized to discontinue, compared with 50 (41.3%) patients who continued, RAS inhibitors [odds ratio (for continuing): 0.77; 95% confidence interval (CI) 0.45-1.31]. Hypertensive adverse events were more frequent when RAS inhibitors were stopped [16 (12.4%)], compared with 7 (5.3%) who continued RAS inhibitors [odds ratio (for continuing): 0.4; 95% CI 0.16-1.00]. Hypotension rates were similar when RAS inhibitors were stopped [12 (9.3%)] or continued [11 (8.4%)].ConclusionsDiscontinuing RAS inhibitors before non-cardiac surgery did not reduce myocardial injury, and could increase the risk of clinically significant acute hypertension. These findings require confirmation in future studies.

Project description:The prevalence of idiopathic oligozoospermia has been esteemed as high as 75%. An Italian survey has reported bilateral testicular hypotrophy in 14% of final-year high school students. The search for determinants of testicular growth in childhood is important for the primary prevention of spermatogenic failure. Therefore, this retrospective study aimed to evaluate the testicular growth and pubertal onset in deficient children treated recombinant human growth hormone (rhGH). To accomplish this, the clinical charts of 93 patients with GH deficiency (GHD) were carefully reviewed. Their mean age at the time of diagnosis was 11.2 ± 2.4 years. rhGH was administered for 44.0 ± 22.4 months, and the onset of puberty was recorded after a mean of 25.8 ± 22.4 months from the first rhGH administration. As expected, serum insulin-like growth factor 1 (IGF1) levels increased significantly after treatment. Before rhGH therapy, the Tanner stage was I in 59 out of 70 boys (84.3%), II in 8/70 (11.4%), III in 3/70 (4.3%). No one was on stage IV or V. The mean Tanner stage was 1.19 ± 0.51. At the last visit, the Tanner stage was I in 8/72 boys (11.1%), II in 6/72 (8.3%), III in 6/72 (8.3%), IV in 16/72 (22.2%), and V in 36/72 (50.0%). After a mean of 44.0 ± 22.4 months of rhGH treatment, the mean Tanner stage was 4.05 ± 1.30. Patients treated with rhGH showed a significant testicular volume (TV) growth over time, whereas no growth was observed in age-matched but not yet treated patients, even when the age was compatible with a spontaneous start of puberty. The multivariate regression analysis showed that the duration of treatment and the mean rhGH dose significantly predicted the percentage of TV increase. In contrast, age, serum FSH, and IGF1 levels, and final rhGH dose did not impact TV growth over time. In conclusion, these findings suggest that GH may play a role in testicular growth and pubertal onset, despite the descriptive nature of this study. Further properly designed studies are needed to confirm these findings. This knowledge may be useful to implement the diagnostic-therapeutic algorithm in case of a lack of testicular growth in childhood.

Dataset Information

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD-a non-inferiority Randomised Controlled Trial (RCT).

Background

Methods/design

Discussion

Trial registration

Publications

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD-a non-inferiority Randomised Controlled Trial (RCT).

Similar Datasets

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