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).
This study could change how we manage growth hormone therapy in children with I-GHD, potentially allowing some to stop treatment safely without affecting their final height.
Where it sits
this study against the rest of the hgh (somatropin) corpusSummary and findings
The GHD Reversal trial investigates the effect of discontinuing growth hormone (GH) treatment versus continuing it in pubertal children with isolated growth hormone deficiency (I-GHD) who have shown early signs of reversal. The study involves 138 children and aims to assess whether those who stop GH therapy achieve non-inferior near final height standard deviation scores compared to those who continue treatment. The primary outcome measures include near final height SDS and various secondary outcomes related to health and cost-effectiveness.
Abstract
<title>Abstract</title> <p>The GHD Reversal trial is a non-inferiority RCT (ISRCTN12552768) funded by the NIHR HTA Programme (NIHR127468) <bold>Background: </bold>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. <bold>Methods/Design: </bold>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 <6.7mcg/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 (1° outcome; inferiority margin 0.55 SD), Target Height (TH) minus near FH , HRQoL, bone health index and lipid profiles (2° outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario. <bold>Discussion: </bold>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.</p>
Background
This paper addresses the clinical question of whether children with isolated growth hormone deficiency (I-GHD) who show signs of reversal during early puberty can safely discontinue growth hormone therapy without compromising their final height. Prior studies have indicated that a significant percentage of children with I-GHD may achieve normal growth without continued treatment. This study is significant as it could lead to changes in treatment protocols and reduce unnecessary medical interventions.
Methods
This is a Phase III, international, multicenter, open-label, randomized controlled trial involving 138 children diagnosed with I-GHD from twelve UK and five Austrian centers. Participants are randomized to either continue or discontinue GH therapy. The primary outcome is the near final height standard deviation score (FH SDS), with a non-inferiority margin set at 0.55 SD. Secondary outcomes include target height, health-related quality of life, bone health index, and lipid profiles.
Results
The primary endpoint is the near FH SDS with an inferiority margin of 0.55 SD. Not reported in abstract.
Interpretation
The findings of this study could align with previous literature suggesting that many children with I-GHD may not require ongoing GH therapy if they demonstrate reversal. However, the clinical significance of the non-inferiority margin and the implications of stopping treatment need careful consideration, especially given the open-label nature of the trial and potential confounding factors. The results could influence clinical practice by reducing unnecessary GH administration in children who are likely to achieve adequate growth naturally.
Key findings
- 1° outcome: near FH SDS with an inferiority margin of 0.55 SD.
- 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.
- Around 500 children are diagnosed with GHD every year in the UK.
Limitations
- open-label design may introduce bias
- multicenter variability in treatment adherence
- reliance on an assumed reversal rate for cost savings