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)
Author:
Brettell ElizabethORCID, Högler Wolfgang, Woolley Rebecca, Cummins Carole, Mathers Jonathan, Oppong Raymond, Roy Laura, Khan Adam, Hunt Charmaine, Dattani Mehul, Ong Ken, Donaldson Malcolm, Harris Victoria, Maghnie Mohamad, Gregory John, Auguste Peter, Binder Gerhard, Gambol Carrol, Dhamaraj Poonam, Gevers Evelien, Saraff Vrinda, Clayton Peter, Randell Tabitha, Mushtaq Talat, Cheetham Timothy, Davies Justin, Abid Noina, Khairi Ranna El, Kapelari Klaus, Gottardi-Butturini Elena, Reiterer-Fröhlich Elke, Bonfig Walter,
Abstract
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
Funder
Health Technology Assessment Programme
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Medicine (miscellaneous)
Reference34 articles.
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