Title: The GHD reversal study
Funder: Department of Health and Social Care

Abstract: Growth hormone (GH) is a hormone essential for normal growth and development, and is produced by the pituitary gland at the base of the brain. GH is transported in the blood all over the body and has many functions; in childhood the most important is growth. If a child does not have enough GH, the speed of growth is much slower and final adult height is reduced. Growth hormone deficiency (GHD) is a condition where the pituitary gland does not make enough growth hormone in childhood. Around 1 in 3500-4000 people in the UK have GHD and approximately 175-200 children born in the UK each year are either born with GHD or develop it later on in life. The cause of most cases of GHD is unknown and these patients are diagnosed as having “idiopathic” GHD. Children can also develop GHD later in life as a result of a brain tumour and its treatment, brain injury or infection. _x000D_ GH treatment allows children with GHD to grow normally. Once other conditions are ruled out, and the diagnosis of “idiopathic” GHD (I-GHD) is made, the doctor can then start GH treatment. GH is given as daily injections under the child’s skin by parents. Currently these daily injections are continued until the child reaches adult height. GH is usually given for 5-10 years and can cost between £10,000-23,000 per patient per year. _x000D_ Children are tested for GHD by measuring the highest amount of GH in the blood following a blood test called a GH stimulation test. When GH production is checked once more after children with I-GHD reach their final adult height, some children are found to have normal levels of GH; these children therefore no longer have GHD. Some doctors think that this change, from GHD to normal, occurs during puberty due to the increase in sex hormones, which are known to increase GH release. Even though many pubertal children currently on GH therapy are assumed to no longer have GHD, doctors usually continue to treat children with daily GH injections until they reach their final adult height. This means that some children must continue to have potentially unnecessary daily injections and this treatment also uses a large amount of NHS time and money. Also, some recent studies suggest that children who produce normal amounts of GH and receive extra GH might develop long-term side-effects such as strokes and bone tumours, although this is by no means certain, and more studies are required. _x000D_ The aim of this ‘GHD reversal’ study is to find out whether certain children with I-GHD can stop their GH injections at puberty and still reach a similar final adult height to those children who continue to have daily GH injections. 16 hospitals will take part in this study. From these hospitals, a total of 138 children with a diagnosis of I-GHD whose stimulated GH levels are found to be normal when tested after they have entered puberty will be invited to take part in this study. After giving their consent, these children (who no longer have GHD) will be randomised (chosen by 50:50 chance by a computer) to either continue or stop their daily GH injections. The study will test whether the children who stop their GH injections reach a similar final adult height to those children that continue their injections. All children will be carefully followed up and any children who stop their GH injections and do not grow normally will be re-tested to see if their GH levels are low, in which case the growth hormone injections will be restarted.

Lay abstract: Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature. It may occur in isolation or combined with other pituitary hormone deficiencies caused by brain tumours, radiotherapy, injury, infection, inflammation, or congenital defects. Prevalence of GHD is 1 in 3500-4000 in the UK and approx. 175-200 children annually will develop GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height. The diagnosis of “isolated GHD (I-GHD)” is made by measuring peak serum GH concentration during a stimulation test. Response to GH stimulation may not be reproducible, and is influenced by body mass index and the use of sex steroids to prime the pituitary. The anterior pituitary is normal/slightly small on brain MRI, and GH therapy is started, given as daily injections usually until final adult height (FH) is reached, often 5-10 years later, and at an annual per-patient cost of £10,000-23,000. However, 26-88% of children with I-GHD outgrow their condition, with normal peak GH at re-testing at FH, questioning the validity of the original diagnosis. Hence, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones. Despite increasing evidence for frequent I-GHD reversal, currently daily GH injections are continued until FH is achieved. Doing so may expose affected children to unnecessary daily injections, with its attendant inconvenience, wastage of substantial NHS resources, and ongoing diagnostic uncertainty about the persistence of I-GHD which may be stressful for the family. Additionally, there is controversy whether children with normal GH secretion who receive high GH doses may be at risk of developing adverse effects, including strokes and bone tumours. Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The 16 tertiary endocrine centres taking part in this study routinely perform a GH re-test in early puberty (approx. 3 years earlier than in other current practice). The proposed study will include 138 children with I-GHD (original peak GH <6.7mcg/L) whose deficiency has reversed on early re-testing. Following consent, children will be randomised to either continue (GH+) or discontinue (GH-) GH therapy. This non-inferiority RCT will assess whether children with early GHD reversal who stop GH therapy (GH-) achieve no worse FH SDS (1° outcome; inferiority margin 0.55 SD), target height-FH, HRQoL and bone health index (2° outcomes) than those continuing GH (GH+). In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario by comparing the proportion of children achieving their sex-specific, mid-parental TH range (lower end of 95%CI) between the GH- and GH+ groups. The cost-effectiveness of early retesting will also be compared separately to traditional late re-testing in a model-based analysis. If this study shows that a significant proportion of children with presumed I-GHD generate enough GH naturally in early puberty to achieve a FH within TH, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide a potential cost saving for the NHS of £1.8-4.6 Million/year in drug costs alone. This new care pathway would also prevent children from unnecessary daily GH injections and consequent unnecessary exposure to adverse effects.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: METABOLIC AND ENDOCRINE