The growth hormone deficiency reversal trial
| ISRCTN | ISRCTN12552768 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12552768 |
| EudraCT/CTIS number | 2020-001006-39 |
| IRAS number | 281209 |
| Secondary identifying numbers | IRAS 281209, HTA - NIHR127468 |
- Submission date
- 16/03/2021
- Registration date
- 18/03/2021
- Last edited
- 12/09/2024
- Recruitment status
- Stopped
- Overall study status
- Stopped
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English Summary
Background and study aims:
Growth hormone (GH) is a hormone essential for normal growth and development. If a child doesn’t have enough GH, the speed of growth is slower and final adult height reduced. Growth hormone deficiency (GHD) is a condition where the pituitary gland doesn’t make enough growth hormone in childhood. GH treatment allows children with GHD to grow normally. GH is given as daily injections continued until the child reaches adult height. GH is usually given for 5-10 years and can cost £10,000-23,000 per patient per year.
Children are tested for GHD by measuring the highest amount of GH in the blood following a test. When GH production is checked after children reach their final height, some children are found to have normal levels of GH; these children therefore no longer have GHD. Some doctors think that this change occurs during puberty. Many pubertal children on GH therapy are assumed to no longer have GHD but doctors usually continue daily GH injections until the child reaches final adult height. Therefore some children continue to have potentially unnecessary, costly daily injections.
The aim of this ‘GHD Reversal’ study is to find out whether certain children 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.
Who can participate?
Children with I-GHD whose stimulated GH levels are found to be normal when tested after they have entered puberty. After giving their consent, these children will be randomised (chosen by 50:50 chance by a computer) to either continue or stop their daily GH injections.
What does the study involve?
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. Children will have 6-monthly trial assessments at their hospitals endocrine clinic where they will have blood samples taken (to look at the level of GH and the lipids in it) and other biometric data (e.g. height, weight) collected. These activities are already done as part of standard care for these children and the trial visits should be matched up to the child's usual visit schedule. At the first and last trial assessments children will have an X-ray of their non-dominant hand, and at some they will be asked to complete a short questionnaire about their quality of life (the CHU-9D questionnaire). At the last trial assessment children will have another GH test.
What are the possible benfits and risks of participating?
If a child is in the group who are not taking growth hormone, this would mean that they no longer need to have daily injections.
If a child is randomised to the group who are continuing with their growth hormone injections they may not directly benefit from taking part in the study, however the information we get from the study may help us to improve the treatment of young people with growth hormone deficiency in the future.
Taking part in this study is very unlikely to cause any child any discomfort or side-effects.
If a child is put in the group who stop their injections of growth hormone then their growth will be monitored closely. At the first sign that a child might be developing another shortage of growth hormone they will be retested and growth hormone treatment restarted.
Where is the study run from?
The Chief Investigator is Professor Mehul Dattani at University College London (UCL). UCL are also the Sponsor. The study is being coordinated by the Birmingham Clinical Trials Unit at the University of Birmingham.
When is the study starting and how long is it expected to run for?
June 2020 to November 2027
Who is funding the study?
National Institute for Health Research - Health Technology Assessment Programme (UK
Who is the main contact?
Professor Mehul Dattani, m.dattani@ucl.ac.uk
Mr Adam Khan, a.r.khan@bham.ac.uk
Contact information
Scientific
UCL Institute of Child Health
30 Guildford Street
London
WC1N 1EH
United Kingdom
 ORCID ID |
0000-0002-0365-5809 |
|---|---|
| Phone | +44 (0)20 7905 2657 |
| m.dattani@ucl.ac.uk |
Public
Birmingham Clinical Trials Unit (BCTU)
Institute of Applied Health Research
College of Medical and Dental Sciences
Public Health Building
University of Birmingham
Birmingham
B15 2TT
United Kingdom
| ORCID ID |
0000-0001-5366-233X |
|---|---|
| Phone | +44 (0)121 415 9131 |
| a.r.khan@bham.ac.uk |
Scientific
Birmingham Clinical Trials Unit (BCTU)
Institute of Applied Health Research
College of Medical and Dental Sciences
Public Health Building
University of Birmingham
Birmingham
B15 2TT
United Kingdom
| GHDReversal@trials.bham.ac.uk |
Study information
| Study design | Multicentre interventional non-inferiority randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Participant information sheet not yet available |
| Scientific title | Effect on final height of discontinuation vs continuation of growth hormone treatment in pubertal children: The Growth Hormone Deficiency Reversal Trial |
| Study acronym | GHD Reversal Trial |
| Study hypothesis | Discontinuation of growth hormone medication (somatropin) at early puberty in children with isolated growth hormone deficiency results in a final height that is no worse than pubertal children who continue taking somatropin until final height is reached. |
| Ethics approval(s) |
Approved 09/04/2022, Wales REC3 (The Caerphilly Suite, Holiday Inn Cardiff North M4/J32, Merthyr Road, Coryton, Cardiff, CF15 7LH, United Kingdom; +44 (0)2922 941107; Wales.REC3@wales.nhs.uk), ref: 22/WA/0005 |
| Condition | Isolated growth hormone deficiency in pubertal children |
| Intervention | Control arm: Standard care - Continuation of growth hormone medication (somatropin) as daily injections, until final height. Treatment will last from the point of randomisation, up until 6 weeks before final assessment (which is variable, as below). Experimental arm: Discontinuation of growth hormone medication (i.e. stopping of daily injections) during early puberty (unless GH treatment is required for clinical reasons) whilst they are in the trial. Participants are randomised 1:1 between the control and experimental arms. Minimisation variables are trial centre, sex and Tanner stage: (B2 (females) or 6-<9 ml testicular volume (males) vs B3 (females) or 9-12 ml testicular volume (males). Randomisation will be provided by a secure online randomisation system at the Birmingham Clinical Trials Unit (BCTU). Follow-up (the same duration in both arms) will continue until each patient reaches their 'near Final Height (FH)'. This is defined as a growth rate of less than 2 cm/year and an X-ray analysis via BoneXpert software, confirming that patients have reached a 'bone age' (a measure of skeletal growth) of 14 in females and 16 in males. It is expected that patients will reach their FH within 36 months, however, this may vary. As such, a standard follow-up duration has not been set for most patients. Follow-up will end for any patients that have not reached FH once the final patient reaches their 36-month assessment, to keep to the trial timeline. |
| Intervention type | Supplement |
| Primary outcome measure | Height (cm) measured in Standard Deviation Score (FH SDS) at end of follow-up |
| Secondary outcome measures | 1. Bone-related: 1.1. Bone age delay measured using BoneXpert X-ray analysis at end of follow-up 1.2. Bone age acceleration measured using BoneXpert X-ray analysis between enrolment and end of follow-up 1.3. Bone health index measured using BoneXpert X-ray analysis at end of follow-up 2. Biochemistry: 2.1. Serum IGF-1 and lipid profiles measured using trial site's usual testing methods at end of follow-up 2.2. Peak stimulated GH measured using insulin tolerance test or argnine test at end of follow-up 3. Adverse events measured using GHD Reversal Trial CRFs over follow-up duration 4. Health Economics: 4.1. Cost per percentage achieving Target Height measured using healthcare contacts costs (captured via GHD Reversal Trial CRFs) over follow-up duration 4.2. Cost per Quality Adjusted Life Year (QALY) gained, measured using CHU-9D questionnaire over follow-up duration 5. Qualitative Research: Trial acceptability (parents, patients and staff); reasons to decline the trial; parent and patient experience of the trial and treatment pathways, measured via interviews with parents, patients and site staff during the pilot phase of the trial |
| Overall study start date | 01/06/2020 |
| Overall study end date | 30/11/2027 |
| Reason abandoned (if study stopped) | Participant recruitment issue |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 8 Years |
| Upper age limit | 17 Years |
| Sex | Both |
| Target number of participants | 138 |
| Total final enrolment | 5 |
| Participant inclusion criteria | 1. Initial diagnosis of I-GHD will have been made by either two GH stimulation tests (peak GH <6.7μg/L) or one abnormal stimulation test with low IGF-1 (below normal range for sex & age), irrespective of sex-hormone priming for GH stimulation tests 2. Children with reversed I-GHD (peak GH ≥6.7 μg/L and a serum IGF-1 within normal reference range for sex and age) and a normal brain MRI (incl. small anterior pituitary) 3. Children in established puberty – Tanner stages B2/3 in girls & 6-12ml testes* in boys (as measured by orchidometer**) 4. Children will have discontinued GH treatment for a minimum of 6 weeks prior to re-testing 5. Children will have remained off GH therapy from time of re-test until randomisation 6. Ability to tolerate the administration of GH therapy 7. Ability to comply with trial schedule and follow up 8. Written informed consent obtained from the patient’s parent/guardian and written assent obtained from patient (where age appropriate). Patients aged 16 years or older will provide their own written informed consent *In the event of discrepancy between the size of an individual’s testicles, the larger testicle should be used **In the event that the size of a patient’s testicle falls between the measuring beads of the orchidometer and it is not clear which bead the testicle is most similar to, the larger bead should be used |
| Participant exclusion criteria | 1. Multiple pituitary hormone deficiency (hypopituitarism) with or without additional pituitary hormone supplementation 2. Known genetic cause of I-GHD 3. Organic GHD (mid-brain tumours, congenital mid-brain malformations, septo-optic dysplasia; radiotherapy to the total body or brain) 4. Ectopic posterior pituitary 5. Other indications for GH therapy 6. Receiving GH treatment during the (minimum 6 week) discontinuation period 7. Receiving prednisolone or dexamethasone for a period of 4 weeks or longer in the time period immediately prior to randomisation 8. Known history of persistent non-compliance with prescribed medication regimens 9. Pregnant or lactating 10. Any malignancy 11. Currently participating in another Clinical Trial of an Investigational Medicinal Product (CTIMP) |
| Recruitment start date | 01/08/2021 |
| Recruitment end date | 09/05/2024 |
Locations
Countries of recruitment
- Austria
- England
- United Kingdom
Study participating centres
London
WC1N 3JH
United Kingdom
Liverpool
L12 2AP
United Kingdom
London
E1 2ES
United Kingdom
Birmingham
B4 6NH
United Kingdom
London
SE5 9RS
United Kingdom
Manchester
M13 9WL
United Kingdom
Norwich
NR4 7UY
United Kingdom
Nottingham
NG7 2UH
United Kingdom
Leeds
LS9 7TF
United Kingdom
Linz
4020 Linz
Austria
Wels
4600 Wels
Austria
Graz
8036 Graz
Austria
Salzburg
5020 Salzburg
Austria
Innsbruck
6020 Innsbruck
Austria
Newcastle
NE7 7DN
United Kingdom
Southampton
SO16 6YD
United Kingdom
Sponsor information
University/education
Gower Street
London
WC1E 6BT
England
United Kingdom
| Phone | +44 (0)207 679 9320 |
|---|---|
| samim.patel@ucl.ac.uk | |
| Website | http://www.ucl.ac.uk/ |
"ROR" |
https://ror.org/02jx3x895 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Health Technology Assessment Programme, HTA
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/11/2028 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | Requests for data generated during this study will be considered by BCTU (to bctudatashare@contacts.bham.ac.uk). Data will typically be available within six months after the primary publication unless it is not possible to share the data (for example: the trial results are to be used as part of a regulatory submission, the release of the data is subject to the approval of a third party who withholds their consent, or BCTU is not the controller of the data). Only scientifically sound proposals from appropriately qualified Research Groups will be considered for data sharing. The request will be reviewed by the BCTU Data Sharing Committee in discussion with the Chief Investigator and, where appropriate (or in absence of the Chief Investigator) any of the following: the Trial Sponsor, the relevant Trial Management Group (TMG), and independent Trial Steering Committee (TSC). A formal Data Sharing Agreement (DSA) may be required between respective organisations once release of the data is approved and before data can be released. Data will be fully de-identified (anonymised) unless the DSA covers transfer of patient identifiable information. Any data transfer will use a secure and encrypted method. |
Editorial Notes
12/09/2024: The following changes were made:
1. Ethics approval added.
2. The link to the study website was updated.
3. Lower and upper age limits (number and units) added.
4. The total final enrolment was added.
5. The recruitment end date was changed from 31/01/2025 to 09/05/2024 and the trial was stopped prematurely as recruitment was not feasible.
06/04/2021: A study contact was added.
16/03/2021: Trial's existence confirmed by the National Institute for Health Research (NIHR) (UK).
