Title: The effects of Growth hormone treatment discontinuation in Adults on Metabolic profile, Body composition and quality Of Life (GAMBOL Study)
Funder: Health Education England

Abstract: Background GHD in adults is characterised by a wide spectrum of manifestations including low mood, poor general well-being, reduced bone remodelling activity, unfavourable body composition, and poor metabolic profile. Treatment with recombinant human GH (rhGH) injection has been shown, in several short-term (4-12 months) studies, to improve these clinical alterations. However, to date, no RCT has consistently demonstrated that rhGH treatment has a sustained beneficial effect on adults with GHD. This, therefore, raises several questions regarding the benefits and risks associated with long-term GH treatment in adults.In clinical practice, some patients question the merit of continuing their long-term rhGH treatment due to the subjective perceived lack of benefits. Currently, there are no guidelines informing the optimal duration of rhGH therapy in adults. As a result, rhGH is prescribed indefinitely without clear evidence on the benefits of long-term treatment. Undoubtedly, an RCT comparing continuation versus discontinuation of rhGH is needed to understand the impacts of discontinuation of long-term rhGH therapy in adults. However, prior to embarking on an RCT, the feasibility of a discontinuation study and the acceptability of randomisation to patients and clinicians need to be assessed. Research aims The aims of this study are:a) to explore the current practice of offering discontinuation of long-term rhGH treatment in adults in the UK; b) to assess the feasibility of conducting an RCT looking at the effects of discontinuing long-term rhGH treatment on the metabolic profile, body composition and quality of life in adults with GHD; c) to explore patients' experience on study participation and understand the barriers or facilitators to retention and non-retention. Methods This is a mixed-method study which will be conducted in three phases over 40 months. Phase 1: Survey of endocrine clinicians using JiscTM online survey. A short questionnaire will be developed to ascertain the current practice of endocrine clinicians in offering discontinuation of long-term rhGH therapy in adult patients with GHD. Phase 2: Interventional feasibility cohort study. This phase will involve recruiting adult patients with GHD (aged more than 25 years), who have been on rhGH treatment for at least 5 years. Two groups of patients will be recruited: (a) an intervention group consisting of 20-25 patients who are willing to discontinue their long-term rhGH treatment for 2 years and (b) a control group consisting of 20-25 patients who agree to be monitored according to the study protocol whilst continuing their rhGH treatment. Phase 3: Qualitative study. Purposive sample of 10-16 participants will be recruited to explore their experiences of participation in the feasibility study. Semi-structured interviews, undertaken in person or by phone, will be audio-recorded, transcribed and analysed using Braun and Clarke's thematic approach, supported by NVivo. Potential benefits This study will provide evidence of current rhGH treatment discontinuation practice in the UK and determine the feasibility of an RCT. Long term, this could promote and underpin the development of the much needed relevant clinical guidance and potentially lead to cost savings for the NHS.

Lay abstract: BackgroundGrowth hormone deficiency (GHD) is a condition that develops when the pituitary gland secretes less growth hormone (GH) than the body needs. In adults, GHD usually occurs when the pituitary gland becomes damaged by tumour (growth), surgery and/or radiotherapy. Over time, adults with GHD begin to feel unwell, experience fatigue and low mood, develop weaker bones, have increased body fat and raised cholesterol levels. Studies of short duration (4-12 months) have shown that treatment with daily GH injections can improve the symptoms experienced by patients with GHD. In the UK, most adults with GHD are prescribed with GH indefinitely. Some adult patients who have been on GH treatment for a long period of time have questioned whether discontinuing their injections has any negative effects; currently this is unclear. Hence, a systematic investigation examining the impact of discontinuing long-term GH treatment is urgently needed. The fairest way to find out whether discontinuation of GH treatment is detrimental, is to monitor the effects on patients by conducting a randomised controlled trial (RCT). However, before a large RCT can be planned, it is important to find out whether existing patients taking GH injections would agree to take part, accept random selection to stop or continue with GH injections and agree to being monitored over a period of time, which is the basis of this proposal.Aims a. To understand how endocrine specialists (physicians and nurses) in the UK are offering a period of GH treatment discontinuation to adult patients with GHD. b. To assess if it would be feasible to conduct an RCT to compare the effects of continuing and discontinuing long-term GH treatment in adult patients with GHD. c. To explore the patients' experiences of participating in the study in order to plan a future RCT.Methods This project proposes a series of studies over three phases: Phase 1: Online survey of endocrine specialists based in UK endocrine centres treating adult patients (over 25 years old) with GHD. Phase 2: Feasibility study involving two groups of adult patients (over 25 years old) with GHD who have been receiving GH treatment for at least 5 years, recruited from two endocrine centres in Birmingham. One group (intervention) will include 20-25 patients who are willing to stop taking GH treatment for 2 years. The second group (control) will include 20-25 patients who wish to continue GH treatment and are willing to undergo study monitoring for 2 years. The monitoring will involve hospital attendance for blood tests and completion of quality of life questionnaires every 6 months, and measurement of body fat, muscle mass and bone mineral density at the beginning and end (2 years) of the study. Participation will be voluntary and if a participant no longer wants to take part, they will automatically resume normal care. Phase 3: Qualitative study involving face-to-face or telephone interviews of 10-16 patients to explore in detail their experiences of participating, completing and/or withdrawing from the study. The interviews will be recorded, transcribed and analysed using a thematic method.Patient and Public Involvement A patient and public advisory group has helped design this proposal and will be involved throughout the research project. The group will review the study protocol, help develop the necessary information resources and inform interpretation of data.Dissemination The results of the study will be submitted for publication targeting leading endocrine journals. The results will also be presented at the Pituitary Foundation meetings and at local, national and international conferences. Members of the patient and public advisory group will also help in sharing the information with the wider public through relevant charities and social media.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE