Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05979480 |
| Other study ID # |
RRK7819 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 28, 2023 |
| Est. completion date |
November 30, 2025 |
Study information
| Verified date |
July 2023 |
| Source |
University Hospital Birmingham |
| Contact |
Mr Criseno |
| Phone |
00441213716950 |
| Email |
Sherwin.criseno[@]uhb.nhs.uk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Background Growth hormone (GH) is a hormone produced by the pituitary gland which sits at the
base of the brain. In adults, GH plays an important role in keeping the bones and muscles
healthy, and in regulating the levels of sugar and fat in the body. Growth hormone deficiency
(GHD) is a condition where the pituitary gland does not make as much GH as the body needs.
The most common cause is damage to the pituitary gland due to tumours (growth), surgery or
radiotherapy. In the UK, around 1 in 10,000 adult people have GHD. If left untreated, adults
with GHD may experience tiredness and low mood, develop weaker bones, have increased body fat
and high cholesterol.
Research has shown that treatment with daily GH injections can improve the symptoms
experienced by patients with GHD, but the beneficial effects of GH treatment have only been
studied over a short period of 4 to 12 months. In the UK, most adults with GHD are prescribed
with GH indefinitely. Some adult patients, who have been on GH treatment for a long time,
have wondered what would happen if they stopped taking GH. Will their symptoms come back or
not? At the moment, there is no research evidence that clearly answer this question. Hence, a
systematic investigation is urgently needed to examine what happens when adult patients with
GHD stop taking GH.
Aims The main aim of this study is to establish if it would be feasible to conduct a robust
and systematic study called a randomised control trial (RCT), to compare the effects of
continuing and stopping long-term GH treatment in adult patients with GHD. This study will:
(1) assess whether patients taking GH injection, would agree to take part in a study
involving stopping their GH injection and being monitored over a period of time and (2)
whether patients would be willing to stop or continue their GH injections by chance (random
selection) if accepted in the study.
Methods
This project includes three separate studies:
- Phase 1: Online national survey of UK GHD specialists treating adult patients with GHD.
- Phase 2: Feasibility study involving two groups of adult patients with GHD who have been
receiving GH treatment for at least 5 years. Patients will be recruited from two GHD
specialist 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 their GH treatment and are willing to
undergo monitoring for 2 years. The monitoring will involve blood tests and completing
quality of life questionnaires every 6 months, and measurements of body fat, muscles
mass and bone mineral density at the beginning and at the end of the study.
- Phase 3: Face-to-face or telephone interviews with 10-16 patients to explore in detail
their experiences of participating, completing and/or withdrawing from the study.
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 for participants and assist
with interpretation of the results.
Dissemination The results of the study will be submitted for publication in medical journals
in the field of GHD. 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 about the study with the wider
public through relevant charities and social media.
Description:
1. BACKGROUND
Growth hormone deficiency (GHD) in adults is caused by decreased secretion of growth
hormone (GH) from the pituitary gland (1, 2). This condition is usually caused by a
tumour, surgery and/or radiotherapy involving the pituitary gland (3). Adults with GHD
present with a constellation of several non-specific features including low mood, poor
general well-being, reduced bone mineral density (BMD), increased body fat, increased
cholesterol level and reduced exercise capacity (3, 4, 5). Treatment with recombinant
human growth hormone (GH) injection has been proven, in short-term studies, to improve
the wide spectrum of health issues associated with GHD (6).
In the UK, the National Institute for Health and Care Excellence (NICE) recommends
treating adult patients with GHD with GH until peak bone and muscle mass have been
achieved (estimated to be at around the age of 25 years) (7) . For adults over 25 years
old, the prescribing of GH treatment is based on the NICE criteria which requires
patients to: a) have severe GHD, defined as peak GH response of less than 9 mU/litre
during a GH stimulation test; b) have a perceived impairment of quality of life (QoL),
as demonstrated by a score of at least 11 in the 'Quality of Life - Adult Growth Hormone
Deficiency Assessment' (QoL-AGHDA) questionnaire; c) be receiving appropriate treatment
for any other pituitary hormone deficiencies. The UK population of adult patients with
GHD receiving GH is quite unique and homogenous as they all have severe GHD and poor
quality of life (QoL) prior to commencing the treatment (4). The UK is the only country
in the world that offers GH to adult patients with GHD only after poor QoL scores have
been confirmed by using the QoL-AGHDA questionnaire (1, 4, 6).
In the UK, provided that a 7-point improvement (or higher) on the 25-point QoL-AGHDA
scale is demonstrated during the first 9 months of GH therapy, adult patients with GHD
can continue with their GH treatment long-term (7). However, it remains uncertain if the
beneficial effects of GH therapy are sustained throughout adult life, as robust evidence
on the risks and benefits of long-term GH treatment is limited. Furthermore, the
evidence of improved QoL in adult patients with GHD having GH treatment over placebo has
not been established (6). Anecdotally, clinicians report encountering patients who
question the merit of continuing with long-term GH treatment. Paradoxically, the same
patients are apparently reluctant to stop GH therapy due to fears of return of symptoms
and uncertainty about the short-term and long-term effects of treatment discontinuation.
Consequently, and in the absence of clear evidence and definitive guidance, replacement
therapy with GH continues indefinitely in many adults.
To date, the optimal duration of GH replacement therapy in adults and the consequences
of treatment withdrawal have not been established. There are only few, mainly
short-term, follow-up studies which, however, provide conflicting results. Overall, the
beneficial effects of GH treatment appear to occur during the first year of therapy with
only a few studies reporting sustained benefits up to 5 years (5, 8-10). It is well
established that GH secretion decreases with advancing age and that low GH levels are
even associated with increased longevity and decreased morbidity (11, 12). Currently,
many adults with GHD are receiving GH indefinitely without knowing if continuing or
discontinuing long-term treatment has sustained beneficial or even adverse effects (13,
14). Similarly, reliable data on the impact of discontinuing long-term GH therapy in
adults is practically not available.
2. RATIONALE
Many questions on the effectiveness of long-term treatment with GH in adults remain
unanswered including its optimal duration and the consequences of treatment
discontinuation. The primary aim of this study is to assess the feasibility of
conducting a large-scale multi-centre study to evaluate the effects of discontinuation
of long-term GH therapy on the metabolic profile, body composition and QoL in a cohort
of adult patients with GHD (aged 25 years and over) over a period of 24 months.
Currently, much of the evidence on safety-related issues associated with long-term GH
therapy comes from uncontrolled retrospective, and observational studies, which are
methodologically inferior compared with randomised control trial (RCT) (1, 6). A
critical assessment of data from limited RCTs did not show consistent beneficial effects
of GH therapy in adult patients with GHD compared with placebo (6). In 2016, several
international endocrine societies collectively highlighted the need for carefully
designed and rigorously conducted cohort studies to monitor the safety of long-term GH
therapy (15). Furthermore, treatment of adults with GHD is also associated with
significant health care costs. In the UK, the average annual cost of GH treatment in
adults is estimated to be around £3,350 per patient, with a life-long therapy cost of
between £42,000 and £45,400 (7). Furthermore, the treatment regimen of daily
self-injections can be inconvenient and burdensome for many patients (14, 16).
The current NICE guidance provides clear criteria for commencing GH treatment for adults
with GHD. However, it but does not offer any recommendations on the optimal duration of
GH treatment in adults or if and when discontinuation should be considered.
Consequently, GH replacement therapy tends to be offered indefinitely even when patients
fail to report any sustained benefits from this treatment. Given that GH treatment is
associated with significant health care costs, it is imperative to clearly establish the
clinical and cost-effectiveness of the therapy. A methodologically robust and
well-designed large-scale multi-centre study will contribute this evidence. However,
Medical Research Council guidelines suggest that feasibility studies are required to
test the methodology and establish the specific parameters prior to any full large-scale
multi-centre study (17). The strict criteria for prescribing GH to adults and the
homogeneity of the UK population of adults with GHD, offers an ideal setting to
undertake a robust study.
3. THEORETICAL FRAMEWORK
In clinical practice, some patients question the merit of continuing their long-term GH
treatment due to the subjective perceived lack of benefits. Currently, there are no
guidelines informing the optimal duration of GH therapy in adults. As a result, GH is
prescribed indefinitely without clear evidence on the benefits of long-term treatment.
Undoubtedly, an RCT comparing continuation versus discontinuation of long-term GH
therapy is needed to understand the impacts of treatment discontinuation 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.
In 2018, NHS England stated that 'new research should only be undertaken in areas where
there is a defined evidence gap and the need for the research can be clearly
articulated, and this project accords with that principle (18). The strict criteria for
prescribing GH to adults and the homogeneity of the UK population of adults with GHD,
offers an ideal setting to undertake a robust study. A methodologically robust and
well-designed large-scale multi-centre study will contribute this evidence. However,
Medical Research Council guidelines suggest that feasibility studies are required to
test the methodology and establish the specific parameters prior to any full large-scale
multi-centre study (17).
4. RESEARCH QUESTION/AIM(S)
The primary aim of this study is to assess the feasibility of conducting a large-scale
multi-centre study that will evaluate the effects of discontinuation of long-term GH
therapy on the metabolic profile, body composition and QoL in a cohort of adult patients
with GHD (aged 25 years and over) over a period of 24 months. In the conduct of this
study, the following questions are anticipated to be answered:
- Is it feasible to conduct a large multi-centre study on the effects of
discontinuation of long-term GH treatment in adults?
- Is it feasible to recruit and retain patients into the study?
- What are the factors influencing recruitment, retention and drop out?
- What are the patients' views about being randomised into a discontinuation or a
continuation group?
4.1 Objectives
The main objectives of this study are:
1. Phase 1: to understand the current practice of endocrine clinicians in the UK of
offering GH treatment discontinuation in adults with GHD who have been on long-term
replacement therapy. It will also determine the willingness of endocrine clinicians
in the UK to take part in a future large-scale multi-centre study;
2. Phase 2: to assess the feasibility of conducting a large-scale multi-centre study
on discontinuation of long-term GH treatment in adult patients with GHD;
3. Phase 3: to explore the experiences of participants in completing and/or
withdrawing from the study, to identify barriers to recruitment and retention and
explore participants' views about the use of randomisation in future large-scale
multi-centre study.
4.2 Outcome
Answering the primary objectives of this study will help assess the feasibility of
future large-scale multi-centre study. The primary outcome measures from the phase 2 and
phase 3 of the study will include:
1. Consent rate
2. Completion rate
3. Withdrawal rate
4. Adverse events
Additionally, the following secondary outcome measures are expected from the study:
1. Measurement of anthropometric parameters (height, weight, body mass index [BMI],
blood pressure, waist and hip circumferences), lipids profile, glycated haemoglobin
A1c (HbA1c) and body composition (bone mineral density [lumbar spine and both
hips], fat mass and muscle mass using dual-energy X-ray absorptiometry [DXA] scan)
over a period 24 months;
2. Barriers for recruiting and retaining participants into the study;
3. Suitability and acceptability for patients of the frequency of follow-up and
assessment;
4. Suitability and acceptability for patients of the QoL questionnaires;
5. Suitability of the study protocol including recruitment, biochemical monitoring,
body composition monitoring and QoL assessment;
6. Safety of growth hormone treatment discontinuation in adult patients with GHD.
5. STUDY DESIGN and METHODS of DATA COLLECTION AND DATA ANALYIS
This is a sequential mixed-methods study which will be conducted in three phases:
- (Phase 1) Survey of endocrine clinicians (Ethics approval is not being sought for this
part of the study as it is not required. Details provided are for information only)
- Phase 2: Observational feasibility cohort study
- Phase 3: Qualitative study
