Download HTA PROJECT NUMBER 13/26/01 V4.0_151116 1. Project Title Full

HTA PROJECT NUMBER 13/26/01 V4.0_151116
1. Project Title
Full title:
Multi-centre randomised controlled trial with economic evaluation and nested qualitative study
comparing early structured physiotherapy versus manipulation under anaesthesia versus arthroscopic
capsular release for patients referred to secondary care with a frozen shoulder (Adhesive Capsulitis)
Trial Acronym:
United Kingdom Frozen Shoulder Trial (UK FROST)
Funding Acknowledgement:
This project was funded by the National Institute for Health Research’s Health
Technology Assessment Programme (project number 13/26/01)
2. Response to board feedback points
This section has been removed but is still incorporated within the protocol.
3. Summary of research
For most people Adhesive Capsulitis (known more commonly as 'frozen shoulder' in the United Kingdom (UK) and is
the term we will use for this study) is a self-limiting condition of approximately 1 to 3 years duration. It can be
extremely painful and debilitating; people with this condition may struggle with basic daily activities and be worn down
by sleep disturbance as a result of shoulder pain (Dawson et al., 2010). In the UK, frozen shoulder is estimated to affect
1% of the population who are seen in a hospital setting with the more resistant form of the condition (Bunker, 2009).
Even after an average of 4 years or more from onset, around 40% of patients can have from mild to severe symptoms
(Hand et al., 2008).
Our proposed research will provide evidence of clinical effectiveness and cost-effectiveness for three interventions
routinely used in the National Health Service (NHS). The trial team, after careful consideration, judged that the more
urgent comparisons needed were ESP based on recent national clinical guidelines for frozen shoulder and the two most
frequently used and more costly surgical interventions i.e. manipulation under anaesthesia (MUA) and arthroscopic
capsular release (ACR). From NHS Reference Costs in 2010 the average cost for out-patient physiotherapy was £36;
therefore 12 sessions could cost £480. MUA cost is £424, with rehabilitation and surgical review is £1446. ACR cost is
£1182 and with similar follow-up is £2204 (Maund et al., 2012). We decided not to include arthrographic distension as
although it is less costly at around £113 (Maund et al., 2012), our national survey of health professionals and potential
Principal Investigators found it to be neither a frequently used intervention nor a priority for research (Dennis et al.,
2010). Recent systematic reviews have neither found sufficiently rigorous evidence to justify the inclusion of distension
as an intervention in this study (Buchbinder et al., 2008; Maund et al., 2012).
We plan to collect patient centred outcomes of treatment, which will include shoulder pain and function; quality of life;
adverse events; cost effectiveness and time to recovery. Health care resource use will be collected prospectively from
hospital forms and using patient completed questionnaires at 3, 6 and 12 months. The economic analysis will take an
NHS and Personal Social Services perspective and use methods consistent with bodies such as NICE. Results will be
summarised in an incremental cost effectiveness ratio. To explore uncertainty around adoption decision, a probabilistic
sensitivity analysis will be used to quantify the joint uncertainty around costs and quality adjusted life years (QALYs).
This will help inform current clinical practice in the NHS.
Evidence about patient experience of a frozen shoulder is limited (Maund et al., 2012). A purposive sample of up to 45
participants will be interviewed about acceptability and satisfaction of their treatment after 12 months based on
treatment pathway, diabetes and gender (Griggs et al., 2000). These patients will also be asked what outcomes are
important to them which should help to facilitate interpretation of the results of the trial. At the end of the trial 10 to 15
health care professionals will be interviewed about acceptability of treatments. Data will be analysed using comparison
method through thematic coding. We will also update the HTA funded systematic review of management of the frozen
shoulder for randomised controlled trial (RCT) evidence of the effectiveness of these interventions in secondary care.
4. Background and rationale
The cumulative incidence of frozen shoulder is estimated at 2.4 per 1000 population per year based on a Dutch general
practice sample (van der Windt et al., 1995). A large UK based primary care study found that frozen shoulder affected
8.2% of men and 10.1% of women of working age (Walker-Bone et al., 2004). Frozen shoulder most commonly occurs
in people in their mid-50s and is thought to be slightly more common in women than in men. Although viewed as a selflimiting condition, there may not be a complete resolution for all patients and there is variation across case series in the
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proportion of patients who do not regain full shoulder motion (Dias et al., 2005). Based on the largest series of patients
with a mean follow-up of 4.4 years from onset of symptoms, 59% had normal or near normal shoulders, 35% had mild
to moderate symptoms with pain being the most common complaint and 6% had severe symptoms at follow-up (Hand
et al., 2008). In contrast, frozen shoulder was estimated to have an incidence of around 1% in the UK population based
on a specialist shoulder surgeon’s hospital care experience (Bunker, 2009). This discrepancy in estimated prevalence
may be explained by the more resistant cases of frozen shoulder being seen in a hospital setting (Hanchard et al., 2012).
Several systematic reviews have been undertaken on interventions for frozen shoulder, some of which focused on
shoulder pain in general and other conditions (Buchbinder et al., 2003; Green et al., 2003; Green et al., 2005). A more
recent HTA funded systematic review, conducted by some of the applicants, of a range of NHS relevant interventions
for the treatment of primary frozen shoulder, concluded that there was limited evidence on the clinical effectiveness of
treatments for primary frozen shoulder, particularly for more invasive treatments (Maund et al., 2012). Furthermore, a
recent systematic review of non-randomised studies found that there were minimal differences in range of motion or
patient-reported outcomes for arthroscopic capsular release instead of, or in addition, to manipulation under anaesthesia
(Grant et al., 2013). Both systematic reviews recommend the need for high quality primary research to evaluate the
treatments for the frozen shoulder. From searching the HTA website and the ISRCTN register, there is no large scale
multi-centre RCT of these interventions with concurrent economic evaluation being undertaken to answer this important
research question, justifying the need for this research.
Our proposed research will further knowledge and understanding of the impact of frozen shoulder on the functioning
and quality of life of patients and the effectiveness and cost-effectiveness of the more invasive interventions commonly
used in its treatment. Our results would have the potential to guide future development of evidence based treatment
pathways in the NHS for this condition. There is increasing awareness that the findings from RCTs should not be
considered in isolation, but are more valuable when considered in the context of existing evidence on all treatments of
interest. Therefore, we will update the recent HTA systematic review about management of the frozen shoulder (Maund
et al., 2012) but with a focus on RCTs of the interventions included in the trial. There will be no language restrictions.
Contextualising our research findings in this way will also help inform clinical practice and provide direction for future
research in this area.
5. Evidence explaining why the research is needed now
There are a number of management options available to clinicians in secondary care for the treatment of frozen
shoulder, both surgical and non-surgical. We undertook a survey of 303 UK health-care professionals to determine the
current management of frozen shoulder patients and the need for a RCT (Dennis et al., 2010). For patients presenting
with persistent global reduction in range of movements and minimal associated pain, for nearly half of respondents
(47%) the preferred treatment was surgery: MUA (21%), ACR (24%) and open capsular release (2%). A further 20% of
respondents recommended physical therapy and only 5% arthrographic distension. The majority of respondents (88%)
thought there was a need for a RCT and that the interventions to be compared should include physical therapy (26%),
surgery (24%), injections (20%) and arthrographic distension (6%). In particular, for patients experiencing persistent
stiffness, surgery and physical therapy were recommended treatments, and were identified as areas for future research.
We also undertook a survey of surgeon PIs from ProFHER and UKUFF trials which confirmed that the most commonly
provided interventions are physiotherapy, MUA and ACR. These are clearly the most important (and MUA and ACR
the more costly) interventions to evaluate in a trial and has informed the design of our study. By producing high quality
evidence for these interventions, this trial will help patients and clinicians make informed choices on the most effective
treatment for this condition. As these are intensive interventions in common use, the results of this research will remain
highly relevant and important to the needs of the NHS in the future.
The main findings from a recent HTA funded systematic review of a range of NHS relevant interventions for the
treatment of primary frozen shoulder were that based on data from two RCTs, there may be short-term benefit from
adding a single intra-articular steroid injection to home exercise, for patients with primary frozen shoulder of less than
six months duration. There may also be benefit, in the same population, from adding physiotherapy (including
mobilisation in eight to 10 sessions over four weeks) to a single steroid injection. In conclusion, however, there was
limited clinical evidence on the effectiveness of treatments for primary frozen shoulder, particularly for more invasive
treatments. High-quality primary research was recommended (Maund et al., 2012). The clinical research being proposed
here will help to address this uncertainty, specifically for treatments delivered in secondary care. In addition, it is to be
supplemented by a qualitative investigation of patient experiences of both the surgical interventions and ESP, providing
important patient-centred insight to further guide clinical decision making.
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6. Aims and objectives
6.1 Aim
The strategic aim of this research is to conduct an independent and objective evaluation of commonly used interventions
for management of the frozen shoulder in secondary care. We will measure the effectiveness and cost effectiveness of
the more invasive and costly surgical interventions that are most commonly used in the NHS and compare them with a
structured and standardised control intervention of early structured physiotherapy. This will be supplemented with a
nested qualitative study exploring the acceptability of these interventions to patients and clinicians.
6.2 Objectives
1.
2.
3.
4.
5.
To undertake a parallel group RCT to determine the effectiveness of ESP versus MUA versus ACR for patients
referred to secondary care for treatment of frozen shoulder. This will be achieved using as our primary outcome
the Oxford Shoulder Score (OSS), which is a patient reported outcome measure at 3, 6 and 12 months. The
primary time point is 12 months after randomisation.
To conduct a detailed economic evaluation to compare the cost-effectiveness of the three management policies, to
identify the most efficient provision of future care, and to describe the resource impact that various policies for
frozen shoulder would have on the NHS.
To qualitatively explore the acceptability of the different treatments to patients and health care professionals and to
provide important patient-centred insight to further guide clinical decision making.
To update the HTA funded systematic review of management of the frozen shoulder for RCT evidence of the
effectiveness of these interventions in secondary care. This will allow our findings to be considered in the context
of existing evidence on all treatments of interest for this condition.
To use networks of health care professionals, patients, health service managers and commissioning groups to
widely disseminate the findings of this study. This will be in addition to publishing the results of the study in key
journals and publishing the HTA report.
7. Research plan
7.1 Design
A pragmatic multi-centre RCT of ESP versus MUA versus ACR for patients referred to secondary care for treatment of
frozen shoulder, with a concomitant economic evaluation. In addition, there is a nested qualitative study to explore the
advantages and drawbacks of treatment from the patient’s point of view. An internal pilot study will check on
assumptions about trial recruitment and feasibility.
7.2 Setting
We need to recruit from 25 NHS Hospitals in the UK. An initial approach from the Chief Investigator to potential
Principal Investigators (PIs) of previous surgical trials of the shoulder (UKUFF and ProFHER) has identified 32
surgeons from 30 sites who are willing to be PIs. This study will ensure wide surgeon involvement and with the
pragmatic design will make findings generalisable. The trial design will involve measures to maximise acceptance of
trial results by ensuring competence in treatment provision for all treatment interventions.
7.3 Randomisation
The research nurse or assessing clinician will identify patients who have been referred for a frozen shoulder to an
outpatient clinic in hospital. In the clinic, a designated individual within the shoulder team (e.g. surgeon,
physiotherapist) will confirm eligibility and invite the patient to consider joining the study. The research nurse will
provide an information sheet and answer any questions. The research nurse or clinician will ask the patient whether they
agree to consent at that time or need up to a week to discuss with family or friends and agree on an arrangement to
confirm their decision.
When patients have consented and their baseline forms have been completed, the recruiting clinician will contact York
Trials Unit (YTU), either by telephone or via the internet, to access a secure randomisation service. YTU will then
perform independent and concealed unequal random allocation (1:2:2), to allow for the potential difference in effect
between treatment comparisons, and stratified by presence of diabetes as it is significantly associated with impaired
shoulder motion in this patient population (Griggs et al., 2000). The patient will be allocated to one of the following
interventions:
1. Early structured physiotherapy (ESP) for 12 weeks ('control') which will include an intra-articular steroid injection.
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2. Manipulation under anaesthesia (MUA) and intra-articular steroid injection [without Arthroscopic capsular release
(ACR)] within 18 weeks from randomisation.
3. ACR with MUA within 18 weeks from randomisation.
We have chosen to evaluate these interventions for the following reasons:
a) MUA and ACR are the most commonly used interventions in secondary care; they are both costly, with ACR with
MUA costing twice as much as MUA alone.
b) There is no randomised evidence on MUA or ACR to indicate superiority of one over the other.
c) It is important to have a non-surgical control arm, as the benefits and risks of MUA and ACR have not yet been
established. As physiotherapy is a commonly provided conservative treatment, ESP with active monitoring is our
proposed control. This will allow us the opportunity to evaluate in secondary care the treatments recommended in
the national physiotherapy guidelines (Hanchard et al., 2012).
To reduce the risk of the randomisation sequence being predictable we will not stratify by centre, which in addition to
using randomly selected permuted blocks, will make the allocation sequence unpredictable for individual trial sites. The
randomisation service will record information and check patient eligibility to avoid inappropriate entry of patients into
the trial. Patients at the time will be informed of their allocations as will the clinician managing each patient. The study
office in York will send an allocation letter to the patient explaining what will happen next. The consultant surgeon and
the participant’s General Practitioner will also receive letters about treatment allocation. As the trial is pragmatic in
design, comparing surgical and conservative treatment options, the blinding of participants and clinicians to treatment
allocation is not possible or desirable.
For those patients who do not improve with ESP they will be referred for further treatment in consultation with the
treating clinician at a 12 week assessment. When further treatment after ESP involves surgical intervention (e.g. MUA
or ACR), patients will be placed on the normal waiting list for such treatment. Any further treatment provided will be
recorded.
7.4 Internal pilot study
There will be two phases to the internal pilot study for the purpose of monitoring the progress of the trial to facilitate
successful completion of the study and confirm its continuation. Our progress will be compared against pre-specified
criteria and monitored by the DMEC at six month intervals. The data from the pilot will contribute to the final analysis.
The purpose of phase 1 of the internal pilot (from months 4 to 9) is to critically test our assumptions about recruitment.
At this time the pilot will comprise three sites where the Trial Co-ordinators are located at and which there is a coapplicant with a track record of recruiting well into surgical trials (Middlesbrough, Oxford and Glasgow). In addition,
we will include a fourth site with less experience in orthopaedics research and at which the PI is not a co-applicant
(North Tees). At six months into recruitment we will use the information about number of eligible patients identified,
approached and consented into the trial to confirm the number of participating sites required to achieve our recruitment
target. We will interpret this cautiously, as we do not want to over-estimate our ability to recruit in the main trial.
Secondary reasons for undertaking this phase of the pilot will be to inform the feasibility of setting up the trial: a)
ensure the participating sites are provided with enough training and documentation; b) review the number of reasons
why patients are not eligible for the trial; c) record the length of time it takes to consent a patient (including the
Research Nurse or clinician recording reasons given by patients for not taking part e.g. willingness to be randomised to
physiotherapy) and complete study materials is determined; d) ensure all suitable clinicians at a site are actively taking
part in the trial and to find out if not why not; and e) to check patient adherence to treatment allocation.
The DMEC and independent TSC will review the pilot data and recommend any changes required to the study team and
the funding body. To determine the success of phase 1 of the pilot study and the decision to continue with the study is
based on the following primary feasibility objectives (Thabane et al., 2010):
1. To have set up a minimum of four sites during the six months and meet a target to recruit 24 patients from these
sites. This will provide evidence of whether sites can recruit into the trial the expected one participant/month.
2. To ensure that adequate progress has been made with setting up other sites to recruit, we will have set up twelve
sites i.e. 50% of sites.
Phase 2 of the internal pilot will continue for a further 18 months (months 10 to 27) and be reviewed at six month
intervals with the DMEC. This phase of the pilot study is important because the refusal of patients to participate (likely
due to randomisation to physiotherapy) and refusal to continue with allocated treatment (again likely to be
physiotherapy) are serious threats to the study. The main recruitment period is for 30 months. Extending the pilot by 18
months will allow us to review the crossover for the trial having recruited approximately 50% of the patients i.e. 250
patients in total or 50 of the patients randomly allocated to physiotherapy. This should be a sufficient number of
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participants for the DMEC to advise whether a three-arm trial is feasible or whether randomisation to physiotherapy
should be omitted. In the latter case, the trial would still answer an important question about the two surgical
comparisons. In previous simulation work we found that with 80% power, a true treatment effect size of 0.2 or 0.4, and
30% crossover, that power is reduced to 54% (Hewitt et al, 2008). If we extrapolate this to UK-FROST, with a sample
size that has 90% power and effect sizes of around 0.3 to 0.4, 20% to 30% crossover in the physiotherapy group would
likely reduce the power to between 70% and 60%. Therefore, if at the 24 month review of the pilot the crossover is
between 20% and 30% the DMEC will advise on the need to convert the trial to a two-arm trial that will continue with
the two surgical comparisons.
During the extended internal pilot we will continue to monitor reasons for patient non-consent into the trial. To achieve
this, patients who do not want to be randomised because of a strong treatment preference will be invited to complete a
short questionnaire about their treatment preferences and reasons for not wanting to participate in the trial. We will also
ask these patients whether they would informally discuss the reasons for not consenting and their treatment preferences
with a member of the research team. We will use these data at the DMEC meetings during the internal pilot to monitor
and review any shortfall in recruitment and inform the continued progress of the trial to more effectively manage patient
preferences. Patient preferences of non-consenting patients will be fed back to sites. The impact of monitoring nonconsenting patients’ preferences and any changes made will be achieved by reviewing at baseline for trial participants:
1) their preferences for surgery, no preference, physiotherapy – and if surgery, which type of surgery and 2) their
treatment expectations in terms of effectiveness (e.g. effective, don’t know, ineffective).
As we will have extended the pilot phase by 18 months, we will also monitor site set up, patient recruitment, and
waiting times from randomisation to intervention.
Therefore the primary criterion to inform the DMEC decision to progress our study at the end of phase 2 of the pilot is:
1) To review the extent of cross-over for the DMEC to advise whether a three-arm trial is feasible or whether
randomisation to physiotherapy should be omitted.
In addition:
2) We will monitor reasons for patient non-consent into the trial, their treatment preferences and informally discuss
these with willing patients.
3) We will have set up all 25 of our sites and aim to have recruited 250 patients (or 50% of our target).
4) We will monitor waiting times at sites from randomisation to intervention and consider the need to substitute sites
that are not meeting the waiting time targets.
The potential for cross-over of patients in the trial is also closely connected to ‘expectation bias’, that is, patients’
knowledge of their treatment allocation influences their completion of the outcome measures. The pragmatic design of
the trial means we are unable to blind participants. Therefore completion of a patient reported outcome as our primary
measure, the Oxford Shoulder Score (OSS), is susceptible to this bias because of the patients’ preferences/expectations
of the treatments being compared (Preference Collaborative Review Group, 2008). To help minimise expectation bias:
1) We will incorporate findings from the qualitative work undertaken by the CSAW trial team and hold a focus group
with patients to further explore the issue of patient treatment preferences for UK FROST and develop an unbiased
information sheet.
2) We will explore again at site set-up visits the shoulder teams’ views and preferences towards the treatments and
ensure they are in equipoise to deliver all of the study interventions, which is important to help ensure a balanced
presentation of the study treatments. We will monitor and feedback to sites any evidence of lack of equipoise when
reviewing the completion of the study eligibility forms.
3) We will explain the importance of a balanced presentation of information to study patients in the Trial Manual and
when training staff during study set up at participating sites. To further facilitate training of sites we will provide a
weblink to a video of the Chief Investigator explaining to research staff about how to present the study to patients. This
will be developed with input from our patient representatives and clinical/academic collaborators. Similarly we will
develop a website including a patient section that will explain the study along with a weblink to a video of the Chief
Investigator presenting the study in laymen terms. This website and video will only be available to patients who have
consented to take part in the trial and will be password protected.
4) We will add a component to the internal pilot described to monitor reasons for patient non-consent into the trial and
treatment preferences.
We need patients to understand that we have to formally evaluate treatments because there is uncertainty about
comparative effectiveness, the need for treatment to be selected by randomisation (rather than clinician or patient
preference) and, finally, to understand that trial participation is to provide evidence to inform decision-making for
patients in the future (Blazeby, 2012). We will achieve this by educating participating sites from our experiences of
conducting several large-scale orthopaedic surgical trials using the training materials that we will develop, at site set up
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visits, regular newsletters and meetings with PIs at specialist society annual conferences. These principles and the
implementation of the procedures described will underpin how we will manage to minimise expectation bias.
7.5 Nested qualitative study
Existing evidence about patient experience of frozen shoulder is limited and an exploration of patient treatment
preference is broadly lacking from the literature (Maund et al., 2012). Therefore the clinical research being proposed
will be supplemented by a qualitative investigation of patient experiences of both the surgical interventions and ESP,
providing important patient-centred insight to further guide clinical decision making.
The nested qualitative study will focus on the following objectives to complement the trial objectives:
1. To explore the experience and acceptability of the different treatments to patients and health care professionals;
2. To provide important patient-centred insight to further guide clinical decision making.
We would also like to use this opportunity to explore, as a subsidiary aim, participants’ experiences of taking part in a
surgical trial. Although this aim is not closely aligned to the overall trial aims, it will help to inform the design and
conduct of future surgical trials, thus contributing to the value of this qualitative study for future funded research. It is
also possible that participants’ experience of taking part in a trial is related to the acceptability and outcome of
treatments.
Up to 45 of the trial participants will be recruited to take part in this aspect of the research. Participants will be drawn
equally from those who have experienced ESP or either of the surgical interventions. As gender and diabetes are likely
to have an impact on outcome from shoulder surgery (Griggs et al., 2000) effort will be made to include interviews with
both men and women, and those with and without diabetes. Those who consent to participate in the trial will be
interviewed at approximately 52 weeks after their enrolment to mirror the primary time point in the analysis. This will
allow time for post-surgical healing and recovery; and for participants to reflect on their experience, expectations and
outcomes from the intervention received. Interviews will be semi-structured with open questions used to guide a
discussion of a patient’s experience of treatment, their opinions about treatment benefits and drawbacks, their
reflections upon frozen shoulder and recovery, and their attitudes towards participating in clinical research. A flexible
interview schedule will be developed following a literature review, discussions with research team, patients with frozen
shoulder, a physiotherapist and surgeon with expertise in this area. Interviews will be open and flexible to allow
participants the opportunity to introduce new topics, and managed so as to generate a detailed, personal perspective
upon the topic (Mason, 2002).
Interviews will be ideally undertaken face-to-face although, given the geographic spread of participants, it may be more
practical to perform some interviews by telephone or face-time interviews on-line (e.g. Skype or ooVoo); it is expected
that up to 50% of interviews will be performed in this way. Interviews will be conducted by the researcher and audiorecorded with permission; recordings will be transcribed in full and data handled using the NVivo computer package.
We will also interview 10 to 15 health care professionals (physiotherapists and surgeons) at the end of the trial about
their experience of delivering the treatment. An interview schedule will be developed to address areas such as: clinical
decision making; treatment preference; and barriers to and facilitators of positive outcome of treatments.
To reflect the exploratory nature of this study, and to ensure that the participants’ perspective is at the heart of any
insight generated, data analysis will be undertaken inductively following the conventions of Grounded Theory (Strauss
and Corbin, 1990; Glaser and Strauss, 1967; Charmaz, 2006). This is considered more fully in section 12.3.
7.6 Update of systematic review
To place the RCT findings in the context of current evidence at the end of the trial, we will update the HTA systematic
review about management of frozen shoulder incorporating the proposed RCT and any other new RCTs completed
since the original searches were undertaken (Maund et al., 2012). The review protocol will be finalised and registered
on PROSPERO prior to the analysis of the trial being undertaken. The updated review will follow the inclusion criteria
and methods of the original systematic review except that only RCTs of interventions included in the trial,
physiotherapy, MUA and ACR, will be eligible for inclusion; compared to each other, no treatment, any form of
supportive care or placebo. The search strategy used in the original review will be adapted to search for primary studies
of these interventions. The following databases will be searched: MEDLINE/PreMEDLINE, CENTRAL, EMBASE,
PEDro, Science Citation Index and Clinicaltrials.gov. The original searches were undertaken in March 2010. The
update searches will have a start date of January 2010, the overlapping to allow for any delays in articles being added to
the bibliographic databases.
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If new RCTs are identified, they will be assessed for inclusion, undertaken independently by two researchers as in the
original review. Included RCTs will be assessed for risk of bias and data will be extracted by one researcher and
checked by a second. Study details will be extracted including study design, number randomised, loss to follow-up,
setting, population, description of the intervention including duration and intensity, concomitant treatments and
outcome measures used. The outcomes of interest will be function and disability, quality of life, pain and adverse
events. Outcome data will be extracted to allow calculation of between group differences and confidence intervals, as
appropriate for the specific outcome measure. Data extraction methods will follow those for the original review
including contacting authors for missing data and using standard imputation methods where data cannot be obtained
(Higgins and Green, 2011).
Given the multiple interventions being included a mixed treatment comparison (MTC) would be an appropriate
approach to the evidence synthesis, though it is unclear at this stage if sufficient studies will be available to construct a
network. If sufficient data are available and trials are sufficiently homogenous to be combined an MTC will be
undertaken in order to explore the relative effectiveness of the interventions with respect to each other (Ades, 2003).
Should such an approach not be possible studies will be combined, where appropriate, in a series of pair-wise metaanalyses i.e. based on clinical and statistical heterogeneity and the necessary data being available (CRD, 2009; Higgins
and Green, 2011).
We will update the results incorporating the proposed RCT and any other new RCTs, and the discussion and
conclusions accordingly. Any differences between the updated and original review will be highlighted.
8. Health technologies being assessed
The description and standardisation of the health technologies to be assessed have been informed by the results of a
survey of which 53 surgeons that responded are PIs for two multi-centre shoulder surgical RCTs funded by the HTA
(ProFHER and UKUFF). Notably, 28 of 35 (80%) responded that they routinely provided a steroid injection with MUA;
14 of 46 (30%) routinely provide steroid injection with ACR; 34 of 46 (74%) routinely perform MUA with ACR; and
13 of 46 (28%) and 8 of 46 (17%) surgeons respectively routinely release the posterior capsule or perform a
subacromial decompression during ACR.
Management of a randomised patient who is waiting for surgery may include adequate analgesia to ensure pain relief,
general advice on care of the arm (e.g. axillary hygiene) and general advice to prevent further stiffness in the limb.
Management should not include a specific home exercise programme (like that provided with the structured
physiotherapy intervention); and a steroid injection should be avoided, as these are considered active interventions.
8.1 Manipulation under anaesthesia with an intra-articular steroid injection
Participants will be placed on the surgical waiting list with routine pre-operative screening. In keeping with NHS
waiting list targets, it is anticipated that the procedure will be performed within 18 weeks of randomisation under a
general anaesthetic usually as a day case. The affected shoulder is manipulated to stretch and tear the tight capsule and
to improve range of movement. The response of the PIs to our survey has led us to conclude that to be consistent with
current practice we should advise surgeons to use intra-articular injection of corticosteroid whilst the patient is under the
same anaesthetic unless it is contra-indicated. Post-operative analgesia including nerve blocks will be provided as per
usual care in the treating hospital. In the unlikely event that the MUA is judged to be incomplete we do not recommend
that the surgeon should cross-over intra-operatively to capsular release. The need for this should be reviewed at another
clinic appointment to allow assessment of outcome of the MUA and the need for any further intervention. The details of
any further intervention will be collected prospectively.
8.2 Arthroscopic capsular release with MUA
Participants will be placed on the surgical waiting list with routine pre-operative screening. In keeping with NHS
waiting time targets, it is anticipated that the procedure will be performed within 18 weeks of randomisation under a
general anaesthetic usually as a day case. Arthroscopic release of the contracted rotator interval and anterior capsule
will be performed, followed by MUA to complete the release of the inferior capsule. The response of the PIs to our
survey has led us to conclude that additional procedures like posterior capsular release, subacromial decompression and
supplementary steroid injections are used in a minority of patients. In particular, the latter is not routinely used as
although it controls pain there is the slight increased risk of an infection and significant morbidity (Babcock et al.,
2002). Therefore, we will not standardise these additional procedures and advise surgeons to use these at their
discretion when there is a clinical need. Post-operative analgesia including nerve blocks will be provided as per usual
care in the treating hospital. The details of this intervention will be collected prospectively.
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8.2.1 Nested shoulder capsular tissue and blood samples study
At selected hospitals, for patients who are allocated to this treatment intervention and not had a steroid injection within
six weeks from the day of the surgery, we plan to undertake a nested study with the aim of determining the key
molecular processes and changes seen in shoulder capsular tissue of patients with frozen shoulder in order to better
understand these processes; and to determine the relationship between tissue changes, serum biomarkers and clinical
symptoms and signs when enrolled into the host trial and also response to treatment.
The objectives of the study are as follows:
a) To determine molecular and cellular abnormalities in tissue obtained during surgery in patients with frozen
shoulder.
b) To determine serum protein and cytokine signatures in patients with frozen shoulder.
c) To correlate any tissue and serum abnormalities detected with clinical presentation and response to treatment.
Patients randomised to arthroscopic capsular release followed by MUA in UK FROST at the agreed sites will be
approached to take part in this study. When the date of the surgery is known at a site, the Research Nurse will post the
patient a letter, Patient Information Leaflet and Consent Form. When the patient attends for their pre-surgery
assessment the Research Nurse will seek to collect informed consent and answer any questions the patient has.
Written consent will be given by patients who wish to be included in the study. Not consenting will not affect their
participation in UK FROST. Consent for this study will be separate from UK FROST.
The capsule is routinely incised or removed normally as part of arthroscopic capsular release. Therefore we do not
anticipate any additional distress or disadvantage to patients by obtaining a capsular tissue biopsy. No other tissue from
other patient groups will be removed for analysis. A venous blood sample will also be collected for these patients
during surgery.
On the day of surgery the tissue and blood samples will be collected at participating sites by a contracted courier firm
that specializes in the transporting of samples in clinical trials and who will handle the samples in accordance with all
applicable statutory requirements and codes of practice. The samples will be fresh-frozen and stored on dry-ice
provided by the courier firm and transported to the University of Oxford Musculoskeletal BioBank housed at the Botnar
Research Centre where formal analysis of the capsular tissue will take place. The samples will be used in accordance
with the protocol, consent of the participant and HRA/REC approval for the study. Both the participating hospital site
and University of Oxford will be responsible for keeping a record of the samples that are transferred between the two
organisations. The excess tissue samples shall be retained for use in future research by the Oxford Biomedical Research
Unit’s Musculoskeletal Biobank (if patient consent is in place). The University of Oxford will be responsible for storing
and managing the samples in accordance with all applicable statutory requirements and codes of practice.
This is an exploratory study for which no formal sample size calculation is necessary. We plan to include 20 patients.
The analysis will involve determination of immunohistochemical changes and neuronal signalling; variations in
peripheral neuronal innervation, nociceptor density, nerve growth factors; and genetic expression. The expression of
pro-inflammatory genes and proteins will also be examined. Findings from this analysis will be linked with variables
about patients’ clinical presentation collected at the time of recruitment into UK FROST and also response to treatment.
When analysis is completed the samples shall not be redistributed to any person other than in accordance with the
protocol or for the purpose of undertaking future studies approved by an appropriate ethics committee and in
accordance with the participant’s consent.
All study data will be entered on a password protected computer network hosted by University of Oxford. The patient
will be identified by their study specific subject number. Their name and any other identifying detail will not be
included in any study data electronic file. The patient’s Consent Form will be stored in a locked filing cabinet in a
locked room at the University of Oxford. The same principles concerning storage and use of personal data during the
study will apply as approved by REC for UK FROST which will be compliant with the requirements of the Data
Protection Act,1998.
Two members of the public with a history of a frozen shoulder who are members of the Trial Management Group have
considered this study and advised on the materials (i.e. Patient Information Leaflet and Consent Form) and are fully
supportive. They will have on going input into the overall conduct of the study.
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8.3 Early structured physiotherapy (control treatment)
Participants will receive 12 sessions of structured physiotherapy over up to 12 weeks. This will comprise essential
‘focused physiotherapy’ and optional ‘supplementary physiotherapy’.
We pre-specified a number of the ‘focused physiotherapy’ interventions, in line with the stronger recommendations of
the national guidelines (Hanchard et al., 2012). Thus the package will include provision of an information leaflet
containing education, advice on pain management and function; an intra-articular steroid injection and ‘hands-on’
mobilisation techniques—increasingly stretching into the stiff part of range as the condition improves—for which there
is reasonable evidence of effectiveness (Carette et al., 2003; Ryans et al., 2005); and instruction on a graduated home
exercise programme progressing from gentle pendular exercises to firm stretching exercises according to stage, which is
accepted good practice. All participants randomised to ESP will undergo all elements of this focused physiotherapy
package unless there is a specific clinical reason for them not to do so (e.g. steroid injection in a patient with
uncontrolled diabetes; or in a patient with a stiff but painless, non-irritable shoulder).
Supplementary physiotherapy will comprise those interventions which have not been identified as essential, but which
are permissible additions, and which will provide physiotherapists with some flexibility. These interventions, which
may have been omitted from the guidelines because they were outside their scope (e.g. acupuncture), because there was
a lack of primary literature (e.g. hydrotherapy, soft-tissue release techniques) or both, were explored using a Delphi
process (Jones & Hunter, 1995), seeking consensus from expert shoulder physiotherapists in secondary care. More
specifically, we conducted a two-round, email-based Delphi survey to elucidate which interventions should be allowed
as optional supplementary interventions and which should be disallowed; but also to inform whether any additional
‘focused physiotherapy’ interventions should be included.
The survey incorporated both the ESP and post procedural physiotherapy (see section 8.4). Thus the round one
questionnaire was in two parts, the first relating to Early Structured Physiotherapy (ESP) and the second to post
procedural physiotherapy (section 8.4). Each part listed potentially relevant interventions, and participants were asked
to separately rate these for (a) pain predominant presentations and (b) stiffness predominant presentations. The possible
ratings were, “Should always be used”, “Should be optional”, “Should not be used”, and “Don’t know”. The
questionnaires also provided an opportunity for participants to suggest and rate additional interventions. The round two
questionnaire was structured similarly, except that it (a) presented the modal round one rating for each combination of
presentation and intervention, (b) reminded the participants of their own round one ratings and (c) gave them the
opportunity to change the ratings if they wished.
There are no agreed rules for setting the level of consensus in a Delphi survey: this depends on the survey’s purpose.
We decided a priori that 90% was convincing, and indeed applied this to “Should not be used”, disallowing
interventions achieving this level of consensus from use in the trial. But on the other hand, applying the 90% threshold
to “Should always be used” risked labelling as ‘mandatory’ certain interventions which some centres (potentially a
substantial minority) lacked the resources to deliver (in terms of facilities, equipment or training). This pragmatic
consideration underpinned our decision to set the level of consensus on “Should always be used” at 100%. For the
purposes of the trial, we defined as optional all of those interventions which lay below both the 100% consensus
criterion for “Should always be used” and the 90% criterion for “Should not be used”, regardless of the level of
consensus on the “Should be optional” response. Retrospectively, we decided that to make best use of our data, we
would apply additional, secondary levels of consensus, in order to create additional “recommended” and “discouraged”
treatment categories. In relation to both “Should always be used” and “Should not be used”, we considered 80% a
reasonable level for this purpose (Table). For the purposes of the trial, we defined as optional all interventions that were
neither mandatory nor disallowed. This approach accommodates the uncertainty surrounding the value of some
interventions.
Table: Delphi survey consensus thresholds and interpretation
Statement
Consensus threshold
“Should always be used”
“Should not be used”
“Should always be used”
“Should not be used”
100%
90%
80%
80%
Interpretation
Mandatory
Disallowed
Recommended
Discouraged
Invitation packs were emailed to 113 shoulder surgeons who were known to have been involved in previous, major
shoulder trials in the UK, two of which (ProFHER and UKUFF) were HTA-funded; and they were each asked to
forward the pack to the most relevant physiotherapist. Reminders were sent after one and two weeks, using the same
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‘gatekeeper’ approach. Round two questionnaires and up to two reminders at weekly intervals, if required, were sent
direct to those physiotherapists who had responded to round one.
There were 46 responses to round one (41% response rate) and 42 to round two, demonstrating a high rate of retention
(91%). Forty-five round one responders (98%) were self-reportedly shoulder specialist physiotherapists.
No interventions achieved 100% “Should always be used” consensus. The only mandatory interventions, therefore, will
be those predetermined on the basis of research evidence or accepted good practice. For pain predominant
presentations, discouraged interventions will be Bowen therapy, shockwave therapy and ultrasound; while interventions
disallowed by the protocol will be provision of a brace, craniosacral therapy, deep tendon friction and laser. For
stiffness predominant presentations, an additional recommended intervention will be one-to-one function-based
exercises; discouraged interventions will be Bowen therapy, deep tendon friction, shortwave diathermy and ultrasound;
and disallowed interventions will be provision of a brace; craniosacral therapy; interferential; laser; and shockwave
therapy. Interventions not specified above will be considered optional in their respective contexts: as anticipated, these
are diverse.
A pro-forma will be designed to facilitate recording of the early structured physiotherapy given at each session (e.g.
injection, advice and education, gentle active exercise).
We will reimburse the travel expenses for trial participants who are randomised to ESP to facilitate their regular
attendance for physiotherapy.
8.4 Post-procedural physiotherapy
Following MUA or ACR, patients will undergo a further 12-week programme of physiotherapy, normally commencing
within 24 hours, with the aim of reducing pain and regaining/maintaining the mobility achieved at operation. This postprocedural physiotherapy is not intended to be identical to the early structured physiotherapy, because it is applied in a
very different context. The research literature is uninformative on this aspect, but we pre-specified two ‘focused
physiotherapy’ interventions on the basis of established good practice. These are provision of an information leaflet
containing education, advice on pain management and function; and instruction on a graduated home exercise
programme. All participants randomised to MUA or ACR will undergo all elements of this focused physiotherapy
package unless there is a specific clinical reason for them not to do so.
Interpretation of the Delphi survey results was as for ESP (Table). As with ESP, no interventions achieved 100%
“Should always be used” consensus. The only mandatory interventions, therefore will be those determined on the basis
of established good practice. Based on the survey results, an additional recommended intervention for pain predominant
presentations will be one-to-one function-based exercises; discouraged interventions will be craniosacral therapy and
ultrasound; and disallowed interventions will be provision of a brace, deep tendon friction, laser and shockwave
therapy. For stiffness predominant presentations, additional recommended interventions will be one-to-one functionbased exercises and one-to-one gentle active exercises; discouraged interventions will be Bowen therapy, electroacupuncture, graded motor imagery, mirror therapy, shortwave diathermy and ultrasound; and disallowed interventions
will be provision of a brace; craniosacral therapy, deep tendon friction, interferential, laser and shockwave therapy.
Interventions not specified above will be considered optional in their respective contexts: as anticipated, these are
diverse.
It is expected that a steroid injection will be avoided during post-procedural physiotherapy.
A pro-forma will be designed to facilitate recording of the post-procedural physiotherapy given at each session.
8.5 Steroid injections
When steroid injections are to be administered for the health technologies being assessed they will be given under
imaging guidance or ‘blindly’ depending on the usual practice of the participating centres. This diversity is acceptable,
because current evidence does not support the superiority of either approach over the other (Bloom et al, 2012).
9. Planned inclusion/exclusion criteria
The correct inclusion of patients with a diagnosis of primary frozen shoulder can be achieved through careful clinical
examination and ruling out secondary causes using plain radiographs. The clinical examination will include the key
diagnostic assessment of restriction of passive external rotation in the affected shoulder (New Zealand Guidelines
Group, 2009). There is evidence of good inter-rater agreement on whether restriction is present (Hanchard, Howe and
Gilbert, 2005) and a high (50% restriction) threshold for inclusion should sufficiently minimise diagnostic uncertainty.
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We shall also routinely perform orthogonal plain radiographs (Antero-posterior and Axiallary projections) of the
affected shoulder to exclude glenohumeral arthritis and other pathology (e.g. locked posterior dislocation).
Therefore, patients, including diabetics, are eligible for inclusion if they are aged 18 years or older, with clinical
diagnosis of frozen shoulder characterised by restriction of passive external rotation in the affected shoulder to less than
50% of the contralateral shoulder, and have radiographs that exclude glenohumeral arthritis and other pathology. This is
a recommended consensus definition for diagnosis of frozen shoulder that can be applied across sites (Vermeulen et al.,
2006). We will exclude patients with bilateral concurrent frozen shoulders, those secondary to trauma (i.e. trauma to the
shoulder that required hospital care) or secondary to other causes (e.g. recent breast surgery or radiotherapy), those for
which any of the trial treatments are contraindicated, and those unfit for general anaesthesia. We will also exclude
patients who are not resident in a catchment area of a trial site or who lack mental capacity to comply with treatment or
data collection.
10. Sample size
The primary outcome is the OSS and will be assessed for three treatment comparisons: ESP compared with MUA; ESP
compared with ACR where for both of these comparisons we are testing for a 5 point difference on the OSS; and MUA
versus ACR where we are testing for a 4 point difference. There is data to suggest a 5 point improvement can be found
on the OSS (effect size of 0.42) between surgically and conservatively treated patients, with a stable standard deviation
of 12 points across different populations. This larger effect size will be required to justify the greater costs and potential
risks associated with surgery. A smaller difference of 4 points on the OSS (effect size of 0.33) is expected to distinguish
between MUA and ACR. To observe the above effect sizes with 90% power and 5% two-sided significance, adjusting
for a conservative estimate (r=0.4) of the correlation between OSS over 12 months and allowing for 20% attrition, a
total sample size of 500 patients is required (ESP: 100; MUA: 200; ACR: 200). Owing to the a priori specified sequence
of treatment comparisons, multiplicity should not be a concern (Schulz and Grimes, 2005). Thus no adjustments are
made to the calculation.
To minimise attrition we will exclude the rare patient in this population who will lack mental capacity to comply with
treatment or data collection. Active and systematic follow-up of all randomised participants is then planned at 3, 6 and
12 months. This will include pre-notification reminders, 2 and 4 week reminders and the option for completion of an
abridged questionnaire (a minimum of the OSS and EQ-5D) via telephone after 6 weeks. At 12 months, the primary
time-point, we will include an unconditional incentive payment of £5 to maximize the completion and return of
questionnaires (Edwards et al., 2002). Text messages will also be sent on the day the patient is sent the postal
questionnaire which has been shown to significantly reduce time to questionnaire response (Ashby et al., 2011). We
will also write newsletters during the trial to keep the participants informed and engaged with the trial which can
enhance response rates (Mitchell et al., 2012).
The sample size recommended for qualitative research is moot (Baker and Edwards, 2012). We will interview men and
women to a point of theoretical saturation (Charmaz, 2006); in short, until no further useful conceptual categories
emerge. Theoretical sampling is used in grounded theory to seek and collect, ‘pertinent data to elaborate and refine
categories in your emerging theory’ (Charmaz, 2006). This method of sampling does not aim to represent a particular
population, but is emergent, allowing analysis to move from an initial tentative category towards a robust theoretical
category (Baker and Edwards, 2012). Although it is not possible to anticipate the exact number required our sample is
likely to include up to 45 trial participants and 15 health care professionals. This number is consistent with
recommendations of qualitative research experts (Baker and Edwards, 2012).
11. Data collection
11.1 Primary outcome
Our primary outcome will be the OSS, a patient-reported measure of functional limitation following shoulder surgery.
Development and validation included patients with frozen shoulder (Dawson et al., 1996) and it has been used in the
long term follow-up of these patients (Hand et al., 2008). The OSS is a 12 item measure with five response categories
and a range of scores from 0 (worst) to 48 (best) (Dawson et al., 2008). It has been validated against the professionallyendorsed Constant Score (Constant et al., 1987) and the SF-36 and responsiveness over a six month period following
surgical intervention has been established (Dawson et al., 2001). The OSS will be posted to trial participants for selfcompletion at baseline, 3, 6 and 12 months after randomisation and will additionally be administered pre-treatment and
6 months from the start of treatment. Twelve months after randomisation has been chosen to be the primary end-point to
allow the interventions and co-treatment interventions to be delivered and the majority of complications to be treated.
These time points are essential to assess rate of recovery and to not miss important differences.
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A potential criticism of using this instrument as the primary outcome is that lack of study blinding may bias item
responses. As a pragmatic trial, this could be argued to be of interest as the knowledge of treatment allocation will
reproduce the “normal” conditions in which a patient would receive their treatment during routine care (Schwartz and
Lellouch, 2009). Nevertheless, to address this criticism the recruitment procedures will be standardised including
unbiased information sheets developed in conjunction with service users; and training packages delivered for study staff
by the Trial Co-ordinator at participating sites; and monitor reasons for patient non-consent and treatment preferences to
inform recruitment into the trial. We will also test the potential effect of patients’ preferences/expectations on patient
outcome.
11.2 Secondary outcomes
11.2.1 Disabilities of Arm Shoulder and Hand (DASH)
Comparative validity of functional limitation measures is currently unclear for frozen shoulder. We will therefore
include a well-validated condition-specific measure for comparison with the OSS. The DASH (Disabilities of the Arm,
Shoulder and Hand) is one of the most widely used, well-validated and reliable measures of symptoms and functional
limitation in the upper extremity (Kennedy et al., 2011). To minimise responder burden we will use the validated short
version, the QuickDASH (Beaton et al., 2005). This 11-item version is scored from 0-100 and endorsed by the
American Association of Orthopaedic Surgeons (Beaton et al., 2005). An 8-unit improvement in scores has been
defined as the minimum clinically important difference (MCID) for patients with shoulder problems (Schmitt and Di
Fabio, 2004). Validity and responsiveness for adhesive capsulitis has been established (Staples et al., 2010). The
QuickDASH will be measured at baseline, 3, 6 and 12 months.
11.2.2 EQ5D-5L
The EQ5D is a validated, generic and health economic self-complete patient-reported outcome measure covering 5
health domains. The original EQ5D contained 3 response options within each of the five domains (EuroQol 1990;
Brooks, 1996). More recently, the EQ5D-5L has been developed to overcome problems with ceiling effects and to
improve sensitivity (Bharmal and Thomas, 2006; Herdman et al., 2011). The 5L version consists of the same five
domains as the original (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), but with five
levels rather than three. While EQ5D-5L has not yet been validated in this patient population, the EQ5D-3L has been
validated for a range of shoulder conditions (Holmgren et al., 2012; Angst et al., 2011). The 5L version should be
preferable in this patient population and will provide a simple descriptive profile of health status that can be used to
estimate QALY scores in economic evaluations. The EQ5D-5L will be collected at baseline, 3, 6 and 12 months.
11.2.3 Pain
Pain will be measured using the Numeric Rating Scale for pain (Farrar et al., 2001), a single 11-point
numeric scale with 0 representing ‘no pain’ and 10 representing ‘worst pain imaginable’, considered the most valid
measure for this population (Hawker et al., 2011). Responses will be collected at baseline, 3, 6 and 12 months.
11.2.4 Time to resolution
To inform time to resolution of symptoms we have developed a simple subjective global question to be administered at
baseline, 3, 6 and 12 months. During Patient & Public Involvement (PPI) consultation with 9 patients undergoing
therapy for frozen shoulder, level of recovered functionality was identified as an important factor in defining treatment
resolution. Current impact of frozen shoulder on a complex range of aspects of daily life, which could be broadly
encompassed by a single question, was identified as a key indicator of the extent of symptom resolution and a question
was devised in those terms. Development of the content, form and language of the question was based on the PPI
discussions with face/content validity, acceptability and relevance established through a further PPI consultation with
six patients. The final global question requires a patient to respond using a 10cm VAS scale with best and worst case
anchors about the extent to which their frozen shoulder impacts on their daily life today. Further validation will be
established against the other quality of life measures during the study.
11.2.5 Complications
All complications will be recorded at 12 months. Infection will be defined as for the “Surgical Site Infection” audit
(NICE, 2008a). Delayed wound healing will be defined as any wound that has not healed by two weeks. Complex
Regional Pain Syndrome is defined after surgery as pain, swelling and stiffness of the operated shoulder, arm and/or
hand restricting full tuck of the fingers. Additional complications like nerve, blood vessel, tendon or bone injury;
complications related to steroid injection including steroid flare and septic arthritis will be recorded.
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11.2.6 Adverse events
Adverse events will be collected over 12 months (see Section 16.3).
11.3
Study assessments
Follow-up assessment of patients will be undertaken at 3, 6 and 12 months post-randomisation follow-up. We will
additionally collect the primary outcome (Oxford Shoulder Score (OSS)) at two time points that are relative to the time
of treatment: pre-treatment and 6 months from the start of treatment. Pre-treatment data will be collected on the day of
the patient’s operation; or for patients allocated to ‘Early Structured Physiotherapy’ on the day when the steroid
injection is given or first visit to physiotherapy, whichever is the first to be delivered.. Outcomes collected at times
relative to the time of treatment will not be included in the primary analysis.
12. Data analysis
12.1 Statistical analysis plan
The flow of participants through each stage of the trial will be presented in a CONSORT diagram (Schulz et al., 2010).
Unadjusted OSS will be summarised descriptively (n, mean, sd, median, minimum and maximum) at each time-point by
treatment group and overall. To inform treatment selection by determining 1) whether the two surgical interventions are
significantly superior to Early Structured Physiotherapy, and if so, 2) whether key hole surgery is superior to
manipulation under anaesthesia, three comparisons will be carried out: ACR versus ESP, MUA versus ESP and ACR
versus MUA. All analyses will be carried out using 2-sided significance tests at the 0.05 significance level.
Our primary analysis will compare the treatment groups at 12 months. For each of the three treatment comparisons, the
primary outcome OSS will be analysed using a linear mixed model, including assessments at all available time points
with reference to the date of randomisation (3, 6 and 12 months, thereby increasing power) and treating patients as a
random effect. The model will adjust for OSS at baseline and include as fixed effects: treatment arm, time, arm by time
interaction and covariates for age, gender, and diabetes. The model will provide an overall treatment effect over 12
months as well as estimates at individual time points. As we specify a clear sequence of tests with a priori effect sizes to
inform treatment selection, no adjustments for multiple comparisons will be made. Different covariance patterns for the
repeated measurements will be explored and the most appropriate pattern will be used for the final model. Data will be
assumed missing at random. Model assumptions will be checked, and if they are in doubt the data will be transformed
prior to analysis or alternative non-parametric analysis methods will be used.
The primary analysis will be conducted on an intention to treat (ITT) basis, including patients in the groups to which
they were randomised. To take account of an expected degree of cross-overs, secondary analyses will be carried out
using Complier Average Causal Effect (CACE) analysis at the 12 month time point which retains the initial randomised
assignments, thus overcoming the problems of per protocol analysis (Hewitt et al., 2006). A separate secondary ITT
model will include the baseline OSS, pre-treatment OSS and 6 month from start of treatment OSS with the same
covariates as the primary analysis to inform the influence of variable waiting times on the results of the study.
Two separate exploratory subgroup analyses will be undertaken: differences in treatment response according to whether
the patient is diabetic (yes or no) and whether the patient reported to have received physiotherapy for their affected
shoulder prior to enrolment into the trial (yes or no). Simple descriptives of the primary outcome will be reported for
the sub-groups. A treatment group by sub-group interaction term will be included in the primary analysis model for
each sub-group analysis. For each sub-group analysis, the estimated treatment by sub-group means with associated
confidence intervals will be reported along with the p value for the interaction term.
To explore the potential effect of patients’ knowledge of treatment on the results of the trial as measured by the primary
outcome, we will take two approaches. First, eligible patients will be asked at baseline if they have any treatment
preference (physiotherapy, no preference or surgery; and if surgery, which type) and their expectations in terms of
effectiveness of each treatment. These preferences and expectations will be descriptively explored by trial arm as well
as for compliant and crossover patients. Separate secondary analyses of the ITT primary outcome model will be
conducted including an interaction of the randomised treatment with: treatment preferences, preference rating of the
allocated treatment, effectiveness expectations of each treatment and effectiveness rating of the allocated treatment. At
the end of the 12 month follow-up period, patients will again be asked to indicate their treatment preference in the event
of a similar shoulder problem given their experience over the past 12 months. Patient preferences at 12 month follow-up
will be tabulated against baseline preferences and against the allocated treatment. Second, it is possible that patients’
knowledge of treatment may result in non-response at follow-up. A logistic regression model will be used to identify
predictors of non-response and will include all baseline data and primary outcome assessments before any missing
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values. If any variables are found to be predictive of non-response they will be included in the model specified for the
primary analysis.
All unadjusted secondary outcomes will be reported descriptively (mean, standard deviation, median, minimum and
maximum for continuous data and counts and percentages for categorical data). The following outcomes will be analysed
using the same ITT methods as the primary analysis adjusting for the same covariates: QuickDASH, pain question and
time to resolution. Separate logistic regression models will be used to determine treatment group differences in having
experienced at least one complication or adverse event.
12.2 Cost-effectiveness analysis
The economic evaluation will determine the relative cost-effectiveness of three interventions for the treatment of frozen
shoulder: MUA versus ACR compared to ESP in patients that are referred to secondary care for the treatment of frozen
shoulder. A cost utility analysis will be performed to compare the incremental health outcome, measured in terms of
QALYs, with the incremental cost among the three treatment options. Costs and QALYs will be evaluated from the
perspective of the NHS and Personal Social Services, consistent with that used by the National Institute for Health and
Clinical Excellence (NICE, 2008b).
Health-related quality of life will be assessed during the trial period using the Euro-QoL (EQ-5D-5L) instrument. The
EQ-5D profiles generated for each patient at baseline, 3, 6 and 12 months, will be valued using a set of estimated
preferences based on the UK population that will be generated by the EuroQoL group during the period of the trial
(Rabin et al., 2011). The summary of the EQ-5D utility scores at each follow-up point by each treatment arm will be
presented and the overall difference in utilities between the arms will be examined through appropriate model. QALYs
will be estimated using the area under the curve analysis (Matthews et al., 1990).
Health care resource data will be collected during the various follow-up points of the trial using patient selfadministered questionnaires and hospital forms. Resource data will include detailed information on the use of primary
and community health services, hospital admissions, outpatients and emergency attendances. The resource use
associated with the surgical interventions (e.g. time in surgery, drugs and hospital bed usage) and ESP will be estimated
using hospital forms and compared with the relevant Health Resource Group. Cost per patient will be estimated by
multiplying the use of resource use by their associated unit costs. Unit costs will be sourced from the NHS Reference
Costs databases (DoH, 2011), the Personal Social Services Research Unit (Curtis, 2011), the British National Formulary
(BNF, 2011), and other published literature. Though the primary perspective of the cost analysis will be that of the NHS
and Personal Social Services, data on indirect costs associated with patient private expenses, days lost from work and
from normal activities (e.g. household chores, shopping) will also be collected and included in a secondary analysis.
Cost and QALY data will be synthesised to generate an incremental cost effectiveness ratio (ICER), which is defined as
the ratio of the mean difference in costs to the mean difference in QALYs between treatments. Multivariate regression
models will be used to assess the heterogeneity in costs, QALYs and cost-effectiveness. Multiple imputation techniques
will be used to address the statistical issues related to the presence of missing data in the economic evaluation (Briggs et
al., 2003). In order to characterise the uncertainty in the data, structural, scenario and probabilistic sensitivity analyses
will be conducted. The uncertainty will be presented using a cost-effectiveness acceptability curve which shows the
probability of the surgical interventions being more cost-effective than ESP conditional on a maximum value being
attached to an additional unit of health outcome (Fenwick et al., 2001).
For the longer term, and if it is appropriate, QALYs for each patient will be calculated by extrapolating results of the
trial based analysis to a longer time horizon. For example, by assessing the longer term impact on health related quality
of life and costs at five years as at this time around 40% of patients continue to have from mild to severe symptoms
(Hand et al., 2008). The potential value of further research in this area will be considered (Claxton and Sculpher, 2006).
12.3 Qualitative study analysis
We will use a constructivist grounded theory approach, which takes the stance that theory is not ‘discovered’ but coconstructed by researcher and participant (Charmaz, 2006). This encourages a flexible rather than rule based approach
to the research process that incorporates progressively focused coding, memo writing, theoretical sampling and
conceptualisation (Charmaz, 2006). A process of constantly comparing data, codes and categories at all stages enables
the researcher to develop theory grounded in the data (Strauss and Corbin, 1998; Charmaz, 2006; Bryant and Charmaz,
2007). Following the conventions of the constant comparative method (Strauss and Corbin, 1990; Glaser and Strauss,
1967) data analysis will be carried out alongside data collection, with interviews transcribed and analysed in batches
before further data are collected. In this way, the process is iterative with models and theories developed from ‘within’
the interviews [rather than from existing theory or clinical practice] and tested or refined in the collection of more data.
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Analysis is iterative, moving from an initial tentative category towards a robust theoretical category. We will use NVivo
9 to assist our organisation of qualitative analysis. This computer programme is particularly well suited to a grounded
theory approach as it allows the researcher to begin conceptual coding as early as is felt appropriate, and to remain
flexible throughout the research process. It also allows the researcher to keep a log of analytic decision-making and to
attach team memos to conceptual categories.
Within a grounded theory study we would expect to generate models which reflect patient experiences of frozen
shoulder and its treatment, which identify difficulties and advantages of the different treatment options. Such models
are likely to focus upon personal and lifestyle attributes as well as physical recovery, and to incorporate a range of nonclinical factors which are not routinely considered in clinical interactions. Insight into participation in a clinical trial will
also be generated.
All interviews will be analysed by the researcher conducting the interviews with a second team member coding a subset
of interviews and commenting on the development of conceptual categories. The aim of this is not to reach consensus
but to challenge the emerging interpretation and ensure interpretive rigour (Toye et al., 2013). We will develop our
conceptual model collaboratively in team meetings.
We will continue to interview men and women to a point of theoretical saturation (Charmaz, 2006); in short, until no
further useful conceptual categories emerge. Theoretical sampling is used in grounded theory to seek and collect,
‘pertinent data to elaborate and refine categories in your emerging theory’ (Charmaz, 2006)[p96]. Theoretical sampling
allows us to explore developing theory in a variety of samples (e.g. men versus women; different ages; with or without
diabetes; dominant versus non-dominant hand). This method of sampling does not aim to be representative of a
particular population, but is emergent, allowing analysis to move from an initial tentative category towards a robust
theoretical category (Baker and Edwards, 2012). Although it is not possible to anticipate the exact number required our
sample is likely to include up to 45 trial participants and 15 health care professionals. This number is consistent with
recommendations of qualitative research experts (Baker and Edwards, 2012).
13. Dissemination and projected outputs
13.1 Plans for dissemination
The research team have extensive experience in translating research findings into clinical practice through the
development of clear, evidence based care pathways to improve patient care. The experience of the research team has
found translating research into clinical practice involves the development of training packages and the findings of this
research will be incorporated to provide workshops to encourage the adoption of our recommendations into clinical
care.
The trial results will be disseminated regardless of the magnitude or direction of effect (Chan et al., 2013). A
fundamental ethical principle in clinical trials is that the potential risks incurred by study participants should be
balanced by the benefit of contributing to publicly available knowledge. We therefore plan to disseminate trial results to
key stakeholders and patients in several ways:
1. The study protocol and final reports will be submitted for publication in peer reviewed journals. We will publish
various reports including the HTA monograph, journal publication, trial registry, trial website and specialist
society reports. We will specifically target health professionals involved in the management of the frozen shoulder
i.e., General Practitioners, Physiotherapists, Rheumatologists and Orthopaedic Surgeons.
2. Our findings will inform the deliberations of Commissioning Reference Groups and thus have access directly to
commissioning instruments to drive changes of proven effectiveness.
3. Findings will be presented at key scientific meetings: the annual meeting of the British Elbow and Shoulder
Society (BESS) and the British Orthopaedic Association (BOA). Member surgeons and physiotherapists of BESS
will be PIs and collaborators on this study, and their help will be sought for dissemination and adoption of findings
into clinical care.
4. Findings and reports will be made available on websites of BESS and BOA to ensure this information can be
accessed by consumer groups.
5. Service users will help generate patient information that is feedback directly to trial participants, for Shared
Decision Making based on findings from this trial, update the entry on Wikipedia and write the Map of Medicine
entry on frozen shoulder management. In this way service users will actively participate in dissemination of the
conclusions of this study in a manner that is easily accessible by patients.
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13.2 Projected output
We intend to produce the following outputs, all of which will involve signposting those interested in further details to
the full HTA report:
1. We shall aim to publish the clinical findings of the trial and cost-effectiveness results in a high impact journal such
as The Lancet or British Medical Journal or alternatively a journal which targets the orthopaedic community such
as Annals of Surgery or The Bone and Joint Journal.
2. To ensure that the key stakeholders such as orthopaedic surgeons and physiotherapists are informed of the trial
results we will present at a variety of conferences (e.g. BESS, BOA, Physiotherapy UK conference) and provide a
summary report to be submitted through networks such as that provided by BESS and the National Physiotherapy
Research Network. Wider dissemination to other health professionals like Rheumatologists, General Practitioners
and community physiotherapists will also be facilitated.
3. We will work with the service users to produce a short non-technical report to feedback directly to the trial
participants and to help generate patient information for Shared Decision Making, update the entry on Wikipedia
and write the Map of Medicine entry on frozen shoulder management to inform the general public.
4. There will be several other articles to publish such as the findings of the acceptability of the treatments to patients
and clinicians and the update of the systematic review.
5. Publication of the findings will be press released through the collaborating Universities and the potential for short
articles in the relevant lay media explored.
6. The qualitative interviews will provide important patient-centred insight to further guide clinical decision making
for patients with frozen shoulder. It will also allow us to further understand the experience of health care treatment
for this group of patients, with a view to improving this experience.
7. Any new intellectual property generated from the study such as development of training materials to inform the
implementation of the ESP intervention will be made available to all and not restricted to the NHS; and therefore
help globally to inform future clinical practice and research in the area.
8. We will explore non-academic routes to dissemination and the best format to communicate the findings. These
outputs will be co-produced with an organisation such as patient.co.uk who specialise in supplying evidence based
information on a wide range of medical and health topics to patients and health professionals.
We will aim to publish these findings as widely, speedily and efficiently as possible to allow their introduction to
clinical practice and for evidence-based medicine to be used in every and each treatment of these patients in secondary
care. Our collaborative effort between health care practitioners, researchers and patients will help to make this possible.
In particular, the involvement of a specialist in PPI and the two service users will ensure that the project is patientorientated and relevant for the end-users. The qualitative investigation of patient experiences of the treatment options
will provide important patient-centred insight to further guide clinical decision making. The economic component we
will help us to identify the most efficient provision of future care and thus savings to the NHS and society. We will also
work with the relevant National Clinical Director in the Department of Health to help ensure the findings of the trial are
considered when implementing policy.
14. Plan of investigation and timetable
14.1 Patient recruitment and expected recruitment rates
For NHS hospitals in England in 2009/10 and 2010/11 using Hospital Episode Statistics that excludes post trauma or
secondary referral from other specialities there is a stable rate of 210 per million patients treated for frozen shoulder in
secondary care. Assuming 50% of frozen shoulder patients presenting in secondary care meet the inclusion criteria and
40% consent (based on the ProFHER trial experience comparing surgical versus conservative care in shoulder fracture
patients) that leaves around 40 patients per million to be recruited into the trial. To recruit 500 trial participants from
Trusts that serve around a half million catchment area we need 25 hospitals to recruit for a minimum of one year. This
estimate, however, requires no delays in set up or problems at any time after that, all surgeons at a site to participate,
and all potential participants to be screened for eligibility. Our experience of successfully conducting other surgical
trials is that setting up 25 hospitals is feasible, but we judge that realistically 30 months is required to meet our
recruitment target. When we undertook a survey of PIs involved in two multi-centre shoulder surgical trials (ProFHER
and UKUFF) of the 53 who responded there were 32 surgeons from 30 sites who were willing to be PIs. Therefore we
already have interest from more than 25 sites with experienced PIs to help achieve the recruitment target.
14.2 Project plan
We will have ethical approval to start the study on 01/10/14 for duration of 57 months. For months 1 to 3 we will
prepare the study materials, trial management database and randomisation service and acquire the local R&D approval
of the four sites involved in the internal pilot study. In addition, we will meet with the independent TSC and DMEC to
approve the trial protocol. From months 4 to 9 we will monitor the feasibility aspects of phase 1 of the internal pilot
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study at the four sites and set up the other sites. From months 10 to 27 we will complete phase 2 of the internal pilot
study and review cross-over and whether to maintain a three-arm trial. From months 10 to 39 we will complete the set
up of sites and the recruitment of participants into the trial. From months 40 to 51 we will complete patient follow-up at
12 months. Finally, from months 52 to 57 we will complete data cleaning, undertake the clinical effectiveness and
health economic analyses, and complete the Draft Final Report.
The key milestones during this study are:
 In month 4, the first participant will be recruited into the trial;
 In month 7, the first participant will be followed-up;
 In month 10, we will review the findings of phase 1 of the internal pilot study;
 In month 22, we will commence the qualitative study;
 In month 27, we will review the findings of phase 2 of the internal pilot study;
 In month 39, we will complete patient recruitment into the trial and begin the systematic review;
 In month 51, we will complete trial participant follow-up, qualitative study and systematic review;
 In month 57, we will complete the Draft Final Report.
Time period (month)
Activity
1–3
Complete local R&D approval and set up for 4 pilot sites
4–9
Initiate early recruitment (phase 1 of internal pilot study at 4 sites and continue
R&D approval for other sites)
10-27
Complete phase 2 of internal pilot study and review crossover and whether a threearm trial is feasible or whether randomisation to physiotherapy should be omitted
10 – 39
Main recruitment for the trial
40 – 51
Complete final 12 month follow-up
52 – 57
Analysis and write up of main HTA monograph
15. Project management
The strength of our application is that the project management will draw upon the expertise from four institutions
experienced in undertaking orthopaedic surgical RCTs: James Cook University Hospital, Middlesbrough (lead site);
University of York’s Trials Unit (YTU); Oxford Clinical Trials Unit (OCTRU); and Glasgow Royal Infirmary
Orthopaedic Research Unit. The Trial Manager at YTU will oversee all aspects of trial management. The Trial Coordinators at James Cook, OCTRU and Glasgow Royal Infirmary will co-ordinate recruitment in the North and South of
England/Wales and in Scotland. These four members of the research team will meet by teleconference on a weekly
basis from the start of the project until the end of the internal pilot study. It will be critical to meet this regularly when
setting up the study to prepare all the study materials, set up sites to recruit and monitor recruitment progress. We will
also maintain contact via email and telephone.
There will be a Trial Management Group (TMG) to monitor the day-to-day management of the trial. This will comprise
all the co-applicants, convened by the Chief Investigator, and will meet face-to-face at alternate venues every three
months from the start of the study until the end of the pilot. The TMG will then meet every four months via
teleconference (or face-to-face as necessary) for the duration of the study. There will be a TSC to monitor the progress
of the trial and provide independent advice and a DMEC that will monitor the data arising from the study and
recommend whether there are any ethical or safety reasons why the trial should not continue. The TSC and DMEC will
comprise of independent clinicians and health service researchers with appropriate expertise. Both the TSC and DMEC
will meet at regular intervals to provide project oversight to the trial. This will include monitoring the acceptability of
waiting times to the study interventions which sites will have committed to being achievable when assessing their
feasibility to take part. The project will also be monitored by the Sponsor for whom a representative will be invited to
attend the TMG and TSC meetings and we will submit regular progress reports to the Funding Body. This project will
help to further enhance the fostering of networks that have been established between these institutions in the design and
conduct of UK-wide orthopaedic surgical trials.
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16. Ethical arrangements
In the context of the lack of robust evidence to determine the best treatment for patients with this condition, the risks are
not increased through trial participation. Measures taken by us, such as our emphasis on good practice and standardised
protocols/care pathways throughout, are likely to reduce risk and could bring additional benefits. We will emphasise the
importance of surgeons performing interventions which they undertake on a regular basis and with which they are
familiar. We will also stress the importance of competence in non-surgical methods. We will adhere to the Research
Governance Framework and MRC Good Clinical Practice Guidance (MRC Ethics Series, 2012; DoH, 2005). The
participant information sheet for the study will be developed with the involvement of service users and will give a
balanced account of the possible benefits and known risks of the interventions. It will state explicitly that quality of care
will not be compromised if the participant decides to a) not enter the trial or b) withdraw their consent. We will make it
clear that there is no obligation to participate. Written informed consent will be obtained from all participants after they
have had sufficient time to read the study materials and ask any questions. An application for ethical approval will be
made through the IRAS system in the pre-funding phase. We do not anticipate major ethical concerns with this study.
The only potential concern would be the inclusion of patients who lack mental capacity to understand the trial
procedures or instructions for rehabilitation procedures and subsequent compliance. We will allow the treating clinician
to exclude these patients from this trial. The local R&D committee of each of the participating hospitals will approve
local involvement in the trial. The trial will be subject to DMEC oversight.
16.1 Risks and anticipated benefits
ACR requires General Anaesthesia (GA) and two or three small surgical incisions, usually over the back and front of
the affected shoulder. MUA also requires GA; corticosteroid injection provided with MUA carries with it a small risk of
infection. The risks associated with this study are predominantly the risks associated with ACR, MUA and GA:
infection, bleeding and the very rare risks of damage to the adjacent structures such as nerves, tendons, bone or joint.
GA may be supplemented with nerve blocks and both ACR and MUA therefore carry the general risks of anaesthesia
and small risk of nerve injury from the block. Temporary worsening of pain (including steroid flare) rarely occurs
with all three treatments in this study – ACR, MUA and Physiotherapy. Participants in ACR and MUA groups will
potentially be at risk from any/all of these complications. However, the evidence available to quantify this surgical
risk is limited. There are no data to suggest that the risk of aggravating pain with intervention is greater in one group
or another. We believe that the overall risk profile is very small for the three interve ntions but we intend to document
the number of complications in each group as a secondary outcome of the study. If ACR or MUA result in earlier
return to function, work and leisure, their associated risks may be justified. Previously reported case series in the
literature indicate benefit to patients from ACR and MUA with reduction of pain and improvement of shoulder
function. Evidence for ESP based on national guidelines remains limited, although improvements with components
of these physiotherapy guidelines have been previously reported. This study will deliver structured interventions
with active monitoring of progress, allowing patients to benefit from best possible outcomes from each of these
interventions. Establishing relative benefits of these interventions and based on that, refinement of pathways of care
in the NHS for frozen shoulder would be a clear benefit to patients and the NHS.
The nature of the qualitative enquiry is to probe sensitive issues, and participants might find it difficult or upsetting to
talk. However, the interviews will be handled sensitively, and patients will be assured that they can withdraw from the
study at any time. The researcher has experience in conducting this type of interview, and other patients have said that it
has been a good experience to talk to a researcher. Although there is no direct benefit to participants, our previous
research has demonstrated that being listened to is an important facet of a therapeutic encounter. We will assure patients
that their decision to take part (or not) does not affect their treatment in any way.
16.2 Informing potential trial participants of possible benefits and known risks
Informed consent will be obtained by the trained local research nurse or clinician using a detailed patient information
sheet developed with the help of service users and explaining the risks and benefits clearly. In the unlikely event that
new information arises during the trial that may affect participants’ willingness to take part, this will be reviewed by
the TSC for addition to the patient information sheet. A revised consent form will also be completed if necessary.
16.3 Adverse event management
Adverse events (AE) are defined as any untoward medical occurrence in a clinical trial participant and which do not
necessarily have a causal relationship with the treatment. Serious adverse events (SAEs) are defined as any untoward
and unexpected medical occurrence that: 1. results in death, 2. is life-threatening, 3. requires hospitalisation or
prolongation of existing inpatients´ hospitalisation, 4. results in persistent or significant disability or incapacity, 5. is a
congenital anomaly or birth defect, 6. includes any other important medical condition not listed above which may
require medical or surgical intervention to prevent one of the outcomes listed.
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At participating sites, all SAEs will be entered onto a pre-designed proforma for return to the ‘UK FROST’ central
office within 24 hours of the investigator becoming aware of them. Once received, causality and expectedness will be
determined by the Chief Investigator. SAEs that are deemed to be unexpected and related to the trial will be notified to
the Research Ethics Committee (REC) within 15 days for a non-life threatening event and within 7 days for a lifethreatening event. For non-serious AEs, the central office will be notified within 5 days of the event being known using
a pre-designed proforma. All such events will be reported to the DMEC at their next meetings. AEs that may be
expected with this shoulder condition that do not need to be reported to the main REC include: infection; bleeding;
delayed wound healing; conversion of planned day case procedure to overnight stay for control of pain; post-procedural
worsening of shoulder pain; injury to adjacent structures like nerve, tendon, bone or joint; recurrent stiffness requiring
further treatment; and transient hyperglycaemia, steroid flare or joint sepsis following corticosteroid injection; injuries
related to heating or cooling of tissues. Follow up reports a month later on all participants experiencing SAEs will be
reviewed by the Chief Investigator to ensure that adequate action has been taken and progress made to manage the
adverse event. For the purpose of this trial, we will only record adverse events that are related to the affected shoulder
during the twelve month follow-up.
16.4 Proposed time period for retention of relevant trial documentation
Essential Trial documentation (i.e. the documents which individually and collectively permit evaluation of the conduct
of a clinical trial and the quality of the data produced) will be kept with the Trial Master File and Investigator Site Files.
The Sponsor will ensure that this documentation will be retained for a minimum of five years after the conclusion of the
trial to comply with standards of Good Clinical Practice. Case Report Forms will be used to record all the information
required from the protocol. These data will be stored for a minimum of five years after the conclusion of the trial as
paper records; and a minimum of 20 years in electronic format in accordance with guidelines on Good Research
Practice (MRC Ethics Series, 2012). All paper records will be stored in a secure storage facility or off-site by York
Trials Unit. All electronic records will be stored on a password protected server. For the qualitative interviews,
recordings and transcripts will be anonymised and kept in a locked office for three years following the completion of
the study. Interview data will only be seen by the research team, and any quotation that could clearly be used to
identify a person would not be used in dissemination of findings.
16.5 Proposed action to comply with the medicines for human use (clinical trials) regulations 2004
There will be no implantable devices used in this trial and therefore no prior authorisation is required by the UK
Competent Authority, the MHRA, under the Medical Devices Regulations 2002. Injections of corticosteroid
preparations (classed as a medicinal product), when used as concomitant interventions, will be those with appropriate
marketing authorisation that are regularly used within the NHS and therefore do not require prior authorisation. These
injections will be prescribed and administered in the usual manner, with no specific diagnostic or monitoring
requirements other than those ordinarily applied following administration of corticosteroid injections during routine
care in the NHS.
17. Patient and Public Involvement
We have worked closely with patients in previous surgical trials. For this trial, two of the lead applicant's patients, have
confirmed their interest to be involved. Mr Andrew Robinson, co-applicant and PPI Lead for North East NIHR RDS,
based at the lead trust, will support their learning and development. The two patient representatives will help develop
key aspects of study protocol such as detailed patient information explaining risks and benefits of this study clearly;
consent process for trial participation; improving compliance and reducing attrition; and commenting on Case Report
Forms to ensure that all aspects of care considered important by patients are captured. They will also advise on the
weblink with video to be provided by the Chief Investigator to research staff at participating sites and for the video and
patient section of the trial website for consenting patients. They will help generate patient information for shared
decision making based on findings of this study, update the entry on Wikipedia and write the Map of Medicine entry on
frozen shoulder management, thus actively participating in dissemination of study findings which are easily accessible
by patients. Patient representatives will also be invited on to the TMG and TSC, providing patient representation and
perspective to the conduct of the trial in line with recognised good practice (Steel, 2003). Their involvement will help us
maintain a clear patient focus throughout the different stages of the project and will be reimbursed for any out-of-pocket
or training expenses (Evans et al., 2013).
Patient involvement has already strongly influenced the development of our application, led by the following.
1. At the lead applicant's unit, we have been asking patients with primary frozen shoulder their views on our proposed
design and sharing with them a draft Patient Information Leaflet. This has confirmed the acceptability of our study
design to patients and their willingness to be randomised.
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2. We have worked with public and patient groups in Lancaster and at Blackpool Teaching Hospitals NHS Foundation
Trust to develop and validate a global patient-reported question measuring resolution of symptoms. This has
included discussion groups that identified treatment-seeking behaviour as a key determinant of treatment resolution
from the patient’s perspective. This has included discussion groups that identified recovered functionality expressed
in terms of broad impact on daily life as a key determinant of treatment resolution from the patient’s perspective.
3. The applicants in Scotland have undertaken a focus group with frozen shoulder patients and clinicians. This
confirmed that the minimal acceptable intervention to patients was physiotherapy and steroid injection (our ‘control’
intervention) and that it was not appropriate to withhold surgical treatment if conservative measures have failed.
Patients confirmed that pain was important which we are capturing in our primary outcome (Oxford Shoulder
Score), for which 4 of the 12 questions ask about pain, and as a secondary outcome measure (see Section 11.2.4).
4. Co-applicants (James Cook & Teesside University) have also completed a qualitative study of patients with frozen
shoulder using semi-structured interviews to explore their experiences, priorities and perceptions. This revealed that
although shoulder pain was a common theme, functional disability was often considered more problematic. Anxiety
was a key theme and the struggle of living and dealing with frozen shoulder was compounded, in some cases, by a
lack of clarity surrounding diagnosis and treatment; and a lack of awareness on the part of healthcare professionals
to recognise and appreciate the difficulties faced by patients with frozen shoulder. The study highlighted the need to
provide standardised, consistent information for patients, designed in collaboration with patients, addressing
patients’ questions and concerns about this condition. Therefore we aim to develop an information leaflet to meet
these concerns for trial participants as part of our on-going PPI work. The findings from these interviews will also
inform the nested qualitative component to this study to understand patients’ treatment experiences..
18. Expertise and justification of support required
18.1 Expertise of project team
Our multi-disciplinary team includes patient representatives, clinicians and health service researchers who have already
fostered a strong research network of collaborating centres for orthopaedic surgical RCTs. The proposed study has been
endorsed by BESS.
Mr Andrew Robinson, co-applicant and PPI Lead for North East NIHR RDS, based at the lead trust, will support the
learning and development of the two patient representatives, which will be tailored to their needs.
Professor Amar Rangan, Chief Investigator (CI), is a specialist shoulder surgeon with considerable experience in
management of frozen shoulders. He is CI for HTA funded ProFHER trial and PI for other trials, Chair of TSC for HTA
funded WOLLF Trial (open fracture management lower limb) and independent member of TSC for ARUK funded
CSAW Trial (shoulder impingement trial). He is also Chairman of Research Committee, BOA and council member,
BESS, the network for this study, as it has already done successfully for ProFHER and UKUFF. Professor Rangan will
provide overall research leadership. Professor Andrew Carr is Nuffield Professor of Orthopaedic Surgery at University
of Oxford, CI on a national HTA funded trial of shoulder surgery for rotator cuff tears (UKUFF) and President of
BESS. He is also the Director of the Oxford Surgical Trials Unit which has core funding from the Royal College of
Surgeons to support the development of new surgical trials and trialists. Professor Joe Dias is a consultant orthopaedic
surgeon and has undertaken RCTs of upper limb disorders and is the CI of the HTA funded trial about fracture
management of the scaphoid bone (SWIFFT). Miss Alison Armstrong is a consultant surgeon with special interest in
shoulder and elbow disorders and PI for orthopaedic RCTs (UKUFF, ProFHER and Clavicle Trial) as is Mr
Charalambos Charalambous who is PI for ProFHER. Dr Nigel Hanchard and Mrs Lorna Goodchild are physiotherapists
with a musculoskeletal interest. Dr Nigel Hanchard is Senior Research Fellow at Teesside University. His interest is in
the diagnosis and management of shoulder pain and is the first author (Lorna Goodchild a co-author) of the Chartered
Society of Physiotherapy endorsed evidence-based clinical guidelines for frozen shoulder which will underpin the
control intervention for this study.
The Scottish team will be led by Mr Andrew Brooksbank and Dr Iain Anthony. Mr Brooksbank is a Consultant
Orthopaedic Shoulder Surgeon and has been involved in a number of multi-centre shoulder RCTs: Primary fixation of
displaced midshaft clavicle fractures; Shoulder Hemiarthroplasty or Reverse Polarity Arthroplasty for Trauma Study).
He also has funding for a basic science project investigating the pathogenesis of Frozen Shoulder (Funded by
TENOVUS Scotland). Dr Iain Anthony is a Clinical Research Manager within the Orthopaedic Research Unit at
Glasgow Royal Infirmary. He has extensive experience of managing orthopaedic RCTs. He currently holds a HTA
grant (Diagnostic Accuracy of the Thessaly Test) and was recently awarded funding by MRC (EME) in the joint call for
Surgical Themed Studies. In addition, he currently holds several commercial grants for major RCT studies. He will
provide overall study co-ordination between the Scottish sites.
Professor David Torgerson is the Director of York Trials Unit (YTU) who provides expertise in trial design, is a coapplicant to the ProFHER trial and Chair of TSC for HTA-funded DRAFFT surgical trial. Dr Stephen Brealey at YTU
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is the Trial Manager and co applicant for two HTA-funded surgical trials (ProFHER and SWIFFT). Dr Catherine
Hewitt is the senior statistician on ProFHER and SWIFFT and provides expertise in trial design and analysis. Dr Hewitt
will support Miss Ada Keding who is the statistician for ProFHER and SWIFFT. Dr Gerry Richardson is a senior health
economist on the SWIFFT trial at Centre for Health Economics, University of York with many years’ experience of
conducting cost-effectiveness analysis alongside trials using the results to inform economic models. Dr Richardson will
support Mrs Belen Corbacho who is the ProFHER trial health economist with a special interest in assessment and
appraisal of health technologies. Mrs Lucksy Kottam is a Career Scientist at the lead site (James Cook) who has been
involved in the set-up, screening, consenting and follow-up of patients in ProFHER and DRAFFT trials and will be the
North of UK Trial Co-ordinator. Professor Sallie Lamb is co-director of OCTRU with extensive experience in NIHR
multi-centre trials and will be on the TMG and provide oversight from Oxford. Dr Francine Toye is a Senior Research
Fellow, Oxford with experience as a mixed methods health services researcher including embedding qualitative
research into RCTs. Mrs Cushla Cooper was the Trial Manager for a HTA funded surgical trial (UKUFF) and will
oversee recruitment in South of UK. Dr Catriona McDaid is a Senior Research Fellow, University of York who led the
recent HTA funded systematic review of frozen shoulder and will oversee the update of the review. Dr Sally Spencer,
Lancaster University is Senior Researcher with expertise in patient reported-outcome measures and systematic reviews
and has advised on the choice and development of outcome measures for this study.
The proposed research on frozen shoulder complements our involvement in other HTA funded RCTs investigating the
management of patients with upper limb disorders (ProFHER, DRAFFT, UKUFF and SWIFFT). Our prior experience
with intricacies and processes involved in running multi-centre surgical trials of shoulder disorders (ProFHER and
UKUFF) has prepared us to conduct this trial. There are similarities in the research infrastructure requirement,
outcomes assessment and recruitment challenges between these trials with UK-FROST. The groundwork in getting
collaborating centres research ready for the HTA funded studies referred to will facilitate the conduct of this study.
18.2 Justification of support required
18.2.1 Research costs
Funding is required to facilitate the full participation of Prof Rangan, the lead applicant, in every aspect of the trial and
to provide clinical support and advice for the recruiting sites. This includes the 0.5 WTE funding of a clinical trial coordinator at the lead site (James Cook) to facilitate set up and recruitment at centres in North of UK and undertaking the
systematic review. In addition, there are nominal small proportions of WTE for other clinical staff (shoulder surgeons
and physiotherapists) who will be involved in recruitment as well as the training and delivering the trial interventions.
For York Trials Unit a key research cost is the Trial Manager for the 57 month funding period. This post is essential for
all aspects of trial management including setting up sites, data collection, undertaking the systematic review and write
up of the monograph. Data management staff, economist, statistician, systematic reviewer, outcome specialist and trial
secretary are required at variable whole time equivalents (WTEs) depending on the stage of the trial. There are costs of
consumables incurred for aspects of data collection and management (e.g. printing of forms, scanning license,
archiving, and randomisation) and travel expenses for attending regular meetings with the TMG, TSC, DMEC and visits
to participating sites.
Funding is required for collaborating with OCTRU to provide specialist expertise in qualitative research for the design,
conduct and analyses of the interviews. A small proportion of funding is allocated for a trial co-ordinator in OCTRU
who will facilitate recruitment from centres in the South of UK. Nominal funding is allocated for Prof Andrew Carr and
Prof Sallie Lamb from OCTRU to advise on the OSS and aspects of trial management including membership of the
TMG. Funding is also required for the collaboration with Glasgow Royal Infirmary, Orthopaedic Research Unit. The
team at Glasgow Royal Infirmary will co-ordinate the Scottish sites. Therefore funding has been requested for 0.5 WTE
trial co-ordinator and nominal funding for the lead clinician (Andrew Brooksbank).
The service users will be reimbursed for travel expenses when attending meetings, as will trial participants who attend
for physiotherapy in the control intervention. Our trial costs include payment per patient recruited to cover costs of
research nurses’ or clinicians’ time for tasks such as assessing eligibility, randomising and subsequent collection of
follow-up hospital data. These activities are not contributing directly to the care of a patient. Therefore as has been
approved previously by the HTA for other surgical trials (ProFHER, DRAFFT and SWIFFT) we propose that these
should be included as research costs.
18.2.2 NHS Service support costs
The NHS Service Support costs are the additional patient care costs associated with the research, which would end once
the R&D activity in question has stopped, even if the patient care service involved continues to be provided. The cost of
the Research Nurse or assessing clinician identifying patients who have been referred for a frozen shoulder to an
outpatient clinic in hospital is a support cost. The cost of obtaining patient consent is also a NHS Service Support cost.
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The consent rate in a similar trial (ProFHER) of conservative care versus surgical intervention with patients who have a
fracture of the shoulder was around 45%. For a sample size of 500 patients we may need to attempt to obtain consent in
around 1000 patients. Therefore the NHS support costs have been calculated based on a Research Nurse requiring 30
minutes to obtain consent for this number of patients. In addition, there is the same cost again in identifying the patient
to be suitable to approach to take part in the study. There are no additional investigations for this study which are
required by the patient’s care team, to ensure patient safety. The payments per patient to re-imburse the Research Nurse
for data collection using Case Record Forms is a research cost (see section 18.2.1).
18.2.3 NHS Excess treatment costs
The excess treatment costs for this trial would be the provision of ESP for 12 weeks, which is the ‘control’ treatment to
the surgical interventions, and is not always routinely provided when patients are seen in secondary care. In addition,
when the patient has completed their physiotherapy, there will be a 12 week review with an orthopaedic surgeon to
decide with the patient whether there is a need for any further treatment. The ESP treatment costs are the responsibility
of the NHS and we will seek their funding through the normal local commissioning arrangements. The surgical
interventions being compared are standard treatment options currently available in NHS hospitals. We anticipate that
there will be no excess treatment costs for these surgical interventions. While this is likely to be the case in the majority
of centres, this may not apply to certain hospitals even when there is a low recruitment rate, or have a low rate of, for
example, arthroscopic capsular release surgery. It will be for the individual providers at the participating sites to
consider the need to fund these treatment costs when deciding on approval for the trial.
19. Protocol amendments since original REC approval
Protocol amendment number (and date): Substantial Amendment 1 (12 January 2015):
 We updated the trial protocol from v1.1 04/11/14 to v2.0 12/01/15.
 In agreement with our Data Monitoring Ethics Committee (DMEC) we are now explicit about adjusting for
age, gender and diabetes and that for presence of diabetes we shall undertake an exploratory subgroup analysis
(Section 12.1).
 We removed the word ‘trauma’ in relation to the site catchment area in Section 9 and the flow diagram as it
does not need to be a ‘trauma’ site to recruit patients.
 In Section 7.5 we removed the word ‘injury’ as this was an oversight and is not a reason for why a patient is
entered into the study.
Protocol amendment number (and date): Substantial Amendment 2 (7 May 2016):
 We updated the trial protocol from v2.0 12/01/15 to v3.0 20/04 16.
 We included an additional sub-group analysis as proposed by our DMEC on 19 June 2015 (see Section 12.1) to
explore differences in patient treatment response depending on whether they had physiotherapy or not before
being enrolled on the study. This could help to inform future research about what treatment the patient should
receive in a hospital setting if they have already had physiotherapy.
 We amended the protocol to advise sites what treatment the patient should receive whilst waiting for surgery
(see Section 8). This is important to ensure that any treatment the patient receives whilst waiting for surgery is
appropriate and compatible with the interventions that are being delivered in the trial.
 We amended the protocol so that patients who receive the ESP treatment should complete the pre-treatment
form before the steroid injection or on the first day of physiotherapy, whichever is first (see Section 11.3).
 We removed the text from Section 2 of the protocol at the request of the Funding Body as this concerned
feedback to the Board’s comments. We inserted some of this text in other sections of the amended protocol to
ensure that these issues are still included i.e. see Sections 7.4 (about how we will manage expectation bias) and
8.3 (about patients being re-imbursed for travel expenses for attending physiotherapy in the ESP group).
Protocol amendment number (and date): Substantial Amendment 3 (15 November 2016):
 We updated the trial protocol from v3.0_20/04/16 to v4.0 15/11/16.
 We have added Section 8.2.1 explaining the nested shoulder capsular tissue and blood sample study we plan to
undertake at selected hospitals because of logistical reasons of implementation.
 We also acquired approval for this nested study an approach letter, consent form and patient information leaflet
(v1.0_15/11/16).
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HTA PROJECT NUMBER 13/26/01 V4.0_151116
19. Flow diagram
Inclusion criteria:
 Patients, including diabetics,
>=18 years old
 Passive external rotation in the
affected shoulder that is <50% of
the contralateral shoulder
 Radiographs to exclude secondary
causes e.g. glenohumeral arthritis
Eligible – obtain consent
No consent:
- Complete Study Eligibility Form
- Complete Consent Status Form
- Complete Patient Preference Form
Patient with frozen shoulder
is identified by a member of
the research team in an outpatient clinic.
Exclusion criteria:
 Bilateral concurrent frozen
shoulders
 Secondary to trauma or other
causes
 Trial treatments contraindicated
 Unfit for general anaesthesia
 Not resident to catchment area of
a participating trial site
 Lack mental capacity to comply
with treatment or data collection
Consent:
- Complete Study Eligibility Form
- Complete Consent Status Form
- Complete Consent Form
- Complete Baseline Form
- Complete Contact Details Form
Not eligible:
- Complete Study Eligibility Form
Randomise
Early Structured
Physiotherapy
(n=100)
Manipulation Under
Anaesthesia with
steroid injection
(n=200)
Arthroscopic
capsular release with
MUA
(n=200)
Completion of forms at 3 months after randomisation:
 Participant postal questionnaire
 Hospital Forms – Surgery & Early Structured Physiotherapy
& Pre-treatment Form
Completion of forms at 6 months after randomisation and
start of study treatment:
 Participant postal questionnaires
 Hospital Form – Post-procedural Physiotherapy
Completion of forms at 12 months after randomisation:
 Participant postal questionnaire
 Hospital Form – Complications
Completion of forms during the trial:
 Hospital Forms – Adverse Events & Trial Withdrawals
23
Qualitative study:
Up to 45 patients [& 10 to
15 health care professionals]
Patient Sampling Frame:
 Treatment group
 Diabetes
 Gender
HTA PROJECT NUMBER 13/26/01 V4.0_151116
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