Trial design (Figure 1)
Experience from a wide range of trials in primary care suggests that obtaining consent within a single consultation is difficult. Therefore all potential trial participants were given an information leaflet by their GP at the first consultation. Patients who were then eligible, but uncertain about whether to participate were encouraged to take at least 24 hours to decide.
In each practice participating GPs or practice nurses randomised eligible and consenting participants to one of the two trial interventions: referral to the local radiology department for an MRI examination underpinned by a provisional orthopaedic referral; or referral as usual to the local orthopaedic department for consultation with a specialist.
Interventions
Direct access to MRI (experimental intervention)
At each hospital, imaging was performed with standard commercially available MR imagers using imaging protocols at the discretion of the radiologist. 'Excess treatment costs' were used to ensure that participants in the experimental group could have early access to MRI within twelve weeks of referral from their GP, who then used the MRI findings to inform diagnosis and plan subsequent management. Participants with normal MRI findings received treatment including advice to return to normal activities, undertake quadriceps exercises, and referral for physiotherapy depending on their clinical history. GPs were advised that when radiologists reported a serious abnormality like a tumour on an MRI examination the participant should be fast-tracked as normal.
To avoid contaminating our evaluation by differences in waiting times between the two clinical policies, we asked GPs to make a provisional referral to orthopaedics at the same time as requesting MRI. This was to ensure that the total waiting time from GP consultation to orthopaedic appointment was similar for both trial arms. Thus the trial will establish the more appropriate sequence of events rather than try to assess the influence of variations in waiting times.
There is evidence that educational interventions to support the dissemination of clinical guidelines can improve GPs' knowledge of MRI use [26] and the routine attachment of educational messages to radiologists' reports can avoid unnecessary GP referral [27]. We therefore delivered educational seminars to GPs about MRI, clinical diagnosis and conservative management and attached the educational message shown in Figure 2 to the radiologists' reports.
Referral to orthopaedic specialist in secondary care (the control intervention)
The potential delay between GP referral and a participant's outpatient appointment with an orthopaedic specialist varied across experimental sites from three to eighteen months. We therefore used 'excess service support costs' when necessary to run extra clinics to reduce the waiting time for an orthopaedic appointment from GP referral to within nine months, and the delay between orthopaedic consultation and arthroscopy to within nine months. Reducing the waiting time from GP referral to arthroscopy to eighteen months meant that following up participants for two years would ensure the evaluation covered most relevant events including arthroscopy. Orthopaedic specialists decided whether to request MRI as normal.
Inclusion and exclusion criteria
The target population for inclusion were people aged between 18 and 55 years inclusive presenting in general practice and for whom the GP was considering referral to see an orthopaedic specialist for suspected internal derangement of the knee (e.g. meniscal or ligamentous injuries). Individual practices decided whether GP Registrars should recruit and manage eligible patients. Consultant radiologists could delegate reporting to Specialist Registrars. Consultant orthopaedic surgeons could also delegate to junior staff if appropriate.
Patients were excluded if:
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Their GP judged that they needed urgent orthopaedic referral at the initial consultation (e.g. gross ligamentous injury or sudden onset of effusion).
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They had suspected osteoarthritis, other non-traumatic arthropathy, or isolated patello-femoral joint pain.
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They had chronic instability of the knee due to history of major injury.
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They had a previous MRI examination within the same episode of care.
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They had previous surgical intervention (excluding diagnostic arthroscopy) on the same knee.
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They had contraindications to the use of MRI, for example pacemaker, intra-cranial aneurysm clips, or orbital metallic foreign body.
Figures 3 and 4 summarise the guidance given to GPs to differentiate between osteoarthritis and internal derangement of the knee and how physiotherapy might be useful before referral to an orthopaedic specialist.
Recruitment and allocation to interventions
The trial was based in sites across North Wales, North East Scotland, and Yorkshire – areas covering urban, mixed and rural settings and a broad socio-economic spectrum. The total population of these geographical areas is around two million people registered in over six hundred general practices.
There is evidence that a multi-faceted strategy including education, financial compensation and regular contact is effective for recruiting GPs and patients [28]. Therefore when practices were approached to participate in the trial we offered GPs the opportunity to attend seminars to learn about and discuss the trial and the choice of receiving payment or postgraduate education accreditation. The seminars were held at places and times most convenient for GPs. We also visited the practices of GPs unable to attend the seminars and contacted others by telephone. To cover expenses each participating practice received payments for committing themselves to the trial, recruiting participants, and for completing all relevant documentation. During recruitment we updated participating practices through a newsletter, and maintained regular contact by telephone and email. Posters were designed to alert patients with knee problems about the study whilst waiting for their appointment in general practice. We publicised the trial through primary care newsletters, articles in local newspapers, the trial website, and leaflets and posters in local Accident & Emergency and Physiotherapy Departments, pharmacies and sports centres. We also asked hospitals to ensure that patient contact with MRI or Orthopaedic Departments triggered referring GPs from participating practices to consider recruiting a patient into the trial if they had not already done so.
Ethical approval
The trial protocol was designed to comply with the Declaration of Helsinki as adopted by the World Medical Association. Northern and Yorkshire Multi-Centre Research Ethics Committee approved the protocol (reference number MREC/1/3/59).
Obtaining consent
When patients consulted their GP with a knee problem, the GP provided the patient with the information leaflet, unless there was any obvious reason for exclusion. Practices that collected computerised data on consultations were also asked to identify and send leaflets to patients not previously identified at the time of their initial consultation who might still be eligible. Patients who were eligible and agreed to consent were asked by their GP to complete the baseline questionnaire.
Randomisation
When a participant completed the baseline questionnaire a designated member of the practice phoned the remote randomisation service at the University of York Trials Unit for the random allocation. They then informed the participant of their allocation and the GP made the appropriate referrals. As the trial was pragmatic in design, so as to reflect the consequences of routine GP access to MRI, blinding of participants or professionals to treatment allocation was not appropriate.
The randomisation service ensured immediate and unbiased allocation of individual participants between the two arms of the trial. The service recorded information to identify all participants and their eligibility. There is evidence of substantial inter-observer variability in radiologist reporting of MRI of the knee [29]; there is also evidence that practice list size [30] and distance from general practice to MRI centre [31] influence referral for MRI. We therefore stratified the randomisation procedure by experimental site, median distance from practice to hospital, and median number of partners in practices as a proxy for practice list size. Within strata a block allocation sequence was used; permuted random blocks of size 2 or 4 were randomly selected to generate the allocation sequence.
When the trial began we recruited participants from practices in Hull and East Yorkshire, York and North Yorkshire, Grampian and North Wales. Delays, for example in the approval of NHS costs from North Wales, led us to extend this invitation to practices to participate in Lothian, Bradford, Rotherham, Sheffield and Tayside. We modified the randomisation procedure for practices from these sites to reduce administration and expedite recruitment. The new procedure required the GP to establish eligibility, obtain consent, make the orthopaedic referral, and provide the participant with the baseline questionnaire and contact details form. The participant posted completed forms to York where the Trial Secretary entered the data into the randomisation database, performed the randomisation, and posted the results of the allocation to the GP and the participant.
Stopping rules
Participants referred to orthopaedic departments were at no greater risk than in normal clinical practice. MRI of the knee has no serious side-effects providing the known contraindications are avoided, which is routine practice in Radiology departments. A very small percentage of patients find lying in the scanner space unpleasant [32]. As this is thus a pragmatic trial with very little risk to participants, interim analyses were unnecessary.
Outcome measures
Participants completed a baseline questionnaire after giving informed consent but before randomisation. The main outcome measures were self-assessed questionnaires asking about participants' knee-related health, general health, and demographic characteristics. Participants received similar questionnaires by post six, twelve, and 24 months after random allocation. Existing evidence about effective follow-up strategies enabled us to maximise the effective sample size and reduce bias [33]. At six months follow-up this included a reminder by post after two and four weeks and by telephone after six weeks if necessary. At twelve and 24 months this strategy was supplemented with a two week pre-notification letter enclosing £5. This money was given whether or not participants completed questionnaires to cover expenses incurred in doing so. At the final reminder six weeks after the 24 month follow up, participants who had not returned the questionnaire could choose to complete an abridged questionnaire by telephone. This comprised the EQ-5D and five questions from the knee-specific instrument that explained most of the variation in participants' responses.
Health outcomes
In the absence of an appropriate patient-assessed health instrument specific to the knee with satisfactory evidence for reliability, validity, and responsiveness [34], we developed our own instrument. We complemented this instrument with two generic measures useful for identifying unexpected effects of interventions and for economic evaluation. The Short Form 36-item (SF-36) health survey is a popular health profile that has been validated for use in the NHS [35]. The EQ-5D generates a single index for valuing health states and is therefore suitable for cost-utility analysis [36]. Both measures are responsive to changes in the health of patients referred for MRI of the knee [37].
Health economic outcomes
Musculoskeletal problems and associated disabilities generate high costs – in health care (both within and outwith the NHS), social security, and lost production [38]. A broad economic evaluation is essential to inform commissioning and service decisions about the most efficient policy for managing patients with continuing knee problems.
To estimate the incremental costs of each policy the economic evaluation takes the perspective of both the NHS and society. When we have completed the prospective collection of data from participants, practices and hospitals on NHS resources consumed we shall use these data to estimate both the quantity of resources consumed and complement this with the unit cost of each resource. Unit cost data will be derived from reliable published sources [39], the Department of Health Central cost estimates, and from manufacturers.
Thus the data available for economic analysis are patient-specific resource use and costs. Given the skewness inherent in most cost data and the focus of analysis on mean costs, we shall use bootstrapping to estimate confidence intervals around the difference in mean costs [40, 41]. The base-case analysis will consider the costs and consequences of direct access to MRI, reporting disaggregated data on incremental costs and on the broad range of consequences. The base-case analysis will consider both the NHS perspective and a broader societal view where patient costs and productivity issues will additionally be incorporated. If one intervention clearly dominates the other in both costs and consequences, then analysis will be essentially complete. If there is no such dominance, however, we shall use both cost-effectiveness (focusing on cost per change in knee specific score) and cost-utility analyses (focusing on cost per quality-adjusted life year (QALY) gained), as estimated from the EQ-5D instrument. Results will be presented using cost-effectiveness acceptability curves to reflect sampling variation and uncertainty in the threshold value of a QALY. We shall also use simple and probabilistic sensitivity analyses to explore whether these results are robust to plausible variations in key assumptions (e.g. average appointment times) and variations in analytical methods, and to consider the generalisability of the results.
Referral process
To measure 'diagnostic and therapeutic impact' of direct access to MRI, we asked GPs to complete a pre-randomisation questionnaire that recorded their diagnosis, management plans and confidence therein [42]. We asked them to complete a similar questionnaire on receipt of the imaging report or orthopaedic specialist letter. We also record the patient waiting times from randomisation to MRI, orthopaedic consultation, and arthroscopy. Adherence to the referral process is one of the outcomes of interest rather than a factor that may jeopardise interpretation of the findings.
Sample size
A similar group of patients followed up six months after referral for MRI of the knee had a mean of 64 and standard deviation (SD) of 25 on the physical functioning sub-scale of the SF-36 [37]. Hence a trial that followed up 434 participants (217 direct access and 217 controls) would have 80% power using a 5% significance level to identify a standardised difference of 0.27, equivalent to 6.75 points on the SF-36 physical sub-scale or an analogous difference on the proposed knee-specific instrument. We judge that a standardised difference of 0.27 in either of these measures should be clinically important. As we estimated that we could achieve 85% response rates to postal questionnaires, we aimed to recruit 500 participants in all.
Statistical analyses
The primary outcome measures are the physical functioning sub-scale of the SF-36 and the knee-specific instrument. The trial is pragmatic in design and therefore the primary analysis will be 'by intention to treat' in that all participants properly randomised will be included in the analysis even if they do not receive the intervention they were allocated to receive. A secondary analysis will be limited to participants who received the treatment to which they were randomised.
Data were collected at four time points: baseline, six, twelve, and 24 months. We shall use PROC, the mixed model procedure in the Statistical Analysis System (SAS), to analyse the data from all four time points within a single model and to adjust for experimental site. This model is robust to data missing at random and can also take the covariance structure of the data into account [43]. We shall check that the data fulfil the assumptions of the mixed model. If the data are not missing at random we shall seek an alternative analytical method providing a better fit. We shall treat missing items within individual outcome measures according to the instructions for that measure. For each outcome measure we shall calculate the number of non-responders and compare the proportion and type of non-response in each group at each time point. We shall also check that the model is a good fit and transform the data if necessary to improve fit.
The secondary outcome measures are the other seven subscales of the SF-36, the EQ-5D itself, the number of days patients take off work for their knee problems, and the number of days they are prevented from doing normal activities by their knee problems. The EQ-5D and the other seven subscales of the SF-36 will be analysed the same way as the primary outcome measures. As the number of days off work or normal activities is likely to follow a skewed distribution we shall transform the data and present the median and inter-quartile ranges for these times.
Secondary analysis of the primary outcome measures will be performed to adjust for the variation in waiting times between GP referral and access to MRI or orthopaedic specialist. Further analyses will test whether variables such as age and sex affect patient outcome, and to compare findings between different types of knee injuries (e.g. meniscal or ligamentous). As this analysis will not have the same power as the trial as a whole it will generate hypothesis rather than test them definitively.