VenUS III: a randomised controlled trial of therapeutic ultrasound in the management of venous leg ulcers

Treating venous leg ulcers

The only therapy so far shown to be clearly effective in the treatment of venous leg ulcers is the application of compression therapy, as either bandaging or hosiery, with high compression (around 40 mmHg pressure at the ankle) being more effective than lower levels of compression [relative risk of healing 1.5, 95% confidence interval (CI) 1.2 to 2.0]. 6 We know from both trials of compression therapy and other prognostic studies that small ulcers [< 5 cm² in area] and new ulcers (< 6 months in duration) treated with high compression heal quickly. For example, in a large trial of compression bandaging the median time to healing of ulcers with pre-trial duration of < 6 months was 77 days. 7 New ulcers treated with high compression, therefore, can be described as generally healing without the need for adjuvant therapies. One high-quality prognostic study has found that 95% of venous ulcers that are both small (< 5 cm² in area ) and new (< 6 months in duration), if treated with high compression, can be expected to heal within 6 months (95% CI 75% to 99%). 8 Audits of healing times using four-layer high compression (widely used in the UK) confirm the importance of ulcer area and duration in predicting healing at 6 months. 9,10 One of the remaining clinical challenges is how to increase healing in those ulcers that are not ‘easy to heal’ (i.e. the big/old ulcers rather than the small/new ulcers). The goal is both to increase the proportion of ulcers healed (20% remained unhealed in a large bandaging trial at 12 months)7 and to decrease the time to healing among people with longstanding ulceration or large ulcers.

Cost of venous leg ulceration

Leg ulceration is a condition associated with large financial costs to health-care providers. The cost of leg ulcer management in the UK in 1989 was estimated to be between £150M and £600M per annum, with > 60% of this cost attributed to community-based nursing services. 11 Recent studies have estimated the annual cost of treating a venous leg ulcer patient as being approximately £700–900, which increases the longer it takes for the ulcer to heal or the larger it becomes. 12,13 The 2004 Healthcare Commission estimated that NHS leg ulcer treatments cost £300–600M per annum and wound dressings accounted for 5 million community prescriptions in England during 2006 at a cost of £122M. 14 With the majority of leg ulcer patients in the UK treated within the community,15 such patients often constitute a large proportion of community nurses’ caseloads. 16

Presumed mechanisms of action

There are two types of mechanisms commonly thought to explain the effects produced by therapeutic ultrasound, and these are classed as thermal and non-thermal effects,18 although ter Haar18 and Baker et al. 21 argue that both effects may be present to varying degrees. They agree that it is difficult to identify the mechanisms involved, let alone separate the thermal and non-thermal effects. Investigators have described the effects of ultrasound on tissues in vitro and in vivo, but it is not clear whether these are responsible for reported clinical effects, or merely incidental.

Many physiological responses to the biophysical effects of therapeutic ultrasound have been described, and the research has been reviewed by Baker et al. 21 and others. 18,20

When ultrasound travels through tissue, a percentage of it is absorbed, which leads to the generation of heat within the tissue. 19 The beneficial effects thought to arise from this heating include an increase in blood flow, reduction in muscle spasm, increased extensibility of collagen fibres and a proinflammatory response. 20 Any problem of excess heat is reduced by using pulsed ultrasound (which has an on/off cycle), as the effective intensity is lower, with the heat being dissipated between the pulses. 22 While ultrasound has historically been used primarily for its professed thermal effects, it is suggested that ‘non-thermal’ mechanisms play a role in producing therapeutic effects. 19 Watson19 concludes that although the therapeutic benefits of tissue heating are well known, the ability of ultrasound to generate sufficient thermal change in tissues to achieve these effects is doubtful.

Purported non-thermal mechanisms are predominantly attributed to ‘cavitation’ – the production and vibration of micron-sized bubbles within the tissue fluids which, as the bubbles move and oscillate within the fluids, can cause changes in the cellular activities of the targeted tissues. 17 An additional outcome of ultrasound is ‘acoustic streaming’, which is described as the ‘localised liquid flow in the fluid around the vibrating bubble’. 22 Baker et al. ,21 however, argue that there is no evidence from in vivo studies in humans that cavitation occurs at the ultrasound doses used for tissue repair. Given the absence of cavitation, except in gas-filled cavities (such as the lungs), it is further argued that acoustic streaming does not occur in vivo. The way in which cavitation or acoustic streaming might contribute to tissue repair is not obvious, but it is postulated that they might lead to a reversible increase in cell membrane permeability and increased protein synthesis. 17

Ultrasound application

Ultrasound is reflected at the skin, as the air–skin interface presents a barrier to the transmission of ultrasound; thus, it is necessary to provide a coupling medium to allow the ultrasound to be transmitted into the tissues. 19 Suitable coupling mediums include gel with a high water content, a film dressing, water or saline. 17

The dose at which ultrasound is delivered at is related to its frequency (Hz), power (W/cm²), duty cycle (pulsed or continuous) and the duration of treatment, which produce a large number of possible combinations. 19

Ultrasound is contraindicated in people with ankle prostheses/metal anywhere in the foot (e.g. pin and plate, shrapnel), because both metal and the bone cement used in the replacement of joints have a high absorption capacity. The application of ultrasound to the ankle area may lead to heat damage of the local area and any prosthetic joints. 23 Ultrasound is also contraindicated for people with suspected thrombophlebitis (the mechanical vibrations may cause an embolism), people with active cellulitis (potential risk of accelerated growth and dissemination of bacteria throughout the body), in cases of suspected or confirmed local cancer/metastatic disease and in cases of obvious ulcer infection. 23

Primary objective

• To compare the effects of low-dose ultrasound plus standard care with standard care alone on the time to healing of the reference (largest) ulcer.

Secondary objectives

• To compare the cost-effectiveness of ultrasound plus standard care with standard care alone.

• To compare the effects of ultrasound plus standard care with standard care alone on the proportion of patients with ulcers healed at 12 months.

• To compare the effects of ultrasound plus standard care with standard care alone on percentage and absolute change in ulcer size.

• To compare the effects of ultrasound plus standard care with standard care alone on health-related quality of life (HRQoL).

• To compare the effects of ultrasound plus standard care with standard care alone on reported adverse events, withdrawals and loss to follow-up.

• To compare the effects of ultrasound plus standard care with standard care alone on the proportion of time patients are ulcer free.

Inclusion criteria

All people with venous leg ulcers were potentially eligible for inclusion in the proposed trial if they met the following criteria:

1. They were receiving care from community/leg ulcer/outpatients nurses in trial centres.

2. They were able to give written informed consent to participate in the study. Information sheets and consent forms were to be provided in languages other than English if required.

3. The primary cause of their ulcer was chronic venous insufficiency. This diagnosis was made using the same diagnostic criteria currently employed by caregivers in the community, namely the clinical appearance of the ulcer, patient history and an ABPI to rule out arterial insufficiency. 33

4. They had ‘hard-to-heal ulcers’ as defined by the presence of at least one of these criteria:

   1. a venous ulcer of > 6 months’ duration

   2. a venous ulcer > 5 cm².

5. They had Doppler-determined ABPI of ≥ 0.8 measured within last 3 months.

6. Those with an ulcer infection (based on a clinical signs and symptoms checklist) at baseline were eligible to participate once the infection had been resolved. 35

7. Those who were unable to self-complete the English language QoL tools were still eligible to participate, but we did not collect QoL data from them [the Short Form questionnaire-12 items (SF-12) is validated in English, Spanish, Italian, French and German and we anticipated that the number of non-English speakers who use these languages would be very small, based on previous trial experience].

Exclusion criteria

Potential participants were excluded if they met the following criteria:

1. Their leg ulcer was due to causes other than venous insufficiency (e.g. arterial insufficiency, malignancy, pyoderma gangrenosum, etc.).

2. They had poorly controlled diabetes, as evidenced by a glycated haemoglobin (HbA_1c) of > 10%.

3. They had ankle prostheses/metal anywhere in the foot (e.g. pin and plate): because bone cement used in the replacement of joints has a high absorption capacity, the application of ultrasound to the ankle area may lead to heat damage of the prosthetic joint. 23

4. They had suspected thrombophlebitis: because the mechanical vibrations may cause an embolism. 23

5. They had active cellulitis: because of the potential risk of accelerated growth and dissemination of bacteria throughout the body. 23

6. They had suspected or confirmed local cancer/metastatic disease. 23

Patients previously enrolled into the study who had become ulcer free were not eligible for rerandomisation into the trial if their ulcer(s) recurred.

Ulcer history and initial assessment

If the patient had more than one ulcer, nurses were asked to define which ulcer was the ‘reference ulcer’ (and therefore the reference leg), which was classed as the largest eligible ulcer. The outline of the reference ulcer was traced onto an acetate film grid marked with 1 cm² squares and an assessment was then made by the recruiting nurse of whether the reference ulcer area was ≤ 5 cm² or > 5 cm². The actual area was calculated at the York Trials Unit at a later date using the mouseyes computer program, Version 3.1 (Dr Robert John Taylor, Salford). 36 The reference ulcer was labelled according to leg (R for right; L for left) and the number 1 given to it (e.g. reference ulcer present on right leg = R1). Nurses completed tracings of all ulcers a patient had and labelled them in descending order of area (R2, R3, etc.) to allow follow-up of all ulcers on the limb.

Measurement of ankle–brachial pressure index

The result of a Doppler-determined ABPI measurement for the reference leg was noted along with the date it was measured. For inclusion in the study, this reading must have been obtained in the last 3 months as readings change over time. 37

Number of ulcer episodes on leg with reference ulcer

Data from VenUS I7 suggested that a greater number of ulcer episodes are prognostic of a longer healing time; we therefore recorded the number of ulcer episodes on the leg of the reference ulcer since the first episode.

Duration of reference ulcer and duration of oldest ulcer

Duration of reference ulcer was recorded based on participant report along with the duration of the oldest ulcer on the reference leg.

Patient mobility

Reduction in mobility can potentially contribute to ulceration by means of reduced venous return, secondary to calf muscle wastage. 38 It was recorded whether the patient was able to move freely, with difficulty or was immobile.

Ankle mobility, patient’s height and weight

The VenUS I7 reported that, as well as ulcer area, duration and number of episodes, ankle mobility (full, reduced range or fixed), and body weight were also prognostic for healing. These data were all collected at baseline.

Ulcer position and image

For monitoring purposes a record of the position of all ulcers on the trial leg including the reference ulcer was made. A dated digital photograph was also taken of the reference ulcer.

Pain

Patients were asked to indicate how intense the pain had been in their reference ulcer during the past 24 hours using a visual analogue scale (VAS) ranging from ‘no pain’ to ‘worst pain imaginable’. The minimum value on the scale was 0 mm and the maximum was 150 mm.

Date of birth

Date of birth was recorded at recruitment, allowing age at recruitment to be calculated. Increased age was associated with slower healing rates in one study. 38

Gender

The gender of participants was recorded, allowing a comparison with the existing information on the population of people with venous ulcers, in which women outnumber men. 39

Compression level

Whether the participant was currently being treated with two-, three- or four-layer high-compression bandaging was recorded.

Health-related quality of life

Participants were given a Baseline Questionnaire to complete prior to randomisation comprising the SF-1240 and the European Quality of Life-5 Dimensions (EQ-5D). 41

Preparation for ultrasound treatment

Prior to the application of the ultrasound the leg would be washed and any loose skin from around the ulcer and remnants of emollients removed. The ultrasound was applied directly to the skin surrounding the ulcer, using a water-based contact gel to ensure passage of the waveform from the transducer to the tissues.

Target ulcer

The ultrasound treatment was applied for 5–10 minutes to the previously defined reference ulcer (see Appendix 6).

Calculating ultrasound treatment time

Previous studies had applied ultrasound for varying amounts of time. We sought to balance the need for larger ulcers to have more treatment time, the need for treatment time to be feasible as an addition to standard practice, and the need for a simple system to help nurses titrate ultrasound to the various patients she or he would see.

Ulcers of area < 5 cm² received 5 minutes’ ultrasound; those of 10 cm² or larger received 10 minutes’ ultrasound. For ulcer areas between 5 and 10 cm², the treatment time in minutes was calculated as the ulcer area in square centimetres (for example: an ulcer calculated as 6 cm² received 6 minutes of ultrasound). Ulcer area was recalculated every 4 weeks using acetate film grids with pre-printed 1 cm² areas.

Concurrent therapy

All dressings and bandages were to be replaced at each visit, as per standard practice. Concurrent therapy for all patients was low-adherent dressings and four-layer high-compression bandaging, reduced compression or no compression, according to the clinical assessment of the level of pressure tolerated by the patient. Should a change from the low-adherent dressing or the prescribed level of compression be required, in the opinion of the clinician, then this was recorded. The patient did not withdraw from the trial should the concurrent therapy change.

Nurse training

Prior to the trial starting, participating nurses attended a training programme on the rationale for the trial, patient eligibility, recruitment procedures (including consent and randomisation), ultrasound treatment application, data collection (completion of trial documentation and tracing ulcer outlines), handling participant withdrawal and adverse event reporting (see Appendix 7). Competency in ultrasound administration was assessed at the end of the training. The trained trial nurses were also permitted to cascade training in delivering ultrasound for the purposes of the trial to other local nurses so that treatments could be maintained during holiday periods or staff absences.

Checks were made by the local trial nurses regarding the use of ultrasound within the trial, to ensure that the ultrasound was being delivered as per protocol.

Ultrasound machines

The ultrasound machines were supplied, at discounted price, by EMS Physio Ltd, the largest UK manufacturer of ultrasound machines. The machine chosen was the EMS Therasonic 355 Physiotherapy system (EMS Physio Ltd, Wantage) which delivers only 1 MHz ultrasound: effective radiation area 4 cm², with a large transducer head, collimated beam, and beam non-uniformity ratio (BNR) < 5. We used a pulsed mode; each pulse lasted 2 milliseconds and the pulse ratio was 1 : 4. Prior to acceptance, all machines were tested at the National Physical Laboratory (NPL) to confirm that they were delivering ultrasound at the necessary frequency and intensity.

Auditing ultrasound machine performance

The ultrasound machines were assessed after 3 months’ recruitment and 3-monthly thereafter to check the intensity of ultrasound delivered. Checks were undertaken by the ultrasound machine suppliers. These originally took place at each clinical site by the ultrasound machine suppliers except where there were no available engineers (Northern Ireland and Scotland). Previous studies have indicated that there are differences between the ‘nominal’ dose and that actually delivered by the machines. 42 Some of this is apparent at machine delivery, and some is due to drift or step changes in output. 43 Each ultrasound machine was numbered so that patients who received treatment from individual machines could be identified. This check took place when a site had been recruiting for 3 months and 3-monthly thereafter.

Ultrasound therapy arm

During the 12 weeks of ultrasound therapy, the date of every nurse visit was recorded in an Ultrasound Treatment Log Booklet by the treating nurse, along with location and whether or not ultrasound had been applied and, if so, for how long, machine number and signature of the nurse applying it for (see Appendix 5). Information relating to dressings and bandaging applied was also recorded. Reasons for any changes in these from the previous visit were requested. If for any reason the patient was not given his or her weekly ultrasound treatment (infection, illness, non-attendance, etc.), that week was not carried over. Thus, the maximum number of ultrasound treatments a patient could receive was 13 (one at baseline plus one per week for a total of 12 weeks).

After the patient’s ultrasound treatment period had finished, treatment reverted to standard care alone with the visit dates, locations, dressings and bandage changes recorded in a separate booklet – Dressing Log Booklet (see Appendix 5). Follow-up then continued as per the protocol.

Standard care arm

Visits to patients allocated to standard care alone with the visit dates, locations, dressings and bandage changes were recorded in the Dressing Log Booklet (see Appendix 5). Follow-up continued throughout their treatment period as per the protocol.

For all patients, acetate film tracings of all ulcers and digital photographs of the reference ulcer were taken every 4 weeks until 12 months after randomisation (or between 6 and 12 months in some cases depending on when they were recruited in the trial recruitment period) or the patient became ulcer free, whichever happened first.

Determination of reference ulcer healing

Healing was defined as ‘full epithelial cover without a scab, where a scab is a thick crust over the wound’. This meant that an ulcer in which there was full epithelialisation overlaid by a thin layer of dry skin could be classified as healed. Clinically, this type of wound would not require a primary contact layer.

When the treating nurse deemed the reference ulcer to be healed, she or he completed an Ulcer Healed Form (see Appendix 5) and took a digital photograph of the healed ulcer (see Appendix 9). In addition, nurses were asked to take another digital photograph 7 days after they had considered the reference ulcer healed.

Two blinded assessors independently assessed all photographs for each participant to determine a date for healing. This assessment followed the same successful process as that used in VenUS II. 44 The assessors discussed any discrepancies with referral to a third assessor for a final decision if required. The primary outcome was calculated using the date of healing as decided by the blind assessors. However, if no photographs were available for a participant, then the date of healing decided by the treating nurse was taken as the healed date.

Collection of resource use data

During their treatment period within the study, data were recorded (see Appendix 5) about treatment received, location of the visit and the level of compression bandaging applied.

At recruitment and 3, 6, 9 and 12 months after randomisation, patients were asked to complete a questionnaire on health and social care resource use during the previous month (see Appendix 5). The questionnaire was designed for participant completion and was returned to the trial office using a reply-paid envelope. Participants indicated how many times in the previous month they had used health services (e.g. seen a GP or nurse or received hospital care) and whether any health service use was ulcer related. The collection of self-reported resource use data was continued until the patient had been in the study for 12 months (or between 6 and 12 months for cases recruited during the last months).

Proportion of ulcers healed at 3, 6 and 12 months

The proportion of reference ulcers healed at 3 and 6 months post randomisation was reported to summarise the effects of the two regimens. Proportions healed are commonly used in wound care trials and hence this allowed us to compare our results directly with other trials which have rarely used time to event data.

Proportions of time patients are ulcer free

Reduction in recurrence would help reduce the prevalence of this condition and thus costs. Crude recurrence rates are potentially biased by any difference in healing rates associated with the two groups (ultrasound or standard care). As the treatment group which experiences faster healing is, by definition, exposed to more risk of recurrence if one group has more rapid healing, then people in that group are at risk of earlier recurrence. To account for this we used the proportion of time that patients were ulcer free. Patients with healed ulcers were contacted by telephone at 6, 9 and 12 months (up to June 2009) after healing in order to obtain recurrence data.

Percentage and absolute change in ulcer size

Data collected at 1, 3 and 12 months post randomisation allowed us to determine the reduction in ulcer area in patients who did not achieve complete ulcer healing. If the ultrasound and standard care groups achieved similar times to complete healing but one resulted in larger changes in ulcer area, then this may be clinically important as smaller ulcers may exude less and therefore require less frequent dressing changes. Furthermore, the recording of ulcer area at these time points allowed further study of the trajectory of healing for venous leg ulcers and the relationship between the reduction in ulcer area and eventual healing.

One study found that increased ulcer area at 1 month after initiation of treatment is a useful predictor for non-healing. 45 Identifying patients who are likely to fail to heal early in treatment allows these patients to have prompt referral to specialist centres for further assessment and treatment. Measurement of ulcer size involved taking tracing using acetate wound grids and a fine-nibbed, indelible pen, taking the outer edge of the ulcer rim as the outer edge of the tracing line (i.e. ulcer area = area enclosed by tracing and area of line). Ulcer area, as determined by acetate tracing, is an accurate and reliable measure. 46

Health-related quality of life

Participants were asked to answer questions relating to their HRQoL throughout the study, when they were asked to complete two generic instruments (EQ-5D and SF-12). Generic instruments were used to measure participants’ perceptions of health outcome in this trial, which have previously been shown to be sensitive to changes venous ulcer healing status. 47 In addition, these instruments are also particularly useful for comparing groups of participants, while also having a broad capacity for use in economic evaluation. Their generic nature also makes them potentially responsive to side effects or unforeseen effects of treatment.

Each participant’s perception of his or her general health was assessed using the acute version of the SF-1248 and the EQ-5D (EuroQol). 41 The SF-12 is a reliable and well-validated questionnaire,49 and has been used in UK populations including older people and leg ulcer patients. 50,51 We used a layout of the SF-12 shown in previous work to yield improved response rates and quality. 52 The EQ-5D is a generic measure of health status, in which health is characterised on five dimensions (mobility, self-care, ability to undertake usual activities, pain, anxiety/depression). 41 Participants were asked to describe their level of health on each dimension using one of three levels: no problems, moderate problems and severe problems. Each response locates a person into one of 243 mutually exclusive health states, each of which has previously been valued on the 0 (equivalent to dead) to 1 (equivalent to perfect health) ‘utility’ scale based on interviews with a sample of 3395 members of the UK public. 53 The EQ-5D has been validated in the UK and questionnaires containing both instruments were administered to patients by postal survey at baseline and at 3, 6, 9 and 12 months.

Optimising questionnaire response rates is of vital importance, and a recent systematic review has investigated strategies to increase questionnaire response rates. 54 The review reported that response rates to postal questionnaires doubled (odds ratio = 2.02, 95% CI 1.79 to 2.27) when a financial reward was included with the questionnaire compared with rates obtained with no incentive. The response rate increased further when the incentive was not conditional on response versus upon return of questionnaire (odds ratio = 1.71, 95% CI 1.29 to 2.26). Based on these data, we enclosed an unconditional payment to participants along with their final (usually the 12th month) questionnaire. They received notification in advance that would receive £5 in recognition of their commitment to our study and the time they spent completing questionnaires.

Adverse events

An adverse event is defined as ‘any undesirable clinical occurrence in a subject, whether it is considered to be device related or not’. 55 Both treatment-related and -unrelated adverse events were reported to the trial office (see Appendix 5). The reporting nurse indicated whether, in his or her opinion, the event was related to trial treatment or not. Events were also classed as serious or non-serious. Serious adverse events (SAEs) were defined as death, life-threatening risk, hospitalisation, persistent or significant disability/incapacity and patient being newly diagnosed as diabetic. For other events the treating nurse made a clinical decision about the seriousness. A list of possible treatment-related adverse events was established a priori, based on reports in the literature and VenUS I and VenUS II. These were pressure damage, infection, skin damage surrounding ulcer, new ulcer, ulcer deterioration and also adverse reaction to the ultrasound treatment or gel.

All nurses were asked to report any SAEs within 24 hours of the event occurring, or within 24 hours of becoming aware of the event. Sites were also provided with review forms in order to follow up all events so that information on eventual outcomes was recorded.

Outcomes

Primary outcome

The primary analysis compared the time to complete healing of the reference ulcer between the two randomised groups using a Cox regression model. 56 The analysis adjusted for centre as a random effect, ulcer area (from baseline tracing), ulcer duration and whether or not the patient was treated with high-compression bandaging. If centres recruited a small number of patients (five or fewer) then the analysis was repeated with no adjustment for centre, as a sensitivity analysis. Hazard ratios and corresponding 95% CIs were presented. The assumption of proportional hazards was checked using log–log plots, inclusion of interaction terms in the model (for each term with time) and by looking at plots of Schoenfeld residuals. The linearity assumption of continuous terms in the model (ulcer area and duration) was assessed using plots of the Martingale residuals and, if necessary, a suitable transformation used.

Kaplan–Meier survival curves were produced for the two groups and the median time to healing with 95% CI, as well as the Kaplan–Meier estimates of the proportions of ulcers healed at 12 and 24 weeks (for comparison with the results of other venous leg ulcer trials) presented.

A sensitivity analysis was performed to repeat the primary analysis using only the data of healing as recorded by the research nurses, and not using the data from the photographs.

Secondary outcomes

Data

Cost and health benefits data used in the economic analysis were extracted from the current trial. There were two sources of cost data: nurse-completed and patient-completed questionnaires. Nurse-completed questionnaires provide detailed information on each treatment the patients received, such as the choice of compression therapy, the duration of ultrasound treatment (if applied) and the treatment setting, whereas patient-completed data, derived from patient self-reported questionnaires at 3-, 6-, 9- and 12-month follow-up, provided information on frequency of health-care consultations, including doctor, nurse and hospital outpatient visits. Two different measures of health benefit were used: the time to healing and QALY. Time to healing was recorded by nurses and assessed by blinded investigators, whereas QALYs, representing years living in full health, were calculated based on information obtained from patient self-reported questionnaires every 3 months. Details of each constituent component of the economic analysis are discussed in the following sections.

Owing to the restricted follow-up period (1 year) as well as death and loss to follow-up, censoring occurred in both cost and health benefits data. To adjust for this censoring issue, in order to obtain more accurate estimation, the inverse probability weight (IPW) approach60 was applied. This method applies a set of different weights to account for the censoring. The same approach was used in VenUS II. 61 Taking the time to healing as an example, in this IPW approach only participants with observed time to healing data contribute with non-zero terms, but their contributions are inversely weighted by the probability of being observed. 61 Consequently, individuals who are less likely to be observed are weighted most heavily. The censoring distribution was estimated through the Kaplan–Meier estimator. Similarly, an IPW approach was adopted in the estimation of mean costs and QALYs to adjust for the censoring issues in the cost and QALY data, respectively.

Outcomes of the economic analysis

The economic analysis used incremental costs and incremental health benefits, estimated from the trial data, to evaluate the value for money of the ultrasound with standard care treatment. Time to healing of the reference ulcer and QALYs were the units of health benefit in the cost-effectiveness analysis and cost–utility analysis, respectively.

Health benefits

Resource use and unit costs

A cost for each trial participant was calculated as the product of resources used and their relevant costs. The analysis was costed at 2007 prices (mid-point of the trial). Three components were considered in the estimation of leg ulcer treatment cost: cost of ultrasound machine, cost of compression therapy and cost of health-care consultations (focusing on cost of health-care provider’s time). Other treatments, such as primary and secondary dressing or skin preparations, were assumed to be used equally across treatment arms; these resources were not included in the economic analyses. Incorporating costs categorised as irrelevant in distinguishing treatments into the analysis will increase the variance (and the standard error) of total costs for each arm and, thus, misrepresent uncertainty in the incremental costs. 66

Cost-effectiveness

To assess cost-effectiveness, the mean difference in costs between trial arms was compared with the mean difference in health benefits. For instance, if ultrasound plus standard care is more expensive and is associated with fewer health benefits than standard care alone, then ultrasound with standard care is dominated by standard care alone and the decision whether or not to adopt ultrasound is straightforward (not adopt). The decision arising from the converse situation (in which ultrasound plus standard care is dominant, i.e. less costly and more beneficial than standard care alone) is similarly straightforward (adopt). However, if ultrasound is more costly and more beneficial or less costly and less beneficial than standard care, we need to assess whether the increased cost of the ultrasound is worth the increased benefit, or whether the reduced benefit conferred by the ultrasound is justified by the reduced cost.

To ascertain the cost-effectiveness of a health-care intervention relative to another in the absence of dominance, an incremental analysis of cost-effectiveness is conducted. The incremental cost-effectiveness ratio (ICER) is the most commonly used cost-effectiveness measure and combines costs and health benefit in a single measure to which a decision rule for cost-effectiveness can be applied. It combines costs and benefits in a ratio of the mean difference in cost between the alternative treatments being compared with the mean difference in health benefits:

where C₁ and B₁ are, respectively, the mean costs and mean health benefits associated with the technology under evaluation (ultrasound with standard care in the current analysis), while C₀ and B₀ are the mean costs and mean health benefits associated with the comparator technology (standard care alone).

The decision rule for cost-effectiveness on the basis of the ICER indicates that a treatment strategy can be considered cost-effective only if the decision maker’s willingness to pay for an additional unit of health benefit (QALYs and ulcer-free days) is greater (or equal) to the ICER. According to NICE, the willingness to pay for an additional QALY ranges between £20,000 and £30,000. 67 Therefore, if the results of a cost–utility analysis (the estimated cost per QALY) is below this threshold, the intervention will be considered cost-effective.

Cost-effectiveness analysis in which the outcome is expressed in a natural unit, for example cost per ulcer-free day, may be more intuitive for clinicians. Despite this, and for the purpose of informing adoption decisions, the results of cost-effectiveness analysis are harder to interpret because there is no information on the willingness to pay for an additional ulcer-free day. Without this information we cannot determine whether or not the new intervention is cost-effective. To inform a decision based on this measure of health benefit, a threshold has to be established, and the decision maker is responsible for establishing this. Another reason to include this type of analysis is to facilitate the comparisons between relevant studies.

Uncertainty assessment

There is uncertainty in the incremental cost-effectiveness between two interventions, and this can be summarised graphically in a cost-effectiveness plane. By plotting the non-parametric bootstrapping results – 4000 replicates of difference in costs and health benefits (QALYs and ulcer-free days), the position of the estimates can indicate the degree of certainty that one of the interventions is dominant (north-west or south-east quadrants).

The ICER is associated with uncertainty because its numerator (expected costs) and its denominator (effectiveness) are estimated with sampling uncertainty. Therefore, a decision on whether or not to adopt a treatment based on the ICER estimate is also associated with uncertainty. In other words, if the trial were repeated, we might observe a different mean incremental cost and effectiveness, resulting in a different ICER estimate. The analysis of the consequences of this uncertainty and the extent to which it impacts on the adoption decision should be investigated to inform whether further research is needed. 70 Thus, the uncertainty around incremental costs and effects estimates and its impact on the adoption decision were investigated here.

Sensitivity analysis

Baseline patient characteristics

In total, 337 patients were recruited to the study: 168 in the ultrasound group and 169 in the standard care group. The baseline characteristics are shown in Table 6.

The majority of patients in the study were female (59%) and the two groups were well balanced for gender: 52% females in the ultrasound versus 48% in the control arm. The mean age of the patients in the study was 69 (SD 15) years, and randomisation resulted in well balanced groups for age, gender, body mass index (BMI), and mobility.

Table 7 shows the baseline ulcer data for both groups. This confirms the chronic, ‘hard-to-heal’ nature of this population. Ulcer duration was high, as expected with the inclusion criteria (> 6 months duration and/or > 5 cm²), with a median of 12 months. Median ulcer area was 12 cm² (mean 28 cm²). The median worst ulcer pain score in the previous 24 hours baseline was 31 (range 0–100). The groups were well balanced for ulcer area, duration and level of pain.

The distribution of baseline ulcer area was highly skewed (coefficient of variation 157%); therefore, to reduce this high variability, in the subsequent analysis the logarithm of baseline ulcer area was used. The baseline ulcer duration was also highly skewed (coefficient of variation of 185%) therefore the logarithm of ulcer duration was used.

Table 7 also shows that the two groups are similar in terms of ulcer history on the affected leg, number of previous ulcer episodes, time since first ulcer on this leg and ankle mobility. There seemed to be no difference between the two treatment arms in the distribution of patients in high compression, the mean ABPI, the median duration of the oldest ulcer and number of ulcers per participant. The median number of ulcer episodes was 1.5 (range: 0–99), and the majority of the patients’ ankles were described as having a full range of motion (63%); only 3% of patients’ ankles were described as ‘fixed’. The median ankle circumference was 24 cm (range 17–37cm), and the two groups were comparable to each other: ultrasound: 25 (SD 3) and standard care: 25 (SD 3).

Determination of healing date

The time to healing (survival time) of the reference ulcer was the defined as the time from the date of randomisation to the date of healing (with healing date decided by two independent, blinded adjudicators looking at photographs of the reference ulcers). Any disagreements were resolved by discussion or referral to a third blinded assessor. If no photographs were available, or if they were unclear, then the date recorded on the Ulcer Healed Form was used. Those patients who were lost to follow-up, withdrew from the study and were followed up until the end of the study without experiencing the event (healing of the reference leg ulcer) were treated as censored observations. Their survival time was the last date they were observed in the study. The explanatory variables – ulcer area, ulcer duration, ulcer compression and participating centre – were recorded at baseline.

The kappa measure of agreement was used to assess the agreement between the two assessors of the blinded photographs as to whether or not the wound had healed. This was also repeated by looking at the agreement between the final decision from the blinded photographs and the nurse’s decision on healing status of the patients.

Table 8 shows the data comparing the outcomes from two independent assessors for photographs of 331 ulcers/ulcer sites. Of these, 185 ulcers were deemed by both assessors to be ‘not healed’ while both agreed that 120 had healed. The assessors disagreed in 26 cases: assessor 1 classified 13 ulcers as healed while assessor 2 did not; similarly, assessor 2 classified 13 ulcers as healed while assessor 1 classified them as not healed. To quantify the strength of this association, the kappa measure of agreement was estimated as 0.84 (standard error 0.03, 95% CI 0.78 to 0.90). This indicates an almost perfect agreement. Where the two assessors disagreed on the date of healing, a third assessor was asked to evaluate the blinded photographs and 13 more patients were found to have healed, bringing the total number of healed patients to 133.

In Table 8 we also summarise the extent to which the nurse decision agreed with the blinded photographs. There was agreement between nurses and the photographic assessment (by two assessors – above) for 164 unhealed and 132 healed ulcers. There was disagreement between the nurse judgement and blindly assessed photographs in 41 cases: in 40 cases, the nurse judged that ulcers had healed but the blinded assessors considered the same photographs to indicate that ulcers had not yet healed. In one case the nurse described the ulcer as not healed when the two independent assessors agreed that it had. To quantify the strength of this association the kappa measure of agreement was estimated as 0.76 (standard error 0.03, 95% CI 0.69 to 0.83). This indicates a substantial agreement.

Healing data by site and treatment group

Twelve centres participated in the study (Table 9). In our analysis, centres that recruited fewer than five patients were combined. Consequently, Dunfermline, Cumbria and Dublin were combined with a total enrolment of nine patients (2.67%).

In total, 133 out of the 337 patients (39%) had a healed reference ulcer during follow-up while 204 out of the 337 patients (61%) did not heal. The percentage of healed patients in each centre was highest in WHSCT (57%) and Leeds Community (50%). The number of adverse events (serious or non-serious) by trial centre is given in Table 8. There were a total of 533 adverse events (88 SAEs and 445 NSAEs).

Record of patient treatment

Table 12 summarises the treatment details of the two groups: for the standard care patients during follow-up and for the ultrasound patients during both the 12 weeks on ultrasound therapy and the post-ultrasound period. For the standard care patients during follow-up, the median number of nurse consultations during study follow-up was 28 (range 1–354). There were a total of 6508 consultations in the home, leg ulcer clinic, nursing home, GP surgery, leg ulcer club and other specified locations. The majority of consultations took place in the leg ulcer clinic (39%), while the fewest were in a leg ulcer club (0.02%). In 40% of consultations knitted viscose dressings were applied (e.g. non-adherent). There were a total of 6473 bandages used during follow-up ranging from four-layer high-compression to non-compressive regimens. The four-layer high-compression system was most frequently applied (35% of consultations).

The median number of nurse consultations during the initial 12 weeks of ultrasound therapy was 13 (range 2–51; total of 2412 consultations). The majority of consultations took place at the leg ulcer clinic (45%) and the fewest at a leg ulcer club (0.04%). The median number of ultrasound applications was 11 (range 1–15). Ultrasound was delivered during most treatment consultations during the initial 12-week period: the median proportion of visits receiving ultrasound was 0.86 (range 0.14–1). In total, patients received more than 1 hour of ultrasound: the median duration of total ultrasound application was 69 minutes (range 9–130). During the post-ultrasound therapy period, the median number of nurse consultations was 33 (range 1–273) mainly in leg ulcer clinics (38%) with no consultations in leg ulcer clubs (0%). Knitted viscose dressings were applied during 40% of these consultations while three-layer high compression was applied in 33%.

Modelling of the primary outcome (time to healing of leg ulcers)

The primary analysis compared the time to healing of the reference ulcer between the two randomised groups: ultrasound plus standard care and standard care alone. This was accomplished by fitting a Cox proportional hazard regression model with the main covariate as treatment adjusting for baseline ulcer area, baseline ulcer duration, ulcer compression and centre.

As seen in Table 9, the number of patients healing in each centre varied. We assumed that the 10 centres in this study were a random sample drawn from a population of centres on which we would like to make inferences. Therefore, centre was treated as a random effect in the Cox proportional hazard regression (shared-frailty effect). Observations from the same centre share the same frailty effect. Hence, observations from the same centre are correlated because they share the same frailty effect. The frailty effect is a latent random effect that enters multiplicatively on the hazard function.

Figure 4 shows that there was a high level of variability in the healing rates between centres, with patients from WHSCT seemingly more frail (healing more) than patients from other centres. Similarly, patients from South Essex were seemingly less frail (healed less) than those from other centres. No patients healed from South Essex. There was a significant difference in the survival time among centres (log-rank test 36.19, p < 0.0001) unadjusted for other covariates in the model. This variability in the healing rates between centres will be accounted for by including a centre frailty effect in the model. So patients from the same centre are correlated because they share the same frailty effect.

FIGURE 4.

Unadjusted Kaplan–Meier survival curves by participating centre showing high variability in healing rates between centres.

There was no evidence of a difference in survival (time to healing) between the two treatment groups using the log-rank statistic (0.2544, p = 0.6140) and the Wilcoxon test (0.3350, p = 0.5628) (Figure 5). In other words, we have identified no evidence that low-dose ultrasound significantly affects the time to healing of hard-to-heal venous leg ulcers.

FIGURE 5.

Unadjusted Kaplan–Meier survival curves by treatment randomised.

Table 13 shows the median time to healing and lower boundary of the 95% CI. Note that the upper 95% CI could not be estimated from the data because fewer than half the patients in each group healed (64 out of 168 patients in the ultrasound group and 69 out of 169 in the standard care group).

The results of fitting the Cox proportional hazard regression model without and with the centre frailty parameter are given in Table 14. For the model without the frailty effect, the hazard ratio of ultrasound versus standard care is 1.01 (p = 0.9520) adjusting for log(area), log(duration) and ulcer compression. There was no evidence that the survival experience (healing time) of patients randomised to ultrasound and standard care is different. The hazard ratio for log(area) is 0.66 (p < 0.0001) adjusting for treatment, log(duration) and ulcer compression. Therefore, there was a significant effect of area on the healing time experience of both groups in that small ulcers healed more quickly than large ulcers. The hazard ratio for log(duration) was 0.57 (p < 0.0001) adjusting for treatment, log(area) and ulcer compression. Therefore, there was a significant effect of log(duration) on the time to healing for all patients in that newer ulcers healed faster than older ulcers. The hazard ratio for compression versus no compression was 0.93 (p = 0.7740). Therefore, there was no effect of compression usage at baseline on the survival experience of the patients in the two arms of the study.

The proportional hazard (PH) assumption assumes that the hazard ratios above do not depend on time (i.e. they are constant over time). This assumption was tested via a statistical test on each covariate separately then globally over all the four covariates in the model. The idea behind this test is that if the PH assumption is valid then the Schoenfeld residuals for the global test and Schoenfeld scaled residuals for separate tests with each covariate should not be correlated with survival time. If, on the other hand, the residuals tend to be positive for subjects who heal at relatively earlier time and negative for subjects who heal at a relatively late time (or vice versa) then there is evidence that the hazard ratio is not constant over time (i.e. PH assumption is violated). 75 The test of the PH assumption was insignificant (ultrasound vs standard care, p = 0.8677; log(area), p = 0.1147; log(duration), p = 0.2914; high compression, p = 0.1270; and global test, p = 0.2548) meaning that the PH assumption was not violated separately for each covariate and globally for all covariates. Hence, the hazard ratios were assumed to be constant over time.

For the model with the centre frailty effect, there was a significant centre frailty effect (p < 0.0001), meaning that the correlation of patients within a study centre could not be ignored. All hazard ratios have the same interpretation, but conditioned on centre (i.e. compares patients from the same centre). The hazard ratio of ultrasound versus standard care was 0.99 (p = 0.9690) adjusting for log(area), log(duration) and ulcer compression for patients from the same study centre.

In the estimation of the centre frailty effect, the significance of the centre frailty effect was tested under the null hypothesis that its variance was equal to zero (centre frailty effects were assumed to be distributed as gamma random variables with mean 1 and variance theta). So the null hypothesis is on the boundary of the parameter space (as variances can never be negative); hence the null distribution of the likelihood ratio test statistic is not just a chi-squared [degrees of freedom (df): 1], but a 50 : 50 mixture of chi-squared (df 0), point mass at 0 and a chi-squared (df 1). As such, the p-value was calculated from a mixture of these two chi-squared distributions. Similarly, as before, the PH assumption was tested here. The results show that the assumption was not violated separately for each covariate [ultrasound vs standard care, p = 0.7230; log(area), p = 0.1467; log(duration), p = 0.2938; high compression, p = 0.2030; or globally, p = 0.3548]. Comparing the models without and with the centre frailty effect we can see that the results are similar; however, the advantage of the model with the centre frailty effect is that it takes into account the fact that participants within each study centre are highly correlated.

Analysis of secondary outcomes

In this section, the results of the secondary analysis of ulcer area, QoL, complete healing of all ulcers at 12 months, rates of ulcer recurrence and finally adverse events are presented.

Complete healing of all ulcers at 12 months

The number of leg ulcers that had completely healed by 12 months was based on nurse-reported data and not on blinded photographs as photographs were not taken after the reference ulcer had healed. After 12 months of follow-up there were 72 patients (48%) in the ultrasound group and 78 patients (52%) in the standard care group whose ulcers had all healed. There is little difference in the proportions of patients with all ulcers healed after 12 months between the two groups.

Kaplan–Meier survival curves for time to healing are shown in Figure 6. The median time to complete healing of all ulcers in the standard care group was 328 days (95% CI 235 days, inestimable) and for the ultrasound group was 365 days (95% CI 224 days, inestimable). Under the null hypothesis of no difference in the survival experience of the two groups of patients, the log-rank test (p = 0.6051) and the Wilcoxon test (p = 0.6357) were not significant; hence, there was no statistically significant difference in the time to complete healing of all ulcers in the two treatment groups. A formal analysis, such as Cox regression analysis, was not performed here as for the primary outcome as any other ulcers that the patient may have had were not receiving ultrasound treatment.

FIGURE 6.

Kaplan–Meier plot of time to complete healing of all ulcers by treatment group.

Resource use and cost

Health benefits

Cost-effectiveness and uncertainty

The base-case analysis shows that ultrasound with standard care is expected to be more costly and less beneficial (as measured by both QALY and time to healing) than standard care alone. As summarised in Table 29, compared with standard care alone, individuals who received ultrasound plus standard care took an average of 14.7 days longer to heal, had 0.009 fewer QALYs and higher treatment costs (by £197.88). Ultrasound therapy plus standard care for leg ulcers was therefore dominated by standard care alone and should not be adopted. However, none of the differences in costs and benefits between these alternative treatments were statistically significant, indicating uncertainty which should be examined using bootstrapping.

The incremental cost-effectiveness plane, shown in Figure 7, was drawn to demonstrate the uncertainty associated with the mean difference in cost and health benefits between two trial arms, by plotting the non-parametric bootstrapping results – 4000 replicates of difference in costs and health benefits (QALYs and ulcer-free days). As shown in Figure 7, in the cost–utility (cost per additional QALY) analysis, the majority of points (67%) fall into the north-west quadrant, indicating that ultrasound with standard care is dominated by standard care alone. The cost-effectiveness analysis (i.e. cost per additional ulcer-free day) similarly indicates standard care to be dominant, with 74% of the estimates falling in the north-west quadrant.

FIGURE 7.

Cost-effectiveness plane.

Figure 8 presents the CEACs. For the cost per QALY analysis, according to the figure, the probability of ultrasound treatment being cost-effective is < 20% given the willingness to pay for additional QALY up to £30,000. Therefore, based on the current trial evidence, it is unlikely that ultrasound with standard care is cost-effective. Similarly, in the cost per ulcer-free day analysis, the probability of ultrasound treatment being cost-effective is around 20% maximum for any willingness to pay for an additional ulcer-free day.

FIGURE 8.

Cost-effectiveness acceptability curve (base-case analysis). WTP, willingness to pay.

Sensitivity analysis

Scenario 1

Sensitivity analysis was conducted to investigate the impact on the cost-effectiveness results of using patient-reported data regarding the health-care consultations. Ulcer-related doctor, nurse and hospital outpatient visits were extracted from postal questionnaires received from patients every 3 months during the follow-up period.

The number of ulcer-related doctor/nurse/hospital outpatient visits is shown in Table 30. Patients reported far fewer health-care consultations than the nurses (see Table 22). On average, patients reported a total of 25 nurse consultations in the standard care arm and 37 consultations in the ultrasound arm whereas the nurses reported 41 (standard care) and 45 (ultrasound) consultations.

TABLE 30 - Number of ulcer-related consultations (visits) reported by patients

max, maximum; min, minimum.

Time	Event		Ultrasound (n = 168)	Standard care (n = 169)
3 months	Doctor visits related to ulcers	Mean (SD)	0.8 (2.7)	0.6 (2.2)
		Median (min, max)	0 (0, 24)	0 (0, 15)
		Missing	41 (25.0)	41 (24.3)
	Nurse visits related to ulcers	Mean (SD)	11.1 (16.3)	8.9 (12.0)
		Median (min, max)	3 (0, 84)	0 (0, 57)
		Missing	39 (23.8)	55 (32.5)
	Hospital visits related to ulcer	Mean (SD)	3.7 (6.9)	3.4 (7.0)
		Median (min, max)	0 (0, 36)	0 (0, 36)
		Missing	27 (16.7)	31 (18.3)
6 months	Doctor visits related to ulcers	Mean (SD)	0.7 (2.5)	0.7 (2.3)
		Median (min, max)	0 (0, 15)	0 (0, 15)
		Missing	57 (34.5)	49 (29.0)
	Nurse visits related to ulcers	Mean (SD)	9.9 (15.5)	8.8 (14.2)
		Median (min, max)	0 (0, 84)	0 (0, 84)
		Missing	56 (33.9)	52 (30.8)
	Hospital visits related to ulcers	Mean (SD)	2.9 (8.3)	2 (6.4)
		Median (min, max)	0 (0, 66)	0 (0, 60)
		Missing	43 (26.2)	34 (20.1)
9 months	Doctor visits related to ulcers	Mean (SD)	1 (3.3)	0.8 (2.2)
		Median (min, max)	0 (0, 21)	0 (0, 12)
		Missing	58 (35.1)	68 (40.2)
	Nurse visits related to ulcers	Mean (SD)	8.4 (15.4)	8.6 (15.3)
		Median (min, max)	0 (0, 84)	0 (0, 84)
		Missing	59 (35.7)	67 (39.6)
	Hospital visits related to ulcers	Mean (SD)	2 (5.8)	2.1 (5.4)
		Median (min, max)	0 (0, 48)	0 (0, 30)
		Missing	51 (31.0)	52 (30.8)
12 months	Doctor visits related to ulcers	Mean (SD)	1 (3.5)	1.4 (5.9)
		Median (min, max)	0 (0, 30)	0 (0, 45)
		Missing	55 (33.3)	67 (39.6)
	Nurse visits related to ulcers	Mean (SD)	8.1 (14.0)	5.9 (13.9)
		Median (min, max)	0 (0, 84)	0 (0, 84)
		Missing	60 (36.3)	72 (42.6)
	Hospital visits related to ulcers	Mean (SD)	1.4 (4.9)	1.7 (5.2)
		Median (min, max)	0 (0, 36)	0 (0, 36)
		Missing	43 (26.2)	56 (33.1)
Total (completed cases only)	Doctor visits related to ulcers	Mean (SD)	2.91 (6.74)	2.32 (7.60)
		Median (min, max)	0 (0, 36)	0 (0, 96)
		Missing	98 (58.3)	94 (55.6)
	Nurse visits related to ulcers	Mean (SD)	36.73 (50.56)	25.32 (35.29)
		Median (min, max)	15 (0, 294)	12 (0, 153)
		Missing	94 (56.0)	103 (60.9)
	Hospital visits related to ulcers	Mean (SD)	8.26 (16.82)	8.84 (19.01)
		Median (min, max)	0 (0, 90)	0 (0, 96)
		Missing	71 (42.3)	76 (45.0)

The unadjusted costs for each arm based on patient-reported data are shown in Table 31. The adjusted mean costs for the standard care arm were £1650.50 per participant per year (95% bias-corrected CI £1439.20 to £1888.30) and £1790.70 for the ultrasound arm (95% bias-corrected CI £1553.60 to £2018.40). The difference in means between two arms was £140.20 and was not significant (95% bias-corrected CI –£186.60 to £438.20). The estimated difference in this scenario was lower than that in the base case.

TABLE 31 - Unadjusted annual costs for each arm

max, maximum; min, minimum.

Total costs (£)	Ultrasound (n = 168)	Standard care (n = 169)
Mean (SD)	1756.1 (2272.7)	1478.9 (2023.7)
Median (min, max)	906.7 (107.8, 14,882.9)	698.3 (0.0, 12,252.7)
Missing (%)	9 (4.8)	10 (5.9)

As only the cost of ultrasound was subjected to sensitivity analysis, the health benefit estimate is equivalent to base case. Similar to the results observed in the base-case analysis, in this scenario ultrasound with standard care is expected to be dominated by standard care alone (as shown in Figure 9) and ultrasound with standard care treatment is unlikely to be cost-effective based on the current trial evidence (as shown in Figure 10).

FIGURE 9.

Cost-effectiveness plane (sensitivity analysis).

FIGURE 10.

Cost-effectiveness acceptance curve (sensitivity analysis). WTP, willingness to pay.

Scenario 2

One-way sensitivity analysis was conducted to investigate the influence of the equipment cost of ultrasound machines on the adjusted cost difference, shown in Figure 11. With a decrease (from 88.05 to 0.00 with every 10% decrease) in the equipment cost of ultrasound machine, the adjusted cost difference between two arms also decreased. The adjusted cost difference dropped from £197.88 with the full equipment cost as used in the base-case analysis to £110.60 with no equipment cost involved. The remaining difference was mostly caused by the incurred cost of extra nurse time in applying ultrasound treatments. However, none of these estimates on cost difference was statistically significant. Thus, the uncertainty around the cost difference remained. The results here were based on 4000 bootstrap replicates and bias-corrected 95% CIs were reported.

FIGURE 11.

One-way sensitivity analysis result (bias-corrected 95% CI based on 4000 bootstrap replicates).

2.1 Inclusion/exclusion

1. We have dropped the exclusion criterion ‘rheumatoid arthritis’. Investigators made a strong case that many people can have venous ulcers in the presence of rheumatoid arthritis and that ulcer is not necessarily due to their rheumatoid disease. We initially excluded this population as they may be more prone to compression damage but given that the clinicians caring for these patients commonly use high compression, then we decided to include them.

2. We have dropped the exclusion criterion ‘diabetes’. Clinical collaborators have argued that people can have venous ulcers in the presence of diabetes mellitus, and that their ulcer may not be secondary to diabetes. We initially excluded this population as according to National Clinical Practice Guidelines, they would not be suitable for high compression, but we are informed that in some clinical centres expert practitioners will treat people with well-controlled diabetes, who have had a vascular assessment, with high compression therapy. Well-controlled diabetes is defined as a recent HbA_1c level of < 10%.

3. We have dropped the exclusion criterion peripheral arterial disease, as this is unnecessary as the inclusion criterion states that the ulcer must be primarily due to venous disease. The clinician has considered someone for the trial as the patients has a clinical diagnosis of ‘ulcer primarily due to venous insufficiency’, and the ABPI reading confirms the lack of significant arterial insufficiency.

4. We have gained ethical approval to recruit people with venous ulceration and an ABPI of at least 0.8 who are unable to tolerate high compression therapies. Our clinicians argue that some people are tolerant of reduced compression therapy and this population represent a particular challenge to heal, as high compression therapy is the single most effective element of treatment.

2.2 Outcome measures

1. We decided to amend the primary outcome measure in the light of advice from the Trial Steering Committee (20 January 2006) and the Trial Management Group (3 March 2006).

   Rationale:

   Initially we had the primary outcome measure as complete healing of all ulcers, as this is clinically the time at which leg ulcer treatment can be said to have achieved its ultimate aim, and the patient no longer requires dressings, bandages or nurses visits. However, in this trial the ultrasound is delivered only to the reference (i.e. largest) ulcer, then any outcome measure which relied on the healing of other ulcers remote from this would have the potential to dilute any treatment effect.

2. We will therefore have the primary outcome as complete healing of the ulcer treated with ultrasound (the reference ulcer) and record the time to complete healing of all ulcers as a secondary outcome measure.

3. We have added a digital photograph for confirmation of healing at day of healing and 7 days later. This photograph will be assessed ‘blind’ at the Trials Unit, for confirmation of healing. We did not ask nurses to take a digital photograph at every visit as we felt this was onerous. Digital photography was not budgeted for in the trial and we have limited resources to provide cameras, however, as many centres have these for the VenUS II trial, we felt that taking healing photographs was important.

4. We confirmed that the patients are followed up until all ulcers are healed as costs to the patient and provider continue until the patient is ulcer free, therefore the economic end points require that we have data on date of complete ulcer healing. In patients with one ulcer, and in those in whom smaller ulcers heal before the largest ulcer heals, then the date of healing of the reference ulcer will be the date of complete ulcer healing.

5. We identified that patient questionnaire return rates in the previous VenUS trials could be improved and therefore we have obtained agreement from collaborators to send £5 as a token ‘thank you’ payment to patients at the end of the trial, with the final questionnaire. This will not be mentioned in the patient information sheet, so that any possibility that it would be interpreted as a financial incentive to taking part in the trial will be minimised. The final questionnaire, at 12 months post-randomisation will be preceded by a letter notifying the patient that their final trial questionnaire is due to arrive shortly, and that it will be accompanied by a £5 note as a thank you for their taking part in the trial and completing the questionnaires. This letter will make it explicit that the £5 is not conditional on the patient retuning the questionnaire.

6. We identified, after discussion with the manufacturers of the ultrasound machines, that 6 monthly checks of the ultrasound machines may be unnecessary as the amount of drift is related to usage of the machines, and each machine will be used for an average of 9 hours (over 2 years) during the trial. They therefore suggested yearly testing was sufficient. We propose to test machines at 3 months, using an ultrasound balance, and if the readings indicate that the machine output is within tolerance, then recheck every 6 months.

2.3 Minor amendments/typographical errors

1. Protocol clarified to reflect that an ankle brachial pressure index (ABPI) of 0.8 or greater is acceptable for definition of non-clinically significant arterial insufficiency. The previous protocol stated ABPI had to be > 0.8. National clinical practice guidelines recommend that compression is used on people with venous ulceration and an ABPI of 0.8 or greater, and this amendment reflects national guidance and local treatment protocols.

2. Protocol amended to clarify that the research objective proportion of ulcers healed at 12 months should read ‘the proportion of patients with ulcers healed at 12 months’.

3.1 Full title of trial

Randomised controlled trial of cost-effectiveness of ultrasound for ‘hard-to-heal’ venous ulcers

3.2 Acronym

VenUS III (Venous Ulcer Studies III)

4.1 Leg ulceration

Leg ulceration is a chronic, relapsing, and remitting condition, affecting 15–18/1000 adults in industrialised countries. 1 It has a significant personal impact on older people’s health and quality of life (QoL). 2,3 Venous leg ulcers represent up to 84% of all leg ulcer cases in developed countries. 3 The total cost of leg ulcer management in the UK in 1989 was estimated to be between £150M and £600M per annum, with more than 60% of this cost attributed to community-based nursing services. 4 The only therapy so far shown to be clearly effective in the treatment of venous leg ulcers is compression bandaging or hosiery, with high compression being more effective than low compression (relative risk of healing 1.5, 95% CI 1.2 to 2.0). 5 Small (< 5 cm² area) and new (< 6 months duration) ulcers treated with high compression heal quickly; in our recent trial of compression, the median time to healing of ulcers with pre-trial duration of < 6 months, was 77 days. 6 New ulcers treated with high compression, therefore, heal without the need for adjuvant therapies. One high-quality prognostic study has found that 95% of venous ulcers that are both small (< 5 cm²) and new (< 6 months duration), if treated with high compression (Unna’s boot, the standard system in the USA), can be expected to heal within 6 months (95% CI 75% to 99%). 7 Audits of healing times using the UK standard compression system (four-layer high compression) confirm the importance of ulcer area and duration in predicting healing at 6 months. 8,9 The challenge is now to increase the proportion of ulcers healed (20% remained unhealed in VenUS I at 12 months)6 and to decrease the time to healing, particularly amongst people with longstanding ulceration or large ulcers.

4.2 Ultrasound

Longitudinal waves with a frequency between 20 hertz (Hz) and 20,000 Hz can be heard, however humans cannot detect frequencies below 20 Hz; these are described as ‘subsonic’, nor those above 20,000 Hz, described as ‘ultrasonic’. In clinical practice, the frequencies for ultrasound treatment are typically between 700,000 Hz and 4,000,000 Hz [0.7–4.0 megahertz (MHz)]. As ultrasound penetrates the skin tissues, absorption of the energy wave means that the intensity of ultrasound decreases as the wave travels into the tissues. The amount of absorption depends on the nature of the tissues and on the intensity of the ultrasound. The absorption coefficient of ultrasound in soft tissue increases linearly with frequency, so using higher frequencies (say 3 MHz rather than 1 MHz), reduces the penetration depth, by about one third (from 37 mm to 12 mm in skin). 10

4.3 Ultrasound and wound healing: the need for a trial

A number of studies have investigated the impact of ultrasound on skin cells (in vitro) and chronic wounds (in vivo). In general there have been few good quality studies demonstrating that any of the ‘in-vitro’ effects have any clinical importance. 11

There have been eight randomised controlled trials (RCTs) of ultrasound for treating venous leg ulcers. Seven of these were summarised in a systematic review by some of the applicants18 and one additional trial has been published subsequently. 19 The sample sizes in these trials ranged from 12–108 patients and five trials used true randomisation with allocation concealment. The trials made various comparisons of ultrasound versus sham (four trials) or ultrasound as an adjunct to standard care versus standard care alone. Various types of ultrasound at different dose were used. Frequency of ultrasound ranged between 0.3 and 3.0 MHz: 0.3 MHz was used in two trials (applied via water bath), 1.0 MHz was used in four trials and 3.0 MHz was used in another two trials. 1.0 MHz has greater depth penetration than 3.0 MHz. Ultrasound doses ranged between 0.1 and 1.0 W/cm². In two trials in which a water bath ultrasound device was used, 0.1 W/cm² was used. Doses of 0.5 W/cm² were used in three trials and 1.0 W/cm² in four trials (one trial compared 0.5 and 1.0 W/cm² against standard care). No trials reported that they confirmed ultrasound equipment output.

The largest trial (108 people) evaluated weekly ultrasound but the other trials administered ultrasound at two- or three-times a week, with one having a reducing frequency from three-to one-time(s) a week. Four trials used ultrasound for 12 weeks, two for 8 weeks and two for 4 weeks. The five trials that described duration of ultrasound regimen used 10 minutes (three trials) or 5–10 minutes, depending on ulcer area (two trials).

The heterogeneity in these trials with respect to the delivery mode, dose, duration, treatment length and frequency used, means that meta-analysis of all these trials may not be reliable. Another problem with synthesising these studies is the likely difference in the ultrasound actually delivered, even when treatment regimens appear similar due to the differences in output between machines and over time (drift). The Cochrane review undertook meta-analysis of the four trials that reported data on proportion of ulcers healed at 8–12 weeks found that the relative risk of healing with ultrasound was 1.44 (95% CI 1.01 to 2.05). The absolute difference in the risk of ulcers healing in the trials against sham ultrasound was 10% (95% CI –10% to 30%), while in the trials comparing against standard care alone it was 15% (95% CI 0% to 30%). Given that data from only four of the eight trials were pooled, and the potential heterogeneity in the interventions, this meta-analysis must be interpreted cautiously.

Given that standard care of venous ulcers, using high compression and simple dressings heals around 80% of all ulcers with 12 months, then ultrasound as an adjuvant therapy is likely to be reserved for those resistant to standard therapy, or are identified at the outset as ‘hard to heal’.

5.1 Research methods

5.2 Study design

A multicentre, pragmatic, RCT with an economic evaluation, comparing low-dose ultrasound with standard care in hard-to-heal venous ulcers.

5.3 Exclusion criteria

Potential participants will be excluded if they meet the following criteria:

1. Their leg ulcer is due to causes other than venous insufficiency (e.g. arterial insufficiency, malignancy).

2. The patient has poorly controlled diabetes, as evidence by a glycolated haemoglobin (HbA_1c) of > 10%.

3. People with ankle prostheses/metal anywhere in the foot (e.g. pin and plate): because bone cement used in the replacement of joints has a high absorption capacity, the application of ultrasound to the ankle area may lead to heat damage of the prosthetic joint. 17

4. People with suspected thrombophlebitis: the mechanical vibrations may cause an embolism. 17

5. People with active cellulitis: because of the potential risk of accelerated growth and dissemination of bacteria throughout the body. 17

6. In cases of suspected or confirmed local cancer/metastatic disease. 17

5.4 Patient recruitment

Patients with venous leg ulcers will be recruited from the following clinical centres:

1. Hull

2. Leeds

3. West Cumbria

4. Bradford

5. Altnagelvin (Londonderry)

6. Selby and York

7. Bolton

8. other centres as required.

Local nursing staff or clinical research nurses (CRNs) will identify potential participants, and will supply them with an information sheet about the trial. Patients will be given a minimum of 24 hours to read the information sheet and consider participation. A research or community/leg ulcer nurse will visit those patients that agree to participate, and at the enrolment visit will:

1. obtain written consent from them to participate in the trial

2. record baseline data

3. telephone the freephone randomisation service to randomise patient

4. administer first ultrasound treatment, if appropriate, and reapply compression bandages.

5.5 Randomisation

Research or community nurses from each study centre will enter patients into the trial by calling a freephone central randomisation service provided by the Trials Unit in York. The following information will be collected at randomisation from the nurse:

1. patient details including full name, gender, date of birth, full postal address

2. trial centre

3. whether ulcer is smaller or larger than 5 cm²

4. whether ulcer has been present for more or < 6 months

5. confirmation of eligibility (including use of high compression therapy)

6. confirmation of written informed consent.

Participants will be randomised by computer in equal proportions, block sizes randomly of size four and six. There will be no stratification.

7.1 Ultrasound therapy

7.2 Training in and monitoring of application of ultrasound intervention

Prior to the trial starting, participating community nurses will attend a full day training programme on the rationale for the trial, patient eligibility, recruitment procedures (including consent and randomisation), ultrasound treatment application, data collection (completion of trial documentation and tracing ulcer outlines), handling participant withdrawal and adverse event reporting. Competency in ultrasound administration will be assessed at the end of the training day. The CRNs will also cascade training in delivering ultrasound for the purposes of the trial to other local nurses so that treatments can be maintained during holiday periods/staff absences.

Clinical Research Nurses will audit the use of ultrasound within the trial, to check that the ultrasound is being delivered as per protocol, i.e. assessment of area of insonation, preparation of skin, application of ultrasound, recording treatment delivered, assessment of unwanted effects, etc.

7.3 Calculating ultrasound treatment time

Ulcers of area < 5 cm² will receive 5 minutes ultrasound, those of 10 cm² or < 10 cm² will receive 10 minutes ultrasound (the maximum time of treatment). For ulcer areas between 5 and 10 cm², the treatment time in minutes equals the ulcer area in square cm (6 cm² means 6 minutes etc.). Ulcer area will be recalculated every 4 weeks.

7.4 Ultrasound machines

The ultrasound machines are supplied, at discounted price, by EMS Physio Ltd, the largest UK manufacturer of ultrasound machines. Their EMS Therasonic 355 Physiotherapy machine delivers only 1 MHz ultrasound.

7.5 Auditing performance of ultrasound machines

The ultrasound machines will be assessed for a check of the intensity of ultrasound delivered. This will take place at each clinical site, by the ultrasound machine suppliers, and takes approximately one day for all the machines at one site. Previous studies have indicated that there are differences between the ‘nominal’ dose and that actually delivered by the machines. 22 Some of this is apparent at machine delivery, and some is due to drift or step-changes in output. 23 This will allow us to determine whether the ultrasound machine output has changed over the duration of the trial. Should significant change in ultrasound output occur, then a per protocol analysis will exclude patients who have not received the prescribed dose of ultrasound (± 20%). Each ultrasound machine will be numbered so that patients who have received treatment from individual machines can be identified. This check will take place when a site has been recruiting for 3 months and 3 monthly thereafter.

8.1 Adverse effects and anticipated benefits to participants and society

Given the chronic nature of venous leg ulceration, the identification of an intervention that increases healing rates at a reasonable cost would be highly beneficial to leg ulcer patients and the NHS. The known adverse effects associated with ultrasound are pain, erythema, allergy to conducting jelly, and pinhead bleeding in the skin around the ulcer. In previous trials these were reported in 5%–10% of patients, and none were classed as serious adverse events. The local nurse, using a proforma, will routinely record any adverse events associated with any of the trial treatments during the trial. Training will emphasise the need to record and report adverse effects.

8.2 Informing trial participants of possible benefits and risks of intervention

All trial participants will be provided with a patient information sheet prior to their giving consent. The information sheet will outline fully the potential benefits and risks of being involved in the trial. This information sheet will meet all the requirements of the local ethics committees.

8.3 Informed consent

Maintenance of confidentiality and compliance with the UK Data Protection Acts will be emphasised to all study participants. Participation in the study will be entirely voluntary and written consent will be sought. All data will be treated with the strictest confidence. A variety of ethnic groups are likely to be involved in this trial. Contact with individuals from all cultures will be handled with suitable care. We will translate information sheets/consent forms and use local translators to negotiate consent in sites where a significant proportion of people with ulcers speak languages other than English (e.g. Leeds/Bradford).

8.4 Proposed action if informed consent is not possible

One of the inclusion criteria is that people are able to provide written informed consent to participate in the study. If a clinician does not feel that the potential participant meets this requirement (e.g. if they have a diagnosis of cognitive impairment) then they would not be eligible for inclusion in the study.

8.5 Proposed time period for retention of trial documents

All paper copies of patient information will be kept in a locked room at the University of York with identifying information kept separate from the coded data collection forms. Computerised data will be password protected on a computer at the University of York. The Trials Unit will retain all study treatment disposition records in a secure data archive for 5 years from the end of the trial.

9.1 Proposed sample size

The majority of data on ulcer healing is presented as proportion of ulcers healed at 12 or 24 weeks but the choice of an arbitrary end point fails to capture the time course of healing and can be misleading. We will therefore base the sample size on median time to healing. There is evidence from audits of healing rates, and a prognostic study of ulcer healing, that ‘hard-to-heal’ ulcers take approximately twice as long to heal as new/small ulcers when treated with four-layer compression. Lambourne et al. 8 and Vowden et al. 9 found that 60% of ulcers > 10 cm², and 60% of ulcers of > 6 months duration (treated with four-layer compression) healed in 24 weeks (168 days). This represents a median time to heal of 15–22 weeks (estimated from survival curve). Our sample will include some smaller ulcers, but importantly it will include people with both high ulcer duration and large area (of whom between 13% and 37% heal at 24 weeks with high compression),7 and therefore, overall we have estimated that 50% of ulcers in the standard care group will heal within 22 weeks.

We estimate that clinicians and patients would value a reduction in healing time of 7 weeks (a 32% reduction in healing time from 22 weeks to 15 weeks) and have based our sample size calculation on this premise. To detect a difference in median healing time of 7 weeks (from 22 weeks to 15 weeks), we require 306 patients in total. When we allow for 10% attrition, this brings the total sample size to 336. A 10% dropout rate has been allowed for in this trial, although VenUS I had no attrition in primary outcome data. Based on this figure and current caseloads, it is estimated that it will take 15 months to recruit sufficient people for the trial, with each area expected to recruit around 50 patients – three patients per month (22 patients total per month). We have allowed 18 months overall for recruitment.

A sample size of 336 patients also gives us 80% power to detect an 8-week reduction in median time to healing from 24 weeks and 90% power to detect this difference from 26 weeks, see Table 2.

9.2 Recruitment rate

Experience from VenUS I has informed the likely recruitment rate. In VenUS I, Cumbria, Leeds and Southport each recruited 36–60 patients per year with venous ulcers (sustained over 1–2 years). A smaller ‘pool’ of people will be eligible for VenUS III as we are excluding people who have small, non-chronic ulcers. In VenUS I, 60% of participants had an ulcer that was both ‘small’ and ‘new’; these would not be eligible for inclusion in this trial. We anticipate that patient and clinician interest will be greater for this trial as it offers an opportunity to improve healing rates in a group of patients in whom standard therapy has a low success rate (and centres report increasing numbers of ‘hard-to-heal’ ulcers). This suggests that each centre could be confidently expected to recruit at least 40% of the patients for VenUS III, which they recruited for VenUS I. The contraindications for ultrasound therapy are unlikely to exclude many patients (few have ankle prostheses, or local cancer) and people with an ulcer infection can be recruited into the trial once the infection resolves.

We have also considered that during the proposed recruitment phase for VenUS III we are also co-ordinating a concurrent HTA funded trial (VenUS II – larval therapy) which is recruiting people with venous or arterial/venous ulcers in whom at least 25% of the ulcer is covered in slough. This is likely to reduce, by a small proportion, the number of people available for the ultrasound trial but we anticipate that the benefits of having a CRN already in place in the sites, identifying people eligible for the larval therapy or ultrasound trials, will increase the efficiency of the recruitment process and reduce some of the start-up costs. Furthermore, at the start of recruitment to the ultrasound trial there will be a cohort of patients with ulcers who did not wish to take part in the larval therapy trial who may be eligible for inclusion in this trial. Throughput data from the sites not involved in VenUS I (these were Cumbria, Southport and Leeds) confirms their ability recruit patients into the trial. Hull has around 140 new ulcers per year, Altnagelvin has 150 new patients per year, and Bradford has more than 300 new ulcers per year; the majority of which are venous.

We will assess recruitment problems by having regular monitoring of recruitment to identify problems, such as needing to extend the catchment area served by a recruitment centre and having monthly newsletters to CRNs. We will also invite CRNs to update meetings at the Trials Unit to encourage sharing of good practice and engender esprit de corps.

In order to recruit 336 patients over 18 months, we require 19 patients per month across all sites. For sites with CRN staffing of 2 days per week this equates to three patients per month, and for sites with 1 day per week, 1.5 patients per month.

Protocol for digital photographs and tracings of ulcers

At baseline (week 1 – first day of treatment equals day 0):

• please take a digital photograph of the reference ulcer (largest) AND

• tracings of all the ulcers the patient has.

Every 4 weeks from the first trial treatment:

• please take a digital photograph of the reference ulcer AND

• tracings of all the ulcers the patient has.

i.e. each time you take a photograph of the reference ulcer you should also take tracings of all the ulcers.

If the reference ulcer heals:

• please take a digital photograph to confirm this on the day of healing AND

• take another digital photograph 7 days later.

If there are still other unhealed ulcers on the patient’s leg:

• please continue to take tracings of the ulcers every 4 weeks as usual and complete dressing log booklets at each visit until they become ulcer free OR one year has passed since they first started in the trial.

NOTE

Please remember to always include a colour target card in the photograph, with the date, patient’s trial number and ulcer ID (e.g. R1 or R2) written on it.

AND

Please write the same information on the acetate grid when you take the tracings.

Prioritisation Group

1. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

2. Professor Imti Choonara, Professor in Child Health, Academic Division of Child Health, University of Nottingham

   Chair – Pharmaceuticals Panel

3. Dr Bob Coates, Consultant Advisor – Disease Prevention Panel

4. Dr Andrew Cook, Consultant Advisor – Intervention Procedures Panel

5. Dr Peter Davidson, Director of NETSCC, Health Technology Assessment

6. Dr Nick Hicks, Consultant Adviser – Diagnostic Technologies and Screening Panel, Consultant Advisor–Psychological and Community Therapies Panel

7. Ms Susan Hird, Consultant Advisor, External Devices and Physical Therapies Panel

8. Professor Sallie Lamb, Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick

   Chair – HTA Clinical Evaluation and Trials Board

9. Professor Jonathan Michaels, Professor of Vascular Surgery, Sheffield Vascular Institute, University of Sheffield

   Chair – Interventional Procedures Panel

10. Professor Ruairidh Milne, Director – External Relations

11. Dr John Pounsford, Consultant Physician, Directorate of Medical Services, North Bristol NHS Trust

    Chair – External Devices and Physical Therapies Panel

12. Dr Vaughan Thomas, Consultant Advisor – Pharmaceuticals Panel, Clinical

    Lead – Clinical Evaluation Trials Prioritisation Group

13. Professor Margaret Thorogood, Professor of Epidemiology, Health Sciences Research Institute, University of Warwick

    Chair – Disease Prevention Panel

14. Professor Lindsay Turnbull, Professor of Radiology, Centre for the MR Investigations, University of Hull

    Chair – Diagnostic Technologies and Screening Panel

15. Professor Scott Weich, Professor of Psychiatry, Health Sciences Research Institute, University of Warwick

    Chair – Psychological and Community Therapies Panel

16. Professor Hywel Williams, Director of Nottingham Clinical Trials Unit, Centre of Evidence-Based Dermatology, University of Nottingham

    Chair – HTA Commissioning Board

    Deputy HTA Programme Director

HTA Commissioning Board

1. Professor of Dermato-Epidemiology, Centre of Evidence-Based Dermatology, University of Nottingham

2. Professor of General Practice, Department of Primary Health Care, University of Oxford Programme Director,

3. Professor of Clinical Pharmacology, Director, NIHR HTA programme, University of Liverpool

1. Professor Ann Ashburn, Professor of Rehabilitation and Head of Research, Southampton General Hospital

2. Professor Deborah Ashby, Professor of Medical Statistics and Clinical Trials, Queen Mary, Department of Epidemiology and Public Health, Imperial College London

3. Professor Peter Brocklehurst, Director, National Perinatal Epidemiology Unit, University of Oxford

4. Professor John Cairns, Professor of Health Economics, London School of Hygiene and Tropical Medicine

5. Professor Peter Croft, Director of Primary Care Sciences Research Centre, Keele University

6. Professor Jenny Donovan, Professor of Social Medicine, University of Bristol

7. Professor Jonathan Green, Professor and Acting Head of Department, Child and Adolescent Psychiatry, University of Manchester Medical School

8. Professor John W Gregory, Professor in Paediatric Endocrinology, Department of Child Health, Wales School of Medicine, Cardiff University

9. Professor Steve Halligan, Professor of Gastrointestinal Radiology, University College Hospital, London

10. Professor Freddie Hamdy, Professor of Urology, Head of Nuffield Department of Surgery, University of Oxford

11. Professor Allan House, Professor of Liaison Psychiatry, University of Leeds

12. Dr Martin J Landray, Reader in Epidemiology, Honorary Consultant Physician, Clinical Trial Service Unit, University of Oxford

13. Professor Stephen Morris, Professor of Health Economics, University College London, Research Department of Epidemiology and Public Health, University College London

14. Professor E Andrea Nelson, Professor of Wound Healing and Director of Research, School of Healthcare, University of Leeds

15. Professor John David Norris, Chair in Clinical Trials and Biostatistics, Robertson Centre for Biostatistics, University of Glasgow

16. Dr Rafael Perera, Lecturer in Medical Statisitics, Department of Primary Health Care, University of Oxford

17. Professor James Raftery, Chair of NETSCC and Director of the Wessex Institute, University of Southampton

18. Professor Barney Reeves, Professorial Research Fellow in Health Services Research, Department of Clinical Science, University of Bristol

19. Professor Martin Underwood, Warwick Medical School, University of Warwick

20. Professor Marion Walker, Professor in Stroke Rehabilitation, Associate Director UK Stroke Research Network, University of Nottingham

21. Dr Duncan Young, Senior Clinical Lecturer and Consultant, Nuffield Department of Anaesthetics, University of Oxford

22. Professor Stephen Morris, Professor of Health Economics, University College London, Research Department of Epidemiology and Public Health, University College London

23. Professor E Andrea Nelson, Professor of Wound Healing and Director of Research, School of Healthcare, University of Leeds

24. Professor John David Norris Chair in Clinical Trials and Biostatistics, Robertson Centre for Biostatistics, University of Glasgow

25. Dr Rafael Perera, Lecturer in Medical Statisitics, Department of Primary Health Care, University of Oxford

26. Professor James Raftery, Chair of NETSCC and Director of the Wessex Institute, University of Southampton

27. Professor Barney Reeves, Professorial Research Fellow in Health Services Research, Department of Clinical Science, University of Bristol

28. Professor Martin Underwood, Warwick Medical School, University of Warwick

29. Professor Marion Walker, Professor in Stroke Rehabilitation, Associate Director UK Stroke Research Network, University of Nottingham

30. Dr Duncan Young, Senior Clinical Lecturer and Consultant, Nuffield Department of Anaesthetics, University of Oxford

1. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

HTA Clinical Evaluation and Trials Board

1. Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick and Professor of Rehabilitation, Nuffield Department of Orthopaedic, Rheumatology and Musculoskeletal Sciences, University of Oxford

2. Professor of the Psychology of Health Care, Leeds Institute of Health Sciences, University of Leeds

3. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

1. Professor Keith Abrams, Professor of Medical Statistics, Department of Health Sciences, University of Leicester

2. Professor Martin Bland, Professor of Health Statistics, Department of Health Sciences, University of York

3. Professor Jane Blazeby, Professor of Surgery and Consultant Upper GI Surgeon, Department of Social Medicine, University of Bristol

4. Professor Julia M Brown, Director, Clinical Trials Research Unit, University of Leeds

5. Professor Alistair Burns, Professor of Old Age Psychiatry, Psychiatry Research Group, School of Community-Based Medicine, The University of Manchester & National Clinical Director for Dementia, Department of Health

6. Dr Jennifer Burr, Director, Centre for Healthcare Randomised trials (CHART), University of Aberdeen

7. Professor Linda Davies, Professor of Health Economics, Health Sciences Research Group, University of Manchester

8. Professor Simon Gilbody, Prof of Psych Medicine and Health Services Research, Department of Health Sciences, University of York

9. Professor Steven Goodacre, Professor and Consultant in Emergency Medicine, School of Health and Related Research, University of Sheffield

10. Professor Dyfrig Hughes, Professor of Pharmacoeconomics, Centre for Economics and Policy in Health, Institute of Medical and Social Care Research, Bangor University

11. Professor Paul Jones, Professor of Respiratory Medicine, Department of Cardiac and Vascular Science, St George‘s Hospital Medical School, University of London

12. Professor Khalid Khan, Professor of Women’s Health and Clinical Epidemiology, Barts and the London School of Medicine, Queen Mary, University of London

13. Professor Richard J McManus, Professor of Primary Care Cardiovascular Research, Primary Care Clinical Sciences Building, University of Birmingham

14. Professor Helen Rodgers, Professor of Stroke Care, Institute for Ageing and Health, Newcastle University

15. Professor Ken Stein, Professor of Public Health, Peninsula Technology Assessment Group, Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth

16. Professor Jonathan Sterne, Professor of Medical Statistics and Epidemiology, Department of Social Medicine, University of Bristol

17. Mr Andy Vail, Senior Lecturer, Health Sciences Research Group, University of Manchester

18. Professor Clare Wilkinson, Professor of General Practice and Director of Research North Wales Clinical School, Department of Primary Care and Public Health, Cardiff University

19. Dr Ian B Wilkinson, Senior Lecturer and Honorary Consultant, Clinical Pharmacology Unit, Department of Medicine, University of Cambridge

1. Ms Kate Law, Director of Clinical Trials, Cancer Research UK

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

Diagnostic Technologies and Screening Panel

1. Scientific Director of the Centre for Magnetic Resonance Investigations and YCR Professor of Radiology, Hull Royal Infirmary

2. Professor Judith E Adams, Consultant Radiologist, Manchester Royal Infirmary, Central Manchester & Manchester Children’s University Hospitals NHS Trust, and Professor of Diagnostic Radiology, University of Manchester

3. Mr Angus S Arunkalaivanan, Honorary Senior Lecturer, University of Birmingham and Consultant Urogynaecologist and Obstetrician, City Hospital, Birmingham

4. Dr Stephanie Dancer, Consultant Microbiologist, Hairmyres Hospital, East Kilbride

5. Dr Diane Eccles, Professor of Cancer Genetics, Wessex Clinical Genetics Service, Princess Anne Hospital

6. Dr Trevor Friedman, Consultant Liason Psychiatrist, Brandon Unit, Leicester General Hospital

7. Dr Ron Gray, Consultant, National Perinatal Epidemiology Unit, Institute of Health Sciences, University of Oxford

8. Professor Paul D Griffiths, Professor of Radiology, Academic Unit of Radiology, University of Sheffield

9. Mr Martin Hooper, Public contributor

10. Professor Anthony Robert Kendrick, Associate Dean for Clinical Research and Professor of Primary Medical Care, University of Southampton

11. Dr Anne Mackie, Director of Programmes, UK National Screening Committee, London

12. Mr David Mathew, Public contributor

13. Dr Michael Millar, Consultant Senior Lecturer in Microbiology, Department of Pathology & Microbiology, Barts and The London NHS Trust, Royal London Hospital

14. Mrs Una Rennard, Public contributor

15. Dr Stuart Smellie, Consultant in Clinical Pathology, Bishop Auckland General Hospital

16. Ms Jane Smith, Consultant Ultrasound Practitioner, Leeds Teaching Hospital NHS Trust, Leeds

17. Dr Allison Streetly, Programme Director, NHS Sickle Cell and Thalassaemia Screening Programme, King’s College School of Medicine

18. Dr Alan J Williams, Consultant Physician, General and Respiratory Medicine, The Royal Bournemouth Hospital

1. Dr Tim Elliott, Team Leader, Cancer Screening, Department of Health

2. Dr Catherine Moody, Programme Manager, Medical Research Council

3. Professor Julietta Patrick, Director, NHS Cancer Screening Programme, Sheffield

4. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

5. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

6. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Disease Prevention Panel

1. Professor of Epidemiology, University of Warwick Medical School, Coventry

2. Dr Robert Cook, Clinical Programmes Director, Bazian Ltd, London

3. Dr Colin Greaves, Senior Research Fellow, Peninsula Medical School (Primary Care)

4. Mr Michael Head, Public contributor

5. Professor Cathy Jackson, Professor of Primary Care Medicine, Bute Medical School, University of St Andrews

6. Dr Russell Jago, Senior Lecturer in Exercise, Nutrition and Health, Centre for Sport, Exercise and Health, University of Bristol

7. Dr Julie Mytton, Consultant in Child Public Health, NHS Bristol

8. Professor Irwin Nazareth, Professor of Primary Care and Director, Department of Primary Care and Population Sciences, University College London

9. Dr Richard Richards, Assistant Director of Public Health, Derbyshire Country Primary Care Trust

10. Professor Ian Roberts, Professor of Epidemiology and Public Health, London School of Hygiene & Tropical Medicine

11. Dr Kenneth Robertson, Consultant Paediatrician, Royal Hospital for Sick Children, Glasgow

12. Dr Catherine Swann, Associate Director, Centre for Public Health Excellence, NICE

13. Professor Carol Tannahill, Glasgow Centre for Population Health

14. Mrs Jean Thurston, Public contributor

15. Professor David Weller, Head, School of Clinical Science and Community Health, University of Edinburgh

1. Ms Christine McGuire, Research & Development, Department of Health

2. Dr Kay Pattison Senior NIHR Programme Manager, Department of Health

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

External Devices and Physical Therapies Panel

1. Consultant Physician North Bristol NHS Trust

2. Reader in Wound Healing and Director of Research, University of Leeds

3. Professor Bipin Bhakta, Charterhouse Professor in Rehabilitation Medicine, University of Leeds

4. Mrs Penny Calder, Public contributor

5. Dr Dawn Carnes, Senior Research Fellow, Barts and the London School of Medicine and Dentistry

6. Dr Emma Clark, Clinician Scientist Fellow & Cons. Rheumatologist, University of Bristol

7. Mrs Anthea De Barton-Watson, Public contributor

8. Professor Nadine Foster, Professor of Musculoskeletal Health in Primary Care Arthritis Research, Keele University

9. Dr Shaheen Hamdy, Clinical Senior Lecturer and Consultant Physician, University of Manchester

10. Professor Christine Norton, Professor of Clinical Nursing Innovation, Bucks New University and Imperial College Healthcare NHS Trust

11. Dr Lorraine Pinnigton, Associate Professor in Rehabilitation, University of Nottingham

12. Dr Kate Radford, Senior Lecturer (Research), University of Central Lancashire

13. Mr Jim Reece, Public contributor

14. Professor Maria Stokes, Professor of Neuromusculoskeletal Rehabilitation, University of Southampton

15. Dr Pippa Tyrrell, Senior Lecturer/Consultant, Salford Royal Foundation Hospitals’ Trust and University of Manchester

16. Dr Sarah Tyson, Senior Research Fellow & Associate Head of School, University of Salford

17. Dr Nefyn Williams, Clinical Senior Lecturer, Cardiff University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

3. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Interventional Procedures Panel

1. Professor of Vascular Surgery, University of Sheffield

2. Consultant Colorectal Surgeon, Bristol Royal Infirmary

3. Mrs Isabel Boyer, Public contributor

4. Mr David P Britt, Public contributor

5. Mr Sankaran ChandraSekharan, Consultant Surgeon, Breast Surgery, Colchester Hospital University NHS Foundation Trust

6. Professor Nicholas Clarke, Consultant Orthopaedic Surgeon, Southampton University Hospitals NHS Trust

7. Ms Leonie Cooke, Public contributor

8. Mr Seamus Eckford, Consultant in Obstetrics & Gynaecology, North Devon District Hospital

9. Professor David Taggart, Consultant Cardiothoracic Surgeon, John Radcliffe Hospital

10. Professor Sam Eljamel, Consultant Neurosurgeon, Ninewells Hospital and Medical School, Dundee

11. Dr Adele Fielding, Senior Lecturer and Honorary Consultant in Haematology, University College London Medical School

12. Dr Matthew Hatton, Consultant in Clinical Oncology, Sheffield Teaching Hospital Foundation Trust

13. Dr John Holden, General Practitioner, Garswood Surgery, Wigan

14. Professor Nicholas James, Professor of Clinical Oncology, School of Cancer Sciences, University of Birmingham

15. Dr Fiona Lecky, Senior Lecturer/Honorary Consultant in Emergency Medicine, University of Manchester/Salford Royal Hospitals NHS Foundation Trust

16. Dr Nadim Malik, Consultant Cardiologist/ Honorary Lecturer, University of Manchester

17. Mr Hisham Mehanna, Consultant & Honorary Associate Professor, University Hospitals Coventry & Warwickshire NHS Trust

18. Dr Jane Montgomery, Consultant in Anaesthetics and Critical Care, South Devon Healthcare NHS Foundation Trust

19. Professor Jon Moss, Consultant Interventional Radiologist, North Glasgow Hospitals University NHS Trust

20. Dr Simon Padley, Consultant Radiologist, Chelsea & Westminster Hospital

21. Dr Ashish Paul, Medical Director, Bedfordshire PCT

22. Dr Sarah Purdy, Consultant Senior Lecturer, University of Bristol

23. Professor Yit Chiun Yang, Consultant Ophthalmologist, Royal Wolverhampton Hospitals NHS Trust

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Pharmaceuticals Panel

1. Professor in Child Health, University of Nottingham

2. Senior Lecturer in Clinical Pharmacology, University of East Anglia

3. Dr Martin Ashton-Key, Medical Advisor, National Commissioning Group, NHS London

4. Mr John Chapman, Public contributor

5. Dr Peter Elton, Director of Public Health, Bury Primary Care Trust

6. Dr Peter Elton, Director of Public Health, Bury Primary Care Trust

7. Dr Ben Goldacre, Research Fellow, Division of Psychological Medicine and Psychiatry, King’s College London

8. Dr James Gray, Consultant Microbiologist, Department of Microbiology, Birmingham Children’s Hospital NHS Foundation Trust

9. Ms Kylie Gyertson, Oncology and Haematology Clinical Trials Manager, Guy’s and St Thomas’ NHS Foundation Trust London

10. Dr Jurjees Hasan, Consultant in Medical Oncology, The Christie, Manchester

11. Dr Carl Heneghan Deputy Director Centre for Evidence-Based Medicine and Clinical Lecturer, Department of Primary Health Care, University of Oxford

12. Dr Dyfrig Hughes, Reader in Pharmacoeconomics and Deputy Director, Centre for Economics and Policy in Health, IMSCaR, Bangor University

13. Dr Maria Kouimtzi, Pharmacy and Informatics Director, Global Clinical Solutions, Wiley-Blackwell

14. Professor Femi Oyebode, Consultant Psychiatrist and Head of Department, University of Birmingham

15. Dr Andrew Prentice, Senior Lecturer and Consultant Obstetrician and Gynaecologist, The Rosie Hospital, University of Cambridge

16. Ms Amanda Roberts, Public contributor

17. Dr Martin Shelly, General Practitioner, Silver Lane Surgery, Leeds

18. Dr Gillian Shepherd, Director, Health and Clinical Excellence, Merck Serono Ltd

19. Mrs Katrina Simister, Assistant Director New Medicines, National Prescribing Centre, Liverpool

20. Professor Donald Singer Professor of Clinical Pharmacology and Therapeutics, Clinical Sciences Research Institute, CSB, University of Warwick Medical School

21. Mr David Symes, Public contributor

22. Dr Arnold Zermansky, General Practitioner, Senior Research Fellow, Pharmacy Practice and Medicines Management Group, Leeds University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Mr Simon Reeve, Head of Clinical and Cost-Effectiveness, Medicines, Pharmacy and Industry Group, Department of Health

3. Dr Heike Weber, Programme Manager, Medical Research Council

4. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

5. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Psychological and Community Therapies Panel

1. Professor of Psychiatry, University of Warwick, Coventry

2. Consultant & University Lecturer in Psychiatry, University of Cambridge

3. Professor Jane Barlow, Professor of Public Health in the Early Years, Health Sciences Research Institute, Warwick Medical School

4. Dr Sabyasachi Bhaumik, Consultant Psychiatrist, Leicestershire Partnership NHS Trust

5. Mrs Val Carlill, Public contributor

6. Dr Steve Cunningham, Consultant Respiratory Paediatrician, Lothian Health Board

7. Dr Anne Hesketh, Senior Clinical Lecturer in Speech and Language Therapy, University of Manchester

8. Dr Peter Langdon, Senior Clinical Lecturer, School of Medicine, Health Policy and Practice, University of East Anglia

9. Dr Yann Lefeuvre, GP Partner, Burrage Road Surgery, London

10. Dr Jeremy J Murphy, Consultant Physician and Cardiologist, County Durham and Darlington Foundation Trust

11. Dr Richard Neal, Clinical Senior Lecturer in General Practice, Cardiff University

12. Mr John Needham, Public contributor

13. Ms Mary Nettle, Mental Health User Consultant

14. Professor John Potter, Professor of Ageing and Stroke Medicine, University of East Anglia

15. Dr Greta Rait, Senior Clinical Lecturer and General Practitioner, University College London

16. Dr Paul Ramchandani, Senior Research Fellow/Cons. Child Psychiatrist, University of Oxford

17. Dr Karen Roberts, Nurse/Consultant, Dunston Hill Hospital, Tyne and Wear

18. Dr Karim Saad, Consultant in Old Age Psychiatry, Coventry and Warwickshire Partnership Trust

19. Dr Lesley Stockton, Lecturer, School of Health Sciences, University of Liverpool

20. Dr Simon Wright, GP Partner, Walkden Medical Centre, Manchester

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Expert Advisory Network

1. Professor Douglas Altman, Professor of Statistics in Medicine, Centre for Statistics in Medicine, University of Oxford

2. Professor John Bond, Professor of Social Gerontology & Health Services Research, University of Newcastle upon Tyne

3. Professor Andrew Bradbury, Professor of Vascular Surgery, Solihull Hospital, Birmingham

4. Mr Shaun Brogan, Chief Executive, Ridgeway Primary Care Group, Aylesbury

5. Mrs Stella Burnside OBE, Chief Executive, Regulation and Improvement Authority, Belfast

6. Ms Tracy Bury, Project Manager, World Confederation of Physical Therapy, London

7. Professor Iain T Cameron, Professor of Obstetrics and Gynaecology and Head of the School of Medicine, University of Southampton

8. Professor Bruce Campbell, Consultant Vascular & General Surgeon, Royal Devon & Exeter Hospital, Wonford

9. Dr Christine Clark, Medical Writer and Consultant Pharmacist, Rossendale

10. Professor Collette Clifford, Professor of Nursing and Head of Research, The Medical School, University of Birmingham

11. Professor Barry Cookson, Director, Laboratory of Hospital Infection, Public Health Laboratory Service, London

12. Dr Carl Counsell, Clinical Senior Lecturer in Neurology, University of Aberdeen

13. Professor Howard Cuckle, Professor of Reproductive Epidemiology, Department of Paediatrics, Obstetrics & Gynaecology, University of Leeds

14. Professor Carol Dezateux, Professor of Paediatric Epidemiology, Institute of Child Health, London

15. Mr John Dunning, Consultant Cardiothoracic Surgeon, Papworth Hospital NHS Trust, Cambridge

16. Mr Jonothan Earnshaw, Consultant Vascular Surgeon, Gloucestershire Royal Hospital, Gloucester

17. Professor Martin Eccles, Professor of Clinical Effectiveness, Centre for Health Services Research, University of Newcastle upon Tyne

18. Professor Pam Enderby, Dean of Faculty of Medicine, Institute of General Practice and Primary Care, University of Sheffield

19. Professor Gene Feder, Professor of Primary Care Research & Development, Centre for Health Sciences, Barts and The London School of Medicine and Dentistry

20. Mr Leonard R Fenwick, Chief Executive, Freeman Hospital, Newcastle upon Tyne

21. Mrs Gillian Fletcher, Antenatal Teacher and Tutor and President, National Childbirth Trust, Henfield

22. Professor Jayne Franklyn, Professor of Medicine, University of Birmingham

23. Mr Tam Fry, Honorary Chairman, Child Growth Foundation, London

24. Professor Fiona Gilbert, Consultant Radiologist and NCRN Member, University of Aberdeen

25. Professor Paul Gregg, Professor of Orthopaedic Surgical Science, South Tees Hospital NHS Trust

26. Bec Hanley, Co-director, TwoCan Associates, West Sussex

27. Dr Maryann L Hardy, Senior Lecturer, University of Bradford

28. Mrs Sharon Hart, Healthcare Management Consultant, Reading

29. Professor Robert E Hawkins, CRC Professor and Director of Medical Oncology, Christie CRC Research Centre, Christie Hospital NHS Trust, Manchester

30. Professor Richard Hobbs, Head of Department of Primary Care & General Practice, University of Birmingham

31. Professor Alan Horwich, Dean and Section Chairman, The Institute of Cancer Research, London

32. Professor Allen Hutchinson, Director of Public Health and Deputy Dean of ScHARR, University of Sheffield

33. Professor Peter Jones, Professor of Psychiatry, University of Cambridge, Cambridge

34. Professor Stan Kaye, Cancer Research UK Professor of Medical Oncology, Royal Marsden Hospital and Institute of Cancer Research, Surrey

35. Dr Duncan Keeley, General Practitioner (Dr Burch & Ptnrs), The Health Centre, Thame

36. Dr Donna Lamping, Research Degrees Programme Director and Reader in Psychology, Health Services Research Unit, London School of Hygiene and Tropical Medicine, London

37. Professor James Lindesay, Professor of Psychiatry for the Elderly, University of Leicester

38. Professor Julian Little, Professor of Human Genome Epidemiology, University of Ottawa

39. Professor Alistaire McGuire, Professor of Health Economics, London School of Economics

40. Professor Neill McIntosh, Edward Clark Professor of Child Life and Health, University of Edinburgh

41. Professor Rajan Madhok, Consultant in Public Health, South Manchester Primary Care Trust

42. Professor Sir Alexander Markham, Director, Molecular Medicine Unit, St James’s University Hospital, Leeds

43. Dr Peter Moore, Freelance Science Writer, Ashtead

44. Dr Andrew Mortimore, Public Health Director, Southampton City Primary Care Trust

45. Dr Sue Moss, Associate Director, Cancer Screening Evaluation Unit, Institute of Cancer Research, Sutton

46. Professor Miranda Mugford, Professor of Health Economics and Group Co-ordinator, University of East Anglia

47. Professor Jim Neilson, Head of School of Reproductive & Developmental Medicine and Professor of Obstetrics and Gynaecology, University of Liverpool

48. Mrs Julietta Patnick, Director, NHS Cancer Screening Programmes, Sheffield

49. Professor Robert Peveler, Professor of Liaison Psychiatry, Royal South Hants Hospital, Southampton

50. Professor Chris Price, Director of Clinical Research, Bayer Diagnostics Europe, Stoke Poges

51. Professor William Rosenberg, Professor of Hepatology and Consultant Physician, University of Southampton

52. Professor Peter Sandercock, Professor of Medical Neurology, Department of Clinical Neurosciences, University of Edinburgh

53. Dr Philip Shackley, Senior Lecturer in Health Economics, Sheffield Vascular Institute, University of Sheffield

54. Dr Eamonn Sheridan, Consultant in Clinical Genetics, St James’s University Hospital, Leeds

55. Dr Margaret Somerville, Director of Public Health Learning, Peninsula Medical School, University of Plymouth

56. Professor Sarah Stewart-Brown, Professor of Public Health, Division of Health in the Community, University of Warwick, Coventry

57. Dr Nick Summerton, GP Appraiser and Codirector, Research Network, Yorkshire Clinical Consultant, Primary Care and Public Health, University of Oxford

58. Professor Ala Szczepura, Professor of Health Service Research, Centre for Health Services Studies, University of Warwick, Coventry

59. Dr Ross Taylor, Senior Lecturer, University of Aberdeen

60. Dr Richard Tiner, Medical Director, Medical Department, Association of the British Pharmaceutical Industry

61. Mrs Joan Webster, Consumer Member, Southern Derbyshire Community Health Council

62. Professor Martin Whittle, Clinical Co-director, National Co-ordinating Centre for Women’s and Children’s Health, Lymington