A multicentre randomised controlled trial and economic evaluation of ion-exchange water softeners for the treatment of eczema in children: the Softened Water Eczema Trial (SWET)

The problem of eczema

Atopic eczema (atopic dermatitis) is the most common inflammatory skin disease in childhood, with a prevalence of around 20% in England, Australia and Scandinavia. There is recent evidence of a worldwide increase in atopic eczema symptoms in primary school-aged children. 1 The term atopic eczema is synonymous with atopic dermatitis. The World Allergy Organization now suggests that the phenotype of atopic eczema should be called just eczema unless specific immunoglobulin E (IgE) antibodies are demonstrated, and we will use the term eczema throughout this report.

The burden of eczema is wide-ranging. The child’s life is affected in many ways, including the suffering of intractable itch, sleep disturbance and ostracism by other children. Family disturbance is also considerable, including sleep loss and the need to take time off work for visits to health-care professionals. 2–4 Wider economic costs are considerable. Reviews of the socioeconomic impact of eczema reveal significant burdens worldwide, including the UK,5,6 the USA7 and Australia. 8

Treatment options for childhood eczema have traditionally focused on topical medications, with topical corticosteroids being the mainstay of treatment of skin inflammation and regular use of emollients for dry skin. 9 However, many parents of children with atopic eczema worry about the side effects of conventional topical medications. 10 Although the degree of public concern about the side effects of corticosteroids, such as skin thinning and growth retardation, has not been supported by long-term studies,2 it is important to recognise these concerns and continue to look for other ways of treating atopic eczema. Options that avoid the possible side effects of conventional pharmacological treatments would be a welcome addition to the management of eczema.

Water hardness and eczema

There is evidence from ecological studies linking increasing water hardness with increasing eczema prevalence in children of primary school age. This was first demonstrated in the UK in a study of 4141 primary school children. 11 The 1-year period prevalence of eczema was 17.3% in the hardest water category and 12.0% in the lowest [odds ratio (OR) 1.54, 95% confidence interval (CI) 1.19 to 1.99 after adjustment for confounders]. Such a gradient was not seen in secondary school children in the same study. Similar results were subsequently reported in a large study in Japan of 458,284 children aged 6–12 years, in which the prevalence was 24.4% in the hardest water category and 22.9% in the lowest,12 and in a study in Spain of 3907 children aged 6–7 years, in which the lifetime prevalence was 36.5% in the hardest water category and 28.6% in the lowest. 13 There are also anecdotal reports from the patients themselves that water softeners are of benefit to eczema sufferers.

Hardness in water is due to a high mineral content, primarily calcium and magnesium ions. Calcium usually enters the water supply as calcium bicarbonate as the water passes through limestone or chalk rocks. Water hardness varies across the UK, but is generally classified as hard to very hard (> 200 mg/l calcium carbonate) throughout southern and central England (Figure 1).

FIGURE 1.

Water hardness in the UK. Soft, < 100 mg/l calcium carbonate; medium, 100–200 mg/l calcium carbonate; hard, > 200 mg/l calcium carbonate.

If the association between water hardness and eczema prevalence is a causative one, a number of possible mechanisms can be put forward to suggest why hard water could exacerbate eczema. Perhaps the most likely explanation is increased soap usage in hard water areas, the deposits of which (‘soap scum’) can cause skin irritation in eczema sufferers. 14,15 This could be from direct skin contact with soap scum during washing or from the irritant effect of residual deposits in clothes and bedding. A direct chemical irritant effect from calcium and magnesium salts is also possible, or an indirect effect of enhanced allergen penetration from skin barrier disruption16 and increased bacterial colonisation of the skin. 14

Water softeners

Ion-exchange water softening is a well-understood and widely available technology. Water softeners are mainly used in households for reducing calcium deposits in appliances. They are usually installed under the kitchen sink and plumbed into the water supply to soften water to the whole house. A typical purchase price, including installation, would be approximately £600 ($900, €700). Ion-exchange water softeners remove calcium and magnesium ions, replacing them with sodium ions (from common salt). They reduce water hardness to < 20 mg/l calcium carbonate.

To fully soften water, calcium and magnesium ions must be removed, and domestic ion-exchange water softeners are the only products specifically designed to do this. Other technologies include water conditioners (also called ‘physical water conditioners’), which reduce limescale build-up by altering the physical properties of calcium and magnesium ions, but they do not affect the chemical composition of the water and therefore do not affect its hardness. For this reason ion-exchange water softeners were installed in the Softened Water Eczema Trial (SWET), and throughout this report the term ‘water softeners’ refers to ion-exchange technology.

Despite interest from people with eczema using water softeners, a Health Technology Assessment (HTA) systematic review of eczema treatments failed to identify any trials evaluating the use of water softeners for patients with eczema. 12 The only trials of possible relevance were an inconclusive one looking at the benefits of salt baths and another that examined the use of biological versus non-biological washing powders. The search for new, relevant studies was updated in 2010 and no new evidence on the use of softened water was found (see Appendix 1 for search strategy). The HTA systematic review identified a randomised controlled trial (RCT) of water softeners as one of six urgent research priorities in eczema. As a result of this, a feasibility study was run by the University of Nottingham in 2002 involving 17 families living in Nottingham, UK. This informed the design of SWET, in which ion-exchange water softeners were compared with usual eczema care in over 300 children recruited from seven hard water areas across England.

Eligibility criteria

Children were candidates for inclusion in the trial if they were aged 6 months to 16 years at recruitment visit, with moderate-to-severe eczema, and living in a property supplied by hard water. Eczema was defined by the UK refinement of the Hanifin and Rajka diagnostic criteria. 17

Eczema was assessed using the Six Area, Six Sign Atopic Dermatitis (SASSAD) score. Moderate-to-severe eczema was defined as a SASSAD score of 10 or above. Children with a SASSAD score of < 10 were excluded in order to avoid floor effects, i.e. they had the potential to improve. Although children with a SASSAD score < 10 at baseline were not randomised into the trial, they were invited to contact the nurse again if their eczema worsened. The home where the child lived was assessed by a water engineer for technical suitability for the installation of an ion-exchange water softener, during a ‘home screening’ visit carried out prior to recruitment. Hard water was defined as containing ≥ 200 mg/l calcium carbonate, and was measured in the home by water engineers using the drop-count titration Hach test (counting the number of drops required to change the solution colour to determine water hardness). In order to be as inclusive as possible, approval for water softener installation was sought from local council housing departments, housing associations and private landlords.

Children were not admitted to the trial if:

• they planned to be away from home for > 21 days during the 16-week study period, or had holidays scheduled during the 4 weeks prior to the primary outcome assessment date (to ensure adequate exposure to the intervention)

• they had taken systemic medication (e.g. ciclosporin A, methotrexate) or ultraviolet light for their eczema within the previous 3 months (because of these treatments’ long-lasting effects)

• they had taken oral steroids within the previous 4 weeks, or, as a result of seeing a health-care professional, had started a new treatment regimen for their eczema within the last 4 weeks

• they lived in homes that already had a water treatment device installed, including ion-exchange softeners, polyphosphate dosing units or physical conditioners

• they lived in a home that was unsuitable for straightforward installation of a water softener.

Screening

On expression of interest in the trial, a two-stage screening process was initiated.

Families were initially contacted by telephone by their local SWET research nurse, who then administered a telephone screen checklist (Appendix 2) to assess eligibility for the trial. This generated a study number and a request for a home screen visit by a water engineer attached to the trial. The water engineer completed a home screen checklist (Appendix 2), which was faxed to the co-ordinating centre. If the home was supplied by hard water and was technically suitable for straightforward installation of an ion-exchange water softener, an appointment was made for the child to be assessed by their local SWET research nurse for recruitment into the trial.

Informed consent

Research nurses took written consent from the child’s primary carer at the initial recruitment visit for all children aged 15 years or less. Children aged 16 years consented in their own right. Children aged 15 years or younger were invited to sign the consent form if they wanted to. Consent included permission for on-site inspection of the installed water softener by the relevant water supply company, under their duties within the statutory water fitting regulations, should this be requested.

Consent to take part in the genetic part of the study (filaggrin status) was additional to consent for the main study, i.e. it was not necessary to participate in the genetic study in order to participate in the main trial.

Primary outcome

As this was a single-blind trial, it was important to use an objective primary outcome measure that could be assessed by blinded observers (research nurses). 20 With this in mind, the primary outcome was the mean change in eczema severity at 12 weeks compared with baseline, as measured using the SASSAD severity scale –(see Appendix 3). SASSAD is an objective severity scale that was completed by the research nurses; it did not involve input from the participant in any way. 21 SASSAD includes assessment of the severity of six signs – erythema (redness), exudation (oozing of fluid), excoriation (scratch marks), cracking, lichenification (skin thickening) and dryness – in each of six areas, the head and neck, trunk, hands, arms, legs and feet. The theoretical range of the scale is 0 to 108, although in practice scores rarely exceed 70.

Nurses were trained in the use of SASSAD during a 2-day training event at the co-ordinating centre. With the exception of one study centre (Chase Farm Hospital) all SASSAD scores for each participant were obtained by the same nurse. In July 2008 the nurse at Chase Farm Hospital went on maternity leave. Prior to her departure she trained two Medicines for Children Research Network (MCRN)-funded nurses in SASSAD scoring. The MCRN-funded nurses attended a number of joint assessment visits by SWET participants, during which the nurses scored SASSAD independently and compared their final scores. Training was deemed complete when scores were within 10% or less of each other for three consecutive assessments.

In addition to the SASSAD score, nurses scored a representative site using the Three-Item Severity (TIS) scale. This measures three clinical signs – excoriation, erythema and oedema/population – at a single representative site. 22 Its simplicity makes it a suitable tool for research studies and clinical practice, and it has been suggested that the score provides as much information about eczema severity as more complex scoring systems. 23 In SWET, this score was recorded for two reasons: (i) to compare with SASSAD for research purposes; and (ii) to assess integrity of observer (nurse) bias (information bias) using digital images of a representative site of the participant’s eczema. These digital images were intended to be scored by two independent dermatologists using the TIS scale. The location of the representative site for TIS was agreed between the nurse, parent and child and photographed using a Samsung S630 CE digital camera (Chelsey, UK).

Secondary outcomes

Assessment visits

Assessment visits were carried out in paediatric dermatology clinic rooms in one of the SWET secondary care referral centres. Occasionally the research nurse agreed to see the child in the family home for the initial recruitment visit, but parents were informed that follow-up visits would all need to take place in the local SWET referral centre, to avoid unblinding of the nurse once the child had been randomised into the trial. SWET research nurses were trained in defining eczema at an initial training session run by a dermatology nurse consultant, by attending eczema clinics run by their principal investigators and consultant colleagues, and by self-testing using the online diagnostic criteria manual (www.nottingham.ac.uk/scs/divisions/evidencebaseddermatology/methodologicalresources/diagnostictools.aspx). Assessments took place at baseline and at 4 weeks and at 12 weeks (primary outcome) and at 16 weeks (Table 1).

Data collection and monitoring

Data generated by all centres were collected on study case report forms, which were entered on to the password-protected SWET database that was created and maintained by the Nottingham Clinical Trials Unit (CTU). Data were entered by the research nurses and by staff at the co-ordinating centre. A 100% check was conducted for the primary outcome (eczema severity) and the time spent moving, and discrepancies were resolved. All other data were subject to a 10% check, which was assumed to be adequate if the maximum error rate was, < 1 in 200 (in practice it was much lower than this). Data were also checked for consistencies in range and missing data. Missing and/or ambiguous data were queried with individual research nurses and resolved wherever possible.

Randomisation

Participants were randomised using web-based randomisation, and allocated on a 1 : 1 basis according to a computer-generated code, using random permuted blocks of randomly varying size. The program was created by the Nottingham CTU in accordance with its standard operating procedure and held on a secure server. Randomisation was stratified by disease severity (baseline SASSAD score ≤ 20 or SASSAD score > 20) and recruiting centre. Access to the sequence was confined to the CTU data manager. The allocation group was indicated to the trial manager only after baseline data had been irrevocably entered into the randomisation programme by the research nurse. The sequence of treatment allocations was concealed until interventions had all been assigned, recruitment and data collection were complete, a signed-off statistical analysis plan had been received and the database locked.

Blinding/bias

Research nurses were blinded to treatment allocation throughout the trial and statisticians analysed the results based on treatment code, using an analysis plan that had been finalised prior to locking the database and prior to the blinded data analysis. The only study personnel in direct contact with study participants were the research nurses and water engineers. The trial manager and study support staff at the co-ordinating centre in Nottingham had telephone contact with parents of participants. Trial participants continued to see health-care professionals for their usual eczema care.

Participants were discouraged from discussing their treatment allocation with the research nurse and the importance of maintaining ‘blinding’ was highlighted in the participant information sheets. Records were kept of all instances when the nurses believed they had become unblinded.

Sample size

Sample size calculations, based on the results of the pilot study and previously published eczema trials, supported a target of 310 participants (155 in each group) in order to show a minimum clinically relevant difference of 20% in the change in SASSAD score between the two groups [assuming a mean baseline SASSAD score of 20 and a standard deviation (SD) in change scores of 10]. This sample size provided 90% power, assuming a significance level of 5% and dropout rate of 15%.

For the planned subgroup analysis, including children with at least one mutation in the gene coding filaggrin, a total of 90 children with the mutation was assumed to be sufficient to detect a 30% difference between the treatment groups in the primary outcome, with 80% power, 5% significance and a SD of 10.

Primary outcome

The full statistical analysis plan is included in Appendix 4. The primary efficacy end point was an intention-to-treat (ITT) analysis including all participants with evaluable data (if < 5% missing values). If > 5% of data were missing, then a general linear model was to be used to handle the missing values.

Baseline characteristics were summarised and, if any major imbalance existed, the analyses were to be adjusted to account for this, along with an adjusted analysis including the stratification variables (recruiting centre and eczema severity).

A secondary, per-protocol analysis was performed in order to establish proof of principle, and subgroup analysis was conducted, based on those with at least one mutation of the gene coding for filaggrin.

Per-protocol analysis excluded the following participants:

• those who were randomised into the study, but who failed to receive their allocated treatment

• those who were deemed to be major protocol violators as defined by the Protocol Violators Group [including independent members of the Trial Steering Committee (TSC)].

Criteria for protocol violators were defined prior to breaking of the code relating to treatment allocation. They were as follows:

• missing SASSAD score at week 12

• group A: exposed to fully softened water for < 75% of the time that their home had an active water softener in place (i.e. sleeping at home + unit fully working for < 75% of the time that their home had an installation)

• group A: participant away from home or with partially functioning water softener for > 2 days/week for each of the 4 weeks prior to the primary outcome assessment

• group B: participant away from home for > 2 days/week for each of the 4 weeks prior to the primary outcome assessment

• unblinding of research nurse prior to primary outcome measurement (which could have caused observer bias)

• participants starting new treatment prior to primary outcome assessment were examined by a dermatologist on a case-by-case basis to determine if they were violating protocol.

Sensitivity analyses

Three sensitivity analyses were planned in relation to the primary outcome: (i) including all randomised participants by replacing missing values; (ii) excluding those for whom the research nurse had become unblinded; and (iii) excluding outliers. For the analysis including all randomised participants, missing values at baseline were replaced by the maximum score from the other five areas of the SASSAD score that were completed. Missing values at week 12 were replaced by the SASSAD score at baseline or week 4, depending on which was greater. For the analysis excluding outliers, these were defined as change scores outside the range of ± 3 SD.

Secondary outcomes

Secondary end points were analysed using a complete case analysis.

In order to aid clinical interpretability, SASSAD scores were grouped into those reporting no change or worse, a reasonable reduction (> 0% and ≤ 20%), a good reduction (> 20% and ≤ 50%), or an excellent reduction (> 50%).

The average percentage of the night spent moving was calculated by taking the average of the first three nights of usable data at baseline and the last three nights of usable data at week 12. Usable data were defined as values between 5% and 95% of the night spent moving to exclude outliers.

The total amount of medication used during the 12-week study period was measured by weighing the medication at each visit. Nurses recorded how confident they were in the measurement.

The number of TCWs and WCWs were compared during the first 12 weeks of the trial. A TCW was defined as a week with zero days with an eczema bother score above 4 and zero days on which ‘stepping up’ of treatment was required. Stepping up of treatment was defined as treatment over and above that defined as ‘normal’ for an individual participant in the daily symptom diaries. Bother scores were assessed on a scale of 0–10 in answer to the following question: ‘How much bother has your child’s eczema been today?’ A WCW was defined as a week with ≤ 2 days with an eczema bother score > 4 and ≤ 2 days on which stepping up was required.

All other outcomes were scored according to the guidelines for the scale, and compared the mean change from baseline to week 12. Continuous data were analysed using a t-test and categorical data were analysed using a chi-squared test for trend.

Analyses of all secondary end points and adjusted analyses were considered to be supportive to the primary analysis, so no adjustments for multiple comparisons were made.

Analyses were performed in stata 10.1 (StataCorp LP, College Station, TX, USA) and all p-values reported are two sided, with a significance level of 5%.

Trial organisation

The trial was managed and co-ordinated from the Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK. Data management was conducted through the Nottingham CTU. Statistical analysis was overseen by Professor Andrew Nunn and conducted at the Medical Research Council (MRC) CTU in London.

The Trial Management Group (TMG) was responsible for overall management of the trial. The TSC had an independent chairperson and vice chairperspon and met annually to provide overall supervision of the trial on behalf of the trial sponsor (University of Nottingham). Training sessions were held for research nurses and water engineers prior to starting the trial, and ongoing training was provided at individual sites as required.

The trial manager was responsible for day-to-day management of the trial. Details of individual participants were kept in a password-protected access database (Microsoft Corporation, Redmond, WA, USA). This included unblinded information relating to home screen outcomes, installation and removal of water softeners and hardness alerts.

As the trial involved the use of a commonly available domestic water softening unit, and did not involve the use of a medicinal product, there was no need for a Data Monitoring Committee.

Membership of the TMG and the TSC are given in Appendix 5.

Engineer co-ordination

Water engineers were subcontracted by the UKWTA. All water engineering aspects on the Isle of Wight were handled by a single subcontractor (MG Heating Ltd, Oxford, UK). Homes on the mainland were assessed by a number of local independent subcontractors co-ordinated by Lorraine Doran at European Water Care Ltd (Essex, UK, May–October 2007) and John Kyle at Kinetico UK Ltd (Hampshire, UK, October 2007 to September 2009). Fourteen subcontractors carried out water engineering aspects over the course of the trial. The majority of the work was done by the following nine subcontractors: Aquastream, Capital Softeners, Clearwater Softeners, European Water Care, Greens Water Systems, Kinetico UK, MG Heating Ltd, Silkstream and Simply Soft Water Softeners.

Consumer involvement

A consumer panel of five service users with experience of living with eczema assessed patient information sheets, symptom diaries and publicity material prior to submission for ethical approval. The panel members shared these documents with children with eczema aged 4 and 13 years. Mr David Potter acted as consumer panel representative on the TSC. Several participants from the trial assisted with trial publicity by agreeing to take part in media interviews (once their direct involvement in the trial was over). The National Eczema Society (NES) and the Nottingham Support Group for Carers of Children with Eczema (NSGCCE) helped with publicity during the recruitment phase of the trial.

Trial finances

This trial was funded by the UK National Institute for Health Research (NIHR) HTA programme. Subcontracts were established between the University of Nottingham and the MRC CTU, the consortium of water treatment companies (through the UKWTA) and the University of Portsmouth. In addition to the funding provided by the NIHR HTA programme, representatives from the water-softening industry covered the costs of the design, testing and supply of generic ion-exchange water softeners, salt supplies, hardness testing of water samples and supervision of water engineers.

Trial participants were offered a standard inconvenience allowance of £5–10 per visit in the form of gift vouchers.

Trial insurance and indemnity

The usual NHS indemnity arrangements for negligent harm applied. The University of Nottingham acted as sponsor for the trial and had third-party liability insurance in accordance with all local legal requirements, including cover for children under the age of 5 years. In addition, study engineers carried their own third-party liability insurance. The water softeners used in the study were covered by product warranty.

SWET website

The SWET website (www.swet-trial.co.uk, Figure 5) was active from May 2007 when recruitment began. The website included a password-protected researcher section where all current trial documentation was accessible for download by research nurses at individual study sites.

FIGURE 5.

Screenshot of the home page of the SWET website.

Lessons from the pilot study.

• The pilot trial generated a lot of interest, although many families were ineligible because their homes were unsuitable for the installation of a water softener; or they had a combination boiler in the home. This led to modifications in the RCT design so that both gravity-fed and combination boiler types were eligible, and an additional home screen visit was introduced prior to randomising the participants into the trial.

• It proved to be extremely difficult to blind participants to their treatment allocation and, as might be expected, this was particularly marked for those who received the real water softener. However, there was no evidence to suggest that the research nurse had been compromised, and so a single-blind study was recommended (with mechanisms in place to record instances when the research nurses had become aware of the treatment allocation).

• In order to maximise exposure to the intervention, it was recommended that water softener units were installed as soon as possible after a child had been randomised into the study, and records kept of periods away from the home.

• The number of technical difficulties experienced with the units during the 12-week study period was higher than expected. For the full study, it was recommended that engineers be employed to work exclusively for the trial, and that regular water testing be introduced.

• Measuring chlorine content of the water proved problematic due to rapid evaporation. For the full study it was recommended that we measure water hardness only.

• Participants randomised to receive a placebo unit expressed regret at not being able to try a ‘real’ unit for themselves. It was felt that this might impact on our ability to recruit into the main RCT, and so an additional 4-week period was introduced between weeks 12 and 16, when the control group would have a water softener installed.

Water-softening industry and their trade associations

British Water is a corporate membership association covering all sectors of the water industry, and was closely involved with the pilot study and setting up the main study. Ian Pallett (Technical Director at British Water) was a co-applicant on the funding application and served as the industry representative on the TSC.

A number of meetings were held with representatives from British Water and the water-softening industry prior to setting up the main trial. These informed practical logistics, including the design of a generic water-softening unit encased in a special SWET cabinet.

Representatives from the following companies gave input to meetings prior to and during the trial: Aqua Focus Ltd (Newport, UK), Aquademic Ltd (Derby, UK), Aqua Nouveau Ltd (Basingstoke, UK), Coleman Water Ltd (Ipswich, UK), Culligan International (UK) Ltd (High Wycombe, UK), EcoWater Systems Ltd (High Wycombe, UK), Harvey Softeners Ltd (Surrey, UK), Kennet Water Components Ltd (Newbury, UK) and Kinetico (UK) Ltd (Hampshire, UK).

The UKWTA was formed in March 2006 and is a national trade organisation for companies involved in the sale and use of water treatment chemicals and equipment in the UK. The UKWTA was closely involved with delivery of the SWET trial, and Tony Frost served as the UKWTA representative on the TMG.

There was a great deal of goodwill in the industry towards the trial; an early example was the professional redrawing of a draught logo by artists working in the publicity department of Aqua Nouveau Ltd. This became the instantly recognisable SWET hippo logo, which was a great hit with children on the trial.

Engineer employment

The intention had been to employ a small number of water engineers, one for each study centre, and to pay each engineer a salary for a fixed number of days/week devoted to SWET. However, this plan was set aside in March 2006, when the UKWTA was formed. By liaising directly through the UKWTA, the trial was able to have a more flexible approach to securing water engineer expertise and cover a wider geographical area extending across south-east and central England, from the Isle of Wight to Lincolnshire. Tony Frost acted as representative on the TMG for the UKWTA, which took over responsibility for subcontracting work to a number of smaller water softener companies.

Engineer training

Over the lifetime of the study, more than 20 water engineers from over 10 companies were involved in the installation and/or removal of study units. It was felt that the advantage of increased flexibility and engineer cover outweighed the disadvantage of losing direct contact with individual engineers. A downside was the effect on engineer training. Information about the trial was passed on through engineer co-ordinators on the Isle of Wight and the mainland, rather than directly in face-to-face training sessions with members of the TMG. In response to a few instances where engineers became involved in unwarranted discussions with parents about softened water and eczema, the trial manager wrote a SWET engineer’s handbook. This was distributed to all engineers in March 2008, and included background information and a list of important ‘dos’ and ‘don’ts’.

Individual engineers’ levels of expertise and professionalism were very high. There were a few occasions when water engineers did not have the skills necessary to adequately screen homes, or to carry out installations, e.g. one engineer underestimated water hardness at home screen by not giving sufficient time for the Hach drop-count test to develop. Action to resolve the situation was swiftly implemented in all cases.

Water engineers work to tight deadlines, often driving many miles between homes and only visiting their company depot/offices as required. As a result, it was difficult for individual engineers to work to good clinical practice (GCP) standards in terms of paperwork trails. The co-ordinating centre spent many hours chasing paperwork, confirming home screens and installations/removals. In an effort to improve rapid communication between engineers and the co-ordinating centre, a dedicated telephone answering machine was introduced for engineers to leave messages whenever they had done anything for SWET.

Understanding research terminology and methodology

In order to collaborate effectively, industry colleagues needed to understand clinical methodology and terminology such as the difference between RCTs and other types of research, and the statistical interpretation of RCT blinded and unblinded outcomes. This was important both during the trial itself in terms of working to GCP standards (data protection, paperwork trails, etc.) and at the end of the trial when understanding trial results and statistical terminology. Hywel Williams, in his role of Chief Investigator, agreed to talk to a meeting of industry colleagues after the trial ended, in order to explain the results.

While the water-softening industry helped inform study design and assisted with the trial conduct by carrying out home screen visits, installing devices and monitoring water samples, it had no involvement in data collection, analysis or interpretation.

Publicity issues

The UKWTA companies involved with SWET were asked to take a responsible approach to publicity about the study on their own websites. While all additional publicity about the trial was welcomed (because it would aid recruitment) it was important that companies remained neutral and did not give any misleading information. Routine monitoring of company websites occasionally revealed problems which were rapidly resolved on our behalf by the UKWTA.

Ongoing commitment to the trial

There were numerous examples of good practice which put the needs of the trial foremost. During the first 6 months of the study the number of homes failing the ‘home screening visit’ was higher than expected, and this was addressed in meetings held within the industry, and in collaborative meetings with staff at the co-ordinating centre. As the trial progressed, the number of samples needing routine analysis for hardness levels increased, and this extra work was absorbed by Culligan UK Ltd. Kinetico UK Ltd had responsibility for building the generic SWET ion-exchange water softeners. Originally the company had been told that 100 units would be required across the 2-year recruitment period, but owing to higher than expected numbers of units being purchased by families, this number increased to 197. At an individual level, engineers attached to the SWET trial were often working in very different environments from usual. This sometimes involved installing softeners into tight or unusual spaces, and finding creative ways to solve technical problems. One engineer discovered additional pipework to a bathroom during a visit to investigate a hardness ‘alert’. As a result of this, the procedure for routine weekly water testing and home screening was changed. Other examples included staff at the co-ordinating centre contacting parents to let them know about a recent hardness alert only to be told that water engineer had already visited and rectified the problem.

Baseline data

The groups were generally well balanced for all baseline characteristics, although to group A (water softener + usual care) included a slightly higher proportion of older children (aged ≥ 7 years) and members of group A, were more likely to use higher potency topical therapy (potent steroids, very potent steroids or calcineurin inhibitors) and slightly more likely to use biological washing powders (Table 2). The possible impact of these differences was explored in sensitivity analysis (primary outcome).

Intention-to-treat analysis

The primary end point of change in disease severity is shown in Table 4. Group A showed a mean reduction of 20% (5.0 points) in SASSAD score from an average of 24.6 at baseline to 19.6 at week 12. Group B showed a reduction of 22% (5.7 points) in SASSAD score from an average of 25.9 at baseline to 20.2 at week 12. The difference between the two groups at week 12 was 0.66 in favour of group B (95% CI –1.37 to 2.69) and was not statistically significant (p = 0.53). An additional analysis adjusting for stratification variables (baseline SASSAD score and centre) was performed, but this did not alter the conclusion. The difference between the two groups was reduced to 0.34 (95% CI –1.65 to 2.33, p = 0.74), in favour of group B.

These results are shown graphically in Figure 8 based on those with complete data at all time points.

As a result of the slight imbalance between the two groups at baseline in relation to age, previous treatment history and use of biological washing powder, a generalised linear model (GLM) was performed that adjusted for these baseline differences. This analysis gave similar results to the univariate t-test analysis. The difference between the two groups was 0.54 (95% CI –1.54 to 2.62, p = 0.61). (More detailed information is given in Appendix 7.)

FIGURE 8.

Six Area, Six Sign Atopic Dermatitis scores to week 12.

Per-protocol analysis

The planned per-protocol analysis supported the findings of the primary ITT analysis (Table 5). There was an 18% reduction (4.5 points) in group A and a 24% reduction (6.3 points) in group B. This represented a difference of 1.87 in favour of group B (95% CI –0.73 to 4.47), which was not statistically significant (p = 0.16).

Sensitivity analyses

Sensitivity analyses were performed (i) including all randomised participants by replacing missing values; (ii) excluding participants for whom the outcome assessor had been unblinded; and (iii) excluding participants with scores that were defined as being outliers (Table 6).

Results from analysis of all randomised participants supported the primary result, as the mean change in SASSAD score was 0.76 in favour of group B (95% CI –1.22 to 2.74; p = 0.45).

Results from analysis excluding unblinded participants showed a difference between the two groups of 1.26 in favour of group B (95% CI –0.77 to 3.28), which was not statistically significant (p = 0.22), and again supported the primary result.

Results from analysis excluding outliers gave a mean difference of –0.11 in favour of group A (95% CI –1.93 to 1.70) and was not statistically significant (p = 0.90).

Planned subgroup analysis – filaggrin status

The laboratory screened for the two most common mutations in the filaggrin gene (loss-of-function mutations R501X and 2282del4); variants (mutations) were either heterozygous or homozygous affected. A sample size of 90 children with at least one mutation was required for this subgroup analysis (see Chapter 2 for further details).

Of the 314 participants with test results, 94 (30%) had at least one mutation in the filaggrin gene. These were affected as follows:

• 11 wild type/heterozygous

• 71 heterozygous/heterozygous

• 12 wild type/homozygous affected.

The p-value for the interaction between the filaggrin status and the intervention was 0.87, indicating no evidence that the treatment effect varied between those with and without the mutation.

The analysis by filaggrin status is given in Table 7. The change in SASSAD score between baseline and week 12 in those in whom the mutation was absent was –5.1 in group A and –5.8 in group B. This represented a difference of 0.68 in favour of group B (95% CI –1.87 to 3.23, p = 0.60). The change in SASSAD score between baseline and week 12 in those in whom the mutation was present was –5.2 in group A and –6.3 in group B. This represented a difference of 1.05 in favour of group B (95% CI –2.36 to 4.47, p = 0.54).

Categories of improvement in Six Area, Six Sign Atopic Dermatitis score

The SASSAD scores grouped into categories of improvement are shown in Table 8. There was no evidence of a difference between the groups (p = 0.62), which supported the primary ITT analysis.

Night-time movement

The percentage of the night spent moving was measured using accelerometers (Table 9). Both groups showed an increase in the percentage of the night spent moving: 3.5% in group A and 4.1% in group B. The difference between the two groups was –0.64 in favour of group A (95% CI –4.68 to 3.40) and was not statistically significant (p = 0.76). Both groups showed an increase in night-time movement during the trial. This is in contrast to the other reported outcomes, which all showed improvements over time in both groups. As a result an exploratory sensitivity analysis was conducted (see below). The correlation between the SASSAD score and the first three nights of usable data from the accelerometers at baseline was 0.11 (p = 0.06), suggesting weak evidence of a weak correlation. Comparing the change in SASSAD score from baseline to week 12 with the change in the percentage of the night spent moving from the accelerometer data gave a correlation of –0.02 (p = 0.77), suggesting no evidence of any correlation.

Amount of medication used

Group A used on average 58.4 g (SD = 96.8 g) of medication over the 12-week period and group B used on average 67.3 g (SD = 97.3 g, Table 10). The difference between the two groups was –8.90 g (95% CI –30.50 to 12.70 g) and was not statistically significant (p = 0.42).

Patient Oriented Eczema Measure scores

Group A showed a drop of 34% (5.7 points) from 16.8 at baseline to 11.1 at week 12 and group B showed a drop of 22% (3.6 points) from 16.6 at baseline to 13.0 at week 12 (Table 11). The difference between the two groups was –2.03 (95% CI –3.55 to –0.51) which was statistically significant (p < 0.01).

The difference between the two groups is shown visually in Figure 9.

FIGURE 9.

Change in POEM scores.

The POEM scores at week 4 also showed a difference in favour of group A, but this was not statistically significant. Group A showed a drop of 22% (3.8 points) from 16.9 at baseline to 13.1 at week 4, and group B showed a drop of 17% (2.8 points) from 16.8 at baseline to 13.9 at week 4. The difference between the two groups was –1.0 (95% CI –2.25 to 0.30), which was not statistically significant (p = 0.13).

Totally controlled weeks and well-controlled weeks

Group A had an average of 8.3 (SD 3.8) WCWs and group B had an average of 7.3 (SD 4.1) WCWs over the 12-week study period. The difference between the groups was 0.99 (95% CI 0.04 to 1.95). This difference of just under 1 week was statistically significant (p = 0.04).

The difference between the two groups can be seen in Figure 10.

FIGURE 10.

Number of well WCWs.

This result was also reflected in the number of TCWs. Although the majority of participants had no weeks when the eczema was totally controlled (Figure 11), group A had an average of 2.9 (SD 3.5) TCWs compared with 1.7 (SD 2.8) in group B. This represented a difference of 1.19 (95% CI 0.43 to 1.95), which was statistically significant (p < 0.01).

FIGURE 11.

Number of TCWs.

Graphs showing the number of WCWs and TCWs for the entire 16-week trial period are shown in Appendix 9.

Dermatitis Family Impact questionnaire

Both groups showed a reduction in DFI score (Table 12). Scores in group A dropped by 32% (3.2 points) and in group B by 16% (1.8 points). This represented a difference of –1.33 points in favour of group A (95% CI –2.63 to –0.03), which just achieved statistical significance (p = 0.05).

European Quality of Life-5 Dimensions

Both groups showed a small improvement in health-related quality of life. Scores in group A increased by 0.119 points and in group B by 0.066 points. The difference between the two groups was 0.054 (95% CI –0.015 to 0.122) and was not statistically significant (p = 0.12, Table 13).

Aim and perspective

The aim was to estimate the cost-effectiveness and cost–utility of ion-exchange water softeners for children with eczema, as compared with usual care. The study adopted an NHS perspective, in order to inform health policy relating to the use of ion-exchange water softeners for children with eczema.

Time frame

Costs and benefits were calculated for the 12-week study period only. As the trial has a short time frame, neither costs nor benefits were discounted.

Resource use and cost analysis

Resources collected during the trial are summarised in Table 17. The resources fall into two main categories: (i) those used to provide the intervention (consultation with a dermatologist, water softener device, installation, salt); and (ii) those that may change as a result of the intervention (NHS resource use, including number of visits to the GP, practice nurse, pharmacist, health visitor, specialist nurse, hospital admissions, hospital doctor and medication use).

The dermatology consultation was included in the intervention group in the base case because it was assumed that an additional clinic visit would be required in order to prescribe a water softener device. The impact of excluding this cost is further explored in sensitivity analysis.

NHS resource use data were recorded by parents in a daily diary over the 12-week trial period. In addition, topical steroids and/or calcineurin inhibitors were weighed by trial nurses at baseline and the end of week 12. Several assumptions were required in order to cost the medication weights recorded:

• Where the medication weights were recorded but no medication name given, the average unit cost across medications in that potency category was assumed.

• Where no weights but some medication names were recorded it was assumed there had been no use of that medication over the 12-week study period. This applied to 25 cases (nine in group A, 16 in group B) where the nurses had rated their confidence in the assessment of weight as ‘not sure’ or ‘not at all sure’. As slightly more of the missing values were in group B, the effect of this assumption would be conservative against the intervention.

• Where there were two medications within a single potency category it was assumed that half the weight had been used on each medication.

• Where there were more than two medications within a single potency category, the average unit cost across medications in that potency category was used.

• Where a medication did not have the strength or application types recorded, an assumption was made. For example, the most frequent omission was with respect to the strength of hydrocortisone. For cases where this was recorded, it was most frequently 1% strength and approximately 30 g had been used. As a result, a unit cost for those with missing information was assumed based on the cost of a 30-tube of 1% hydrocortisone.

It was assumed that all intervention households had one water softener device installed. This assumption was made despite knowing the exact number of devices installed into each home because in this study the devices were being installed into multiple homes for short periods of time. Therefore, although a minority of homes had to have replacement devices, we did not include the cost of these replacement machines because this is likely to be a consequence of the study design rather than some inherent failing of the devices, which have an expected average life span of 12 years. Salt consumption was assumed as a standard rate based on household size and the agreed amounts of salt engineers left at the time of installation (Table 18).

The unit costs for the resources were identified from published sources, or from expert opinion where necessary. The value and source of the proposed unit costs for each resource item are shown in Table 17. The unit cost for the actual water softener device and installation has been estimated as the appropriate proportion of the equivalent annual cost (i.e. estimated as an equivalent 12-week cost to accurately reflect the fact that the device has a typical lifespan of 12 years and depreciation has been assumed to be zero). This was done in order to express all costs on a 12-week basis. On this basis the average 12-week cost of the device and installation was £19.82. The cost analysis was undertaken using individual patient level data.

All costs are reported in UK pounds sterling for the year 2009. Mean resource use and costs per patient for group A and group B are presented along with mean difference in resource use and cost per patient and 95% CIs comparing the groups.

Outcome measurement and valuation

Two cost-effectiveness analyses are presented using (i) the proportion of participants showing a 20% reduction in SASSAD score at week 12; and (ii) the proportion of participants showing a 50% reduction in SASSAD score at week 12. This enables health policy decision-makers to compare the cost-effectiveness of water softeners for the treatment of eczema with the cost-effectiveness of other eczema treatments.

An additional, cost–utility analysis is presented using health-related quality of life (EQ-5D). Data were captured using the children’s version of the EQ-5D for children aged 7 years and over, or the proxy version of the EQ-5D for children aged 3–6 years. 30,31 A utility weight has been attached to the health state descriptions using the currently accepted UK adult tariff, calculated using the York A1 tariff. 32 Children under 36 months were excluded from this analysis, as the EQ-5D has not been designed for use in children aged < 3 years.

Quality-adjusted life-years (QALYs) for individual participants have been calculated using linear interpolation between the baseline and 12-week utility value (Figure 13). Using the area under the curve technique, the number of QALYs for the 12-week trial period was estimated for each participant as displayed in Equation 1.

FIGURE 13.

Quality-adjusted life-years.

where UB is utility at baseline, U12 is utility at 12 weeks, 0.5 reflects that we are measuring a triangle not a square and 0.230769 reflects the 12-week study period (12 weeks divided by 52 weeks).

The shaded area in Figure 13 shows an example of the QALY area being measured for each individual participant, as the area between the linear interpolation line and a line drawn horizontally from the baseline value for the 12-week study period. Figure 13 shows a gain in utility over time such that this individual would have gained a positive number of QALYs. If a loss of QALYs had occurred the diagonal line measuring utility over time would be reversed so that the line sloped downwards rather than upwards, and if there was no change in QALYs over the 12-week period then there would be no diagonal line indicating that utility had remained constant over time.

Mean QALYs per patient for group A and group B are presented along with the mean difference in QALYs per patient and 95% CIs comparing the groups. This analysis allows health policy decision-makers to compare the value of water softeners for eczema with other health technologies in other areas of health.

Resource use and costs

Just 2.5% of weekly diaries were not completed, therefore data were not imputed for these entries. The mean total cost per patient in group A was £332 (SD £170) compared with £134 (SD £288) in group B (difference £198, 95% CI £146 to £250, p < 0.001). This significant cost difference was due to the cost of the intervention; all other resource categories (health professional visits, medications and other medical items) were not significantly different between groups (see Table 19 for resource use and Table 20 for resource costs).

Cost and resource-use data for children aged ≥ 3 years (as required for the cost–utility analysis) are included in Appendix 12.

Cost-effectiveness analysis

The proportion of participants showing a 50% reduction in SASSAD score at week 12 compared with baseline was 18.87% (30/159 participants) in group A compared with 21.95% (36/164 participants) in group B, a difference of –3.08% (p = 0.492). The proportion of participants showing a 20% reduction in SASSAD score at week 12 compared with baseline was 48.43% (77/159 participants) in group A compared with 54.88% (90/164 participants) in group B, a difference of –6.45% (p = 0.246).

As the incremental mean cost is greater and incremental mean benefits lower for group A than for group B, it was not appropriate to estimate an incremental cost-effectiveness ratio because ion-exchange water softeners were dominated by usual care alone, i.e. they were both more expensive and no more effective than usual care, such that the NHS would not consider them a cost-effective use of NHS resources. The decision uncertainty is depicted in Figures 14 and 15. These cost-effectiveness acceptability curves show that there is around a 20% chance of the wrong decision being made if ion-exchange water softeners are not funded by the NHS.

FIGURE 14.

Decision uncertainty: plots of the cost-effectiveness acceptability curves for the proportion of participants showing a 50% reduction in eczema severity (SASSAD).

FIGURE 15.

Decision uncertainty: plots of the cost-effectiveness acceptability curves for the proportion of participants showing a 20% reduction in eczema severity (SASSAD).

Cost–utility analysis

Group A gained a mean of 0.119 on the EQ-5D health-related quality of life scale and group B a mean of 0.066. The mean difference in EQ-5D was 0.054 (95% CI –0.015 to 0.122) (see Table 13).

The mean total cost per patient aged ≥ 3 years in group A was £315 (SD £64) compared with £143 (SD £343) in group B (difference £172, 95% CI £101 to £243, p = 0<001). (For full details, see Appendix 12.)

Group A gained a mean of 0.014 QALYs per patient and group B a mean of 0.008 QALYs per patient. The mean difference in QALYs per patient was 0.006 (95% CI –0.002 to 0.014, p = 0.117). Using the incremental mean cost reported in Table 20, the incremental cost per QALY was estimated as £28,002. Figure 16 shows the cost-effectiveness acceptability curve for the 12-week study period. At all levels of WTP, usual care (group B) had a higher probability of being cost-effective.

FIGURE 16.

Decision uncertainty – plots of the cost-effectiveness acceptability curves for the base-case cost–utility analysis of year 3- to16- year-olds.

Modelling of long-term effects

As ion-exchange water softeners were not found to be clinically effective or cost-effective over the trial horizon, it was not felt to be appropriate to model the longer term cost-effectiveness of water softeners. However, an indication of the likely long-term cost of an ion-exchange water softener is helpful. For a typical family, the cost would be somewhere in the region of £3250. This assumes a 12-year lifespan for the device (covering initial purchase, installation and ongoing salt use) and a household of four or five people.

Willingness to pay for water softeners before the trial

The majority of participants (333/336) provided an answer to the contingent valuation question, which asked parents to estimate the financial value of an ion-exchange water softener to them (the three not answering were all in group A). Given that water softeners are essentially private goods, it was felt that asking directly about participants’ WTP for this product would be relatively intuitive. The mean (median/SD) WTP value was £506.68 (£500/£387.73) with a range from £0 to £3000 (see Figure 17 for distribution of WTP responses). Just five (1.5%) participants (three in group A and two in group B) gave a value of zero and all were genuine zeros. Reasons given by these parents included not being willing to pay anything until proven to be of benefit for eczema, and the child’s eczema not currently causing problems.

FIGURE 17.

Willingness to pay for water softeners for children with eczema.

The results of the univariate general linear regression analysis in which hypothetical WTP was the dependent variable are reported in Appendix 14. The statistically significant variables associated with a positive relationship with WTP included participants stating that their value reflected the anticipated benefits of the ion-exchange water softener (such participants were willing to pay on average £126.73 more than those not stating this reason); those households with an income of ≥ £50,000 (willing to pay £173.72 more on average than those not with this income); and number of nights at home (those with more nights at home willing to pay more). Participants who found the WTP task difficult, or who stated that their WTP reflected their ability to pay, reported significantly lower values of WTP.

The typical cost of an ion-exchange water softener is £600, but could range between £300 and £1800 (based on industry opinion). Using the mean WTP prior to using the water softener as a measure of benefit for the family, it can be inferred that families perceive the benefits of an ion-exchange water softener for their family to be a mean of £506.68. As the scenario provided to families included a description of the likely non-eczema-related cost savings (resulting from less lime scale and improved efficiency of household appliances leading to less fuel consumption and soap use for instance), this estimate of WTP can be taken to mean that families would find an ion-exchange water softeners to have a positive cost–benefit ratio for the family only at the lower price end of the market (i.e. where price is < £506.68). As shown above (see Secondary analyses), there were no significant cost savings for the families associated with costs incurred by the family as a result of their child’s eczema, so these are not considered again here.

Willingness to pay for water softeners after the trial

At 12 weeks a subsample of 146 respondents (those recruited first to the study) were asked the same WTP question as at baseline to see if experience influenced valuations. Of these, only 97 (66%) provided a value (in addition two respondents stated ‘priceless’). Not all 336 participants were asked this question because during the trial it became clear that parents wanted to have some idea of the actual price of the device they could buy at the end of the study in order to save for it. Once this information was divulged this question was felt to be inappropriate.

Mean (median/SD) WTP at the end of the trial was £375 (£300/£282) with a range from £0 to £1500 (Figure 18). Values for the same 97 participants prior to the trial were £475 (£400/£346 with a range from £0 to £1500). On average, experience of using the water softeners lowered their mean WTP by approximately £100. Overall, 26% gave higher WTP values at the end of the trial, 29% gave the same value and 44% gave a lower value.

FIGURE 18.

Demand curves for water softeners before and after participation in the trial.

The reasons given for WTP values before and after the trial are summarised in Table 21 (respondents could give multiple responses).

Hypothetical versus real willingness to pay for an ion-exchange water softener

Table 22 shows the number (percentage) of participants who stated a hypothetical WTP value that was either above or below the actual discounted price they were offered at the end of the study (rows), and whether they actually chose to purchase the ion-exchange water softener (either a study device or private device – columns). Although the percentage who indicated a hypothetical WTP above the actual asking price and bought the device and those giving a WTP below the actual asking price and not buying the device account for over 50% of the relevant participants, clearly a large number changed their preferences during the trial, some changing in favour of buying the device and others choosing not to purchase, despite initially indicating that they thought the device might be worthwhile. The two groups account for a similar percentage of respondents.

To try to understand what influenced the decision to purchase or not, a binary logistic regression analysis was conducted. The results are shown in Appendix 15. Only the number of medications at baseline, water hardness at baseline and household income were significant determinants. An increase in the first two explanatory factors made it more likely that an ion-exchange water softener would be purchased; however, a household income of < £30,000 per annum made it less likely that an ion-exchange water softener would be purchased.

Main findings

The mean costs were consistently higher for the water softener group than for those receiving normal care as a result of the intervention costs. All other costs were similar between the groups and sensitivity analysis supported these findings. It is clear that on the basis of this trial, there is no evidence to suggest that ion-exchange water softeners provide a cost-effective treatment option for the treatment of children with eczema.

The results of the cost–utility analysis supported the cost-effectiveness analysis. Despite a slight (non-significant) improvement in the EQ-5D scores for those receiving the water softener, the cost–utility analysis estimated the use of water softeners to have an incremental cost per QALY of £28,018 in the base case. Sensitivity analyses revealed that this could range from £4548 per QALY (best case) to £53,957 per QALY (worst case).

For interventions with a cost per QALY > £20,000, the latest available National Institute for Health and Clinical Excellence (NICE) methods manual43 states that decisions about whether an intervention represents a good use of NHS resources will depend on a number of factors including the uncertainty surrounding the incremental cost-effectiveness ratio and whether the assessment of health-related quality of life was adequate or unlikely to have captured benefits of an innovative technology. Although, clearly, ion-exchange water softeners are a potentially innovative technology in the health-care context and this study used NICE’s preferred measure of health-related quality of life (the EQ-5D, p. 38), this study found a large degree of uncertainty around estimates of the incremental cost per QALY, suggesting that this technology is unlikely to be viewed as offering the NHS value for money in treating the condition and age range considered.

Evidence from the contingent valuation study suggested that experience of using a water softener during the trial reduced the average WTP by approximately £100. This is possibly to be expected, given that people who believed in the value of water softeners would have been more likely to take part in the trial, and belief in the benefits of the water softeners was a significant factor in determining how much participants felt that they would be willing to pay prior to experiencing the intervention. However, the fact that many families opted to purchase the units despite little improvement in the eczema suggests that other factors were also important.

Strengths and weaknesses

This is the first economic evaluation of ion-exchange water softeners in the context of eczema care. The strengths of this economic evaluation are that it has been conducted alongside a RCT, which enabled comprehensive prospective data collection and suffered very few missing data. However, in line with all economic evaluations, it has had to employ some assumptions as detailed in Chapter 2. The uncertainty created by the most important of these was tested in sensitivity analyses, testing the extremes, but we did not include a probabilistic sensitivity analysis approach. It is a limitation of current health-related quality of life instruments as used in economic evaluations that they have not been developed or validated for very young children such that there is currently no best practice approach to valuing child health within a cost–utility framework. Although a child version of the EQ-5D has been tested in a survey of UK children aged 7–17 years,31 which is completed by parental proxies,44,45 and more recently, a revised youth version has been tested internationally,46,47 there are still a number of methodological issues in this area of valuation, including questions about the relevance of included health dimensions and who, and from what perspective, the appropriate respondents are to attach a value to children’s health states. 48,49 Consequently, we did not measure the health-related quality of life of those children aged < 3 years and these children were excluded from the cost–utility analysis. For those children aged > 3 years who had either a parental proxy or self-completed health-related quality of life score, a QALY was estimated for the trial period based on the utility weights of the York A1 tariff,32 which were derived from non-institutionalised adults. Whether this is deemed acceptable depends on whether or not one believes voters’/taxpayers’ perspectives are legitimate even when these perspective were elicited without specific reference to children’s health status. Clearly, future research and consensus in this research area is needed. Given this context, the results of the cost–utility analyses reported above should be read with some caution.

Conclusion

Ion-exchange water softeners are unlikely to be a cost-effective intervention for children with eczema from an NHS perspective because of the lack of objective evidence of benefit and because they incur a cost. We find no basis for the NHS and other government bodies to consider funding ion-exchange water softeners for childhood eczema as they do not appear to work for this condition. The contingent valuation study taking a family perspective suggests that ion-exchange water softeners may be perceived as cost beneficial to certain individual families provided the cost of the device is at the lower end of the market price range.

The primary outcome

This study is the only RCT to date assessing whether the installation of an ion-exchange water softener can help relieve the symptoms of eczema in children with moderate-to-severe eczema. The main findings based on a blinded evaluation of the primary end point of mean change in eczema severity at 12 weeks compared with baseline (as measured using the SASSAD) showed that installing water softeners was no better than usual care in relieving the symptoms of eczema. Furthermore, there was a narrow CI around that difference, excluding small but important clinical differences.

One possible reason for the discrepancy between our null trial findings and those of previous observational studies that found that increased prevalence of eczema in children living in hard water areas is that children in the observational studies ingested the water. In other words, it is possible that ingestion of hard water or a component to water that is related to water hardness actually induces skin inflammation directly or indirectly through inflammatory gene interactions, although we are not aware of any such mechanisms in the literature to date.

It is also possible that eczema represents a heterogeneous group of distinct genetic conditions, some of which will respond to water softeners and some of which will not. Previous research has suggested an association between the presence of eczema/dry skin and mutations of the filaggrin gene. A subgroup analysis based on the presence or absence of mutations of the filaggrin gene found no evidence that the treatment effect varied between those with and without the mutation.

We wish to stress that those who participated in the study were not formally tested for atopy by means of circulating specific IgE antibodies. They did, however, represent the sort of patients with eczema typically seen in clinical hospital practice. It is possible that a subgroup analysis of atopic versus non-atopic individuals might have shown that one group benefits while the other does not. Based on our previous observation that IgE responsiveness adds little information to our predictive ability about eczema,50 added to our desire to minimise the number of subgroup analyses to avoid inappropriate post hoc findings, we chose not to measure atopic status in this pragmatic trial.

Other outcomes

In addition to our primary outcome measure, which was assessed blindly, we had a number of secondary outcomes, some of which were assessed blindly (proportion showing reasonable, good or excellent improvement, night-time movement, medication used) and some of which were assessed by parents who were not blinded (POEM, TCWs and WCWs, DFI, and EQ-5D).

For all of the blinded outcomes, there was no difference between the treatment groups. Of the unblinded secondary outcomes, all but one showed small, but statistically significant, differences in favour of the water softener group. However, the magnitude of improvement seen in these outcomes was small and unlikely to be clinically meaningful. It is also possible that our emphasis on objective outcomes meant that some important potential benefits were not captured in the primary analysis. Other factors, such as improvements in quality of life or a reduction in symptoms (e.g. dry skin), may be important drivers in determining whether or not parents perceived a benefit.

High Priority

Medium priority

Low priority

Details of MEDLINE search

1. randomised controlled trial.pt.

2. controlled clinical trial.pt.

3. randomised.ab.

4. placebo.ab.

5. drug therapy.fs.

6. randomly.ab.

7. trial.ab.

8. groups.ab.

9. 6 or 3 or 7 or 2 or 8 or 1 or 4 or 5

10. (animals not (human and animals)).sh.

11. 9 not 10

12. Exp Dermatitis, Atopic/

13. atopic dermatitis.mp.

14. atopic eczema.mp.

15. exp NEURODERMATITIS/

16. neurodermatitis.mp.

17. infantile eczema.mp.

18. childhood eczema.mp.

19. Besniers’ Prurigo.mp.

20. Exp Eczema/or eczema.mp.

21. 17 or 12 or 20 or 15 or 14 or 18 or 13 or 16 or 19

22. 11 and 21

23. Limit 22 to yr = ‘2000 to 2009’

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