Chapter overview
This chapter identifies the appropriate the methodology for a trial of WED for improving depression in adults with a LTPC, which meets the requirements specified in chapter three. The appropriate design, population, intervention implementation, comparison exposure, outcomes, approach to effectiveness analyses, exploratory analyses, measures, data collection schedule and feasibility investigation are considered, in addition to the substantial patient safety issues encountered in this context and the measures required to address them. Finally, the user and expert consultation process is described briefly.
Design
The MRC framework for complex interventions is an established framework that delineates the sequential phases of investigation in the evaluation of complex interventions, identifying the objectives to be met before progressing to the next stage (Campbell, Fitzpatrick, Haines, Kinmouth, Sandercock, Speigelhalter & Tyer, 2000; Craig, Dieppe, Macintyre, Michie, Nazareth & Petticrew, 2008; MRC, 2000). In phase one trials, the intervention is modelled, which entails improving understanding of the intervention and identifying and defining the key components (i.e. the active ingredients). For example, these data might be obtained via qualitative interviews and focus groups with patients and HCPs. In phase two ‘exploratory’ trials design-related issues are identified prior to a full effectiveness trial; the optimal trial and intervention design are defined. Specifically, the anticipated treatment effect is identified and tested, intervention and trial parameters are piloted, and other feasibility issues are identified (i.e. the feasibility/effectiveness
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of delivering the intervention and the trial protocol is established). Importantly, variations of the intervention can be tested to identify which seem to be the most appropriate for a full scale trial. This entails a direct comparison of two of more variations of an intervention; the only way to provide conclusive evidence of the utility, practicality or desirability of one approach over another (MRC, 2000).
Chapters two and three identified that the WED evidence base is confounded by heterogeneity, as study parameters have been unsystematically manipulated in search of the most effective design. Few studies have modelled WED and systematically manipulated it’s parameters to identify the optimal design or ‘recipe’ (e.g. manipulated the number of writing sessions or the spacing of sessions within study). Such studies, consistent with phase one trials and the intervention development element of phase two trials, are certainly required. This would have been an interesting and important piece of research. However, it would entail a dedicated programme of research addressing each of the many parameters of WED, which given the constraints on time was beyond the scope of the present study. The objective of the present study was additionally to identify the preliminary effectiveness and feasibility of WED when applied to the clinical issue of depression in LTPCs.
Consequently, it was decided that given the remit and objectives of the present endeavour the most appropriate study design was a phase two trial, focussing on testing preliminary effectiveness, piloting intervention and trial parameters and identifying other feasibility issues, with some further exploration of the former. Consistent with the objective of testing the evidence gained thus far the anticipated effect should be explored further, specifically whether WED works as anticipated and whether it works differently for different people as anticipated should be explored, and a prior economic analysis should be undertaken. Some of the trials
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considered in the systematic review specifically investigated feasibility (Broderick et al, 2004; Gellaitry et al, 2010; Taylor et al, 2003; Walker et al, 1999), yet these were few and are required. Whilst not the ideal scenario, the WED evidence base was considered as a whole and the optimal parameters of WED were inferred from this (discussed below). The MRC phases and corresponding objectives, and the status of the investigation of WED for improving depression for adults with LTPCs in relation to each phase are illustrated in Table 5.
It is typical for phase two trials to include a before and after design in order to gauge the preliminary effectiveness of an intervention. However, in the absence of a control group any change observed cannot be attributed specifically to the intervention. In these designs internal validity is compromised; causal inferences cannot be drawn (Nezu & Nezu, 2008). It is not uncommon, however, for a RCT design to be employed in feasibility trials including those testing WED (Klapow, Schmidt, Taylor, Roller, Li, Calhoun, Wallander & Pennebaker, 2001) and other psycho-social interventions in diabetes (Sturt, Whitlock, Hearneshaw, Farmer, Wakelin, Eldridge, Griffiths & Dale, 2008). A RCT provides the most robust investigation of effectiveness to inform evidence-based practice (Barton, 2000); randomization minimizes systematic variation between groups promoting the equal distribution of confounding variables and thus enhancing the degree to which any effect can be attributed to the intervention. In order to provide the most informative assessment of WEDs preliminary effectiveness for improving depression in LTPCs, a RCT was considered appropriate.37
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Incidentally a RCT was preferable to natural and quasi-experimental designs as WED is not currently employed in practice thus natural allocation to groups is unavailable and in the absence of controlled manipulation and or randomisation alternative explanations for observed effects cannot be ruled out (again internal validity is compromised and causal inferences cannot be drawn) (Nezu & Nezu, 2008).
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Table 5 MRC framework for complex interventions and the status of WED in LTPCs
Phase/objectives for each phase Status of WED & how objectives have been/should be met
Pre-clinical/theoretical phase
Establish the theoretical basis/evidence base that the intervention is likely to have the anticipated effect (i.e. before
substantial evaluation an intervention must be developed to a point where it can reasonably expected to be effective)
Satisfied: The WED evidence base is inconsistent and the mechanisms of WEDs effects are unclear. However, there is reason to believe that it may be effective for improving
depression in LTPCs and it is seemingly associated with various empirically supported influencing mechanisms, which are similar to those underpinning other effective psychotherapies. Hence it may be considered to have a sound theoretical grounding for improving health (chapter two). There is also evidence that interventions like WED which target emotional aspects of stressors and thus presumably distress may optimise improvement in depression in LTPCs (chapters one & two) If there is no high quality systematic
review evidence of the relevant evidence one should be conducted
Satisfied: Previous systematic reviews have been limited in their utility for determining the effect of WED for depression in LTPCs (chapter two). A more focussed review with more appropriate methodology was thus conducted, and identified that WED may be effective for improving depression and associated outcomes perhaps for specific LTPCs (chapter three).
Identify the likely/anticipated processes of change
Satisfied: The likely/anticipated mechanisms of
change/mediating processes underpinning WEDs effects have been offered and again somewhat supported empirically yet require further testing (chapter two).
Identify strategic design issues Satisfied: The systematic review (chapter three) and the LTPC/depression & WED evidence (presented below) provide some indication of the methodological parameters within which WED should be tested. Ethical review identified further design- related issues (discussed below).
Phase 1: Modelling
Improving understanding of the intervention and identifying and defining the key components (i.e. the active ingredients)
Required but beyond the scope of and not consistent with the objectives of the present study.
Phase 2: Exploratory trial: defining optimum trial and intervention design
Testing variations of the intervention to identify which seem to be the most appropriate for a full scale trial
Required but beyond the scope of and not consistent with the objectives of the present study.
Testing the evidence gathered thus far (e.g. obtaining evidence to support theoretically expected treatment effect and anticipated effect sizes)
Required: Whether WED is likely effective for improving depression, and associated outcomes, in LTPCs, and the anticipated effect sizes should be estimated.
Whether WED works as anticipated and whether it works differently for different people as anticipated should also be explored.
Undertake a prior economic evaluation Required: This should be attempted for WED in LTPCs.
Investigating the feasibility/effectiveness of intervention delivery (e.g. compliance, intervention fidelity & acceptability)
Required: These issues must be established for WED in LTPCs.
Investigating the feasibility/effectiveness of a trial protocol (i.e. identifying an appropriate control group, follow up, outcome measures, estimates of recruitment/retention & other issues that may undermine a main effectiveness trial e.g. feasibility and effectiveness of the randomization method)
Required: These issues must be established for WED in LTPCs.
Phase 3: Main effectiveness RCT
Testing a fully defined intervention with a theoretically defensible protocol, and with attention to achieving adequate statistical power and standard features of well-designed trials (e.g. randomisation, blinding & allocation concealment)
Requires completion of phase 2.
Phase 4: Long-term surveillance
Determining whether the intervention and results can be reliably replicated in uncontrolled settings in the long-term
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Indeed, randomization is advocated to identify and estimate anticipated effect sizes, which inform sample size calculations (Campbell et al, 2000). Piloting of the method of randomization and as such establishing the feasibility and effectiveness of this prior to a full effectiveness trial is also recommended practice (MRC, 2000).
The RCT design should be parallel groups, wherein the intervention and control are applied simultaneously to two separate groups of participants. This is preferable to alternative designs, for example cross-over RCTs in which participants are randomly assigned to a sequence of treatments (i.e. they all receive the same treatments in a different order). This design affords further control of confounders yet requires long ‘wash-out periods’ to avoid carry-over of treatment effects and is susceptible to order effects (i.e. the order in which people receive the treatments may influence effects) and learning effects (i.e. WED participants may react to a neutral writing control task in a different way than naive controls). Moreover, withholding WED from controls was justified (discussed below).
Phase two exploratory trials do not normally attend to issues such as internal validity/risk of bias and statistical power. These issues could additionally be considered in a preliminary manner, however, to further maximise the informative potential of the trial with respect to identifying and estimating anticipated effects and feasibility issues with regards to achieving these standards. Specifically, trials could endeavour to adhere to the CONSORT standards of randomisation, allocation concealment (i.e. preventing researcher’s prediction of group allocations before enrolment and thus allocation based on baseline characteristics) and blinding (i.e. preventing participants’ inference of group assignment) (Moher et al, 2001). An à priori sample size calculation could additionally be specified, with the feasibility of achieving the sample size requirements and the appropriateness of the parameters identified.
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As identified in chapter three, achieving blinding in WED trials is particularly complicated. Ideally, the trial should be double blind. In endeavouring to achieve this, a placebo comparison must be employed and the information received at enrolment must be sufficiently vague to prevent participants’ inference of allocations on receipt of writing; the exact nature of the intervention and the existence of an intervention and control group must be withheld. This additionally prevents contamination in controls and pre-disclosure priming (i.e. protecting patent safety, discussed in chapter three). Given the difficulty in achieving blinding, the success of participant blinding should be specifically assessed. Participants should also self- administer the intervention and self-reported outcome measures, such that intervention implementation/outcome assessment is additionally blind.
HCPs will need to be aware of the study purpose but should not be informed of participating patients’ group allocation, and the risk of discussion between patients and HCPs about the study should be minimised.
Population
Piloting WED for improving depression in diabetes
WED should be considered for improving depression in diabetes. The research team had a keen clinical interest in diabetes, and incidentally to date, no published studies had investigated this. This investigation is, however, timely and warranted, the reasons for which are discussed below.
Diabetes
The amount of glucose in the blood is controlled by insulin, a hormone produced by the pancreas. This moves glucose derived from the food we eat, from the blood
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stream into cells where it is broken down to energy. Diabetes is a metabolic disorder in which the body is unable to break glucose down to energy. In type 1 diabetes the pancreas is unable to produce insulin (insulin-dependent diabetes) and in Type 2 diabetes the pancreas is unable to produce enough insulin or the cells in the body are unable to utilise the insulin that is produced (i.e. cells require insulin to absorb glucose); termed insulin resistance (i.e. non-insulin dependent diabetes). In both, hyperglycemia (i.e. high blood glucose levels) can result and produce long-term microvascular complications including retinopathy (i.e. damage to the retina at the back of the eye), neuropathy (i.e. nerve damage), foot ulcers (i.e. damage to the nerves of the foot) nephropathy (i.e. kidney disease), sexual dysfunction (i.e. erectile problems owing to damage to nerves and blood vessels), and macrovascular complications such as CAD and stroke. Diabetes cannot be cured, instead the treatment goal is to maintain blood glucose levels as close to normal as possible to prevent the development of the aforementioned medical complications later in life. In Type 1 diabetes this is achieved via patient initiated SMBs including adjustment in diet and exercise, self-monitoring of blood glucose and importantly self-administering insulin. Type 2 diabetes is usually managed initially via adjustment in diet and exercise, and weight loss, yet some cases additionally require oral hypoglycemic agents and perhaps insulin (i.e. it is a progressive condition).
Diabetes is one of the biggest health challenges facing the UK (DUK, 2010a). The UK is facing an obesity epidemic, which is a particular risk factor for Type 2 diabetes (DUK, 2010a). Indeed, it is estimated 2.6 million people have diabetes (DUK, 2010a), with many more cases unrecognised (Holt, Stables, Hippisley-Cox, O’Hanlon & Majeed, 2008; NHS The Information Centre for Health and Social Care, 2008). Indeed, the incidence (Shaw, Sicree & Zimmet, 2010) and thus prevalence (Wild, Sicree, Roglic, King & Green, 2004) of diabetes is increasing, more notably
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than for other LTCPs (DoH, 2009). Again, diabetes is a major risk factor for further LTPCs (Fillenbaum et al, 2000; WHO, 2002) and with the aging population people are now living longer hence the impact of complications is increasing (Rubin, Walen & Ellis, 1990). Indeed, a decline in mortality rates is reported for some LTPCs (see chapter one), yet not diabetes.
Depression in diabetes
To maximise effectiveness, the systematic review recommended investigation of WED for reducing negative affect, for example depressive symptoms, in LTPCs that are associated with negative affect and in which negative affect has a significant impact. Systematic reviews of cross-sectional studies have consistently indicated that having diabetes doubles the risk of elevated depressive symptoms and MDD, which is consistent across diabetes type and equates to one in six people with diabetes (17.6%) being likely to experience depression of a magnitude that may impair functional health (Anderson, Freedland, Clouse & Lustman, 2001; Ali et al, 2006). Depression is also particularly persistent in diabetes; at follow up, up to 47% still report significant depressive symptoms (Fisher, Skaff, Mullan, Arean, Glasgow & Masharani, 2008; Hermanns, Kulzer, Kubiaz & Haak, 2004; Peyrot & Rubin, 1999; Pibernik-Okanovic et al, 2008) and 79% of those with MDD report dysthymia or at least one recurrent episode (average 4.2 episodes) despite some form of treatment during this period (Lustman, Griffith & Clouse, 1988). Indeed, 37% of patients indicating remission experience significant symptoms at follow up (Peyrot & Rubin, 1999). The substantial impact of depression upon important outcomes in diabetes was presented in chapter one.
Current access to E&P support in diabetes
Whilst an improvement on previous years, in 2008 only just over half of the PCTs in the UK agreed that psychological support was provided to adults with diabetes
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(DUK, 2007d; 2009a). A survey of psychological input into secondary care diabetes services for UK adults also reported that only 15% have access to specialist service provision, thus 85% of people with diabetes have no defined access to E&P support or at best have access to local generic services (i.e. with no diabetes input). Moreover, where specialist services do exist, only 13% have input into primary care, 17% report unacceptable waiting times and 3% comply with all relevant NSF standards (DUK, 2008). Indeed, HCPs report that they can recognise E&P need yet they lack the time and skill to deal with this and insist more training and psychological input is required; only 38-61% feel able to meet this need and 51-65% perceive external support (DUK, 2008; DUK, 2007c; DUK, 2006a; DUK, 2005b; Pouwer et al, 2006). This unmet need consistently ranks amongst the top concerns reported by people with diabetes and HCPs (DUK, 2007a; 2009c; 2010b), and has been confirmed in a number of patient surveys reported in Table 6.
Policy imperatives for improving provision of E&P support in diabetes
As the prevalence of diabetes rises, the impact of depression will increase and the unmet support need will worsen, thus action is required now (DUK, 2008). There have been a number of diabetes specific-initiatives prioritising E&P support, recognising this as a barrier to SMBs and advocating that this should be integral in diabetes care, and receive Government investment, increased resource allocation and research investigating the benefits associated with different types of support (DUK, 2007c; DUK, 2006a; DUK, 2005a; DUK, 2005b; DUK, 2008). DUK have joined the campaign advocating the importance of talking therapies described in chapter one (Mental Health Foundation, Mind, Rethink, The Sainsbury Centre for Mental Health & Young Minds, 2006) and advocates that all self-management, education and empowerment programmes should comprise components targeting E&P need (DUK, 2007c). Indeed, as reported in chapter one provision of E&P support is a diabetes NSF standard.
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Table 6 Patient surveys identifying an unmet need for E&P support in diabetes
Year Survey Finding
2005 Diabetes Dialogue38 A lack of E&P support available is a significant gap in the provision of diabetes services.
2006 Diabetes Listening Project 239 At diagnosis 40% report receiving E&P support but 36% reported wanting and not receiving this.
2006 Health Care Commission diabetes patient survey40
3% expressed a need for specialist
psychological support yet only 53% received this.
2006 DUK Membership Survey41 48% reported receiving emotional support and 4% expressed a need for specialist
psychological support yet 51% could not access this.
2006 A UK service development consultation in diabetes42
Access to psychological support was the most requested priority (identified by 36% of responders), and people that wanted to talk about emotional problems were those
experiencing significant depressive symptoms.
2009 DUK Membership Survey43 42% of members report wanting to talk primarily to their HCP, of which 74% were able to do so.
Recent changes in UK clinical practice with respect to E&P support in diabetes These imperatives have spurred endeavours to improve service delivery. In addition to the introduction of the QoF indicators for depression in LTPCs including diabetes,