Recruitment, intervention delivery and clinical outcomes

In this chapter we will describe recruitment to CODES, the baseline characteristics of our sample, treatment delivery and fidelity, and the clinical outcomes.

Recruitment and sample characteristics

Introduction

Participants were initially identified and then recruited from neurology/specialist epilepsy services in 27 NHS trusts. Of the 698 initially recruited patients, 568 patients attended psychiatry assessments at a neuropsychiatry/liaison psychiatry service in 1 of 17 NHS trusts around 3 months later, and 368 patients were subsequently randomised into the trial. CBT was delivered in 1 of 18 NHS trusts linked to the psychiatry services for the purpose of the study (see Chapter 2 for the list of sites contributing to the different aspects of the study).

Participant flow through the study

Recruitment

Recruitment into the screening phase of the study (i.e. from neurology/specialist epilepsy clinics) ran from October 2014 to February 2017. Randomisation from this pool of patients into the RCT ran from January 2015 to May 2017. As a result of initial concerns regarding loss to follow-up rates, these timelines included an extension of recruitment to both phases of the study by 3 months.

Neurologists recruiting patients for the study were asked to provide information on all patients with DSs attending their clinics. Although this may be an underestimate of the number of DS patients attending neurology/epilepsy clinics, 901 patients were identified whose eligibility details were provided [the Consolidated Standards of Reporting Trials (CONSORT) flow diagram for CODES, part 1; Figure 2]. Recruitment in the liaison/neuropsychiatry settings involved psychiatrists further assessing patients’ eligibility for the RCT. This was undertaken for the 568 patients attending their psychiatric assessment session.

FIGURE 2 The CONSORT flow diagram: part 1. (Figure not reproduced here; see the original article.)

Enrolment

Of the 901 patients identified in neurology settings, 698 were consented to the screening phase of the study (i.e. consented for psychiatric assessment) (see Figure 2). This was the upper limit of the extended recruitment target for this phase of the study and was possible because of a surge in recruitment in the last month of recruitment. In addition to not meeting eligibility criteria (n = 56), as seen in Figure 2, the majority (n = 85) of the 147 patients not enrolled did not want to take part in the study, and 61 patients did not respond to attempts to make contact.

Recruitment into the screening stage occurred across all sites in parallel (Table 3). As anticipated, sites varied considerably in the number of patients recruited; this was, in part, influenced by the number of clinics held at each site.

The 27 neurology/specialist epilepsy sites (NHS trusts) have been listed in order of the date that the first participant consented rather than by name to help anonymise data from participants from sites with small numbers of participants (fewer than participants). In alphabetical order, the neurology/specialist epilepsy services were at the following NHS trusts: Barts Health NHS Trust; Birmingham and Solihull Mental Health NHS Foundation Trust; Brighton and Sussex University Hospitals NHS Trust; Cambridge University Hospitals NHS Foundation Trust; Cardiff and Vale University Health Board; Chesterfield Royal Hospital NHS Foundation Trust; Croydon Health Services NHS Trust; Dartford and Gravesham NHS Trust; East Kent Hospitals University NHS Foundation Trust; East Sussex Healthcare NHS Trust; Guy’s and St Thomas’ NHS Foundation Trust; Imperial College Healthcare NHS Trust; King’s College Hospital NHS Foundation Trust; Leeds Teaching Hospitals NHS Trust; Lewisham and Greenwich NHS Trust; Maidstone and Tunbridge Wells NHS Trust; Medway NHS Foundation Trust; Newcastle upon Tyne Hospitals NHS Foundation Trust; NHS Lothian; Royal Berkshire NHS Foundation Trust; Royal Free London NHS Foundation Trust; Sheffield Teaching Hospitals NHS Foundation Trust; St George’s University Hospitals NHS Foundation Trust; University College London Hospitals NHS Foundation Trust; University Hospital Southampton NHS Foundation Trust; University Hospitals Birmingham NHS Foundation Trust; and Western Sussex Hospitals NHS Foundation Trust.

Once patients consented to the screening phase of the study in the neurology/specialist epilepsy clinics, research workers maintained fortnightly contact with the patients wherever possible to obtain seizure diary data and remind patients about their psychiatry assessment. A total of 130 people did not attend their psychiatric assessment appointment, so could not be considered for the RCT. Of the 568 people who were assessed by a psychiatrist, 426 were considered eligible for the RCT and 368 were consented to the RCT (Figure 3). The number consented to the RCT slightly exceeded our extended target (n = 356); however, we could not ethically refrain from recruiting some rather than other eligible participants. Our recruitment graphs for both phases of the study are shown in Figure 4.

FIGURE 3 The CONSORT flow diagram: part 2. a, One participant allocated to SMC received CODES CBT by mistake. b, Treatment receipt of CBT (compliance) was defined as receiving at least nine sessions. (Figure not reproduced here; see the original article.)

FIGURE 4 Cumulative target vs. achieved recruitment and randomisation. Note that recruitment targets were subsequently revised from November 2016 to a total of 698 in phase 1 with an extended recruitment period to February 2017 and a revised RCT total of 356 (phase 2), similarly extending recruitment by 3 months from February to May 2017. (Figure not reproduced here; see the original article.)

Enrolment into the RCT took place across all sites in parallel and was completed at the end of May 2017 (Table 4).

The 17 psychiatry sites (NHS trusts) have been listed in order of the date that the first participant was randomised rather than by name to help anonymise data of participants from sites with small numbers of participants (fewer than five participants). In alphabetical order, the psychiatry sites are as follows: Berkshire Healthcare NHS Foundation Trust; Birmingham and Solihull Mental Health Foundation Trust; Cambridgeshire and Peterborough NHS Foundation Trust; Cardiff and Vale University Health Board; Derbyshire Healthcare NHS Foundation Trust; East London NHS Foundation Trust; Kent and Medway NHS and Social Care Partnership Trust; Leeds and York Partnership NHS Foundation Trust; NHS Lothian; Northumberland Tyne and Wear NHS Foundation Trust; Sheffield Health and Social Care NHS Foundation Trust; South London and Maudsley NHS Foundation Trust; Southwest London and St George’s Mental Health NHS Trust; Sussex Partnership NHS Foundation Trust; University College London Hospitals NHS Foundation Trust; University Hospital Southampton NHS Foundation Trust; and West London NHS Trust.

Unblinding

Table 5 reports the data from the study research worker (RW) treatment guess forms to assess whether or not blinding of treatment allocation was successful. Forms were completed at 12 months post randomisation or at participant withdrawal. Forms were available for 342 out of 368 participants. The data in Table 5 imply that blinding was generally successful, with only eight randomised participants being reported to have unblinded RW(s) in some way. Most guesses were completely at random.

To formally test whether or not trial arm predicted type of guess, ‘Strongly think he/she was allocated CBT’ was combined with ‘Think he/she was allocated CBT’, and ‘Strongly think he/she was allocated SMC only’ was combined with ‘Think he/she was allocated SMC only’. A Fisher’s exact test was then run to compare guesses between trial arms and indicated that there was an association between trial arm and RW guess (p < 0.001). For participants allocated to the SMC-alone arm, RWs guessed that the majority were allocated to SMC alone (81.3%), whereas this percentage fell to 49.7% for the CBT + SMC arm. This implies that the RWs may have been able to guess when participants were having CBT to some extent.

Baseline characteristics

We gained clinical and other demographic data at initial recruitment of the 698 participants into the study from neurology clinics, and again prior to randomisation into the RCT for 368 participants. Some data were obtained only once, whereas some data were gained at both time points. Tables 6–8 present clinical and demographic data for those consented to the screening phase (n = 698), those subsequently eligible for the RCT (having attended the psychiatric assessment, n = 426) and those randomly allocated to the two treatment arms (n = 368). Although there were some fluctuations in terms of values across study stages, Tables 6–8 indicate that those randomised into the RCT were very similar to the initially recruited sample (n = 698), and characteristics were similar for those randomised to the two treatment arms.

As described in Chapter 2, key characteristics that were measured after consent to the screening phase were compared using statistical tests between participants in our trial sample (n = 368) and participants who were eligible for the trial but did not go on to be randomised (n = 58). None of the comparisons was significant at the p-value < 0.05 level.

Our participants had a median age in the mid-30s, and the proportion of women in the randomised subsample, at around three-quarters, was in line with expectations and was very similar to the proportion of women in the overall pool of 698 participants from which the subsample was drawn (see Table 6). We have described the total sample of 698 participants in detail elsewhere133 and reported that, although overall there were more women than men, women were more likely than men to develop DSs at a younger age, whereas men were equally likely to develop DSs across the age span.

The IMD scores, reflecting levels of deprivation based on participants’ postcodes, indicated that, when examining quintiles, > 50% of participants from England, Scotland and Wales fell in the two quintiles indicating areas of the highest levels of deprivation.

The majority of the participants were white, and > 50% had attained secondary-level education or vocational qualifications. Across all subgroups, approximately two-thirds of participants were not employed or in education. We defined ‘unemployed and not in education’ as including those who were unemployed, employed full-time/part-time but off sick, students whose studies were interrupted because of illness, retired owing to age or ill-health, or househusbands/housewives. Those categorised as being employed (approximately one-third of cases) were employed full- or part-time (and working), students or self-employed. The clear majority of those aged < 65 years and not working were receiving disability benefits, in contrast to those of working age and working. Most participants lived with other people, although roughly equal proportions were either married/cohabiting or single. Most (> 60%) reported having no dependants; around one-third (> 35%) reported having a carer, with this most often being a partner.

For the most part, at each stage of the study just over 50% of the patients had received their DS diagnosis based on video EEG (see Table 7). The median age at onset of DSs in our initial sample and those subsequently randomised was late 20s (not all participants were able to say when their DSs had started). The median duration of experiencing DSs until the delivery of the diagnosis in this study was mostly 3 years. Around two-thirds of patients were reported to have predominantly hyperkinetic DSs. The percentage of patients self-reporting a previous diagnosis of epilepsy was generally slightly higher than the percentage of patients thought by clinicians to have had a previous epilepsy diagnosis. Clinicians indicated that an appreciable number of patients were thought to have been previously misdiagnosed with epilepsy, and indicated that for between one-quarter and half of those patients it was not possible to verify the previous diagnosis. Although around one-third (30.3%) of the initially recruited (n = 698) sample self-reported that they were taking AEDs (30.9%), this percentage was nearer 20% in those entering the RCT.

The majority of patients indicated a strong belief in their diagnosis (scores between 8 and 10), with a median score of 8 (out of a maximum of 10) across all subgroups. A negligible percentage of participants had previously received CBT for their DSs. Around two-thirds had previously sought help for a mental health problem and > 70% of those entering the RCT reported suffering from another medical problem.

Psychological comorbidities and other characteristics measured pre randomisation

The Mini-International Neuropsychiatric Interview and Standardised Assessment of Personality Abbreviated Scale, Self-Report

The M.I.N.I. diagnoses are shown in Table 9 for those randomised overall and by trial arm. Of note, although this is not a diagnosis as such, 232 people (63.0%) overall met criteria for suicidality and 136 (37.0%) did not. The suicidality risk level was low for 151 (65.1%), moderate for 29 (12.5%) and high for 52 (22.4%) participants indicating suicidality, although none of the high-level risk participants was judged to be at imminent risk of harm by their psychiatrists. The most common diagnosis was a previous diagnosis of major depressive disorder and the most common current diagnosis was agoraphobia, followed by a current diagnosis of major depressive disorder, generalised anxiety disorder, PTSD and social anxiety disorder, all of which were reported by > 20% of participants.

Although some patients met the diagnosis criteria for current substance (n = 2; 0.5%) or alcohol (n = 4; 1.1%) dependence, these diagnoses had not been identified by the diagnosing neurologists or psychiatrists during their assessments of the patients.

On the SAPAS-SR, 211 (58.1%) participants had scores that potentially indicated the presence of maladaptive personality traits.

Treatment preference and expectations of outcome

Patients were asked to indicate their treatment preferences prior to randomisation. Of 367 patients responding, 228 (62.1%) indicated a preference for CBT, 15 (4.1%) indicated a preference for SMC and 124 (33.8%) did not know which treatment they would prefer. There were no clear differences in preference proportions among actual allocations, although for both the CBT + SMC and the SMC-alone treatment arms, around 60% indicated a preference for CBT + SMC. Around 3% of the SMC-alone arm and 5% of the CBT + SMC arm indicated a pre-randomisation preference to be allocated to the SMC-alone arm (see Table 10).

Expectations of treatment outcome prior to randomisation are shown in Table 10. Median ratings of how logical the different treatments seemed and how confident participants were that they would be helped by them were more positive than negative, and were similar for all three treatment arms.

For each treatment (CBT, treatment by neurologist and treatment by psychiatrist), scores are combined for how logical the treatment seems and how confident the person is that this will help them.

Treatment delivery and fidelity

Healthcare practitioners involved in delivering CODES

A wide range of neurologists, psychiatrists and therapists participated in the CODES trial; SMC was delivered via local permutations of neurology and psychiatry appointments. Of the 63 CBT therapists who were trained to deliver CODES CBT, 39 were subsequently allocated patients. Reasons for non-allocation of patients to trained therapists included therapists changing job between training and patient randomisation, therapists’ change of job role at the site and parental leave.

The demographics and clinical experience of the three types of HCPs are summarised in Appendix 6.

Numbers of sessions attended for each intervention

Table 11 presents the number of SMC appointments that participants were offered and received across both trial arms. SMC consisted of neurology and/or psychiatry appointments. All participants allocated to CBT + SMC were offered up to 13 CBT sessions, whereas the number of SMC appointments that were offered varied.

Table 11 indicates that, as anticipated, participants in both trial arms were offered more psychiatry SMC appointments than neurology SMC appointments. The median number of neurology and psychiatry SMC appointments attended was one and three, respectively, in line with expectations. There were some participants who were offered and attended > 10 SMC appointments because of clinical need; however, overall, the number of SMC appointments offered and attended was similar across trial arms.

The median time between randomisation and the first CBT session was 38.5 days (IQR 26–59 days). Over half (55.9%) of participants who were randomised to receive CBT attended all 13 sessions; only eight (4.3%) participants did not attend any, and the median number of attended CBT sessions was the full course of 13. Three-quarters (75.3%) of participants attended at least nine CBT sessions, which meant that the majority were defined as treatment compliant. One participant received three extra sessions beyond the 13 offered in the trial design because they were considered to be at high risk by their therapist. For this participant, there was also no interval between session 12 and the booster session. Figure 5 illustrates the distribution of the number of CBT sessions attended in the CBT + SMC arm (n = 186). One participant who was randomised to the SMC arm was mistakenly offered the CODES CBT and subsequently attended all 13 sessions.

FIGURE 5 Number of CBT sessions attended in the CBT + SMC arm. (Figure not reproduced here; see the original article.)

Over 700 CBT sessions were scheduled and missed; around 30–40 participants missed different sessions. Although most missed appointments were cancelled in advance, over one-quarter (28.4%) were non-attendances without notification. Of 410 appointments cancelled by patients, feeling unwell (43%) and other (work and family) commitments (22%) were the most common reasons for participant non-attendance; however, nearly 12% of cancelled sessions were because of patients reporting being unable to travel alone and 7% were cancelled because of seizures. Nearly all sessions (95.8%) were attended face to face, and most participants (78.6%) attended alone. Only 10 (5.4%) participants of the total allocated to the CBT + SMC arm informed their therapist that they wished to withdraw from therapy, which included three participants who had not attended any sessions and seven participants who had attended more than one CBT session (range 2–12 sessions).

For the second CBT session onwards, therapists were asked to complete a series of questions about participant adherence to treatment. Of these responses (n = 1725), 84.4% were reported to have implemented therapy techniques well from the previous session (moderately well, very well or completely) and 80.9% were perceived by the therapists to have completed at least half of their homework. The mean duration of the therapy sessions (therapist reported) was 60.5 minutes; we did not collect data concerning the time of day that the sessions were held.

Information collected on participants who experienced a seizure during therapy indicated that only 42 (2.2%) of the attended CBT sessions were significantly disrupted by a person having a seizure; this corresponded to 18 participants in total. Most of these seizures were between 3 minutes and 10 minutes in duration, and only four resulted in the participant suffering physical injury.

Therapy protocol deviations

We observed only two deviations from the therapy protocol, one in each treatment arm. In the SMC arm, one participant received CODES CBT in error. In the CBT + SMC arm, one participant received more than 13 sessions of CBT; the participant had an additional three sessions after the standard 12th session and booster session because of clinical need.

Treatment fidelity

As described in Chapter 2, two independent CBT therapists undertook blind ratings of one session from each therapist, with half of the ratings being undertaken for session 3 and half for session 7. In total, 18 tapes for each session were rated using the rating scale described in Chapter 2, Evaluation of treatment fidelity (see Appendix 3). As indicated, scores were converted to standardised scores out of 100. For the single-item subscales (i.e. Overall Therapist Adherence, Therapeutic Alliance and Overall CBT Delivery), scores were calculated by dividing the score by 7 and then multiplying by 100. For the specific DS skills scale (i.e. DS skills items 3–6 in Appendix 3), scores were totalled and divided by [7 × number of relevant (yes-rated) items scored] × 100 to generate standardised scores. The median values are shown in Table 12.

Overall, the median ratings for the therapy being delivered in accordance with the CODES therapy manual, the therapeutic alliance and whether or not the therapy being delivered was CBT all fell in the upper end of the scales (between considerably and extensively for adherence to the manual; just below excellent for therapeutic alliance; and between considerably and extensively for delivery of CBT). More mid-range median scores were obtained for DS-specific techniques, but it was possible that, although DS control techniques were expected to take place in session 3, by session 7 therapists may have adopted some flexibility in session content (see Wilkinson et al.135) and teaching seizure control techniques may have become less relevant by then.

Retention of participants

As seen in the CONSORT flow diagram (see Figure 3), we obtained primary outcome data for 313 (85%) of the randomised participants. The follow-up rate did not differ in the two arms [84% (156/186) in the CBT + SMC arm; 86% (157/182) in the SMC-alone arm]. Fifty-five participants withdrew or were lost to follow-up (CBT + SMC, n = 30; SMC alone, n = 25) but in no case was withdrawal accounted for by death or other AEs (Table 13). In only one instance (in the SMC arm) was the withdrawal decision initiated by the clinician rather than the participant, but no further information was provided for this withdrawal.

Clinical outcomes

Descriptive statistics for all primary and secondary outcomes are shown in Tables 14 (seizure outcomes) and 15 (other outcomes). Formal statistical comparisons of the outcome measures between the treatment arms at 12 months post randomisation are shown in Table 16. The first two sets of results (estimated trial arm difference and standardised treatment effects) were derived using the MICE procedure (100 imputations), and the third set of results was derived using the CC analysis. As explained in Chapter 2, the MI results are treated as the primary formal comparisons and CC as a sensitivity analysis. Statistical significance was assessed at the 5% test level unless stated otherwise.

Primary outcome: seizure frequency

Our primary outcome measure for the RCT was participants’ monthly DS frequency at 12 months post randomisation. As described in Chapter 2, these data were also collected at baseline and 6 months post randomisation, and these were used as auxiliary variables in the MICE procedure. The outcome was defined as DS occurrence over the previous 4 weeks and data were collected using seizure diaries. Participants were also asked how many seizures they had experienced in the past 4 weeks as a single-item measure to impute diary seizure frequency for those who had not provided it, and to help estimate the reliability of the diary data.

Both trial arms appeared to show a decrease in monthly DSs from baseline to 12 months post randomisation. An illustration of the observed change over time by trial arm is shown in Figure 6a. Geometric means have been used because they are arithmetically similar to the median and allow 95% CIs to be constructed. The between-group comparison of monthly DS frequency did not reach statistical significance at 12 months (IRR = 0.78, 95% CI 0.56 to 1.09; p = 0.144), although the inferential statistics estimated a 22% advantage for the CBT + SMC trial arm (see Table 16). When comparing the MI and CC results (see Table 16), the size, direction and significance of the treatment effect are very similar (IRR = 0.80, 95% CI 0.58 to 1.09; p = 0.156); indeed, all CC models in Table 16 lead to the same substantive conclusions as the ITT analysis models.

FIGURE 6 Plot over time of the primary outcome and a secondary seizure experience outcome. (a) Monthly seizure frequency; and (b) longest period of seizure freedom in the last 6 months. T0, baseline; T1, 6-month follow-up; T2, 12-month follow-up. Adapted with permission from Goldstein et al.134 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure. (Figure not reproduced here; see the original article.)

Furthermore, the CACE effect estimate of the primary outcome, as described in Chapter 2, leads to the same effect size as the ITT analysis (IRR = 0.78), with a similar p-value (p = 0.217). This shows that the ‘efficacy’ estimate is the same as the ‘effectiveness’ estimate. Finally, the ICC between the two methods of collecting the primary outcome (seizure diary and single measure) was 0.95, which implies very high agreement; the results of a second sensitivity analysis for the primary outcome (for which the seizure diary was treated as the only acceptable measure, resulting in 21 participants being treated as having missing outcome data) yielded a similar result again (IRR = 0.74, 95% CI 0.53 to 1.04; p = 0.086). We can, therefore, conclude that the primary outcome analysis was not sensitive to how we constructed monthly seizure frequency.

Secondary outcomes

Other aspects of seizure experience

For seizure-related secondary outcomes, all ITT analyses estimated a difference in the direction indicating an additional benefit of CBT, despite not always reaching statistical significance (see Table 16).

Seizure severity and bothersomeness

On the Seizure Severity Scale, the change in ratings of seizure severity did not reach significance (see Table 16), but the CBT + SMC arm reported their DSs as being less bothersome than the SMC-alone arm at the 12-month follow-up (standardised treatment effect –0.30, 95% CI –0.56 to –0.05; p = 0.020).

Longest seizure-free period in the last 6 months of the study

The CBT + SMC arm recorded a significantly longer seizure-free period (consecutive number of days) than the SMC-alone arm during the last 6 months of the study (IRR 1.64, 95% CI 1.22 to 2.20; p = 0.001). An illustration of the observed change over time by trial arm is shown in Figure 6b.

Seizure freedom in last 3 months of the study

The CBT + SMC arm was not significantly more likely than the SMC-alone arm to be seizure free in the last 3 months of the study.

Reduction of > 50% in dissociative seizure frequency

Although the CBT + SMC arm had higher odds than the SMC-alone arm of having a > 50% reduction in DS frequency, the odds ratio contrasting DS frequency reductions of this magnitude between trial arms was not significant.

Informant rating of dissociative seizures

As only 27 informants provided these data at 12 months post randomisation, we had insufficient data for meaningful inferential statistics to be applied. Available data are shown in Appendix 7.

Health-related quality of life

For neither the SF-12v2 Physical Component Summary score nor the Mental Component Summary score was the between-group difference at 12 months statistically significant. On the EQ-5D-5L VAS at the 12-month follow-up, the CBT + SMC arm reported higher overall health scores than the SMC-alone arm (standardised treatment effect 0.27, 95% CI 0.06 to 0.47; p = 0.010). An illustration of the observed difference between arms over time is shown in Figure 7a.

FIGURE 7 Plot over time of HRQoL and psychosocial functioning secondary outcomes by trial arm. (a) EQ-5D-5L VAS; and (b) WSAS. T0, baseline; T1, 6-month follow-up; T2, 12-month follow-up; EQ-5D-5L VAS: 0 = worst health, 100 = best health; WSAS: 0 = minimum impact, 40 = maximum impact with higher scores reflecting worse functioning. Adapted with permission from Goldstein et al.134 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure. (Figure not reproduced here; see the original article.)

Psychosocial functioning

The CBT + SMC arm had WSAS scores indicating significantly lower levels of impairment than the SMC-alone arm (standardised treatment effect –0.39, 95% CI –0.61 to –0.18; p < 0.001) at the 12-month follow-up. Although the SMC-alone arm’s score was still indicative of at least moderate-severe impairment, this was no longer the case for the CBT + SMC arm. An illustration of the observed difference between arms over time is shown in Figure 7b.

Psychiatric symptoms, psychological distress and somatic symptoms

There were no significant between-group differences on either the GAD-7 or the PHQ-9 at the 12-month follow-up. On the CORE-10, the CBT + SMC arm reported significantly lower levels of psychological distress than the SMC-alone arm at the 12-month follow-up (standardised treatment effect –0.25, 95% CI –0.45 to –0.05; p = 0.013).

In the context of similar median total numbers of symptoms at baseline, as measured by the modified PHQ-15, at the 12-month follow-up the CBT + SMC arm reported significantly fewer symptoms than the SMC-alone arm on this scale (standardised treatment effect 0.26, 95% CI –0.45 to –0.07; p = 0.008).

Clinical impression of improvement

Patient-rated improvement

The CBT + SMC arm reported significantly greater improvement in their health than the SMC-alone arm (standardised treatment effect 0.39, 95% CI 0.16 to 0.62; p = 0.001), with 52.7% of the CBT + SMC arm and 35.2% of the SMC-alone arm reporting feeling ‘much better’ or ‘very much better’.

Standardised medical care clinician-rated improvement

At the 12-month follow-up, clinician ratings indicated that the CBT + SMC arm, on average, experienced significantly greater improvement in their health than the SMC-alone arm (standardised treatment effect 0.37, 95% CI 0.17 to 0.57; p < 0.001), with 54.7% of the CBT + SMC group and 30.9% of the SMC-alone arm being rated as ‘much better’ or ‘very much better’.

CBT therapist-rated improvement

Although measured for the CBT + SMC arm only and, therefore, not formally analysed, CBT therapists rated 53.9% of their patients as ‘much better’ or ‘very much better’ at the end of treatment.

Satisfaction with treatment

At 12 months, the CBT + SMC arm participants rated themselves as significantly more satisfied with treatment than the SMC-alone arm (standardised treatment effect 0.50, 95% CI 0.27 to 0.73; p < 0.001), with 93 (62.8%) of the CBT + SMC arm and 56 (38.6%) participants in the SMC-alone arm rating themselves as ‘very satisfied’ with their treatment.

Effect sizes

To be able to compare sizes of estimated treatment effects between outcomes on different scales, we standardised all effect sizes for continuous outcomes (standardised treatment effects are shown in Table 16). Where the outcome was measured at baseline, we divided the estimated difference between arms by the SD of the baseline score; for other measures, the difference was divided by the pooled SD of the outcome.

Figure 8 displays the standardised treatment effects with 95% CIs for all continuous secondary outcomes. For outcomes in Table 16 that are interpreted as showing better outcomes from the CBT + SMC arm if the standardised treatment effect is negative (< 0), the estimated treatment effect has been reversed (multiplied by –1) in Figure 8 so that a positive standardised effect size (> 0) is in favour of CBT + SMC compared with SMC. Figure 8 shows that the estimated treatment effects for all 13 outcomes are positive (above the dashed line at d = 0), which illustrates a trend that favours the CBT + SMC arm.

FIGURE 8 Forest plot of standardised treatment effects and 95% CIs of CBT + SMC compared with SMC alone for all outcomes analysed on a continuous scale (standardised treatment effect of > 0 favours CBT + SMC). Adapted with permission from Goldstein et al.134 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure. (Figure not reproduced here; see the original article.)

All p-values in Table 16 are prior to any adjustment for multiple testing, which is consistent with the formally agreed and published SAP. However, if conservative adjustments were to be made to the level of significance (α = 0.05), for example a Bonferroni adjustment (α/17), five of the secondary outcomes still strongly suggest that offering CBT plus SMC provided significant benefit compared with offering SMC only (i.e. at p < 0.003). Specifically, participants in the CBT + SMC arm experienced larger numbers of consecutive seizure-free days, better psychosocial functioning, better self-reported and doctor-rated CGI and greater treatment satisfaction than those in the SMC-alone arm.

Adverse events and other indices of harm

In total, 176 AEs were reported during the RCT by 110 participants (Table 17). In the CBT + SMC arm, 97 AEs were reported by 57 participants, and in the SMC-alone arm 79 AEs were reported by 53 participants; the incidence of AEs was, therefore, similar across trial arms. In the RCT, 49 out of 368 (13.3%) randomised participants reported SAEs: 31 SAEs were reported by 25 participants in the CBT + SMC arm and 27 SAEs were reported by 24 participants in the SMC-alone arm. None of the AEs or SAEs recorded in the RCT in the CBT + SMC arm was deemed likely to be related to the study intervention [likelihood of relatedness: remote, n = 33 (34%); none, n = 64 (66%)]. An example of a SAE for which the relatedness was judged as ‘remote’ was sickness and inability to eat or drink anything for several days after a seizure and resulting in the patient's admission to hospital. No AEs were considered to be SARs.

Only one patient reported a decrease of 20 points on the SF-12v2 Physical Component Summary score between baseline and both the 6-month and the 12-month follow-up assessments (i.e. a change in scores of 2 SDs).

Regarding self-reported scores of ‘much worse’ or ‘very much worse’ on the participant-rated CGI scale change score at the end of the study, 25 (13.7%) participants in the SMC-alone arm and 13 (6.9%) in the CBT + SMC arm self-reported being ‘much worse’ or ‘very much worse’ on the CGI scale at the 12-month follow-up.

Discussion

Summary of results

In the CODES trial, participants with DSs who met other eligibility criteria were first recruited to a screening phase; eligible and consenting patients were subsequently randomised to receive SMC alone or CBT + SMC, with a 12-month post-randomisation follow-up. We randomised 368 people in total: 182 to the SMC-alone arm and 186 to the CBT + SMC arm. At baseline, the median 4-weekly DS frequency overall was 15 DSs (IQR 4–47 DSs), indicating often frequent DSs. There was also evidence of a high level of comorbidity and functional impairment. The study demonstrates the feasibility of delivering a CBT intervention for this group of patients across multiple centres and by therapists of different levels of seniority and experience. Patients demonstrated a high rate of belief in the diagnosis and the treatment offered. Our SMC, given the guidance we provided to clinicians in terms of its content and delivery and the information booklets provided to patients, might be suitably considered to be standardised and specialist medical care rather than standardised medical care.

The characteristics of the trial arms were generally well balanced at baseline. Our overall primary outcome follow-up rate at 12 months was 85% (313/368), balanced by treatment arm. Our analysis adopted the ITT approach with MI and followed our published SAP,92 whereby we evaluated outcomes at 12 months post randomisation only.

Regarding our primary outcome, DS frequency at 12 months post randomisation, the inferential statistics (using the MICE procedure and statistical modelling) estimated a 22% advantage for the CBT + SMC arm; however, this was not statistically significant (p = 0.144). Raw data suggested that both trial arms appeared to show an overall reduction in DS occurrence at 12 months.

All secondary outcomes for which analysis was possible were in the same direction and suggested an overall benefit of CBT + SMC over SMC alone. In 9 of the 16 comparisons this was accompanied by statistical significance (p < 0.05) and, of these, five outcomes were significantly better in the CBT + SMC arm at a p-value of ≤ 0.001. Thus, compared with the SMC-alone arm, the participants in the CBT + SMC arm were found to be less functionally impaired by their DSs, as measured by the WSAS (p < 0.001); they reported longer periods of DS-free days in the last 6 months of the study (p = 0.001), with inferential statistics estimating a 64% advantage in the CBT + SMC arm; their CGI scale scores were better when self-rated (p = 0.001) and clinician rated (p < 0.001); and their satisfaction with treatment was greater (p < 0.001). Effect sizes were moderate and, given that there is no other information on our outcomes from studies that have asked patients with DSs what might represent a clinically meaningful change for them, we cannot say whether or not these effect sizes were clinically meaningful.136 It is the case that the CBT + SMC arm’s scores on the WSAS, for example, were in the range associated with significant functional impairment but less severe clinical symptomatology than at baseline.117

Further considerations of the data

Raw data suggested that in the CBT + SMC arm an improvement in DS frequency was observable at the 6-month follow-up point, although our SAP did not allow formal testing at that time point. Although we cannot evaluate which component(s) of the CBT intervention offered particular benefit, our DS-specific CBT approach did include seizure control techniques, which were generally viewed positively by patients and therapists.135,137

In a related manner, raw data suggest that the SMC-alone arm experienced a reduction in DS frequency at a later follow-up point than the CBT + SMC arm. It is not clear what led to this apparently later improvement in the SMC-alone arm and whether or not this could be attributed to discussion (but not practice) of distraction techniques during SMC sessions or whether direction to self-help websites containing descriptions of potential seizure control approaches may have resulted in the use of techniques to attempt to reduce DSs, but at a slower rate than in the CBT + SMC arm.

Considering the apparent reduction in both trial arms’ DS frequency, it is important to note that we do not know whether or not this overall pattern simply represents the natural progression of the disorder over a comparable period either in general or for people with DSs specifically involved in a RCT. Although other studies have included long-term follow-up after diagnosis and information provision,55 such data are not comparable to those for people in a RCT with frequent research team contact and in a different cultural context. We are aware that SMC might itself be considered to be an active intervention, although we had not conceived of it as such when designing the study. Thus, the material in the information booklets given to participants at both study stages may have led to a better understanding of their disorder that they could share with families (see Chapter 5). Furthermore, the frequent contact by research workers and the interest shown in the participants as a result, and the requirement to self-monitor DSs throughout the study, may have served as an unintended intervention. We know from our qualitative work that many participants also found the contact with the SMC psychiatrists to be supportive, which may have helped reduce arousal levels and DS occurrence.

We did not seek to quantitatively investigate participants’ own perceptions of any advantages deriving from more rapid seizure reduction; however, for recent-onset cases in particular, this might be hypothesised to facilitate their return to work or study and may prevent progression to chronicity, although this requires detailed empirical study. Although CBT + SMC arm participants also seemed to show an earlier decrease in how bothersome they considered their DSs to be (see Table 14), and in their WSAS scores (see Table 15 and Figure 7b), further studies could usefully consider the real-life implications of benefit of CBT + SMC on DS frequency and WSAS scores and whether these are accompanied by improved actual work status or whether any ongoing seizures continue to pose a barrier. Again, although we cannot know which components of the CBT approach were selectively effective, our DS-specific CBT did address avoidance behaviour and this may potentially relate to the improvements seen on the WSAS.

Relation to other studies

Our findings support and extend those in our pilot RCT,1 yielding a similar trajectory for DS frequency over the course of the study. Thus, this pattern of improvement in DS occurrence is not limited to a single centre or set of therapists. The current findings, from the first adequately powered trial in this area, however, indicate a wider range of benefits from CBT + SMC than from SMC alone than we were able to demonstrate previously, even if they were not reflected in our primary outcome. The only other relevant pilot RCT68 that suggested the value of what was termed CBT-informed psychotherapy for seizure reduction was conducted on a much smaller scale, was not powered to permit a comparison between groups and did not evaluate findings at 12 months post randomisation; in addition, that study excluded patients with an epilepsy diagnosis.

Our study suggests that it is possible to engage patients with DSs in psychotherapy at an acceptable level and for the most part in SMC. Our guidance to neurologists in terms of what they should tell patients about the treatment pathway included asking them to communicate to patients some of the advantages of seeing a psychiatrist. It is possible that the guidelines given to neurologists about diagnosis delivery and the information they should convey to patients communicated a level of interest in their condition by professionals that encouraged them to participate in therapy.

Strengths and limitations

We will consider the strengths and limitations of the study overall in Chapter 6, along with recommendations for future research.