Condition category
Nervous System Diseases
Date applied
02/03/2014
Date assigned
05/03/2014
Last edited
29/06/2015
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
About 12-20% of patients who attend neurology or specialist epilepsy clinics because of seizures do not in fact have epilepsy. Most of these people have what are referred to as dissociative (non-epileptic) seizures (DS). This means that they have episodes that resemble epileptic seizures but which have no medical reason for their occurrence and instead are due to psychological factors. In younger adults DS are about four times more common in women than men. A high percentage of these people will have other psychological or psychiatric problems and may have other medically unexplained symptoms. It is generally thought that people with DS will benefit from psychological treatments. However, studies on this have been small or have not compared the psychological therapy with the treatment people normally receive (standardised medical care). There is some evidence that cognitive behavioural therapy (CBT), which is a widely accepted talking therapy that focuses on the person's thoughts, emotions and behaviour, as well as considering the physical reactions and sensations that may occur in people's bodies, may lead to a reduction in how often people have DS. We have previously developed a CBT package for people with DS. In a relatively small study, people receiving CBT overall showed greater reduction in how often they had their DS. We are now proposing a larger study, across several different hospitals, to obtain more definite results about the effectiveness of our CBT approach for DS.

Who can participate?
We plan to invite about 500 adult patients with DS (but without current epilepsy), who have been given their diagnosis by a neurologist or specialist in epilepsy, to take part in our study.

What does the study involve?
We will collect some initial information about these people and ask them to keep a record of how often they have their DS following diagnosis. Three months after the diagnosis, those who have agreed to take part in the study will be seen by a psychiatrist, who will undertake a psychiatric assessment and ask them about factors which may have led to the development of their DS. Those people who have continued to have DS in the previous 8 weeks will be randomly allocated to standardised medical care or CBT (plus standardised medical care) as further treatment for their seizures. These people will continue to complete seizure diaries and questionnaires, provide regular seizure frequency data following receipt of DS diagnosis and be willing to attend weekly/fortnightly sessions if allocated to CBT.

What are the possible benefits and risks of participating?
By taking part in the study, people will receive information leaflets about their condition as a minimum before they receive any further assessment and treatment. This will give them access to information to which they can refer at a later date. By taking part in the comparison between treatments they will help us understand more about treatments that are effective in helping people with DS as we cannot be sure at this stage which of the two treatments we are comparing will help the most. If the CBT plus standardised medical care is found to be more effective, this may affect what treatments are offered to people in the future by the NHS. In terms of risks, when people are seen by a psychiatrist, attend CBT sessions (if they are allocated to that part of the study) and fill in some of the questionnaires, they may end up thinking and talking more about their feelings and about things that have happened to them as well as about their seizures. For some people, this may be upsetting. However, psychiatrists and CBT therapists are used to helping people in distress and may be able to help patients manage these feelings. Patients will not be entered into the comparison study if they and their doctor do not feel this is suitable for them. In addition, completing questionnaires, attending CBT and research interviews all take people's time.

Where is the study run from?
The study is run from the lead centre - the Institute of Psychiatry, King's College London, UK.

When is the study starting and how long is it expected to run for?
The study is expected to start in June 2014 and will run for 50 months.

Who is funding the study?
The study is funded by the National Institute of Health Research (NIHR) (UK).

Who is the main contact?
Professor Laura H. Goldstein
laura.goldstein@kcl.ac.uk

Trial website

http://www.codestrial.org

Contact information

Type

Scientific

Primary contact

Prof Laura Goldstein

ORCID ID

Contact details

Department of Psychology
PO77
Henry Wellcome Building
Institute of Psychiatry
De Crespigny Park
London
SE5 8AF
United Kingdom

Type

Scientific

Additional contact

Mr Iain Perdue

ORCID ID

Contact details

Henry Wellcome Building
Denmark Hill
London
SE5 8AF
United Kingdom

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

3.0

Study information

Scientific title

COgnitive behavioural therapy vs standardised medical care for adults with Dissociative non-Epileptic Seizures: a multicentre randomised controlled trial (CODES)

Acronym

CODES

Study hypothesis

The study sets out to test the hypothesis that Cognitive Behavioural Therapy plus Standardised Medical Care (SMC) will have greater clinical and cost effectiveness than SMC alone in treating adult patients with dissociative seizures which had not initially ceased following diagnosis.

Ethics approval

NRES Committee London - Camberwell St Giles, 18/12/2013, ref. 13/LO/1595

Study design

There is an initial observational phase followed by a parallel group two-arm multi-centre pragmatic randomised controlled trial (interventional phase)

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Dissociative seizures (also referred to as psychogenic nonepileptic seizures)

Intervention

How the CBT will be delivered:
CBT will be delivered over 12 sessions (each approximately one hour in length) over a 4-5 month period with one booster session at 9 months post randomisation. Our model has been developed from a single case study, trialled in an open label study and then in a Pilot RCT. Thus, based on our Pilot RCT we will assess a 12-session (plus one booster session) package of CBT specifically modified for treating DS. The model is based on the two-process fear escape-avoidance model and conceptualises DS as dissociative responses to cues (cognitive/emotional/physiological or environmental) that may (but not in all cases) have been associated with profoundly distressing or life-threatening experiences, such as abuse or trauma, at an earlier stage in the person’s life and which have previously produced intolerable feelings of fear and distress. There are essentially five stages to the treatment; engagement and rationale giving; teaching and use of seizure control techniques; reducing avoidance exposure technique; dealing with seizure-related cognitions and emotions; and relapse prevention. The treatment is manualised, which is important for subsequent rollout, but the structure allows treatment to be formulation-based so that particular issues raised in therapy that might be maintaining seizure occurrence (e.g. trauma-related issues) can be addressed. Written handouts supplement the content of face-to face therapy sessions. We will record therapy sessions and undertake treatment fidelity ratings. Therapists will receive training prior to treating study patients.

SMC will be provided to study patients by neurologists and psychiatrists. Neurologists will have a key role in delivering the initial diagnosis of DS, when they will:
1. Explain the disorder: i) what patients do not have (epilepsy) and why (explanation of diagnosis, i.e. a restatement of why tests have not shown organic basis, drawing attention to positive aspects of the diagnosis); ii) what they do have (describing dissociation/switching off)
2. Reassure the patient: i) they are not suspected of 'putting on' the attacks - DS are real events; ii) the disorder is common
3. Explain causes of DS: i) relation to 'stress' may not be immediately apparent; ii) the best understanding of the disorder is that there is an underlying psychological mechanism; this is a complex matter and does not simply reflect a reaction to immediate stresses
4. Regarding treatment: i) explain that AED withdrawal should be gradual; ii) many people may lose their DS following diagnosis alone; iii) cognitive behavioural therapy may be helpful for some people but not yet clear for whom
5. Provide the patient with an information sheet including direction to self-help information.

Psychiatrists’ provision of SMC of patients begins post diagnosis. The initial pre-randomisation clinical psychiatric assessment will include the following components and partly have a psychoeducational function:
1. Explanation of any psychiatric comorbidity and its psychopharmacological treatment
2. Reiteration of the points covered by the neurologist at diagnosis
3. Discussion of factors emerging from the clinical history that seem to have aetiological significance: relevance of predisposing, precipitating and perpetuating factors in their case if apparent
4. Acknowledge fears about a psychiatric label
5. Provision of an information sheet including direction to self-help information (as above)
6. General information provision about distraction but not specific techniques and not discussed repeatedly so that this does not become therapy.

Further SMC by psychiatrists will include support, consideration of psychiatric comorbidities and any associated drug treatment and general review but no CBT techniques.

We allow for some local variation in the number of neurology and psychiatry SMC sessions after randomisation.

Joint/co-sponsor details
South London & Maudsley NHS Foundation Trust
c/o Ms Jennifer Liebscher, Joint SLaM / IoP R&D Office,
Institute of Psychiatry, De Crespigny Park, London SE5 8AF

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measures

Monthly DS frequency. This is a continuous variable that comprises a count of seizures over a month and therefore will reflect all participants' outcomes, whether they improve or not during the study. Seizure frequency has been used as an outcome measure in other studies of psychological interventions for DS.

Secondary outcome measures

1. A rating by an informant as to whether, compared to study entry (i.e. time of diagnosis) the patient’s seizure frequency is worse, the same, better or whether they are seizure free. For those randomised we will collect this data at the 6- and 12-month follow-up.
2. Self-rated seizure severity: we will use two items from the Seizure Severity Scale (Cramer et al., 2002), asking how severe and bothersome DS were in the past month. For those randomised we will collect this data at the 6- and 12-month follow-up. In seizure diaries we will also ask patients to indicate how many seizures that they have had they would consider to have been severe.
3. Seizure freedom: we will record patients’ self-reported longest period of seizure freedom between the 6- and 12-month follow-up and whether or not the patient is seizure free in the last 3 months of the trial.
4. The number of patients in each group who at the 6- and 12-month follow-up show >50% reduction in seizure frequency, compared to baseline.
5. Quality of life (QoL): we will use a generic measure of health-related QoL, the SF-12v2 (Ware et al.,1996) to allow more direct comparison to be made with other disorders. This will also allow us to calculate QALYs, although the principal measure for doing that in this study is the EQ-5D-5L (EuroQol group, 1990), a 5-domain, 5-level, multi-attribute scale which will also be used.
6. Psychosocial functioning: we will use the 5-item Work and Social Adjustment Scale (WASAS) (Mundt et al., 2002) to measure patients' own perceptions of the impact of DS on their functioning in terms of work, home management, social leisure and private leisure activities, family and other relationships.
7. Psychiatric symptoms and psychological distress: we will measure anxiety, depression and somatisation with the GAD7 (Spitzer et al., 2006), PHQ9 (Kroenke et al., 2001) and an extended PHQ15 (Kroenke et al., 2002; Sharpe et al., 2010), derived from the Patient Health Questionnaire which reflects DSM-IV diagnoses. The GAD7 is a 7-item anxiety scale with good internal consistency (Cronbach’s alpha = 0.92), test-retest reliability (intraclass correlation = 0.83), sensitivity (89%), specificity (82%) criterion, construct and factorial validity. The PHQ9 is a 9-item depression scale that can be used to diagnose major depression (DSM-IV). It has good internal consistency (Cronbach’s alpha = 0.86-0.89) and test-retest reliability (r=0.84); sensitivity and specificity and construct validity are good. The PHQ15 has been shown to have high internal validity (Cronbach’s alpha = 0.8) and strong convergent and discriminant validity. We will also use a general measure of psychological distress, the CORE-10 (Connell & Barkham, 2007); this assesses self-reported global psychological distress.
8. At the 6- and 12-month follow-ups, and in line with many CBT studies, we will measure patients’ self-rated global outcome and satisfaction with treatment. The Clinical Global Impression (CGI) (Guy 1976) change score yields a self-rated global measure of change and has been used in previous trials of CBT interventions.
9. The CGI change scale will be rated by CBT therapists at the end of session 12 and by the SMC doctor at the 12-month follow-up.
10. Health service use (including hospital attendances and admissions, GP contacts), informal care, lost work time and financial benefits (which will be used as predictors of outcome in our analysis) will be measured via the self-report Client Service Receipt Inventory (Beecham & Knapp, 2001).
11. Objective measure of health service use; we will seek to obtain linkage data sets from NHS Health and Social Care Information Centre (Hospital Episode Statistics) eDRIS (NHS National Services Scotland Information Services Division (ISD) and Wales (NHS Wales Informatics Service) to allow quantification of objective measures of hospital attendances and admissions pre-randomisation and during follow-up using ICD-10 codes.

Overall trial start date

01/06/2014

Overall trial end date

31/07/2018

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 14/05/2015:

Our inclusion criteria applied at the initial recruitment stage will be as follows:
1. Adults (≥18 years) with DS that have continued to occur within the previous 8 weeks and have been confirmed by video EEG telemetry or, where not achievable, clinical consensus; patients who have chronic DS can be included if they have been seen by the relevant Study Neurologist who has reviewed their diagnosis and communicated this to them according to the study protocol
2. Ability to complete seizure diaries and questionnaires
3. Willingness to complete seizure diaries regularly and undergo psychiatric assessment 3 months after DS diagnosis
4. No documented history of intellectual disabilities
5. Ability to give written informed consent

Inclusion criteria evaluated at the randomisation stage will be as follows:
1. Adults (≥18 years) with DS initially recruited at point of diagnosis;
2. Willingness to continue to complete seizure diaries and questionnaires;
3. Having provided regular seizure frequency data to research team following receipt of DS diagnosis;
4. Willingness to attend weekly/fortnightly sessions if randomised to CBT
5. Both clinician and patient agree that randomisation is acceptable
6. Ability to give written informed consent;

Previous inclusion criteria:

Our inclusion criteria applied at the initial recruitment phase will be as follows:
1. Adults (≥18 years) with DS confirmed by video EEG telemetry or, where not achievable, clinical consensus
2. Patients who have chronic DS can be included if they have been seen by the relevant study neurologist who has reviewed their diagnosis and communicated this to them according to the study protocol
3. Ability to complete seizure diaries and questionnaires
4. Willingness to complete seizure diaries regularly and undergo psychiatric assessment 3 months after DS diagnosis
5. No documented history of intellectual disabilities
6. Ability to give written informed consent

Inclusion criteria evaluated at the randomisation phase will be as follows:
1. Adults (≥18 years) with DS initially recruited at point of diagnosis
2. Willingness to continue to complete seizure diaries and questionnaires
3. Provision of regular seizure frequency data following receipt of DS diagnosis
4. Willingness to attend weekly/fortnightly sessions if randomised to CBT
5. Both clinician and patient think that randomisation is acceptable
6. Ability to give written informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Observational phase 501; interventional phase 298

Participant exclusion criteria

Current exclusion criteria as of 14/05/2015:

Our exclusion criteria applied at the initial recruitment stage will be as follows:
1. Having a diagnosis of current epileptic seizures as well as DS
2. Inability to keep seizure records or complete questionnaires independently
3. Meeting DSM-IV criteria for current drug/alcohol dependence
4. Insufficient command of English to later undergo CBT without an interpreter or to complete questionnaires independently
5. Having previously undergone a CBT-based treatment for dissociative seizures at a trial participating centre
6. Currently having CBT for another disorder, if this will not have ended by the time that the psychiatric assessment takes place

Exclusion criteria evaluated at the randomisation stage will be as follows:
1. Current epileptic seizures as well as DS, for reasons given above
2. Not having had any DS in the 8 weeks prior to the psychiatric assessment, 3 months post diagnosis
3. Having previously undergone a CBT-based treatment for dissociative seizures at a trial participating centre
4. Currently having CBT for another disorder
5. Active psychosis
6. Meeting DSM-IV criteria for current drug/alcohol dependence; this may exacerbate symptoms/alter psychiatric state and health service use and affect recording of seizures
7. Current benzodiazepine use exceeding the equivalent of 10mg diazepam/day
8. The patient is thought to be at imminent risk of self-harm, after psychiatric assessment or structured psychiatric assessment by the Research Worker with the MINI, followed by consultation with the psychiatrist
9. Known diagnosis of Factitious Disorder

Previous exclusion criteria:

Our exclusion criteria applied at the initial recruitment phase will be as follows:
1. Having a diagnosis of current epileptic seizures as well as DS
2. Inability to keep seizure records or complete questionnaires independently
3. Meeting DSM-IV criteria for current drug/alcohol dependence
4. Insufficient command of English to later undergo CBT without an interpreter or to complete questionnaires independently

Exclusion criteria evaluated at the randomisation phase will be as follows:
1. Current epileptic seizures as well as DS, for reasons given above
2. Not having had any DS in the 8 weeks prior to the psychiatric assessment, 3 months post diagnosis
3. Having previously undergone a CBT-based treatment for dissociative seizures at a trial participating centre
4. Currently having CBT for another disorder
5. Active psychosis
6. Meeting DSM-IV criteria for current drug/alcohol dependence; this may exacerbate symptoms/alter psychiatric state and health service use and affect recording of seizures
7. Current benzodiazepine use exceeding the equivalent of 10 mg diazepam/day
8. The patient is thought to be at imminent risk of self-harm, after (neuro)psychiatric assessment and structured psychiatric assessment by the Research Worker with the MINI
9. Known diagnosis of Factitious Disorder

Recruitment start date

01/10/2014

Recruitment end date

01/02/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Guy’s and St Thomas’ NHS Foundation Trust
SE1 7EH
United Kingdom

Trial participating centre

Croydon Health Services NHS Trust
CR7 7YE
United Kingdom

Trial participating centre

Lewisham and Greenwich NHS Trust
SE13 6LH
United Kingdom

Trial participating centre

King’s College Hospital NHS Foundation Trust
SE5 9RS
United Kingdom

Trial participating centre

University College London Hospitals NHS Foundation Trust
NW1 2BU
United Kingdom

Trial participating centre

St George’s University Hospitals NHS Foundation Trust
SW17 0QT
United Kingdom

Trial participating centre

Barts Health NHS Trust
EC1A 7BE
United Kingdom

Trial participating centre

Imperial College Healthcare NHS Trust
W2 1NY
United Kingdom

Trial participating centre

Royal Free London NHS Foundation Trust
NW3 2QG
United Kingdom

Trial participating centre

Western Sussex Hospitals NHS Foundation Trust
BN11 2DH
United Kingdom

Trial participating centre

East Sussex Healthcare NHS Trust
BN21 2UD
United Kingdom

Trial participating centre

Brighton and Sussex University Hospitals NHS Trust
BN1 6AG
United Kingdom

Trial participating centre

Dartford and Gravesham NHS Trust
DA2 8DA
United Kingdom

Trial participating centre

Maidstone and Tunbridge Wells NHS Trust
TN2 4QJ
United Kingdom

Trial participating centre

East Kent Hospitals University NHS Foundation Trust
CT1 3NG
United Kingdom

Trial participating centre

Medway NHS Foundation Trust
ME7 5NY
United Kingdom

Trial participating centre

Cambridge University Hospitals NHS Foundation Trust
CB2 0QQ
United Kingdom

Trial participating centre

Sheffield Teaching Hospitals NHS Foundation Trust
S5 7AU
United Kingdom

Trial participating centre

Chesterfield Royal Hospital NHS Foundation Trust
S44 5BL
United Kingdom

Trial participating centre

University Hospitals Birmingham NHS Foundation Trust
B15 2TH
United Kingdom

Trial participating centre

Birmingham & Solihull Mental Health NHS Foundation Trust
B1 3RB
United Kingdom

Trial participating centre

The Leeds Teaching Hospitals NHS Trust
LS1 3EX
United Kingdom

Trial participating centre

Cardiff & Vale University Health Board
CF5 2LD
United Kingdom

Trial participating centre

The Royal Berkshire NHS Foundation Trust
RG1 5AN
United Kingdom

Trial participating centre

NHS Lothian
EH1 3EG
United Kingdom

Trial participating centre

South London and Maudsley NHS Foundation Trust
SE5 8AZ
United Kingdom

Trial participating centre

South West London & St Georges Mental Health NHS Trust
SW17 7DJ
United Kingdom

Trial participating centre

East London NHS Foundation Trust
E1 8DE
United Kingdom

Trial participating centre

West London Mental Health Trust
UB1 3EU
United Kingdom

Trial participating centre

Sussex Partnership NHS Foundation Trust
RH1 5RH
United Kingdom

Trial participating centre

Kent and Medway NHS and Social Care Partnership Trust
ME16 9PH
United Kingdom

Trial participating centre

Cambridgeshire and Peterborough NHS Foundation Trust
CB21 5EF
United Kingdom

Trial participating centre

Sheffield Health and Social Care NHS Foundation Trust
S10 3TH
United Kingdom

Trial participating centre

Derbyshire Healthcare NHS Foundation Trust
DE22 3LZ
United Kingdom

Trial participating centre

Berkshire Healthcare NHS Foundation Trust
RG12 1BQ
United Kingdom

Trial participating centre

Leeds and York Partnership NHS Foundation Trust
LS15 8ZB
United Kingdom

Trial participating centre

Derbyshire Community Health Services NHS Trust
DE45 1AD
United Kingdom

Sponsor information

Organisation

King's College London (UK)

Sponsor details

c/o Mr Keith Brennan
Director of Research Management
Director of Administration (Health Schools)
Room 1.8
Hodgkin Building
Guy's Campus
London
SE1 4UL
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

National Institute of Health Research (NIHR) (UK) - Health Technology Assessment (HTA), ref. 12/26/01

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

To be confirmed at a later date

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2015 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/26111700

Publication citations

Additional files

Editorial Notes