HTA - 13/28/02: Randomised controlled trial of the selective serotonin reuptake inhibitor Sertraline versus Cognitive Behavioural Therapy for anxiety symptoms in people with Generalised Anxiety Disorder who have failed to respond to low intensity psychological interventions as defined by the NICE GAD guidelines
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|Project title||Randomised controlled trial of the selective serotonin reuptake inhibitor Sertraline versus Cognitive Behavioural Therapy for anxiety symptoms in people with Generalised Anxiety Disorder who have failed to respond to low intensity psychological interventions as defined by the NICE GAD guidelines|
|Research type||Primary Research|
|Status||Waiting to publish|
|Start date||August 2014|
|Chief Investigator||Dr Marta Buszewicz|
|Co-investigators||Professor Philip Cowen (University of Oxford), Professor Nick Freemantle (Primary Care & Population Health, UCL), Miss Rachael Hunter (University College London), Dr Thomas Kabir (Kings College London), Professor Glyn Lewis (UCL Mental Health Sciences Unit), Professor Irwin Nazareth (University College London), Dr Marc Serfaty (UCL Mental Health Sciences Unit), Professor Rosamund Shafran (UCL Institute of Child Health), Dr Helen Tyrer (Imperial College London), Professor Peter Tyrer (Imperial College London), Dr John Wood (University College London), Professor John Cape (Camden and Islington NHS Foundation Trust), Professor Michel Dugas (Université du Québec en Outaouais)|
|Contractor||University College London|
|Plain English summary||Background: Generalised Anxiety Disorder (GAD) is common, causes unpleasant symptoms and impairs people's functioning. It is often chronic and may be accompanied by depression. Recent NICE guidelines have outlined the best initial treatments but it isn t clear whether medication or psychological therapy provides better outcomes for those not responding to simpler low intensity treatments. Trial: We propose a randomised trial of the medication Sertraline versus intensive Cognitive Behavioural Therapy (CBT) for people with GAD who have not responded to low intensity psychological treatments. Methods: We will recruit people via the Improving Access to Psychological Therapies (IAPT) service from up to 15 sites in England. People scoring highly on a specific anxiety measure (GAD-7) despite having received a low intensity psychological intervention will be given a study information sheet about the trial. The study information will explain that the medication being tested, Sertraline, although not having current marketing authorisation for GAD, is recommended by NICE on the basis of its effectiveness in clinical trials. The study team will be available to clarify any issues arising from this. Those interested in taking part in the trial will meet a research team member and be assessed against trial inclusion and exclusion criteria. They will need to be at least 18 years old and to meet psychiatric criteria (DSM-IV) for GAD assessed with a computerised version of a standardised psychiatric instrument called the MINI. We will also use this to assess if they have depressive symptoms and any other anxiety disorder(s). Exclusion will be presence of current major depression or any other anxiety disorder causing more distress than their GAD, significant dependence on alcohol or illicit drugs and having had treatment with any anti-depressant in the past 8 weeks or high intensity psychological therapy within the past 6 months. Interventions: Eligible participants will be consented and randomised via an independent computerised system to one of two interventions. (a) The medication sertraline prescribed by their GP according to a trial protocol matching current clinical recommendations. We will inform the GP that their patient knows sertraline does not have a marketing authorisation for GAD and has agreed to being prescribed this. We will ask GPs to review patients regularly (up to 6 times in 12 months) and patients to take the medication for a year unless they have significant adverse effects. Side-effects will be regularly monitored. (b) The other intervention is CBT delivered by high intensity therapists from local IAPT services. They will provide 14 to 16 sessions of a manualised treatment developed for use in GAD and will be trained in its delivery. Sessions will be digitally recorded and a random 10% assessed for quality according to pre-specified criteria. Outcomes: Participants will be monitored at baseline, 3, 6, 9 and 12 months for the primary outcome of interest which is anxiety levels as measured by the self-report 7 item questionnaire the GAD-7. Depressive symptoms and quality of life will also be measured by simple self-report questionnaires at these time intervals. Other secondary outcomes will include other anxiety symptoms, levels of functioning and use of health and social care and will be measured at baseline and 12 months. Our main aims are to compare the clinical and cost-effectiveness of the two treatments at 12 months|
|Scientific summary||Primary aim: To assess the clinical effectiveness at 12 months of treatment of the SSRI Sertraline compared to CBT for patients with persistent GAD which has not improved with low intensity psychological interventions. Secondary aim: To calculate the cost-effectiveness at 12 months of the SSRI Sertraline compared to CBT for patients with persistent GAD which has not improved with low intensity psychological interventions. Design: Participant randomised trial comparing treatment with Sertraline with high intensity CBT for service users with GAD who have failed to respond to low intensity psychological interventions recommended by NICE (1). Setting:Community based & linked with local Improving Access to Psychological Therapy (IAPT) services (2). We will work with up to 15 recruitment sites across England where we have excellent links with local IAPT services in a range of urban, suburban & more rural settings. Recruitment: From people who have not responded to step 2 low intensity psychological interventions for anxiety or depression who are being considered for a step 3 intervention. Identification will be by low intensity IAPT workers reviewing the patients who routinely administer the GAD-7 anxiety measure (3) and PHQ-9 depression measure (4). Those scoring 10 or more on GAD-7 will be given a study information sheet. If interested in taking part their permission will be sought for contact by the research team. Inclusion Criteria: Aged 18 or above; Positive score of 10+ on GAD-7; Primary diagnosis of GAD as diagnosed on the Mini International Neuropsychiatric Interview (MINI) (5); Failure to respond to NICE defined low intensity interventions. Exclusion Criteria: Inability to complete questionnaires due to insufficient English or cognitive impairment; Comorbid major depression or other anxiety conditions more distressing than GAD; Significant dependence on alcohol or illicit drugs; Comorbid psychotic disorder; Treatment with antidepressants in past 8 weeks or any high intensity psychological therapy in past 6 months. Randomisation: Eligible consenting participants randomised to one of two intervention arms via an independent computerised service. We will stratify by depressive symptoms. Health technologies assessed: (a) The SSRI sertraline - potential participants will have been informed that sertraline, although not having current marketing authorisation for GAD was recommended by NICE on the basis of its effectiveness in GAD clinical trials and will have agreed to be prescribed this if so randomised. Their GP will be informed about their recruitment to the trial, asked to prescribe sertraline following a detailed protocol and to review participants at least 6 times over the 12 month follow-up during which we ask them to continue the medication provided no significant adverse effects (b) CBT - provided by high intensity psychological therapists within local IAPT services and delivered according to a widely available standardised manual (5) specifically designed for use in GAD. A two day training course will be provided and therapists will have monthly small group supervision. Trial participants will be offered 14 +/-2 CBT sessions according to clinical indications and all sessions tape-recorded. A random 10% of sessions will be independently rated and reviewed for integrity and competence by accredited research team members Baseline Assessment: We will use the MINI (6) to establish participants DSM-IV psychiatric diagnoses with regard to GAD and other depressive and anxiety disorders. Using a computerised version enables us to store data for later export and analysis. Potential participants will be asked to confirm that their GAD symptoms distress them more than those from depressive or other anxiety disorders and that this is a problem that they wish to address. Participants will also be asked to complete a patient treatment preference questionnaire prior to randomisation. Outcomes: Participants will be monitored at baseline, 3, 6, 9 and 12 months for the primary outcome of interest which is anxiety levels as measured by the self-report 7 item questionnaire the GAD-7. Depressive symptoms and quality of life will also be measured by simple self-report questionnaires at these time intervals. Other secondary outcomes will include other anxiety symptoms, levels of functioning and use of health and social care and will be measured at baseline and 12 months. Analysis: The principal analyses will be conducted according to a pre-specified statistical analysis plan which will be finalised before database lock. The principal analyses will be conducted according to the intention to treat principle using generalised mixed models. The primary analysis will use a generalised mixed model accounting for clustering of therapist effects, investigational sites (both as random effects) and a limited number of pre-specified patient level factors including the baseline GAD-7 score and the presence of co-morbid depression. The principal analyses will be based upon available data and supportive analyses will examine the extent to which the principal analyses are robust to the challenge presented by the observed loss to follow up. Exploratory analyses will be carried out to describe how patient preferences along with a limited number of other pre-specified characteristics of participants may modify treatment effects. We will adhere to the CONSORT guidelines in the analysis and reporting of the trial. Economic evaluation: We will calculate the net monetary benefit (NMB) of CBT compared to SSRIs for patients with persistent GAD which has not improved with low intensity psychological interventions. Health and social care resource use will be collected for both interventions over the 12 month duration of the trial using patient GP files where possible and a significantly reduced version of the CSRI, focusing mostly on secondary acute care and mental health care contacts. Resource use will be multiplied by costs from nationally published sources to calculate the total cost per patient. The health care resource use associated with the intervention will also be captured in both arms: the cost of SSRIs and any follow up, training or monitoring costs; the cost of CBT based on the number of sessions attended per patient, session duration, the staff type and grade delivering the CBT, training and any overhead costs. The mean cost per patient for SSRIs and CBT will be calculated and confidence intervals reported, calculated using non-parametric bootstrapping with replacement. The mean QALY per patient will be calculated from the EQ-5D and the UK algorithm for calculating utility scores. The EQ-5D will be collected at baseline, 6 and 12 months to allow us to calculate the area under the curve over the 12 month trial duration for the SSRI group and CBT group, adjusting for baseline differences. The net monetary benefit (NMB) of both interventions will be calculated for a range of values of willingness to pay (WTP) for a QALY. Confidence intervals will be constructed using non-parametric bootstrapping. A cost-effectiveness acceptability curve (CEAC) will report the percentage of times that each intervention has the highest NMB for a range of values of WTP for a QALY. One, two and multi way sensitivity analysis will be conducted for any assumptions made. References: (1) National Institute for Health and Clinical Excellence. Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults: management in primary, secondary and community care. 2011. (Clinical guideline 113) http://guidance.nice.org.uk/CG113 (2) Improving Access to Psychological Therapies. www.iapt.nhs.uk (accessed 30th April 2013). (3) Spitzer, R. L., Kroenke, K., Williams, J. B. W. & Lowe, A Brief Measure for Assessing Generalized Anxiety Disorder: The GAD-7 . Arch. Intern. Med., (2006) 166, 1093-1097. (4) Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure , J Gen Intern Med. (2001) Sep;16(9):606-13. (5) Dugas, M. J., & Robichaud, M. (2007). Cognitive-behavioral treatment for generalized anxiety disorder: From science to practice. New York: Routledge (6) Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10 , J Clin Psychiatry (1998) 59 Suppl 20:22-33;quiz 34-57.|
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