Title: A multicentre double-blind placebo-controlled randomised trial of SerTRaline for AnxieTy in adults with Autism (STRATA)
Funder: Department of Health and Social Care

Abstract: Aims: This study aims to find out whether the drug sertraline is an effective treatment for anxiety in adults with a diagnosis of autism. Sertraline is a commonly prescribed antidepressant and is also recommended for the treatment of anxiety problems. We will compare the use of sertraline in autistic people with placebo, a non-active identical capsule. We are interested to see whether the treatment improves symptoms of anxiety, enhances quality of life, and is effective in the longer term. We are also interested in understanding side effects of the treatment._x000D_ _x000D_ Background to the research: Anxiety is common in autistic adults and can be more disabling than the core features of autism. Medications for anxiety are often prescribed for autistic adults but their effectiveness or side effects in this population are not well known. Research findings in non-autistic populations may not apply to autistic adults. _x000D_ _x000D_ Design and methods used: We will run this trial in five centres in England and Western Australia. Adults with an autism diagnosis will be screened for anxiety. If eligible and consenting, they will be enrolled on the study. We aim to include 306 people who will be allocated at random by a computer to receive either sertraline capsules or identical inactive placebo capsules, which they will be asked to take for up to 12 months. Participants, their GPs and the researchers will not know whether they are receiving sertraline or placebo until the study ends. Participants will continue receiving all other care as usual. They will be asked to complete questionnaires about themselves, their anxiety and mental health, use of services, and any adverse effects they may experience at several time points. The design of the questionnaires will be autism-friendly and co-produced with autistic adults. The questionnaires can be done face to face or if participants prefer, by skype/telephone. Participants can reduce and stop the capsules at any time but will be encouraged to continue completing the study questionnaires. We will interview some participants about their experiences of being in the study and taking the study medications, and their reasons for continuing or withdrawing from the study. The results will help understand whether sertraline is an acceptable treatment and whether it is better or not than placebo in the treatment of anxiety in autistic adults._x000D_ _x000D_ Patient and public involvement: We have designed the study with input from an advisory group of four autistic adults. They have agreed to champion the project, and to be involved at all stages in helping train researchers, provide feedback, help develop study procedures and materials, and help disseminate results. We worked with the charity Autistica, and with autistic people, their families and professionals in a priority setting exercise which identified mental health research as the top autism research priority. _x000D_ _x000D_ Dissemination: The results will be of interest to autistic people, their families/carers, clinicians, researchers and policymakers. We will publish them in high impact peer-reviewed journals in open access format, present them at national and international conferences, and develop accessible summaries. We will partner with Autistica and other UK and Australian autism charities to disseminate results widely through news media, newsletters, blogs, social media and policy briefs.

Lay abstract: Aims: i) to determine the effectiveness of the Selective Serotonin Reuptake Inhibitor (SSRI) sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and quantify its adverse effects; ii) to determine its cost effectiveness; iii) to explore patients' views and experiences of taking study medication and identify reasons for completing/not completing the study. _x000D_ _x000D_ Methods: _x000D_ Design: Two parallel group multi-centre pragmatic randomised placebo-controlled trial with internal pilot and an embedded QuinteT Recruitment Intervention. Allocation will be at the level of the individual._x000D_ Setting: Autism services in 5 centres in the UK and Western Australia, with further recruitment from cohorts/registries and other sources. _x000D_ _x000D_ Target population: Adults with an autism diagnosis (including those with a mild intellectual disability) made by a specialist and anxiety as measured by GAD-7 score>=10. _x000D_ _x000D_ Health technology: Sertraline, recommended as the first-choice SSRI for anxiety disorders. Primary Outcome: GAD-7 scores at 16 weeks post randomisation (continuous outcome). Secondary Outcomes: Adverse effects (Toronto side effects scale, suicidality, open ended questions); Response (50% reduction in GAD-7 score); Other anxiety constructs: Liebowitz Social Anxiety Scale; Obsessive compulsive symptoms (OCI-R); Intolerance of uncertainty (IUS-12); Repetitive behaviours (RBQ-2A); depressive symptoms (PHQ-9); work and social adjustment (WSAS); quality of life (WHOQOL-BREF with ASQOL); utility (EQ-5D-5L); adherence to medication, and carer burden (caregiver burden scale). Data will be collected face-to-face or if participants prefer, by skype, phone or web at 16, 24- and 52-weeks post-randomisation, with brief contact at 2 and 8 weeks. _x000D_ _x000D_ Economic evaluation: the incremental cost per quality-adjusted life year (QALY) calculated from a health and social care payer perspective, and a societal perspective. Resource-use will be measured at 24 and 52 weeks. _x000D_ _x000D_ Qualitative study: semi-structured interviews will take place at various times during the study. _x000D_ _x000D_ Sample size: Based on ADEPT data, a sample of 306 participants, estimating 20% attrition at 16 weeks and a correlation of 0.37 between the baseline and 16-week GAD-7 scores will give us 90% power (alpha 0.05) to detect a mean difference of 2.2 points (0.39 SD) in GAD-7 scores between groups. _x000D_ _x000D_ Statistical analysis: Intention-to-treat analysis (ITT) using linear regression to estimate mean difference in GAD-7 scores at 16-weeks post-randomisation between groups, adjusted for baseline score and stratification/minimisation variables (primary analysis). A Complier Average Causal Effect analysis to examine the efficacy of sertraline based on treatment compliance status for comparison with the ITT estimate and a repeated measures analysis to examine the effect of the intervention over 52 weeks. _x000D_ _x000D_ Timelines: Preparation 6 months. Internal pilot with recruitment progression criteria 9 months. Further 15 months recruitment all sites. Follow-up 12 months. Analysis/Reporting 6 months. Total 48 months. _x000D_ _x000D_ Impact/dissemination: The results will contribute to guidelines on managing anxiety in adults with a diagnosis of autism. We will publish findings in high impact journals in open access format, present them at relevant conferences, and develop accessible summaries. We will also disseminate results widely through news and social media, newsletters, blogs, and policy briefs.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH