Investigating a therapist-guided, parent-assisted remote digital behavioural intervention for tics in children and adolescents—‘Online Remote Behavioural Intervention for Tics’ (ORBIT) trial: protocol of an internal pilot study and single-blind randomised controlled trial

Introduction Tourette syndrome and chronic tic disorder are common, disabling childhood-onset conditions. Guidelines recommend that behavioural therapy should be offered as first-line treatment for children with tics. However, there are very few trained behaviour therapists for tics and many patients cannot access appropriate care. This trial investigates whether an internet-delivered intervention for tics can reduce severity of symptoms. Methods and analysis This parallel-group, single-blind, randomised controlled superiority trial with an internal pilot will recruit children and young people (aged 9–17 years) with tic disorders. Participants will be randomised to receive 10 weeks of either online, remotely delivered, therapist-supported exposure response prevention behavioural therapy for tics, or online, remotely delivered, therapist-supported education about tics and co-occurring conditions. Participants will be followed up mid-treatment, and 3, 6, 12 and 18 months post randomisation. The primary outcome is reduction in tic severity as measured on the Yale Global Tic Severity Scale total tic severity score. Secondary outcomes include a cost-effectiveness analysis and estimate of the longer-term impact on patient outcomes and healthcare services. An integrated process evaluation will analyse quantitative and qualitative data in order to fully explore the implementation of the intervention and identify barriers and facilitators to implementation. The trial is funded by the National Institute of Health Research (NIHR), Health Technology Assessment (16/19/02). Ethics and dissemination The findings from the study will inform clinicians, healthcare providers and policy makers about the clinical and cost-effectiveness of an internet delivered treatment for children and young people with tics. The results will be submitted for publication in peer-reviewed journals. The study has received ethical approval from North West Greater Manchester Research Ethics Committee (ref.: 18/NW/0079). Trial registration numbers ISRCTN70758207 and NCT03483493; Pre-results.

Despite these recommendations, only 1 in 5 young people with TS are currently able to access behaviour therapy for tics, while around 50% receive medication, 6 which is associated with a significant risk of adverse effects including weight gain and sedation. 4 5 Furthermore, those young people who manage to access behaviour therapy typically receive four or fewer face-toface therapy sessions, 6 less than half the number recommended. 7 Commonly used behaviour therapies include: habit reversal training (HRT), whereby patients are taught to implement and maintain an action referred to as a 'competing response' when a premonitory urge to tic is experienced (the urge to tic often felt before the tic is expressed); comprehensive behavioural intervention for tics (CBIT), which includes HRT and adds additional elements of relaxation training, functional analyses (identification of situations which could exacerbate tics) and social support; and exposure and response prevention (ERP), where patients tolerate premonitory urge sensations and learn from their therapist how to resist their tics. The effectiveness of behavioural therapy for reducing tics has been well established, 1 with systematic reviews demonstrating a similar magnitude of effect for HRT/CBIT compared to pharmaceutical interventions. 1, 4 A recent trial compared 10 weeks of behavioural therapy (either HRT or ERP) with education and pharmacological treatment and found the behavioural therapy to be as effective as pharmacological treatment for reducing tic severity, with both being superior to education. 8 Additionally, although there is a lack of evidence from randomised controlled trials (RCTs) for ERP, the evidence from available studies suggests both HRT and ERP may be at least equally effective in reducing tics, with some evidence showing a tendency to favour ERP. 3 The effectiveness of these behavioural interventions in conjunction with the lack of side effects compared to pharmacotherapy supports the use of behaviour therapy as a first-line intervention.. However, there is a lack of trained therapists across many European countries, leaving many patients unable to access evidence-based behaviour therapy. This need for improved access to therapy was highlighted in a recent study whereby families of children with TS noted the struggle to access limited behavioural therapy resources, despite 76% of parents saying they would want behavioural therapy to be available for their child. 6 Over the last decade, internet-delivered cognitive behaviour therapy (ICBT) has developed, enabling the delivery of effective, but less therapist intensive, cognitive and behavioural interventions remotely, which can increase the availability of evidence based treatments. Across diagnostic conditions, studies have not only shown efficacy of ICBT compared to no-treatment control conditions, but meta analyses comparing face-to-face delivered CBT with ICBT have demonstrated comparable results in terms of symptom reduction for adults with mental health problems, 9 ,10 which could also result in 50% cost savings. 10 However, therapist guidance during ICBT has been shown to be an important contributing factor in determining outcome. 11 Although self-guided ICBT is superficially attractive, given the very low costs of implementation, research evidence demonstrates very low adherence rates. 12,13 Recently, researchers at the Karolinska Institutet, Sweden, have developed a technical platform for ICBT called BIP (Barninternetprojektet, Swedish for Child Internet Project; http://www.bup.se/bip). The platform has been used to deliver therapist-supported ICBT for a range of different conditions, including phobia, 14 anxiety, 15 and obsessive-compulsive disorder. 16 The findings support the use of therapist guided ICBT using the BIP system, however, there is little research evidence with regards to the effectiveness of ICBT and TS. In a recent systematic review of digital health interventions, Hollis and colleagues 17 found the majority of interventions have been designed to help children and young people at risk for developing, or with a diagnosis of, an anxiety disorder and/or depression, with areas such as TS being largely overlooked.
Innovations in behavioural therapies for tics include delivery of CBIT treatment remotely via video over the internet with a therapist. Two pilot RCTs have compared CBIT delivered remotely via videoconference to traditional face-to-face delivery in children with TS. Results showed significant tic reduction for both groups, with no difference between the modes of delivery. 18,19 The method of delivering CBIT was rated as highly acceptable by the participants. 18 One Swedish pilot study, upon which this current trial is based, has used the BIP platform to deliver ICBT with remote therapist support. The study compared tic reduction in children aged 8-16 years randomised to receive either ERP or HRT delivered online via the BIP platform. 20 Participants in both groups showed improvement after treatment completion, but only participants in the ERP arm showed significant reduction on the primary outcome measure Yale Global Tic Severity Scale (YGTSS) total tic severity score. . The gains were maintained for at least 12 months after the end of treatment. Although this study was not designed or powered as a definitive efficacy trial, these findings show that ERP treatment delivered online via BIP is acceptable to participants and shows promise in reducing tics. Furthermore, the study reported no severe adverse events. There were no drop-outs and no data loss for the primary outcome, and 83% of parents and children rated the treatment as good or very good, indicating the trial was highly acceptable to patients in Sweden.
However, the evidence available for the BIP treatment programs has all been gathered in Sweden and we have limited experience of delivering therapist supported online ERP to children and adolescents in the UK. There is evidence that uptake and use of digital health interventions is highly context dependent 21,22 and it would therefore be unwise to assume that a delivery package that works in Sweden will work equally well in the UK.
The overarching aim of the Online Remote Behavioural Intervention for Tics (ORBIT) trial is to evaluate the clinical and cost-effectiveness of BIP TIC, a therapist-guided, parent-assisted ERP programme for tics in young people with TS in the UK.
Specific objectives are to: 1. To optimise the design and delivery of BIP TIC in partnership with young people with TS, carers and healthcare professionals (HCPs) to maximise acceptability, effectiveness and long-term uptake.
2. To undertake an internal pilot to assess whether recruitment, engagement with the intervention and retention to the trial outcomes are sufficient to allow the trial to progress and provide a definitive answer on effectiveness. 3. To determine the clinical effectiveness of BIP TIC compared to online tic-related education in reducing tics, as measured by the masked assessor-rated Yale Global Tic Severity Scale (YGTSS) total tic severity score (primary outcome).
4. To evaluate the cost-effectiveness of BIP TIC. 5. To estimate the longer-term impact on patient outcomes and health service costs.
6. To conduct a process analysis in line with MRC guidelines for complex interventions to determine barriers and facilitators to implementation.
The primary hypothesis is that the BIP TIC therapist-guided remote digital ERP intervention will be superior to a comparator intervention of therapist-guided online tic-related education in reducing tics, as measured by the masked assessor-rated YGTSS total tic severity score 23 .

Trial design
The design is a 10-week, parallel-group, single-blind, non-commercial, randomised controlled superiority trial with an internal pilot. Participants will be randomised to receive 10-weeks of online, remotely-delivered, therapist-supported ERP for tics, or online, remotely-delivered, therapist-supported education for tics. Participants will be followed-up mid-treatment, and at 3-, 6-, 12-, and 18-months post-randomisation. Up until the 6-month follow-up participants are encouraged not to change medication or start alternative therapies for tics. Months 12 and 18 are naturalistic follow-up points where participants are free to access any treatments in accordance with standard practice recommended by their usual treating clinician. A sub-sample of participants and parents will be purposively selected to participate in process evaluation interviews after the 3-month follow-up. Interviews will also be conducted with therapists, clinicians recruiting to the study and commissioners. The process evaluation will also link data on usage of the intervention with outcomes. A schematic diagram of the study design is shown in Figure 1 and a more detailed participant flow is shown in Figure 2.
An internal pilot will be conducted until the end of the 9 th month to determine whether recruitment, engagement with the intervention and retention to the trial are sufficient to allow the trial to progress, the stop/go rules for proceeding are: 1) The study needs to have recruited 30% of the sample (66 participants).
2) At least 60% of participants need to have completed the intervention (defined as the child/adolescent completing at least their first four chapters).
3) 80% of participants who have reached the relevant time window need to have completed the primary outcome measure.

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Setting The intervention will be remotely delivered from two national centres for treating tics in the U.K.

Participant identification
Participants will be identified and recruited by either: (1) clinic staff or clinical study officers (CSOs) at Patient Identification Centres (PICs) across National Health Services (NHS) Trusts in England; or (2) the two study sites (Nottingham and London) or (3) via Tourettes Action (tic disorder charity) website, our study website, or social media, based on the following criteria: Inclusion criteria 1) Aged 9 to 17 years-old.
2) Suspected or confirmed Tourette syndrome or chronic tic disorder.
3) Competent to provide written, informed consent (parental consent for child aged <16 years).

4) Broadband internet access and regular PC/laptop/Mac user, with mobile phone SMS.
Exclusion criteria 1) Receipt of/engaged in structured behavioural intervention for tics (e.g. HRT/CBIT or ERP) within the last 12 months.
2) Change to medication for tics (start or stop) within the previous 2 months.
3) Diagnoses of alcohol/substance dependence, psychosis, suicidality, or anorexia nervosa. 4) Moderate/severe intellectual disability. 5) Immediate risk to self or others. 6) Parent or child not able to speak or read/write English. Patients will be provided with a brief information sheet and a 'consent to contact' (C2C) form: for NHS referred patients, these forms will be given by a member of the usual care team (or CSO); for self-recruited patients, these will be completed online.

Initial screening
Upon receipt of a C2C, a member of the research team will undertake a telephone screening interview with the potential participant to determine basic eligibility. Potential participants who meet the initial eligibility requirements will be invited to attend a face-to-face screening/baseline appointment held at one of the two study sites. All participants will be reimbursed for their travel costs to attend this appointment.
Before participants attend the face-to-face screening/baseline appointment parents will be asked to complete an online parent and teacher Development and Wellbeing Assessment (DAWBA) 24 (see secondary outcomes for further details). Completion of the parent DAWBA is a requirement for enrolment into the trial; findings from the DAWBA will be used to exclude people who score highly on self-harm, psychosis, anorexia nervosa or suicidality. It is the parent's decision to involve the teacher in completing the teacher DAWBA.

Face-to-face screening appointment
Potential participants found eligible from the initial telephone screening will be invited to the faceto-face screening/baseline appointment. Consent will be taken at this appointment by a researcher/assessor trained in Good Clinical Practice (GCP), further details about which are listed under 'ethics and dissemination'. Participants will be provided with information sheets which have been developed with our patient and public involvement (PPI) group. Families will be encouraged to ask the research team any questions. Where the participant is a child (under 16-years-old) an age appropriate participant information sheet will be provided. A trained assessor will conduct the YGTSS 23 assessment to determine the presence of tics (inclusion criteria) and the Child and Adolescent Intellectual Disability Screening Questionnaire (CAIDS-Q) 25 to screen for intellectual disability (exclusion criteria). Details of the YGTSS are described under the primary outcome.
Patients who are not eligible because they have recently changed their tic medication (within 2months), or received a behavioural therapy for tics within the specified exclusion time frame (12 months), may be eligible for re-screening at a later date when these time exclusions have passed.
Patients who meet the eligibility criteria, after completion of all screening assessments, will be asked to complete baseline measures and will be introduced to the BIP system.

Interventions
The BIP treatment programs are delivered via a secure internet platform that enables presentation of different treatment content to different patient populations. Patients log in via personal user names and passwords to access the treatment content which usually includes text, pictures, instructional videos and worksheets (see link for video of the intervention https://vimeo.com/294763841/628b99ddfb). The treatment content for both groups is presented in chapters, like a self-help book.
Both the ERP (intervention) and the education (active control) are delivered via the BIP platform. The interventions consist of 10 separate child-and parent/carer-chapters which are designed to be delivered over 10 weeks, with access to therapist support during this time.
The child/young person and their parent/carer are provided with their own separate login to the BIP platform to access the relevant child or parent/carer chapters. The first four chapters cover Both children and parents/carers have regular contact with a therapist during the 10 weeks via messages that can be sent inside the treatment platform (resembling an email) or telephone if needed. The therapist can also directly comment on exercises that the participant has been working on, and give specific feedback to motivate the patient. The participant typically has contact with the therapist several times a week, although the contact is asynchronous. The therapist is available to support the participants during these 10-weeks, although support may be delivered over a 12-week period if necessary to allow for breaks during holiday and festive periods. Access to the BIP treatment program is granted for 1-year after the 10 weeks of therapist-guided treatment, with the remaining access to the BIP platform being unsupported.
The therapist manuals for both interventions were written by the co-applicants.

Therapist guided, internet-delivered ERP Intervention (BIP TIC; experimental group)
The treatment consists of evidence-based interventions adapted from previously published treatment manuals on ERP and established behavioural intervention for tics protocols. 26,27 During the treatment, participants are instructed to practice suppressing their tics: this is known as 'response prevention'. Then, with the help of their parent/carer, the participant is instructed to provoke premonitory urges and control all of their tics: this is known as 'exposure'. Through treatment, the child gains mastery in tolerating the urge, controlling the tics, and is able to do so for increasingly longer periods of time. The participants also receive detailed education about tics and strategies to promote tic management at school. The parent modules contain information regarding parent coping strategies, how to support their child in working with BIP and functional analysis relating to tics.

Therapist guided, internet-delivered education (active control group)
An active comparator intervention was chosen to ensure that all participants still received an internet-delivered therapist-guided intervention over-and-above what would typically be received in standard care. Education about tics (without a specific focus on training behavioural strategies to reduce tics) was chosen to enable a comparison to previous trials of face-to-face behaviour therapy for tics. 28 The comparator intervention was developed for the trial and consisted of educational information about TS and co-occurring conditions. The material was adapted and updated from the educational intervention used in two previous randomised controlled trials. 26,28 The chapters have been matched in length to that of the behavioural intervention. The comparator intervention reviews the definition of tics, natural history, common presentations, prevalence, aetiology, risks and protective factors and strategies for describing tics to other people etc. Problem-solving and development of expertise in tic disorders is emphasised. The parent modules emphasise parent coping strategies and self-care in caring for a child with tic disorder. There is no information on tic control within the comparator intervention.

Start of treatment
The participant will agree a start date for commencing therapy with their assessor at the screening/baseline appointment (typically within 24-48 hours of the baseline appointment). The participant will be reminded that it is important to log-on and start the therapy on the allocated date. At the start, the therapist will release the first two chapters of the intervention for the participants to complete and monitor their progress, sending reminders and feedback where necessary. If the participant does not start the intervention at the agreed start time, the 10-week start date does not alter.
All therapists will undergo training delivered by a supervisor (TM or JK) before commencing either intervention. Therapists will be closely supervised by TM or JK to ensure adherence to protocol. The team from the Karolinska Institutet will provide technical support throughout the trial.

Primary outcome
The primary outcome is the severity of tics as measured by the TTSS (0-50) on the YGTSS . 23 The primary end point is 3-months post-randomisation. The TTSS combines separate scales for motor tics (0-25) and for vocal tics (0-25). The primary outcome measure (TTSS) will be measured at baseline (pre-intervention), 3-months, 6, 12 and 18-months post randomisation.
The YGTSS is administered by a blinded assessor as an investigator-based semi-structured interview focussing on motor and vocal tic frequency, severity and tic related impairment over the previous week. The baseline assessment will be conducted face-to-face at the baseline/screening appointment. When possible, the follow-up assessments will be conducted by the same blinded assessor that conducted the baseline assessment, via video-conference call/WebEx or telephone.
With the participants' permission, all YGTSS assessments will be recorded for quality checks.
All assessors/researchers will be trained in conducting YGTSS by a clinical expert (TM).
Agreement with the expert rater will be established at the start of the trial and monitored every six-months. Assessors have to be within 15% of the expert rater (TM) for the Total Motor Tic  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   17   score, the Total Vocal Tic score and the Total Tic Score on 3 YGTSS recordings at baseline and   4 randomly selected recordings at follow-up. Assessors who do not meet this threshold of agreement will be re-trained.

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 YGTSS -Impairment scale: 23 The impairment scale (0-50) forms part of the YGTSS described above. The rating focuses on distress and impairment experienced in interpersonal, academic, and occupational domains.
 Parent Tic Questionnaire (PTQ): 29 The PTQ assesses the number, frequency, and intensity of motor and vocal tics.

 Concomitant interventions:
To assess what other treatments/interventions the child/young person is accessing during the study period, parents will be asked to complete a short questionnaire documenting other interventions (including medication) in progress.

Additional baseline measures
To further characterise the sample at baseline, the following measures will also be recorded:  Demographics questionnaire: Records the child's age, gender, ethnicity, parental education/ occupation, list of the child's current diagnoses and interventions (including medications) and general practitioner (GP) and school details.  41 The PUTS is a self-report instrument that measures premonitory urges in tic disorders.
 Swanson, Nolan, and Pelham Rating Scale (SNAP-IV): 42 The SNAP-IV is a behavioural rating scale that includes the core symptoms of ADHD and oppositional defiant disorder (ODD).

Process evaluation
The process evaluation will follow the Medical Research Council (MRC) guidelines for evaluating the implementation of complex interventions 43 44 . It will explore the fidelity and implementation of intervention, and make recommendations for adaptations. It will also examine the potential mechanisms underlying participant behaviour change and probe for unexpected consequences.
Interviews will be conducted with therapists and their supervisors supporting the intervention (target n>5), clinicians recruiting to the study (n = >10), children (n=>20 in each arm) and parents of children in both arms (n=>20 in each arm). Online feedback from participants will also be analysed together with indices recorded as part of the BIP system such as total therapist time, number of chapters clicked through and number of patient log-ins.

Patient and public involvement (PPI)
A group of PPI members was created to shape and guide the study. The group is comprised of four parents and four children and young people with a diagnosis of Tourette syndrome, plus two • guiding interview topics and shaping questions for process evaluation, • co-creation of lay summaries and other dissemination materials The PPI group mainly contributes remotely, in order to enable involvement from members who are not geographically close. Face-to-face input occurs at key points, for example attendance at trial team meetings.

Sample size
To detect a clinically important average difference of 0.5 of a standard deviation between intervention and comparator with 90% power at p<0.05 (2-sided), after allowing for 20% dropout, requires a total sample size of 220 participants. A systematic review found the average estimate for the standard deviation (SD) of the YGTSS (TTSS) from 19 trials of behavioural intervention for tics was 6.6. 17 Thus, the trial is powered to detect an average difference of 3.3 on the YGTSS.
Recruitment is planned to be conducted within an 18-month period. We are not aware of any other competing studies that are in progress or planned that would affect recruitment. Input received from young people and carers in developing this trial indicates that participation in the trial will be attractive as it guarantees access to an intervention. Our national recruitment network of specialist (PIC) clinics, including multiple community child and adolescent mental health services (CAMHS) and paediatric clinics and the charity Tourettes Action, have the capacity to meet the recruitment target within the time window. Recruitment figures will be monitored monthly by the Trial Manager (CLH) and any shortfall will be reported to the project management group (PMG).

Randomisation
Randomisation will be conducted using the Sealed Envelope online randomisation system and managed by Priment Clinical Trials Unit (CTU). Participants will be randomised online by the researcher/assessor. Randomisations will be distributed equally between the two arms (ratio 1:1) and stratified by study site using block randomisation with varying block sizes. The researcher will remain blind to the treatment allocation, and the therapist will be notified of the treatment allocation. Therapists will set up participants' treatment on the BIP system.
All participants receive the same outcome measures so assessors will not know which group the participant is in by the measurements. If an assessor becomes unblinded, subsequent assessments for that participant will be conducted by a different assessor (blind to arm allocation) where possible. In case of a medical emergency, participants will be able to disclose to the treating physician (e.g. GP) what treatment they received without unblinding the researchers. Outcome assessors will guess the treatment allocation after each assessment, to be able to calculate if the guesses are better than random.

Data management and analysis
Participants who do not complete therapy or measures at a given time point will still be followed up until the end of the trial unless they inform the research team they would like to withdraw from the trial. Participants will be reimbursed with £20 vouchers for completing measures at baseline and each follow-up time point, except the mid-treatment follow-ups (3 and 5 weeks).
All aspects of data management of the study will comply with the UK Data Protection Act 1998/ General Data Protection Regulation (GDPR), Priment's standard operating procedures (SOPs) and GCP. Outcome measures will be stored in BASS, a rating platform stored on a Swedish server.
Participant completed outcome measures are directly entered into an online database by the participant. Assessor/researcher completed measures may initially be entered on a paper case report form (CRF) or directly into the database. Data extraction will be performed within the UK.

Statistical analysis
All baseline variables will be summarised by randomised group. Categorical data will be reported as frequencies (%) and continuous data will be reported as mean (SD) unless skewed then they will be reported as median (interquartile range). No statistical tests will be carried out comparing baseline variables. The primary outcome (total tic severity score [TTSS] of the YGTSS at 3months post-randomisation) will be analysed using a linear regression model, including baseline TTSS and centre (the stratification variable). If the assumptions of linear regression are violated, another suitable method will be used. Primary analyses will be performed using intention to treat principles. Predictors of missingness will be examined. If any are found, they will be included in statistical models in a supportive analysis. There are no planned subgroup analyses.
Secondary outcomes will be analysed using similar statistical methods as the primary outcome.
Continuous outcomes will be analysed with linear regression. Dichotomous outcomes will be analysed using logistic regression. Results will be presented as estimated differences or odds ratios as appropriate, with accompanying 95% CI. P values will not be reported for secondary outcomes.

Economic analysis
The primary cost-effectiveness analysis for the within-trial evaluation will be the mean incremental cost per point change in YGTSS of treatment as usual (TAU) plus BIP TIC compared to TAU plus online education with therapist support at 3 months, from an NHS and personal social services cost perspective.
A secondary analysis of the mean incremental cost per quality-adjusted life-year (QALY) of the intervention compared to the active control from a health and social care cost perspective will also be calculated. A decision model projecting costs and QALYs into adulthood will also be developed.

Qualitative analysis
Interview data collected from the process evaluation will be analysed using thematic analysis. 45 Data will be analysed using NVivo to establish themes and subthemes. A mixed-methods approach will be used to integrate quantitative and qualitative data in order to fully explore implementation of the intervention.

Management and oversight
There are three committees in place to oversee the trial, including: a Project Management Group (PMG), Trial Steering Committee (TSC) and Data Monitoring and Ethics Committee (DMEC).
The PMG consists of all the co-investigators listed on the protocol who will meet at least every six months to discuss the study progress and overall conduct of the trial. The role of the TSC will be to provide overall supervision for the trial on behalf of the Trial Sponsor and Trial Funder, to ensure that the trial is conducted in accordance with GCP, and to review the findings of the internal pilot. The DMEC is the only body involved in the trial that has access to the unblinded comparative data. The role of its members is to monitor these data and make recommendations to the TSC on whether there any ethical or safety reasons why the trial should not continue. There are no interim analyses planned, however this does not preclude the DMEC from requesting analyses. The TSC and DMEC will meet annually. The charters are available on request from the corresponding author.

Adverse events
There are no anticipated serious adverse events. All adverse events will be recorded and monitored and the Chief Investigator and medical expert (CH) will determine seriousness and causality and report the event to the DMEC and ethics committee where necessary. Side effects will be formally monitored via completion of the side-effects scale throughout the intervention and for 3-months after the intervention finishes (month 6).

Audit
The Trial Manager, or a nominated designee of the Sponsor, shall carry out monitoring of trial data as an ongoing activity. The Sponsor may decide to carry out a full audit of the trial and the trial management systems/ procedures in the event of serious breaches to GCP or protocol. Trial data and evidence of monitoring and system audits will be made available for inspection by the Research Ethics Committee (REC) as required. Trust; neither the sponsor nor the funders will be involved in the analysis of study data or report writing. Only the UK research team will have access to the study data, which will be stored in secure locked files or password protected databases. Data will be available for inspection by the Individual participant medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited unless warranted by an adverse event.

ETHICS AND DISSEMINATION
Participant confidentiality will be further ensured by utilising identification numbers to correspond to treatment data in the computer files. No post-trial care is required; however, participants will have access to the intervention for one-year after starting the treatment, although this access will be without therapist support after the 10/12weeks. The Chief Investigator and site principal investigators declare no financial or competing interests. At the end of the trial, the data belongs to the Chief Investigator and the study sponsor. All members of the team will have access to the final trial dataset. The findings will be published in peer-reviewed journals, presented at relevant conferences and disseminated to the public via lay summaries co-created with our PPI group. All outputs will be authored by the research team and will not involve professional writers. Access to the full protocol is available upon request to the corresponding author.        Note: The CSRI includes a measure of school attendance. The YGTSS includes both a measure of severity and impairment.        Note: The CSRI includes a measure of school attendance. The YGTSS includes both a measure of severity and impairment. 6. I understand that I/my child may be asked to take part in research interviews, which will be recorded and anonymous direct quotes from these interviews may be used in study reports.
7. I agree for me and my child (named below) to take part in the above study. 6. I understand that I may be asked to take part in research interviews, which will be recorded and anonymous direct quotes from these interviews may be used in study reports.
7. I agree to take part in the above study. 3. I understand that the ORBIT team may look at my medical records and the data will be kept in a database both in England and in Sweden. This will be kept safe and only the research team will see my data.
4. I understand that the research team will write a report about the project. My name will not be mentioned in any reports.
5. I agree to my Doctor knowing that I am taking part in the ORBIT study.

ABSTRACT Introduction
Tourette syndrome and chronic tic disorder are common, disabling childhood-onset conditions. Guidelines recommend that behavioural therapy should be offered as first-line treatment for children with tics. However, there are very few trained behaviour therapists for tics and many patients cannot access appropriate care. This trial investigates whether an internet-delivered intervention for tics can reduce severity of symptoms.

Method and analysis
This parallel-group, single-blind, randomised controlled superiority trial with an internal pilot will recruit children and young people (aged 9-17 years) with tic disorders. Participants will be randomised to receive 10-weeks of either online, remotely-delivered, therapist-supported exposure response prevention (ERP) behavioural therapy for tics, or online, remotelydelivered, therapist-supported education about tics and co-occurring conditions. Participants will be followed-up mid-treatment, and 3-, 6-, 12-, and 18-month post-randomisation.
The primary outcome is reduction in tic severity as measured on the Yale Global Tic Severity Scale (YGTSS) total tic severity score. Secondary outcomes include a cost-effectiveness analysis and estimate of the longer-term impact on patient outcomes and healthcare services.
An integrated process evaluation will analyse quantitative and qualitative data in order to fully explore the implementation of the intervention and identify barriers and facilitators to implementation. The trial is funded by the National Institute of Health Research (NIHR), Health Technology Assessment (16/19/02).

Ethics and dissemination
The findings from the study will inform clinicians, healthcare providers and policy makers about the clinical and cost-effectiveness of an internet delivered treatment for children and Trial registration: ISRCTN70758207 and ClinicalTrials.gov (NCT03483493).

STRENGTHS AND LIMITATIONS OF THIS STUDY
 This study is a 10-week, parallel-group, single blind, non-commercial, randomised controlled superiority trial with an internal pilot; the first large trial for internet delivered therapy for tics in the UK.
 The study design and methodology are based upon an initial pilot study of internetdelivered ERP for tics conducted in Sweden.
 The protocol was created with a multidisciplinary team of experts including, healthcare professionals, patient and public involvement members, and health service researchers.
 This trial is only available to English-speaking participants with access to a computer/internet.  Despite these recommendations, only 1 in 5 young people with TS are currently able to access behaviour therapy for tics, while around 50% receive medication, 6 which is associated with a significant risk of adverse effects including weight gain and sedation. 4 5 Furthermore, those young people who manage to access behaviour therapy typically receive four or fewer face-to-face therapy sessions, 6 less than half the number recommended. 7 Commonly used behaviour therapies include: habit reversal training (HRT), whereby patients are taught to implement and maintain an action referred to as a 'competing response' when a premonitory urge to tic is experienced (the urge to tic often felt before the tic is expressed); comprehensive behavioural intervention for tics (CBIT), which includes HRT and adds additional elements of relaxation training, functional analyses (identification of situations which could exacerbate tics) and social support; and exposure and response prevention (ERP), where patients tolerate premonitory urge sensations and learn from their therapist how to resist their tics. Over the last decade, internet-delivered cognitive behaviour therapy (ICBT) has developed, enabling the delivery of effective, but less therapist intensive, cognitive and behavioural interventions remotely, which can increase the availability of evidence based treatments.
Across diagnostic conditions, studies have not only shown efficacy of ICBT compared to notreatment control conditions, but meta analyses comparing face-to-face delivered CBT with ICBT have demonstrated comparable results in terms of symptom reduction for adults with mental health problems, 9 ,10 which could also result in 50% cost savings. 10 However, therapist guidance during ICBT has been shown to be an important contributing factor in determining outcome. 11 Although self-guided ICBT is superficially attractive, given the very low costs of implementation, research evidence demonstrates very low adherence rates. 12,13 Recently, researchers at the Karolinska Institutet, Sweden, have developed a technical platform for ICBT called BIP (Barninternetprojektet, Swedish for Child Internet Project; http://www.bup.se/bip). The platform has been used to deliver therapist-supported ICBT for a range of different conditions, including phobia, 14 anxiety, 15 and obsessive-compulsive disorder. 16 The findings support the use of therapist guided ICBT using the BIP system, however, there is little research evidence with regards to the effectiveness of ICBT and TS. In a recent systematic review of digital health interventions, Hollis and colleagues 17 found the majority of interventions have been designed to help children and young people at risk for developing, or with a diagnosis of, an anxiety disorder and/or depression, with areas such as TS being largely overlooked. Innovations in behavioural therapies for tics include delivery of CBIT treatment remotely via video over the internet with a therapist. Two pilot RCTs have compared CBIT delivered remotely via videoconference to traditional face-to-face delivery in children with TS. Results showed significant tic reduction for both groups, with no difference between the modes of delivery. 18,19 The method of delivering CBIT was rated as highly acceptable by the participants. 18 One Swedish pilot study, upon which this current trial is based, has used the BIP platform to deliver ICBT with remote therapist support. The study compared tic reduction in children aged 8-16 years randomised to receive either ERP or HRT delivered online via the BIP platform. 20 Participants in both groups showed improvement after treatment completion, but only participants in the ERP arm showed significant reduction on the primary outcome measure Yale Global Tic Severity Scale (YGTSS) total tic severity score. . The gains were maintained for at least 12 months after the end of treatment. Although this study was not designed or powered as a definitive efficacy trial, these findings show that ERP treatment Furthermore, the study reported no severe adverse events. There were no drop-outs and no data loss for the primary outcome, and 83% of parents and children rated the treatment as good or very good, indicating the trial was highly acceptable to patients in Sweden.
However, the evidence available for the BIP treatment programs has all been gathered in Sweden and we have limited experience of delivering therapist supported online ERP to children and adolescents in the UK. There is evidence that uptake and use of digital health interventions is highly context dependent 21,22 and it would therefore be unwise to assume that a delivery package that works in Sweden will work equally well in the UK.
The overarching aim of the Online Remote Behavioural Intervention for Tics (ORBIT) trial is to evaluate the clinical and cost-effectiveness of BIP TIC, a therapist-guided, parent-assisted ERP programme for tics in young people with TS in the UK.
Specific objectives are to: 1. To optimise the design and delivery of BIP TIC in partnership with young people with TS, carers and healthcare professionals (HCPs) to maximise acceptability, effectiveness and long-term uptake.
2. To undertake an internal pilot to assess whether recruitment, engagement with the intervention and retention to the trial outcomes are sufficient to allow the trial to progress and provide a definitive answer on effectiveness.
3. To determine the clinical effectiveness of BIP TIC compared to online tic-related education in reducing tics, as measured by the masked assessor-rated Yale Global Tic Severity Scale (YGTSS) total tic severity score (primary outcome).
4. To evaluate the cost-effectiveness of BIP TIC.

5.
To estimate the longer-term impact on patient outcomes and health service costs. 6. To conduct a process analysis in line with MRC guidelines for complex interventions to determine barriers and facilitators to implementation.
The primary hypothesis is that the BIP TIC therapist-guided remote digital ERP intervention will be superior to a comparator intervention of therapist-guided online ticrelated education in reducing tics, as measured by the masked assessor-rated YGTSS total tic severity score 23 .

Trial design
The design is a 10-week, parallel-group, single-blind, non-commercial, randomised controlled superiority trial with an internal pilot. Participants will be randomised to receive 10-weeks of online, remotely-delivered, therapist-supported ERP for tics, or online, remotelydelivered, therapist-supported education for tics. Participants will be followed-up midtreatment, and at 3-, 6-, 12-, and 18-months post-randomisation. Up until the 6-month followup participants are encouraged not to change medication or start alternative therapies for tics.
Months 12 and 18 are naturalistic follow-up points where participants are free to access any treatments in accordance with standard practice recommended by their usual treating clinician. A sub-sample of participants and parents will be purposively selected to participate in process evaluation interviews after the 3-month follow-up. Interviews will also be conducted with therapists, clinicians recruiting to the study and commissioners. The process evaluation will also link data on usage of the intervention with outcomes. A schematic diagram of the study design is shown in Figure 1 and a more detailed participant flow is shown in Figure 2. An internal pilot will be conducted until the end of the 9 th month to determine whether recruitment, engagement with the intervention and retention to the trial are sufficient to allow the trial to progress, the stop/go rules for proceeding are: 1) The study needs to have recruited 30% of the sample (66 participants).
2) At least 60% of participants need to have completed the intervention (defined as the child/adolescent completing at least their first four chapters).
3) 80% of participants who have reached the relevant time window need to have completed the primary outcome measure.

<<INSERT FIGURE 1>>>
Setting The intervention will be remotely delivered from two national centres for treating tics in the Identification Centres (PICs) will be involved in recruiting participants into the two research sites.

Participant identification
Participants will be identified and recruited by either: (1) clinic staff or clinical study officers  (tic disorder charity) website, our study website, or social media, based on the following criteria: Inclusion criteria 1) Aged 9 to 17 years-old.
2) Suspected or confirmed Tourette syndrome or chronic tic disorder.
3) Competent to provide written, informed consent (parental consent for child aged <16 years).

4) Broadband internet access and regular PC/laptop/Mac user, with mobile phone SMS.
Exclusion criteria 1) Receipt of/engaged in structured behavioural intervention for tics (e.g. HRT/CBIT or ERP) within the last 12 months.
2) Change to medication for tics (start or stop) within the previous 2 months.
4) Moderate/severe intellectual disability. 5) Immediate risk to self or others. 6) Parent or child not able to speak or read/write English.
Patients will be provided with a brief information sheet and a 'consent to contact' (C2C) form: for NHS referred patients, these forms will be given by a member of the usual care team (or CSO); for self-recruited patients, these will be completed online. Upon receipt of a C2C, a member of the research team will undertake a telephone screening interview with the potential participant to determine basic eligibility. Potential participants who meet the initial eligibility requirements will be invited to attend a face-to-face screening/baseline appointment held at one of the two study sites. All participants will be reimbursed for their travel costs to attend this appointment.

Initial screening
Before participants attend the face-to-face screening/baseline appointment parents will be asked to complete an online parent and teacher Development and Wellbeing Assessment (DAWBA) 24 (see secondary outcomes for further details). Completion of the parent DAWBA is a requirement for enrolment into the trial; findings from the DAWBA will be used to exclude people who score highly on self-harm, psychosis, anorexia nervosa or suicidality. It is the parent's decision to involve the teacher in completing the teacher DAWBA.

Face-to-face screening appointment
Potential participants found eligible from the initial telephone screening will be invited to the face-to-face screening/baseline appointment. Consent will be taken at this appointment by a researcher/assessor trained in Good Clinical Practice (GCP), further details about which are listed under 'ethics and dissemination'. Participants will be provided with information sheets which have been developed with our patient and public involvement (PPI) group. Families will be encouraged to ask the research team any questions. Where the participant is a child (under 16-years-old) an age appropriate participant information sheet will be provided.
A trained assessor will conduct the YGTSS 23 assessment to determine the presence of tics (inclusion criteria) and the Child and Adolescent Intellectual Disability Screening Questionnaire (CAIDS-Q) 25 to screen for intellectual disability (exclusion criteria). Details of the YGTSS are described under the primary outcome. Patients who are not eligible because they have recently changed their tic medication (within 2-months), or received a behavioural therapy for tics within the specified exclusion time frame (12 months), may be eligible for re-screening at a later date when these time exclusions have passed. Patients who meet the eligibility criteria, after completion of all screening assessments, will be asked to complete baseline measures and will be introduced to the BIP system.

Interventions
The BIP treatment programs are delivered via a secure internet platform that enables therapist is available to support the participants during these 10-weeks, although support may be delivered over a 12-week period if necessary to allow for breaks during holiday and festive periods. Access to the BIP treatment program is granted for 1-year after the 10 weeks of therapist-guided treatment, with the remaining access to the BIP platform being unsupported. The therapist manuals for both interventions were written by the co-applicants.

Therapist guided, internet-delivered ERP Intervention (BIP TIC; experimental group)
The treatment consists of evidence-based interventions adapted from previously published treatment manuals on ERP and established behavioural intervention for tics protocols. 26,27 During the treatment, participants are instructed to practice suppressing their tics: this is known as 'response prevention'. Then, with the help of their parent/carer, the participant is instructed to provoke premonitory urges and control all of their tics: this is known as 'exposure'. Through treatment, the child gains mastery in tolerating the urge, controlling the tics, and is able to do so for increasingly longer periods of time. The participants also receive detailed education about tics and strategies to promote tic management at school.
The parent modules contain information regarding parent coping strategies, how to support their child in working with BIP and functional analysis relating to tics.

Therapist guided, internet-delivered education (active control group)
An active comparator intervention was chosen to ensure that all participants still received an internet-delivered therapist-guided intervention over- The comparator intervention was developed for the trial and consisted of educational information about TS and co-occurring conditions. The material was adapted and updated from the educational intervention used in two previous randomised controlled trials. 26,28 The chapters have been matched in length to that of the behavioural intervention. The comparator intervention reviews the definition of tics, natural history, common presentations, prevalence, aetiology, risks and protective factors and strategies for describing tics to other people etc. Problem-solving and development of expertise in tic disorders is emphasised. The parent modules emphasise parent coping strategies and self-care in caring for a child with tic disorder. There is no information on tic control within the comparator intervention.

Start of treatment
The participant will agree a start date for commencing therapy with their assessor at the screening/baseline appointment (typically within 24-48 hours of the baseline appointment).
The participant will be reminded that it is important to log-on and start the therapy on the allocated date. At the start, the therapist will release the first two chapters of the intervention for the participants to complete and monitor their progress, sending reminders and feedback where necessary. If the participant does not start the intervention at the agreed start time, the 10-week start date does not alter.
All therapists will undergo training delivered by a supervisor (TM or JK) before commencing either intervention. Therapists will be closely supervised by TM or JK to ensure adherence to protocol. The team from the Karolinska Institutet will provide technical support throughout the trial.
The YGTSS is administered by a blinded assessor as an investigator-based semi-structured interview focussing on motor and vocal tic frequency, severity and tic related impairment over the previous week. The baseline assessment will be conducted face-to-face at the baseline/screening appointment. When possible, the follow-up assessments will be conducted by the same blinded assessor that conducted the baseline assessment, via video-conference call/WebEx or telephone. With the participants' permission, all YGTSS assessments will be recorded for quality checks.
All assessors/researchers will be trained in conducting YGTSS by a clinical expert (TM).
Agreement with the expert rater will be established at the start of the trial and monitored every six-months. Assessors have to be within 15% of the expert rater (TM) for the Total Motor Tic score, the Total Vocal Tic score and the Total Tic Score on 3 YGTSS recordings at baseline and 4 randomly selected recordings at follow-up. Assessors who do not meet this threshold of agreement will be re-trained.
 Treatment satisfaction and need for further treatment: 7-items ask about the child's/parent's satisfaction with the treatment and an additional question asks whether they feel more tic treatment is required.

 Concomitant interventions:
To assess what other treatments/interventions the child/young person is accessing during the study period, parents will be asked to complete a short questionnaire documenting other interventions (including medication) in progress.

Additional baseline measures
To further characterise the sample at baseline, the following measures will also be recorded:  Demographics questionnaire: Records the child's age, gender, ethnicity, parental education/ occupation, list of the child's current diagnoses and interventions (including medications) and general practitioner (GP) and school details.
 Social Communication Questionnaire (SCQ): 40 The SCQ is a screening tool for Autism Spectrum Disorder (ASD).

Process evaluation
The process evaluation will follow the Medical Research Council (MRC) guidelines for evaluating the implementation of complex interventions 43 44 . It will explore the fidelity and implementation of intervention, and make recommendations for adaptations. It will also examine the potential mechanisms underlying participant behaviour change and probe for unexpected consequences.
Interviews will be conducted with therapists and their supervisors supporting the intervention (target n>5), clinicians recruiting to the study (n = >10), children (n=>20 in each arm) and parents of children in both arms (n=>20 in each arm). Online feedback from participants will also be analysed together with indices recorded as part of the BIP system such as total therapist time, number of chapters clicked through and number of patient log-ins.

Patient and public involvement (PPI)
A group of PPI members was created to shape and guide the study. The group is comprised of four parents and four children and young people with a diagnosis of Tourette syndrome, plus two PPI members with previous experience of large studies. The design of the trial and its dissemination will also have been shaped by PPI in the following ways: • reviewing and selection of outcome measures • co-development of study materials and recruitment processes • reviewing the interventions and providing feedback on all chapters  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   22 • attending ongoing trial team meetings to provide PPI perspective and assist with troubleshooting (e.g. recruitment and retention) • guiding interview topics and shaping questions for process evaluation, • co-creation of lay summaries and other dissemination materials The PPI group mainly contributes remotely, in order to enable involvement from members who are not geographically close. Face-to-face input occurs at key points, for example attendance at trial team meetings.

Sample size
To detect a clinically important average difference of 0.5 of a standard deviation between intervention and comparator with 90% power at p<0.05 (2-sided), after allowing for 20% dropout, requires a total sample size of 220 participants. A systematic review found the average estimate for the standard deviation (SD) of the YGTSS (TTSS) from 19 trials of behavioural intervention for tics was 6.6. 17 Thus, the trial is powered to detect an average difference of 3.3 on the YGTSS.
Recruitment is planned to be conducted within an 18-month period. We are not aware of any other competing studies that are in progress or planned that would affect recruitment. Input received from young people and carers in developing this trial indicates that participation in the trial will be attractive as it guarantees access to an intervention. Our national recruitment network of specialist (PIC) clinics, including multiple community child and adolescent mental health services (CAMHS) and paediatric clinics and the charity Tourettes Action, have the capacity to meet the recruitment target within the time window. Recruitment figures will be monitored monthly by the Trial Manager (CLH) and any shortfall will be reported to the project management group (PMG).  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 23

Randomisation
Randomisation will be conducted using the Sealed Envelope online randomisation system and managed by Priment Clinical Trials Unit (CTU). Participants will be randomised online by the researcher/assessor. Randomisations will be distributed equally between the two arms (ratio 1:1) and stratified by study site using block randomisation with varying block sizes. The researcher will remain blind to the treatment allocation, and the therapist will be notified of the treatment allocation. Therapists will set up participants' treatment on the BIP system.
All participants receive the same outcome measures so assessors will not know which group the participant is in by the measurements. If an assessor becomes unblinded, subsequent assessments for that participant will be conducted by a different assessor (blind to arm allocation) where possible. In case of a medical emergency, participants will be able to disclose to the treating physician (e.g. GP) what treatment they received without unblinding the researchers. Outcome assessors will guess the treatment allocation after each assessment, to be able to calculate if the guesses are better than random.

Data management and analysis
Participants who do not complete therapy or measures at a given time point will still be followed up until the end of the trial unless they inform the research team they would like to withdraw from the trial. Participants will be reimbursed with £20 vouchers for completing measures at baseline and each follow-up time point, except the mid-treatment follow-ups (3 and 5 weeks).
All aspects of data management of the study will comply with the UK Data Protection Act 1998/ General Data Protection Regulation (GDPR), Priment's standard operating procedures (SOPs) and GCP. Outcome measures will be stored in BASS, a rating platform stored on a Swedish server. Participant completed outcome measures are directly entered into an online

Statistical analysis
All baseline variables will be summarised by randomised group. Categorical data will be reported as frequencies (%) and continuous data will be reported as mean (SD) unless skewed then they will be reported as median (interquartile range). No statistical tests will be carried out comparing baseline variables. The primary outcome (total tic severity score [TTSS] of the YGTSS at 3-months post-randomisation) will be analysed using a linear regression model, including baseline TTSS and centre (the stratification variable). If the assumptions of linear regression are violated, another suitable method will be used. Primary analyses will be performed using intention to treat principles. Predictors of missingness will be examined. If any are found, they will be included in statistical models in a supportive analysis. There are no planned subgroup analyses.
Secondary outcomes will be analysed using similar statistical methods as the primary outcome.
Continuous outcomes will be analysed with linear regression. Dichotomous outcomes will be analysed using logistic regression. Results will be presented as estimated differences or odds ratios as appropriate, with accompanying 95% CI. P values will not be reported for secondary outcomes.

Economic analysis
The primary cost-effectiveness analysis for the within-trial evaluation will be the mean incremental cost per point change in YGTSS of treatment as usual (TAU) plus BIP TIC compared to TAU plus online education with therapist support at 3 months, from an NHS and personal social services cost perspective. A secondary analysis of the mean incremental cost per quality-adjusted life-year (QALY) of the intervention compared to the active control from a health and social care cost perspective will also be calculated. A decision model projecting costs and QALYs into adulthood will also be developed.

Qualitative analysis
Interview data collected from the process evaluation will be analysed using thematic analysis. 45 Data will be analysed using NVivo to establish themes and subthemes. A mixed-methods approach will be used to integrate quantitative and qualitative data in order to fully explore implementation of the intervention.

Management and oversight
There are three committees in place to oversee the trial, including: a Project Management Group (PMG), Trial Steering Committee (TSC) and Data Monitoring and Ethics Committee (DMEC). The PMG consists of all the co-investigators listed on the protocol who will meet at least every six months to discuss the study progress and overall conduct of the trial. The role of the TSC will be to provide overall supervision for the trial on behalf of the Trial Sponsor and Trial Funder, to ensure that the trial is conducted in accordance with GCP, and to review the findings of the internal pilot. The DMEC is the only body involved in the trial that has access to the unblinded comparative data. The role of its members is to monitor these data and make recommendations to the TSC on whether there any ethical or safety reasons why the trial should not continue. There are no interim analyses planned, however this does not preclude the DMEC from requesting analyses. The TSC and DMEC will meet annually. The charters are available on request from the corresponding author.

Adverse events
There are no anticipated serious adverse events. All adverse events will be recorded and monitored and the Chief Investigator and medical expert (CH) will determine seriousness and causality and report the event to the DMEC and ethics committee where necessary. Side effects will be formally monitored via completion of the side-effects scale throughout the intervention and for 3-months after the intervention finishes (month 6).

Audit
The Trial Manager, or a nominated designee of the Sponsor, shall carry out monitoring of trial data as an ongoing activity. The Sponsor may decide to carry out a full audit of the trial and the trial management systems/ procedures in the event of serious breaches to GCP or protocol. Trial data and evidence of monitoring and system audits will be made available for inspection by the Research Ethics Committee (REC) as required.

ETHICS AND DISSEMINATION
The study received ethical and Health Research Authority (HRA) approval from North West Trust; neither the sponsor nor the funders will be involved in the analysis of study data or report writing. Only the UK research team will have access to the study data, which will be stored in secure locked files or password protected databases. Data will be available for inspection by the ethics committee upon request. Changes to the protocol will be communicated to the ethics committee, funders, and trial registries by the trial manager  C). In the event of any conflict between the parent and child, the child will not enter the study.
Individual participant medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited unless warranted by an adverse event.
3. I understand that the ORBIT team may look at my medical records and the data will be kept in a database both in England and in Sweden. This will be kept safe and only the research team will see my data.
4. I understand that the research team will write a report about the project. My name will not be mentioned in any reports.
5. I agree to my Doctor knowing that I am taking part in the ORBIT study.
6. The researcher might ask me to take part in an interview about my experiences of the ORBIT trial. I do not have to take part. If I agree to take part, the interview will be recorded but only the research team will know that I did the interview.

Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained ___10_____ Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

____11____
11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered ____12-15__ 11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease) ____NA_____ 11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)

_____15_____
Interventions 11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _____11_____ Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended 15-21+Table 1 Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) __Fig1,2, Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions

___22-23_____
Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

___22-23_____
Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions ____22-23____ Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how ____22-23____ 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial ___22-23_____

Methods: Data collection, management, and analysis
Data collection methods 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol

__15-21____
18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols __23-24_____ Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) ___24_____

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed ___25____ 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial ____9-10 + 25___

Harms 22
Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct _____19+26____ Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor ____26______ How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial ___27____