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Article History

Received: 9 May 2025

Accepted: 4 August 2025

First Online: 26 September 2025

Declarations

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: Ethical and professional guidelines will be followed at all times, in line with Good Clinical Practice guidelines. Institutional review board approval has been obtained from the FHLS Psychology Ethics Committee at the University of Exeter on 27 September 2022 (Ref: Ethics Application ID: 523095). All participants will provide electronic informed consent (see Appendix 2). Data will be collected in a pseudonymized manner and stored securely.The study is currently using trial protocol version 4.0 dated 31st May 2024. The trial sponsor is the University of Exeter, Exeter, UK. Protocol modifications are recorded and communicated to trial partners, sponsors, review boards, and Trial Steering Committee (TSC), with significant protocol changes updated in the trial registry (ISRCTN) and communicated to trial participants.A Trial Steering Committee (TSC) with independent experts in ethics, psychiatry, statistics, and a representative from a patient’s association will provide independent oversight of the trial and expert advice, meeting every 6 months, and ensure that it is being conducted in accordance with the principles of Good Clinical Practice and the relevant regulations. There will also be an independent Data Monitoring Committee (DMC) to review adverse events and monitor data with access to group allocation with respect to recruitment, retention, and safety, and report to the TSC. The DMC has a formal charter and consists of an independent expert chair, an independent statistician, and an independent clinician. The DMC will be responsible for monitoring serious adverse effects, protocol violations and any risks emerging from the trial. It has the capacity to conduct an unblinded analysis if concerned about serious adverse effects. Interim analyses will only be conducted at the request of the DMC if there is a concern about harmful effects of intervention; based on these analyses, the DMC will make recommendations to the TSC, who will decide if the trial or a particular intervention should be discontinued on the basis of participant well-being and safety. The risk level of the trial does not warrant a formal audit, and oversight through the TSC and DMC is deemed sufficient.The trial psychological wellbeing practitioners (PWPs) have contacted and set up all trial participants on the digital platform, whether in the guided or unguided i-CBT, and are thus unblinded to each individual participant’s condition and can respond if any issues arise with any individual participant with respect to risk management and AE/SAE without additional unblinding being required; in the eventuality of emergency unblinding of an individual participant being required, the Principal Investigator would contact the PWPs for this information, with this documented in our Trial Management Folder and the DMC and TSC informed.Adverse events and other unintended effects of trial interventions or trial conduct will be self-reported on the EDC through open questions asking about any problems arising from participation, standardized questions about self-harm and symptoms at each follow-up, healthcare use (including hospitalization and emergency care) asked at the 3-month assessment, plus spontaneously reported feedback from participants. All SAEs recorded in the EDC must be reported to the ExeCTU Trial Manager within 24 working hours/1 working day of becoming aware of the event. When a potential Adverse Event (AE) or Serious Adverse Event (SAE) is self-reported, designated clinicians (PWPs) will contact individual participants to collect more information, provide support and relevant signposting or onward referral, and record details on the event in the relevant form in the electronic data capture system. The principal investigator, as the senior clinician, will then review these reports to assess the severity and causality of these reported events against a priori criteria. These a priori criteria are: (a) Adverse Events (AE) defined as significant worsening symptoms of anxiety, worsening symptoms of depression, as operationalized by a reliable deterioration of movement from ‘mild’ to ‘severe’ or ‘moderate’ to ‘severe’ levels of symptoms on GAD7 or PHQ9 AND a change of ≥ 4 points on GAD7 or ≥ 6 points on PHQ9 from baseline assessment to 3-month assessment; new instance of self-harm; new instance of suicidality; (b) Serious Adverse Events (SAEs) operationalized as including death, suicide attempt, life-threatening self-harm, serious accident or violent incident, referral to crisis care or admission to psychiatric hospital. The SAE relationship to the study or trial procedures will be determined as not related, unlikely to be related, possibly related, definitely related, or unknown by the Principal Investigator based on clinical judgement and the information provided. Only serious adverse events (SAE) that are related to the trial and unexpected will be reported to the sponsor, who will decide if onward reporting to the research ethics committee is required. All SAEs and Adverse Events (AEs) are collated in a report for each TSC/DMC meeting.The trial has a risk and safety protocol, which includes action for ancillary care for participants with mental health disorders, including signposting to help, aiding with onward referrals, and contact with a clinician in the team. The sponsor has trial insurance that has provision for compensation for those who suffer harm from trial participation, in the unlikely event it is required. The PWP providing the intervention or a researcher in contact with a participant may request that the trial intervention be discontinued for reasons of participant safety at any time; such requests will be made to and approved by the PI or an appointed deputy where possible, based on a clinical judgement on the potential benefit or harm to the participant. Advice on a case-by-case basis may be sought from the DMC where necessary.All participants will provide electronic informed consent prior to baseline assessment. All participants can discontinue allocated interventions at their own choice and request. After participants have been randomized and are actively participating in the trial, there are no limits on what concomitant care is permitted and no concomitant care is prohibited.

: Not applicable.

: In the past 3 years, Dr. Kessler has been a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc., and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM, and Roga Sciences. The other authors declare no competing interests.