The aim of this multi-center, two-armed, randomized controlled trial is to assess the effect of a novel internet-based therapist-assisted treatment program "One step at a time" designed for the treatment of patients with moderate to severe functional somatic disorder (FSD).

The trial will enroll 166 patients with FSD who will be randomized (1:1) to either the experimental condition (14 weeks' treatment with "One step at a time") or the active control condition ("GetStarted"), which is a non-guided internet-based treatment program for patients with FSD. The trial will include patients aged 18-60 years with an established single/oligo-organ or multi-organ FSD diagnosis, with a duration of minimum 6 months. The primary outcome measures will be based on self-reported physical health (SF-36 PPH) and treatment satisfaction (CGI-I). The trial will be considered effective if a higher proportion of patients in the experimental condition report a clinically significant outcome compared with patients in the active control condition at the 3-month follow-up after treatment.

OBJECTIVE: To assess the clinical efficacy of the therapist-guided internet-delivered treatment program "One step at a time" for functional somatic disorders (FSDs) compared with an active control "Get Started".

DESIGN: The trial will employ a two-armed randomized, controlled design with an active control condition.

PARTICIPANTS: We will include adult patients (18-60 years) with a medical diagnosis of functional somatic disorder. For a description of eligibility criteria, see the section "Eligibility".

PROJECT GROUP: Thomas Tandrup Lamm (Psychologist, MSc.); Lisbeth Frostholm (Professor, Psychologist, MSc., Ph.D.); Heidi Frølund Pedersen (Associate Professor, Psychologist, MSc., Ph.D.); and Brjánn Ljótsson (Associate Professor, Psychologist MSc., Ph.D.).

The trial will be conducted by the research group at the Dept. of Functional Disorders (www.functionaldisorders.dk), based at Aarhus University Hospital, Denmark. The clinic was established in 1999 and offers assessment and specialized treatment to patients with severe FSD.

The Pain and Headache Clinic (PHC) based at Aarhus University Hospital and the Center for Functional Disorders (CFD) based at Sygehus Lillebælt in Southern Region Denmark will take part in the assessment and recruitment of the patients. The treatment will be conducted by trained therapists, at the Dept. of Functional Disorders.

MAIN HYPOTHESIS: We hypothesize that a statistically significant higher proportion of patients receiving "One-step" will report a clinically relevant improvement in self-reported physical health and self-reported overall health (SF-36 PPH; CGI-I) compared with "Get Started" 3 months after end-of-treatment. Secondarily, that "One step" will be superior to "Get Started" in terms of increasing helpful illness perceptions (IPQ) and behaviors (BRIQ) and reducing illness worry (WI-6-R) 3 months after end-of-treatment.

INTERVENTION: "One step at a time" consists of 11 internet-delivered modules delivered over 14 weeks. The modules are based on previous treatment manuals for group-based psychoeducation and treatment for severe FSD.

The treatment program is developed as a therapist-assisted interactive treatment program. Each module has a specific theme and contains on average between 7 and 10 pages with elements such as psychoeducation; videos of former patients sharing their narrative and treatment experiences; videos of health professionals talking about FSD, symptom understanding, and illness behavior; interactive exercises, graded exercise and exposure, and videos of guided physical stretching and mindfulness exercises.

The modules concerning sleep, diet, and exercise will also be included as additional resources that can be accessed on an-as-needed basis.

The treatment is assisted by a therapist with the purpose of motivating the patient to engage with the treatment, answer questions, and provide assistance with exercises. The interaction is primarily written communication and takes place in an embedded secured message system on the platform. The therapist writes to the patient 1-2 times on a weekly basis. Furthermore, patients are offered 3 supportive telephone consultations during the treatment: 1) A start-up conversation within the first 2 weeks of the treatment, 2) a conversation after module 5 focusing on what the patient has learned so far and what he/she wishes to focus on in the remaining treatment period, and finally 3) an end-of-treatment conversation focusing on how the patient can proceed with those treatment elements from the program that have been most useful. Finally, a module for relatives consisting of videos with health professionals and relatives to patients with severe FSD has been developed.

Treatment is considered completed if the patient has worked actively (logged into the module and completed at least one interactive exercise) in each of the first 5 modules of the treatment program. This was chosen because the enrolled patients will have received the fundamental treatment elements including psychoeducation and an introduction to graded exercise and exposure at this point. The participating therapists are supervised weekly by specialized psychologists with focus on the written interaction in the program.

"Get started" is an internet-delivered non-guided self-help program consisting of 4 brief modules based on pamphlets developed at the Dept of Functional Disorders addressing psychoeducation in severe FSD and a better balance in basic needs like sleep, diet, and exercise. The modules consist of psychoeducation provided by texts giving specific advice on how to improve sleep quality and diet and increase physical activity by applying graded exercise. Participants are encouraged to focus on either sleep, diet, or exercise during the 14-week treatment period.

MEASUREMENTS: Self-reported measures will be administered to both groups at several timepoints during the course of treatment, including before assessment (-2 weeks), before the start of the program (baseline, 0 weeks), after treatment (14 weeks), at the 3-month follow-up (26 weeks, primary endpoint) and at the 12-month follow-up (62 weeks). Beyond this, a smaller selection of process and outcome measures will be administered at weeks 3, 6, and 9. Participants will answer a short list of questions after the completion of each module.

Furthermore, medical doctors will evaluate patients' eligibility and motivation after the initial diagnostic assessment, and after the post-treatment consultation after the 3 month follow-up. Therapists will record number and time usage of telephone consultations throughout the treatment. Both treatment program will continually log the participants' data during the treatment period.

For a detailed list of the measures and measurement time points included, see the section "Outcome measures".

POWER CALCULATION: The power calculation for SF-36 PPH is based on the proportion of patients experiencing a minimum of a 4-point increase in the aggregate score (PPH) from baseline to the 3-month follow-up, which may be regarded as a clinically relevant change (Norman, 2003) and has been used as an indicator of a clinically relevant response to treatment in patients with severe FSD (Schröder et al., 2012; Pedersen et al., 2018).

Based on previous studies, we estimate the proportion experiencing a minimum of a four-point improvement at the primary outcome, PPH to be between 35%-50% in the intervention group and 10-25% in the active control group (Schröder et al., 2012; Fjorback et al., 2013; Pedersen et al., 2018; Pedersen et al., 2019). With a total sample size of N=150 and a proportion in the control group equal to 15%, we will with a power of 81.4% be able to establish a difference between groups if the proportion in the intervention group is a minimum of 35%.

For the CGI-I, patients grade their health as "much worse", "worse", "unchanged", "better", "or much better". In the analyses we collapse "much worse" and "worse" into one category, and "better" and "much better" to one category, which gives us 3 outcomes in each category (worse, unchanged, better). The power analysis is based on an analysis of a proportional odds model with 5% significance level, and 75 patients in the intervention group and 75 persons in the control group. At OR = 2.5 the power will be 79.1%.

We expected an attrition rate of 10% in both groups. Therefore, we chose to include 15 patients beyond the 150 needed. In order to achieve equal group size, we added one more patient. Thus, we aim to include 166 patients in the trial.

ANALYSIS: "Intention to treat" analyses and "completer analysis" will be performed. Directed acyclic graphs will be used to determine the appropriate variables to adjust for. "Completers" are defined as patients who have accessed all of the first 5 modules. A priori hypotheses will be analyzed using logistic regression, mediation analysis (simplex cross-lagged as well as latent growth curve models), and multiple regression. For main analyses single/oligo- and multi-organ BDS patients will be combined and analyzed as an aggregated cohort. We will supplement this with sensitivity analyses, where it will be tested whether FSD type (single/oligo or multi organ) moderates effects. An in-house statistician will be continuously involved in the project.

ETHICAL CONSIDERATIONS: The trial presents low risks (side-effects and/or disadvantages) for the patients who may end their participation at any time point and can get into contact with a physician if their physical/mental health state deteriorates significantly. After patients have reached their final end-point, at the 3-month follow-up, they will be invited to a follow-up consultation with a medical doctor where their health/mental status will be assessed, and the need for further treatment discussed.

A study protocol has been approved by the Research Ethics Board of Aarhus University Hospital for approval (case.nr. 1-10-72-361-21). A pre-registration of the trial has been submitted to ClinicalTrials.gov before the onset of the trial. Data will be handled according to Danish law on the Data Protection Act and the Data Protection Regulation, and have been approved by the Danish Data Protection Agency (case.nr. 772917).

Inclusion Criteria:

• Patients must fulfil the criteria for moderate-severe FSD operationalized as being diagnosed with either single/oligo-organ BDS, with 2 organ systems that are each affected by 3 or more symptoms, or multi-organ BDS, with 3 or 4 organ systems that are each affected by 3 or more symptoms.
• Patients must have symptom duration > 6 months.
• If older than 25, patients must have been active in the labor market or educational system for at least 12 months during the last 2 years.
• Patient must have access to a computer or tablet with internet connection.
• Patient must be able to understand, read, and write Danish fluently.

Exclusion Criteria:

• Patients are excluded from participation if they present with severe comorbid somatic or psychiatric disease that is insufficiently treated at the time of assessment and is deemed to constitute a potential barrier for engaging in the treatment.
• Patients are excluded if they lack motivation to engage in internet-delivered treatment.
• Patients are excluded if they have poor self-reported IT skills.
• Patients are excluded if they lack informed consent.
• Patients are excluded if they have ongoing treatments with opioids and benzodiazepines.
• Patient's use of psychoactive medications should be stable.