Taking the LEAP: study protocol for a randomized, multicentre, naturalistic, efficacy trial of the compuLsive Exercise Activity theraPy (LEAP) - a cognitive behavioral program specifically targeting compulsive exercise in patients with eating disorders

The project aims to evaluate the efficacy of LEAP at reducing pathological exercise and improving ED pathology in Swedish patients diagnosed with AN, BN, or OSFED, in a naturalistic randomized controlled trial (RCT).

The trial is a naturalistic two-armed parallel open-label superiority randomized efficacy trial, with recruitment from four Swedish specialist ED clinics. Eligible adult patients will be recruited via the clinics and randomized to treatment as usual (TAU) or TAU+LEAP, where LEAP will run in parallel with TAU. Key outcome variables in both arms are measured at initial assessment, after 3 months, and 6 months after initial assessment. Although most TAU+LEAP participants are expected complete the LEAP program prior to T2 assessment, a few may terminate LEAP prior to T3 (see Participant timeline).

The project is a collaboration between Karolinska Institute (KI) and four Swedish specialist ED treatment units: Eriksbergsgården in Örebro, Region Örebro; Ätstörningsenheten in Göteborg; Ätstörningsenheten in Uppsala; and Stockholms Centrum för Ätstörningar in Stockholm. Project management is done at KI while recruitment and the intervention take place at the units. These are medium to large units providing equivalent evidence-based care. The project related processes are equivalent at the units.

Inclusion criteria: male and female patients, ≥18 years, with AN, BN or OSFED (1. Atypical AN, 2. BN with low frequency and/or limited duration of symptoms, 4. purging disorder/compensatory behaviors after small food amounts), reporting CE at initial assessment (e.g., measured by EDE-Q version 6, item 18, see Instruments), and receiving outpatient care at the specialized ED treatment units. As more females than males seek treatment, there will be more females than males in the final sample.

Subjects are first informed orally by project affiliated unit staff with extensive knowledge on the project, followed by oral or written information from the project manager (also the LEAP principal investigator; PI) or project coordinator (PC). Formal participant information and written study consent are managed and collected through the online data collection and participant management system BASS Core Facility (BASS; see Data collection and management) using a governmentally and financially approved secure electronic signature system (Bank-ID; https://​www.​bankid.​com/​en). Written participant information in BASS include details about the project, participation, potential risks and benefits of participation, usage of participant data, how to find study results, insurance and remuneration, and the voluntary basis of participation. Contact details to the PI, the KI Data Protection Officer and the Swedish Data Protection Authority are also provided. Patients consent to project participation, to medical records being collected and to have their data collected as described. There are no ancillary studies; all collected data are related to this project.

The intervention group receive LEAP in addition to standard outpatient care (TAU) running in parallel, while the control group receive only TAU. Standard outpatient care includes a medical contact, psychoeducation about EDs, in most cases a CBT-based treatment via a personal therapeutic contact and/or group therapy, and meal-support. Everyone has a personalized treatment plan. There are no systematic interventions focusing on pathological exercise in TAU, which means that TAU+LEAP will clearly deviate from standard care.

The LEAP intervention begins with an individual session where the intervention is individually conceptualized, assumed to increase personal relevance and motivation. All group sessions begin with an opportunity to raise questions and homework is always followed up. Participants are continually reminded of the importance of actively participating in the session and the importance of completing homework tasks, self-monitoring and behavioral experiments. Potential obstacles are examined to improve adherence.

All patients receive individually personalized TAU. CE will not receive systematic attention since this is not standard practice. However, the attention given to exercise as a symptom may vary between therapists. Thus, to control for potential deviations from standard practice in this regard, both study and control participants will answer questions about treatment content at the last assessment point, that is, questions about the content of their treatment including how much attention has been given to pathological exercise, if so, in which ways. Additionally, LEAP therapists are encouraged not to have LEAP participants (neither controls nor study) in individual treatment. However, due to smaller unit size for three of four units, there might be violations to this guideline. If so, LEAP therapists are instructed to have equal numbers of intervention and control patients in individual treatment.

Most participants are expected to remain within their TAU after project participation, however, no ancillary or post-trial care is expected due to project participation. All participants are covered by the KI insurance and a patient injury insurance (‘Patientskadeförsäkring’), covering compensation for those suffering potential harm from trial participation.

Participants come to the clinic via clinical or self-referral. Within the first three visits, they are assessed using standardized diagnostic interviews, clinical rating scales, and self-report questionnaires. Eligible patients will be asked if they are interested in study participation by clinicians on participating units. Those who are interested will be contacted and formally recruited by the project manager or assistant. They are provided a link to BASS for study consent and the first assessment battery which can be completed directly. Afterwards, they are allocated to either control or intervention group. All participants continue TAU independent of group allocation; for those in the intervention group, LEAP starts when there are enough allocated patients (> 4 patients). After consent, study timeline is at minimum 182 days (three assessment points 90 days apart). Most participants in the intervention group will complete the LEAP program prior to T2 assessment, but due to variation in patient influx at units, some may instead terminate LEAP prior to T3. Participants are no longer included in the study after completed 6-month assessment (T3).

Based on pilot data and power analysis with beta = .80, alpha = .05, effect size f = .25 and an estimated correlation between pre- and post-measures of .50, a total of 98 patients are required: 49 patients receiving LEAP and 49 controls. With an estimated drop-out rate of 30%, we will enroll 128 participants (64/arm). As there is a minimum of 4 participants in a LEAP group, length of time between initial assessment and first session of LEAP will vary for patients. This variation will need to be considered a covariate.

Patients are recruited at the four participating units. All clinicians at each unit are informed about the project and eligibility criteria and will help identify potential participants; the two LEAP therapists and/or dedicated research managers at the units are formally responsible for recruitment. Eligible patients will be informed about the study; advertisement material is also visible in waiting rooms and from clinicians. To reduce waiting time between recruitment and intervention start, participating units will identify as many potential participants as possible (ideally > 10 patients) prior to asking for participation interest. Upon interest, research contacts at each unit provide contact details to the PI or PC, who will then give oral or written study information to potential participants and provide the link for study consent and first assessment. Non-sensitive personal data (age, gender) for declining participants are collected. Pace of recruitment depends on patient influx on units. One group at a time per unit can be held with a maximum of two groups per semester. With a minimum of four participants per group, each unit could potentially include 16 LEAP participants per year. With four units, the participation goal would then be met within 12 months if equally many control participants are recruited. However, due to covid-19 restrictions, patient influx, and the randomization, a conservative time estimate for inclusion is 24 months (spring 2021 – summer 2023). Status of recruitment is monitored at least monthly with participating units through phone calls and/or e-mails.

Each eligible patient consenting to participate will be assigned experimental condition using an online random number generator, stratified by site. An allocating investigator (AI) performs the randomization procedure and inform LEAP-therapists and participants. The AI is the only person with access to randomization group data.

Participants and clinicians cannot be blind to group, since LEAP deviates too much from standard ED treatment. However, the PI will not have access to randomization group data until after the main treatment effects have been analyzed. Most assessments are self-report, but clinicians conducting diagnostic pre- and post-assessments are blinded. The LEAP therapists do not conduct assessments, neither do the PI or PC.

Participant retention is promoted by several strategies. Consenting and completing baseline measures through BASS is simple, works on several devices and can be completed at any time of the day. As few measures as possible are used so that assessments consume as little time as possible. Participants assigned to LEAP are given increased attention which is usually regarded as positive. It also begins with an individual session where the intervention is individually conceptualized, assumed to increase personal relevance and motivation. All participants are rewarded with gift cards after completed T2 and T3 assessments. A total of three reminders for late individual assessments are sent automatically every third day, all reminders include a link to BASS. Participants not responding to reminders will then be contacted by project managers. Retention in the LEAP intervention is managed locally at each unit.

Personal data (name, contact details) needed for study informing are stored locally at participating units in secure research registries. It is transferred regularly to project managers by phone and entered into a registry. Medical record data are transferred to project managers by phone, matched to the correct patient ID (created within BASS upon study consent) and entered into a separate dataset. Recruitment and intervention data (non-sensitive personal data (age, gender) for declining participants; intervention related process data) are stored locally at participating units in secure research registries and transferred to project managers after project termination. Survey, interview, and assessment related data are stored securely within BASS during the project time; only the project managers and BASS Data Base Administrator (DBA) have access to the database and activity within BASS is logged. After project completion, data will be exported into a separate dataset excluding personal data and deleted in BASS. Overall project management data are entered into a research registry at Karolinska Institute. Here, number of participants in each condition is entered as well as information on number of participants, dates, and LEAP therapists for each intervention group at participating units; no personal data are entered here. Allocation information including personal data and group is entered into a dataset by the AI and communicated to research contacts at each unit and the participants by phone. All these registries and datasets are stored on a secure server on Karolinska Institute (P-disc under DATA). After study completion, a pseudonymized master datafile will be compiled and stored on the secure KI server (P). A code key matching social security number and patient ID (retrieved from BASS) will be created and stored securely on an encrypted USB-stick in a fireproof safe separate from other data. All other registries containing personal data are destroyed. After project termination, the master datafile will be stored within the KI system for research documentation (ELN) along with the list of variables and related publications. Long-term storage of data follows the KI Archive Act.

All data are kept confidential through the pseudonymized patient ID. During the project time, all project related data that can be connected to individual participants are stored securely at participating units and KI with limited access. The code key matching social security number and patient ID is encrypted and stored securely separate from other data. Analyses will only be performed in pseudonymized datasets.

Only the PI and PC have access to the registries kept during the project time on the secure KI server (P) (except allocation information). After project termination, only the PI and PC has access to the master datafile and code key. Selected data may be shared within the project group trough secure transfer for project related research. The PI determines the appropriateness of such research questions and only permits data access if they are clearly project related and covered by ethical permits.

To evaluate the LEAP treatment effect (primary objective) the data will be analysed per protocol and based on intention to treat. The first analysis will include all controls (TAU) and participants that complete the program (LEAP+TAU) and answer the questionnaires. The T3 assessment point will be used for post treatment data unless the participants completed the program before T2. Each continuous outcome measure will be used as a response variable in a linear regression model with group allocation and baseline value as predictors. Logistic regression will be used for categorical outcomes. Additional covariates in the models will include gender, clinic, and time between T1 and first treatment session. Since the removal of drop out and noncompliant subjects in the per protocol analysis may lead to overestimation of the treatment effect, we will also perform the same analysis on the basic of intention to treat. Here all subjects who were randomized to LEAP and answered the questionnaires will be included in the treatment group, independently whether they participated in the LEAP sessions. Assessment points with at least CET and EDE-Q will be included in analyses in relation to the primary outcome. If data is missing on CET and/or EDE-Q, the timepoint will not be considered for analysis. There will be no item level missing data (technically prohibited in BASS). The percentage of patients withdrawing from the program despite the initial intention to participate will be considered as a feasibility marker. To compare proportions of dropout and loss to follow-up within the groups, conventional two-sample Z-tests will be used. To identify prognostic factors associated with a good response to LEAP (secondary objective), the treatment group will be subjected to additional analysis where the outcome of interest is used as response variable in linear or logistic regression model and potential prognostic factors (e.g., BMI, type of ED) are used as predictors. These analyses will include all participants with complete data for each specific model.

As the intervention has a short duration and minimal known risks, there is no need for a formal data monitoring committee or interim analyses. The principal investigator and project coordinator keep close contact with all participating units and any issues regarding recruitment, intervention, and project overall will be managed continuously. The principal investigator and project coordinator also continuously monitor the project progress and project data (i.e., its completeness and accuracy), and if necessary, consult others in the data management group.

No harms are expected through participation. However, LEAP participants sacrifice time and energy to take part in a treatment program with uncertain benefits while individuals randomized to control group may be disappointed that they will not receive LEAP. Further, although self-rating symptoms as all participants do through BASS is unlikely to be harmful, it may raise concern. Therefore, in all stages of data collection (in visible materials, in BASS, etc.), contact details to the PI are provided, encouraging participants to contact her in case of questions or concerns. Both PI and PC are clinical psychologists and clinicians and/or participants can contact any of them for guidance if needed. As LEAP is delivered in groups, sensitive information might be shared, why the therapists need to make sure that in the first session of every new LEAP group that all participants agree upon a code of conduct. All LEAP therapists are experienced clinicians at the units where participants have an active treatment. Thus, if adverse events arise, participants have access to care and can be monitored. LEAP therapists are also instructed to register any issues related to the LEAP intervention groups, including potential adverse events. This is reported to the PI and managed with appropriate actions.

No formal auditing is included in the project.

Modifications in the protocol are communicated to participating units (i.e., LEAP-therapists, research staff; managers, other staff when necessary). Minor modifications may be communicated via e-mail to those concerned, other modifications are communicated through meetings. For significant modifications related to the participants (e.g., eligible criteria, recruitment, assessment, intervention, etc.) or other significant changes, amendments to the ethical permit are applied for. Major modifications (e.g., delays due to covid-19) are also reported to financers and updated in the ISRCT registry.

Trial results will be published in peer-reviewed psychiatric journals, preferably Open Access to enable wider dissemination. Results will be presented for staff at participating units, to other health-care professionals (e.g., through interest organizations, at research conferences). Results may also be promoted by a public press release and posts on social media. The PI (EFM) is main or senior author, the PC (EM) is co-author on all manuscripts from the project, and the LEAP originator CM is expert advisor. Other authors are based on manuscript contribution. The intervention manual will be available upon demand from the LEAP originator and the PI. Data will not be shared outside of the project group, but meta data will be available upon demand if ethical permits exist (e.g., for meta-analyses).

Everything is prepared for the study to commence. Collaboration with units is well established, procedures for data collection and recruitment procedures are finalized, and the LEAP training for therapists are completed. However, due to Covid-19 restrictions prohibiting non- essential group interventions at the clinics, recruitment has not been able to start yet. As Covid-19 vaccinations are currently initiated and restrictions possibly eased later on as a result, we plan to start recruiting during the late spring of 2021 with LEAP intervention groups starting as close to recruitment as possible.