Transdiagnostic group CBT vs. standard group CBT for depression, social anxiety disorder and agoraphobia/panic disorder: Study protocol for a pragmatic, multicenter non-inferiority randomized controlled trial

The current trial is an investigator-initiated, partially blinded, pragmatic, parallel, non-inferiority, multi-center randomized clinical trial (RCT). Two equally sized intervention arms, UP-CBT and STD-CBT, are compared. In total, we include 248 patients recruited from three Danish regional MHS. A CONSORT diagram is provided in Fig. 1. Data management is purely digital and is managed by a private enterprise, EasyTrial©, who also assists with randomization, treatment allocation and concealment.

The three Danish MHS clinics participating in the study conduct CBT groups for anxiety disorders and/or depression and have previously been engaged in clinical trials. Psychotherapeutic Clinic, Mental Health Centre Copenhagen is located in the inner center of the Capital, the Outpatient Clinics at Risskov Psychiatric Hospital is located in Aarhus, and Psychiatric Outpatient Clinic in Slagelse is located on the isle of Zealand. The number of attending patients and staff is lower at the Slagelse location, hence the sites contribute unequally to the trial. In total, 1400 patients with depression and 550 patients with relevant anxiety disorders attend the participating MHS clinics per year. The clinic in Copenhagen has piloted the UP-CBT as group therapy and two of the researchers have hands-on experience with group UP-CBT and training of UP-CBT therapists for the pilot trial.

We aim to include 248 patients that satisfy the inclusion criteria: (1) a principal DSM-5 diagnosis of DEP (single episode or recurrent) (app. 50%), SAD (app. 25%), and Ag/PD (app 25%), (2) age 18-65 years, (3) the patient is currently not using any antidepressants or use accepted antidepressants (according to a predefined protocol, available on request), which have been unchanged for at least 4 weeks before intervention onset and no change in antidepressants is anticipated, (4) sufficient knowledge of the Danish language. Patients will be excluded if (1) risk of suicide is high or moderate according to clinicians or assessment researchers, (2) they have alcohol or drug dependency, (3) they are diagnosed with a cluster A or B (DSM-5) personality disorder by intake clinicians or assessment researcher, (4) they have co-morbidity of pervasive developmental disorder, psychotic disorders, eating disorders, untreated attentional disorder, bipolar disorder, or severe physical illness, (5) they receive psychopharmacological treatments other than those predefined as acceptable, (6) they receive concurrent psychotherapy, (7) they do not accept to stop the use of anxiolytics within the first four weeks of intervention.

Patients are typically referred by general practitioners, when they have failed to respond to one or two different treatments (medication and/or psychotherapy). During intake, the patients will be evaluated by clinicians to be eligible for psychotherapeutic treatment in regional MHS as part of the standard procedure in the psychotherapeutic unit and they will be screened for eligibility according to the above described criteria. If patients are eligible for treatment, they will be approached for participation and provided with information about the project. Patients who cannot or will not participate in the study will be offered treatment as usual, i.e. group STD-CBT.

Patients who accept participation, will receive an invitation for further assessment using Mini International Neuropsychiatric Interview ((MINI, v 7.0 for DSM-5) and if eligibility is confirmed, informed consent is acquired. In the same consultation, supplementary baseline ratings and administration of the web-based patient questionnaires on stable patient characteristics, hypothesized to moderate outcome, are performed (see Table 2 for an overview of procedures and time points). Next, after randomization and blinding (see below), within 3 weeks of intervention onset additional baseline ratings are gathered by an outcome assessor making telephone-based interviews and encouraging the patient to answer the web-based outcome assessment questionnaires.

Randomization is performed in blocks of 4 participants, stratified by diagnosis and site, when 16 patients (8 with DEP and 4 with SAD and 4 with Ag/PD) are included (see study flow chart, Fig. 1). EasyTrial © perform the randomization and intervention allocation of study participants. Allocation to experimental intervention or comparison intervention will be computer-generated. In psychotherapy trials, therapists and patients cannot be blinded to intervention type. However, the researcher designated to report the main intervention effects (NR) will be blind to treatment allocation and will not participate in the treatment of study patients. As NR is the only Danish certified UP supervisor she is, however, in charge of UP-CBT training (see below) and continuous supervision of study therapists. The latter will be based on verbal report, and the therapists will be instructed to anonymize the patients in their reports (leaving out name, specific age and other identifiers). EasyTrial© is designed with several access layers, where the data administrators have full access to all data, researchers have access to entered information and treatment allocation, while outcome assessors and NR have limited access, only having lists with names of participants, their timelines and contact details. In this manner, outcome assessors and NR will be blinded to treatment allocation. Furthermore, outcome assessors and NR will not participate in any clinical routines in the clinic. The patients are asked not to discuss their therapy with the outcome assessors and they will not communicate with the therapists. Outcome assessors are asked to guess about treatment allocation after the interviews to be able to analyze possible bias.

For the statistical analyses of intervention effects, intervention type is concealed in the data extraction from EasyTrial©. The analysis of the primary outcome will be conducted with treatment allocation blinded. The intervention and control arm will randomly be coded as “A” and “B” and the deciphering will not be done before conclusions have been formulated based on these codes.

The experimental treatment, group UP-CBT, consists of 8 treatment modules delivered in 14 group sessions given weekly in 2 h sessions. The group manual has been modified from a Danish translation of the published UP for individual therapy [5, 13] and recommendations on group delivery from the UP Institute, Center for Anxiety and Related Disorders (CARD), Boston University. (personal communications) [22].

The SAD STD-CBT manual is based on the main principles described in the individual CBT manual by [35] and the PD/Ago STD-CBT manual is based on the principles described in the individual CBT manual by [36]. The manuals are adapted for use in Danish MHS settings and in groups. The two anxiety manuals are supplemented with frequently used Danish CBT handouts from [37, 38].

The DEP STD-CBT manual is based on a Danish group CBT manual for depression [39]. The manual has previously been used in research studies in Danish MHS [40], and is in line with the interventions described in an American manual [41]. In order to adjust the manual to the settings of group therapy in the TRACT-RCT, an individual group preparation session was added as well as 2 extra group sessions (session 7 and session 12). The work sheets added for these extra sessions are based on [37].

Treatment intensity (number and duration of group sessions) will be equal in both treatment arms. Psychiatric evaluation, extraordinary individual sessions and supplementary occupational counselling or physiotherapy are possible in both intervention arms.

Data are gathered through a number of ratings from patients, therapists and observers prior to inclusion, weekly throughout the intervention period, at the end of therapy, and at 6 months follow-up. An overview of assessment procedures is given in Table 2, and instruments in each category are detailed below. Outcome assessors are medical or psychology students, who will be certified in the use of relevant rating scales and will be trained to excellent agreement on the observer instruments by experienced psychotherapy researchers prior to inclusion start and with continuous monthly co-ratings and reliability assessments based on audiotaped interviews. Main outcomes are collected by outcome assessors along with patient self-ratings at end of the intervention and at 6 months follow-up. Every week, patients and therapists will fill out brief questionnaires immediately before and after the group session. If participants discontinue the intervention, we will attempt to gather all data, except those relating to intervention participation (session ratings, therapy evaluation), unless the patient explicitly denies participating in data collection (Table 3).

Sample size estimation is based on the primary outcome measure, WHO-5. In our initial naturalistic study of group UP, pre-treatment WHO-5 was 34.5 (SD 17.3) and end-of-treatment 44.8 (SD 17.4) (N = 46) (22). WHO-5 has a minimum clinical significant difference of 10 (Bech, personal communication, 2016). For non-inferiority trials, it is paramount to select a relevant limit for the possible difference in WHO-5 score that will lead to rejection of the hypothesis of non-inferiority [91]. We have set the limit to 9, i.e., one point below the minimum clinical significant difference. Alpha is set to 5% to avoid type I error, resulting in a 95% one-sided confidence interval for decision of non-inferiority. Beta is generally set to 0.1, i.e. a power of 90%. Applying end-point WHO-5 SD of 17,4 and limit of difference delta: 9 points, if UP-CBT is no less effective than TAU-CBT, 204 patients are needed (102 in each arm) to be 90% sure that the lower limit of a 95% one-sided confidence interval will be above the non-inferiority limit of - 9. Meeting the risk of drop-outs with an increase of 20% we will include 124 participants in each arm, in total 248 patients.

Main outcomes will be analyzed in an intention-to-treat (ITT) design, where we will use multiple imputations to handle missing data. All primary analyses will be adjusted for the stratification variables (site, diagnosis). We will use mixed regression analyses that will enable us to use all outcome ratings and enter separate levels for groups, therapists and clinical sites. For exploratory mediator analyses, we will use per-protocol data as well as ITT and both Autoregressive Cross-Lagged Modeling and Structural Equation Modeling [92].

The trial will be conducted according to national and international standards of good clinical practice. All participants will be provided with written and verbal information on the trial so that they can make an informed decision about their participation. Data will be collected and handled confidentially in accordance with the rules of the Danish Data Protection Agency. The protocol has been approved by the Ethics Committee Region Zealand (Registration number: 3084871-SJ-582) and the Danish Data Protection Agency Region Zealand (Registration number: REG-104-2016). Protocol amendments will be communicated at https://​clinicaltrials.​gov and detailed in publications. STD-CBT is considered an appropriate and ethically justified control group, as it is the recommended treatment for the target group prescribed by the Regional and National treatment programs in Denmark.

Waiting time to treatment may be slightly increased due to the project, as the UP-CBT groups reduce the number of patients available for the STD-CBT groups, but it is not expected to increase above the limit of the clinically acceptable.

We monitor for adverse events, in particular suicidal behavior/ideation. Change of medication or withdrawal from the study will be considered in case of increased suicidal ideation/behavior. First step of change in medication will, if possible, be dose increase of already instituted treatment. Next step will be to initiate or cross over to another type of medication according to a predefined protocol (available on request) established in accordance with the clinical guidelines in the participating clinics and the Danish Health Authorities. In case the responsible psychiatrist considers it necessary to initiate treatment with hypnotics or anxiolytics, it is possible to do so, within a limited dose range and according to a predefined protocol (ibid). If it is necessary to institute medical treatment, not listed in the predefined guidelines, the patient will continue in group therapy and in the trial, but the incident will be recorded as an important change of medicine and as an adverse event.

The first author, SMA, is principal investigator (PI) and initiated the project. Following a formal collaboration agreement between the participating regions, Region Zealand owns the data, and PI has the right to extract and distribute data to participating researchers. A steering committee consisting of the heads of the participating units, ensures the integration of the project with the day-to-day running of the units, while the scientific project group consisting of the authors of this protocol, headed by the PI, is in charge of scientific decisions related to design, data collection, data analysis and reporting and conducting the study in line with Good Clinical Practice guidelines. Signed contracts describe the rights of the involved young researchers as to writing up manuscripts and authorships. The study does not have a data monitoring committee, as allocation is not concealed for therapists.