Efficacy, Safety, and Acceptability of Internet-based Cognitive Behavioral Therapy

Overview

This is a prospective, randomized, multicenter, double-blind, placebo-controlled phase III trial evaluating the efficacy and safety of WL-iCBT - a smartphone-based digital therapeutic combining cognitive behavioral therapy and attention bias modification. The study enrolls 315 participants aged 18-60 with mild-to-moderate MDD (MADRS score 18-30) across 11 clinical centers in China. Participants will be randomized to receive either active WL-iCBT or placebo software for 8 weeks, followed by a 26-week observational extension phase. Primary endpoint is change in MADRS score from baseline to Week 8. Secondary endpoints include treatment response rate, remission rate, anxiety symptoms (HAMA), functional impairment (SDS), and cognitive function (PDQ-D), and Clinical Global Impression rating scale (CGI). Safety monitoring includes AE/SAE recording and device deficiency assessment. Acceptability will be assessed by device performance evaluation.

This investigation is a combined study that consists of an 8-week randomized controlled trial and a 26-week extended observational follow-up. It adopts a superiority design. Participants are stratified and randomly assigned in a 1:1 ratio. They are divided into two groups. One group is the active intervention group, which uses the WL-iCBT software. This software provides structured cognitive behavioral therapy (CBT) modules and attention bias modification training. The other group is the control group, which uses a placebo software. The placebo software has a matched interface but contains non-therapeutic content. The intervention protocol requires participants to have 56 sessions over 8 weeks. Each day, they have one session, and each session lasts for 10-15 minutes. To meet the requirements, participants need to complete at least 42 sessions. The blinding of the trial is maintained through identical device interfaces for both groups. The assessment timeline is divided into two phases. During the core treatment phase, which lasts from Week 0 to Week 8, assessments are carried out at baseline, Week 4 (±7 days), and Week 8 (±7 days). In the 26-week extended observation phase quarterly follow-ups are conducted for relapse monitoring and long-term safety assessment. There are key assessments in this study. The primary endpoint is the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to Week 8. The secondary endpoints include the MADRS response rate, which is defined as a ≥50% improvement; the MADRS remission rate, which means a score ≤10; changes in the Hamilton Anxiety Rating Scale (HAMA); functional improvement as measured by the Sheehan Disability Scale (SDS); clinician assessments using the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I); and scores on the Perceived Deficiencies of Depression Questionnaire (PDQ-D) for cognitive function. Safety monitoring is an important part of the study. All adverse events (AE) and serious adverse events (SAE) are recorded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 27.0. Device-related adverse events are also assessed. Thyroid function is monitored through measuring thyroid-stimulating hormone (TSH) levels, and suicide risk is tracked via Item 10 of the MADRS. The study population has specific characteristics. Participants are diagnosed with major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, which are confirmed by the Mini-International Neuropsychiatric Interview (MINI) 7.0.2. Those with treatment-resistant depression, those using psychotropic medications, and those with comorbid psychiatric disorders are excluded from the study. The statistical plan of the study involves a sample size of 315 participants, with 155 in each group, taking into account a 20% dropout rate. There are three analysis sets: the Full Analysis Set (FAS), the Per Protocol Set (PPS), and the Safety Set (SS). The primary analysis uses a mixed-model for repeated measures (MMRM) to analyze the change in MADRS scores, with a superiority margin greater than 0. This integrated design enables a comprehensive evaluation of both the acute therapeutic effects and the sustained outcomes while maintaining the integrity of the trial throughout the extended observation period.