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

Efficacy, Safety, and Acceptability of Internet-based Cognitive Behavioral Therapy Delivered Via Smartphone for Mild-to-moderate Major Depressive Disorder: a Multi-center, Double-blind, Randomized Controlled Trial

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.

Inclusion Criteria:

1. Voluntary participation in the trial with signed informed consent
2. Age 18-60 years (inclusive), any gender
3. Clinical diagnosis of Major Depressive Disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, confirmed by the Mini-International Neuropsychiatric Interview (M.I.N.I.7.0.2), with either single episode or recurrent episodes without psychotic features
4. Montgomery-Asberg Depression Rating Scale (MADRS) score ≥18 and <30 at screening
5. No antidepressant medication within 2 weeks prior to screening (6 weeks for fluoxetine), and assessed by the investigator as able to maintain without antidepressant medication during the trial period
6. Education level of primary school or above, able to understand the content of assessment scales, and proficient in using smartphones

Exclusion Criteria:

1. Current clinical diagnosis meeting DSM-5 criteria for psychiatric disorders other than Major Depressive Disorder (confirmed by M.I.N.I.7.0.2)
2. Treatment-resistant depression (defined as patients who failed to respond to adequate doses and duration (at least 4 weeks at maximum recommended dose) of 2 or more antidepressants with different chemical structures)
3. History of alcohol and drug dependence
4. Pregnant or lactating women, or men or women planning pregnancy during the clinical trial period
5. Current serious physical disease, thyroid disease (thyroid stimulating hormone (TSH) exceeding the upper limit of normal at screening), or patients considered by investigators to have hypothyroidism or hyperthyroidism (at the investigator's discretion, laboratory tests meeting exclusion criteria may be rechecked once within the screening period)
6. Obvious suicidal attempt or behavior, with a score ≥4 on item 10 "Suicidal Thoughts" of the MADRS scale
7. Patients who have received other antidepressant treatments within 3 months prior to enrollment, including Chinese herbal medicine, modified electroconvulsive therapy, transcranial magnetic stimulation, biofeedback therapy, light therapy, acupuncture, and other physical or systematic psychological treatments
8. Patients who explicitly express unwillingness to participate in psychological therapy or believe psychological therapy is ineffective
9. Patients who have participated in or are currently participating in drug clinical trials within 3 months prior to screening, or in other device clinical trials within 1 month prior to screening
10. Other conditions deemed unsuitable for enrollment by the investigator