Portable Transcranial Electrical Stimulation and Internet-Based Behavioral Therapy for Major Depression Study
Condition: Major Depressive Disorder; Unipolar Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional

Summary: 
      First-line treatments for major depressive disorder (MDD), antidepressants and psychotherapy,
      are associated with refractoriness and discontinuation due to side effects, and logistical
      burdens, respectively. In this scenario, transcranial electrical stimulation (tES) is
      nowadays considered effective and safe for MDD, albeit with a modest effect size, and also
      prone to logistical burdens when performed in external facilities. In this regard, clinical
      investigation involving portable tES (ptES), and the potentiation of ptES with
      remotely-delivered psychological interventions, have shown positive, but preliminary,
      results.

      Here, the investigators present the design and rationale of a single-center, multi-arm,
      randomized, double-blind, sham-controlled clinical trial with digital features, using ptES
      (ptES) and internet-based behavioral therapy (iBT) for MDD (PSYLECT). This study will
      evaluate the efficacy, safety, tolerability and usability of (1) active ptES + active iBT
      ("double-active"), (2) active ptES + sham iBT ("ptES-only"), and (3) sham ptES + sham iBT
      ("double-sham"), in adults with MDD, with a Hamilton Depression Rating Scale - 17 item
      version (HDRS-17) score ≥ 17 at baseline, during 6 weeks. No antidepressant washouts will be
      performed during the trial.

      Three co-primary hypotheses are presented: changes in HDRS-17 will be greater in (1)
      "double-active" compared to "ptES-only", (2) "double-active" compared to "double-sham", and
      (3) "ptES-only" compared to "double-sham".

      The investigators aim to enroll 210 patients (70 per arm). The results of this trial should
      also offer new insights regarding the feasibility and scalability of combined ptES and iBT
      for MDD, in the area of digital mental health.
    

Detailed description: 
      Major depressive disorder (MDD) is a prevalent, debilitating and chronic mental disorder,
      characterized by frequent recurrences and resistance to first-line treatments:
      antidepressants and onsite cognitive-behavioral therapy (CBT) are associated with
      discontinuation due to side-effects, and logistical burdens, respectively.

      Non-invasive brain stimulation techniques (NIBS), such as repetitive transcranial magnetic
      stimulation (rTMS) and transcranial electrical stimulation (tES) (of which the most widely
      studied format is transcranial direct current stimulation - tDCS), are considered safe and
      tolerable interventions for MDD. While rTMS is already approved by the FDA for MDD, it
      involves daily visits to external facilities and is costly.

      tES, on the other hand, albeit having failed to prove non-inferiority to a conventional
      antidepressant (escitalopram 20mg/day) in a previous trial, is less expensive than rTMS, and
      portable. Therefore, tES could be suitable for home-use under remote supervision by trained
      clinical staff, especially as an add-on intervention for MDD. In this scenario, recent pilot
      trials have suggested a possible combined effect of tES with psychological interventions,
      based on a mechanism known as "functional targeting", that is, using two or more
      interventions to engage the same brain area of interest.

      The PSYLECT study is a parallel, 3-arm, randomized, double-blind, sham-controlled,
      single-center clinical trial, with digital features, devised to assess the efficacy,
      tolerability, safety and usability of: (1) active portable tES (ptES) + active internet-based
      behavioral therapy (iBT) ("double active"), (2) active ptES + sham iBT ("ptES-only"), and (3)
      sham ptES + sham iBT ("double-sham"), for the treatment of MDD, in adults, during 6 weeks.

      The investigators will enroll 210 adult patients (70 per arm) diagnosed with MDD per DSM-5
      criteria, regardless of being in treatment with conventional antidepressants, to receive
      either: "double-active", "ptES-only" or "double-sham", during 6 weeks.

      The use of sham (placebo) is necessary in order to better estimate the combined active
      treatment effect, but patients will be invited to receive the active treatments at endpoint,
      in an open-label 6-week, crossover phase, if they were previously randomized to receive
      "double-sham", and did not display response at endpoint (defined ≥ 50% reduction in
      depressive symptoms). Furthermore, patients who were randomized to "double-active" or
      "ptES-only" and display response at endpoint, will be invited to participate in a maximum
      6-month open-label follow-up phase (including those patients that respond at the end of the
      cross-over period). However, participants who were randomized to "ptES-only", but do not
      achieve response, will not be eligible for open-label follow-up, as it is unlikely they would
      profit from a continuation.

      The study has received approval by the Ethics Committee of the University of Sao Paulo, in
      accordance with the Declaration of Helsinki guidelines. Prior to enrollment, participants and
      researchers will receive and jointly sign an informed consent document.

      In this study, 3 co-primary hypotheses are presented: (1) changes in depression scores in the
      Hamilton Depression Rating Scale 17-item version (HDRS-17), from baseline to endpoint, will
      be larger in the "double active" compared to the "ptES-only" arm; (2) changes in depression
      scores (HDRS-17), from baseline to endpoint, will be larger in the "double active" compared
      to the "double-sham" arm; and (3) changes in depression scores (HDRS-17), from baseline to
      endpoint, will be larger in the "ptES-only" as compared to the "double-sham" arm.

      The secondary hypotheses are that: (1) changes in depression scores will be larger in
      "double-active" compared to "ptES-only", in "double-active" compared to "double-sham", and
      "ptES-only" compared to "double-sham" arms, using additional depression-rating scales; (2)
      response (defined as ≥ 50% reduction in HDRS-17) and remission (defined as HDRS-17 ≤ 7) will
      be larger in "double active" versus "ptES-only", "double-active" versus "double-sham", and
      "ptES-only" versus "double sham" arms; (3) reduction in anxiety symptom scores will be
      greater in "double-active" compared "ptES-only", "double-active" compared to "double-sham",
      and "ptES-only" compared to "double-sham"; (4) the clinical usability of the "double active"
      protocol will be regarded as (very) easy by ≥ 80% of recipients, according to a Likert scale;
      (5) all three protocols will be equally safe and tolerable, according to the tDCS Adverse
      Events Survey.

      Prior to performing online home-based sessions, participants will receive proper onsite
      training with the ptES device and iBT app, and from then on, will have remote access to the
      investigators through a phone line and email for questions and management of adverse events.
      In this case, patients can be redirected to the research institution's clinical facilities
      (including its emergency departments), in case of clinical and/or psychiatric adverse events
      which are deemed to need onsite evaluation and follow-up. The aforementioned clinical
      facilities are situated at the Clinics and University Hospitals of the University of Sao
      Paulo, Brazil, which are, respectively, tertiary and secondary care centers, and reference
      public hospitals in the Sao Paulo city area.

      The ptES devices used in this trial are manufactured by Flow Neuroscience (Malmö, Sweden),
      and consist of a one-size-fits-all headset with circular electrodes, with the anode
      positioned over the left prefrontal cortex and the cathode over the right prefrontal cortex.
      The device comes with a set of 21 sealed, saline-humidified disposable sponges, an electrical
      charger, and has pre-set and fixed stimulation parameters. This device has been previously
      tested by the investigators in a computer-modeling procedure, with simulations displaying
      adequate electrical field strength and distribution in prefrontal brain areas of interest
      (ie, dorsolateral prefrontal cortex). Furthermore, the Flow device has been approved in the
      United Kingdom, European Union and Brazil (National Agency of Sanitary Vigilance, ANVISA),
      for home-use in patients with MDD.

      The investigators' team will consist of 2 separate groups: (1) unblinded "session
      supervisors", who will offer an initial onsite training session to participants and will be
      available remotely for supervised guidance for the following online home-based sessions; (2)
      blinded clinical evaluators, who will evaluate participants online weekly until study
      endpoint, while being able to refer patients to onsite evaluation, as deemed necessary.

      For data collection, the investigators will use REDCap (Research Electronic Data Capture),
      created at Vanderbilt University (Tennessee, USA) with NIH support. REDCap is a free-source
      software, that works in offline and online modes and runs on tablets, smartphones and
      computers, and was designed to build and manage online surveys and databases, replacing paper
      notebooks. It also has tools that allow dynamic data management and data quality examination.
      REDCap can be installed in a variety of environments for compliance with such standards as
      HIPAA, 21 CFR Part 11, FISMA (low, moderate, high), Brazlian regulations (LGPD) and
      international standards.

      Periodically, the data will be exported and saved offline in password-protected external HDs
      and flash drives. REDCap access will be restricted using individual usernames and passwords.
      No user will have permission to modify or export the data (except for generating security
      copies) during the trial. If data edition is necessary (e.g., incorrect input), a new data
      version will be generated. All changes in the data will be reported.

      For data management and quality control, the investigators hired an information technology
      (IT) specialist for technical support in the project. Data will be coded according to a
      previously developed data dictionary. Quality of data collection will be monitored by random
      data quality checks for consistency (e.g., depression scores compatible in different scales)
      and completeness (absence or few cases of missing data). The investigators will also have
      access to an online dashboard, that remotely monitors participant adherence to study
      protocol.

      If unblinding is necessary, the PI holds special codes for the procedure, while having to
      specify the reason for unblinding, which are: an increase ≥ 25% from baseline scores on the
      Hamilton Depression Rating Scale-HDRS (17-item version) on 2 consecutive clinical
      evaluations, development of suicidal ideation, serious clinical and psychiatric adverse
      events, development of hypo(mania) and/or psychotic symptoms, low adherence (missing 2
      clinical evaluations or failing to comply with at least 75% of tDCS sessions at home) or
      patient consent withdrawal.

      For the sample size calculations, baseline depression scores and standard deviation (SD) of
      25 (±5) on the HDRS-17 were used, distributed equally between groups, based on previous
      studies. Furthermore, the investigators consider that: (1) placebo effects in the double-sham
      arm will impact baseline depression scores equal to 1 effect size (ES) in SD units (ES =
      difference in mean change divided by SD); (2) the "ptES-only" arm will have the same placebo
      effects present in the double-sham arm (ES = 1), plus a treatment response of ES = 0.4; and,
      (3) the "double-active" arm will have placebo effects (ES = 1) plus a larger response of ES =
      0.8. Therefore, probable endpoint scores of 20, 18 and 16 were used, for "double-sham",
      "ptES-only" and "double-active", respectively. The effect sizes were also chosen based on the
      results from previous trials, and considering that tDCS and online behavioral therapies have
      small to moderate effect sizes.

      Sample size per arm was calculated based on the smallest detectable group difference (ES tDCS
      vs. combination = -0.4, ES sham vs. tDCS = -0.4). Significance levels were Bonferroni
      corrected for 3-way pairwise comparisons (α = 0.05/3) to control family-wise error rate,
      while still allowing for more anti-conservative adjustment in the final analysis. Dropouts
      were assumed to be monotonically increasing (Weibull) and equally distributed between
      treatment arms. The investigators obtained a total n = 210 participants, assuming a 10%
      attrition rate (therefore, 70 persons per arm).

      Results will be considered statistically significant if a two-sided p<0.0167
      (Bonferroni-corrected) is obtained. For the analysis of the co-primary outcomes, a linear
      mixed-effect model (LLM) will be employed, using a first order regressive covariance
      structure, which includes all observed variables without the need of imputing missing data.
      The dependent variable is score change on the HDRS-17. Independent variables are time (all
      observations until week 6), and group ("double-active", "ptES-only" and "double-sham"). The
      investigators will test the statistical significance between the pairwise comparisons per our
      primary hypotheses. The investigators will employ an intention-to-treat (ITT) approach. For
      the analysis of the secondary outcomes, linear mixed-effects models will be employed
      analogically to the analysis for the primary outcomes. Binary outcomes (response and
      remission) will be modeled using mixed logistic regression at each time-point. Improvement in
      other depressive domains will be evaluated using the same linear hierarchical models
      described.
    

Intervention name(s): Double Active: Active portable transcranial stimulation (ptES) and active internet-based behavioral therapy (iBT); ptES-only: Active portable transcranial stimulation (ptES) and sham internet-based behavioral therapy (iBT); Double-sham: Sham portable transcranial stimulation (ptES) and sham internet-based behavioral therapy (iBT)
Intervention type(s): Device; Device; Device
Intervention description(s): ptES is delivered by the Flow device (Flow Neuroscience, Malmö, Sweden), consisting of a one-size-fits-all, transcranial direct current stimulation (tDCS) headset with circular electrodes (area = 22.9cm2). The anode is positioned over the left prefrontal cortex, and the cathode over the right prefrontal cortex. Current strength is set at 2mA (current density = 0.087mA/cm2) for 30 minutes, daily for 5 continuous days (with a 2-day pause) for the first 3 weeks, with twice-weekly sessions for the following 3 weeks (total of 21 sessions in 6 weeks). Active iBT consists of a smartphone app with an electronic therapist-avatar. The iBT sessions are delivered concomitantly to the tDCS sessions (the tDCS device connects via bluetooth to the participant's smartphone app).; ptES is delivered by the Flow device (Flow Neuroscience, Malmö, Sweden), consisting of a one-size-fits-all, transcranial direct current stimulation (tDCS) headset with circular electrodes (area = 22.9cm2). The anode is positioned over the left prefrontal cortex, and the cathode over the right prefrontal cortex. Current strength is set at 2mA (current density = 0.087mA/cm2) for 30 minutes, daily for 5 continuous days (with a 2-day pause) for the first 3 weeks, with twice-weekly sessions for the following 3 weeks (total of 21 sessions in 6 weeks). The sham iBT sessions are delivered concomitantly to the active ptES sessions (the ptES device connects via bluetooth to the participant's smartphone app).; Sham ptES for this trial is delivered by the Flow device (Flow Neuroscience, Malmö, Sweden), consisting of a one-size-fits-all transcranial direct current stimulation (tDCS) headset, with circular electrodes (area = 22.9cm2). The anode is positioned over the left prefrontal cortex, and the cathode over the right prefrontal cortex. The sham protocol consists of a fade-in and fade-out phases of 1mA for 45 seconds, followed by a silent period in between for the remaining 28 1/2 minutes. The sham iBT sessions are delivered concomitantly to the sham ptES sessions (the ptES device connects via bluetooth to the participant's smartphone app).
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a multi-arm, randomized, double-blind, sham-controlled clinical trial with digital features, using portable transcranial electrical stimulation (ptES) and internet-based behavioral therapy (iBT) for major depressive disorder (MDD). The aims of this study are to evaluate the efficacy, safety, tolerability and usability of (1) active ptES + active iBT ("double-active"), (2) active ptES + sham iBT ("ptES-only"), and (3) sham ptES + sham iBT ("double-sham"), in adults with MDD, with a Hamilton Depression Rating Scale - 17 item version (HDRS-17) score ≥ 17 at baseline, during 6 weeks.
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: major depressive disorder; transcranial electrical stimulation; transcranial direct current stimulation; internet-based behavioral therapy; non-invasive brain stimulation; neuromodulation; home-use transcranial electrical stimulation