Practical Application of Accelerated iTBS for MDD
Condition: Major Depressive Disorder; Major Depressive Disorder, Recurrent Episode, Severe; Major Depressive Disorder, Recurrent, Moderate
MeSH terms: Recurrence; Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional

Summary: 
      The goal of this observational study is to evaluate the feasibility and efficacy of
      accelerated iTBS in adults diagnosed with Major Depressive Disorder. The main question it
      aims to answer is:

      What is the efficacy and tolerability of an accelerated iTBS regimen without radiological
      imaging in adults who have been diagnosed with Major Depressive Disorder and experience
      treatment resistant symptoms?

      Participants will complete 36 iTBS treatments in an accelerated schedule over five days. They
      will also complete several clinical assessments throughout their enrollment to evaluate their
      depressive symptoms and response to treatment.
    

Detailed description: 
      The primary objective of this study is to demonstrate the preliminary effectiveness,
      tolerability, and feasibility of an accelerated, intermittent theta burst stimulation (iTBS)
      protocol for adults diagnosed with Major Depressive Disorder who are currently experiencing a
      Major Depressive Episode that does not rely on radiological imaging for the individualized
      targeting of desired treatment location of the dorsolateral prefrontal cortex and that is
      limited to 36 total treatments.

      The study will be performed at a single site, where MDD patients, if eligible, can be
      consented to participate. Prior to iTBS Stimulation the Motor Threshold (MT) will be
      established for each subject individually. Each subject will be evaluated for 5 days during
      their iTBS treatment protocol and at 4 weeks post-treatment. The total study duration is
      expected to be approximately 8 months depending upon enrollment rate. The study consists of 8
      visits. Each subject will be treated with an accelerated iTBS regimen for 5 days. This
      consists of 6-8 daily treatments which begin at 60-minute intervals for a total of 36 total
      treatments.

      Visit 1 for subject intake with study physician. Visit 2 will consist of the establishment of
      baseline ratings. During visits 3-7 subjects will receive study protocol iTBS treatments.
      Visit 8 will be at 4 weeks post-treatment and will consist of administration of assessments.
      Study visits on treatment days are estimated to take between 5-7 hours depending on the day.

      The Beam F3 System will be used to target the desired F3 location of the International 10-20
      System. These coordinates are used to triangulate the desired treatment site on each patient
      on the first day of treatment and are saved for further treatments.

      A Neuronetics NeuroStar XPLOR System version 3.6 will be used to deliver iTBS therapy. This
      consisted of 20 cycles of 5 bursts of 3 pulses at 50 Hz every 200 msec delivered in 2 second
      trains with an 8 second interval. Treatment sessions will be delivered hourly. Six or Eight
      sessions will be applied per day (3,600/4,800 pulses/day) for 5 consecutive days (21,600
      pulses in total). Stimulation will not exceed 120% rMT.

      Evaluations will consist of the Patient Health Questionaire-9 (PHQ-9), Quick Inventory of
      Depressive Symptomology (QIDS) Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton
      Depressive Ratings Scale (HAM-D). The primary endpoint is Change in MADRS scores from
      baseline to 4 weeks post treatment. Secondary endpoints include changes in the scores of all
      evaluations from baseline throughout the study. Response and remission rates will be
      calculated using both the MADRS and HAM-D at both the end of treatment and 4 weeks post
      study.

      Staff handling data are trained in secure handling of Protected Health Information. Multiple
      layers of physical access will be employed, including individually assigned access cards and
      locked filing cabinets. Electronic records may be captured on the Sonder Wellness HIPAA
      compliant EMR database, Sonder Wellness managed and compliant shared network drive with
      controlled access to research staff, and/or a Sonder Wellness approved and secured external
      drive. All study data will exclusively use a de-identified code. Participant identifiers and
      corresponding code will be limited to key documents and maintained separately from the study
      data. Data will be collected and stored at a single site. Paper data will be stored on-site
      and electronic data on Sonder Wellness servers. Only Sonder Wellness research staff will have
      access to identifiable information. Data will be de-identified for affiliate analysis or
      summary reporting. No specimens will be collected or transported.

      A sample size of 20 total subjects was selected as sufficient to perform a preliminary
      assessment of the effect size. The sample size is not based on formal power requirements for
      a statistical hypothesis test but is based on a desire to obtain a reasonable initial data
      set for exploratory and planning purposes.

      All statistical analyses will be performed using SAS® version 9.4 (or higher). The full
      analysis set (FAS) will include all subjects who receive at least thirty treatment sessions.
      The FAS will be used for analyses of all efficacy outcome measures. The Safety population
      will include all subjects who receive at least one treatment session. This population will be
      used for demographic & Baseline characteristics and Safety outcome measures.

      For efficacy endpoints, the Tables, Listings and Figures analysis and reporting will be
      performed on FAS population. A subject level listing will also be provided for each of these
      efficacy outcome MADRS, HAM-D, QIDS-16 and PHQ-9 separately presenting total score and each
      subscale score by different visits.

      The primary endpoint of change in MADRS total score from baseline to 4 weeks post treatment
      will be analyzed using paired t test or Wilcoxon signed rank test. Mean change with the
      associated standard error and 95% CIs for the change will be presented along with the
      p-value.
    

Intervention name(s): NeuroStar TMS
Intervention type(s): Device
Intervention description(s): NeuroStar TMS treatment - 90-120% of Observed MT, 3 pulses/burst, 5 bursts/sec, 2 sec stimulation, 20 msec interval, 20 trains, 600 total pulses/session for 36 treatments in 5 days. 6 treatments on day 1, 8 treatments on days 2, 3, and 4, 6 treatments on day 5.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: rTMS; Depression; MDD; TMS; iTBS; Accelerated; Theta Burst