Clinical trial NCT03693105: The Effects of SAINT® Neuromodulation System on Explicit and Implicit Suicidal Cognition
Official title: A Multi-Site, Randomized, Double-Blind Trial Assessing The Effects of SAINT® Neuromodulation System on Explicit and Implicit Suicidal Cognition
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Major Depressive Disorder
Major Depressive Episode
Suicidal Ideation
Keywords: Suicidality
Neuromodulation
Transcranial magnetic stimulation
Depression
Intermittent theta burst stimulation
Lead sponsor: Magnus Medical
Sponsor class: INDUSTRY
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2018-10-02
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will receive either active or sham stimulation to the DLPFC. Patients will be randomized to either condition with a 50:50 chance.
Primary purpose: TREATMENT

Brief summary: This multi-site, double-blind, randomized, sham-controlled mechanistic trial aims to test the effects of Magnus Neuromodulation System (MNS) with Stanford Accelerated Intermittent Neuromodulation Therapy (SAINT®) Technology on the neural circuitry of suicidal cognitions in psychiatrically hospitalized patients with Major Depressive Disorder (MDD) and active suicidal ideation (SI). This will be accomplished by applying the MNS with SAINT to a customized target within the left dorsolateral prefrontal cortex (L-DLPFC) identified with fMRI for five consecutive days and measuring resting-state functional connectivity (RS FC) between the subgenual anterior cingulate cortex (sgACC) and the default mode network (DMN) at baseline and immediate-post visit. The relationship between changes in RS FC and changes in both Explicit and Implicit Suicidal Cognitions (ESC and ISC, respectively) will be determined. This study will also determine the relationship between changes in RS FC in neural networks underlying mediators of suicidal cognitions and changes in such mediators with active versus sham SAINT.

Detailed description: This multi-site, double-blind, randomized, sham-controlled mechanistic trial aims to test the effects of Magnus Neuromodulation System (MNS) with Stanford Accelerated Intermittent Neuromodulation Therapy (SAINT®) Technology on the neural circuitry of suicidal cognitions in psychiatrically hospitalized patients with Major Depressive Disorder (MDD) and active suicidal ideation (SI). This will be accomplished by applying the MNS with SAINT protocol (10 applications per day to a customized target within the left dorsolateral prefrontal cortex (L-DLPFC) identified with fMRI for five consecutive days) and measuring resting-state functional connectivity (RS FC) between the subgenual anterior cingulate cortex (sgACC) and the default mode network (DMN) at baseline and immediate-post visit. The relationship between changes in RS FC and changes in both Explicit and Implicit Suicidal Cognitions (ESC and ISC, respectively) will be determined. This study will also determine the relationship between changes in RS FC in neural networks underlying mediators of suicidal cognitions and changes in such mediators (i.e., depression, hopelessness, anhedonia) with active versus sham SAINT.

The mechanistic hypothesis is that active SAINT modulates RS FC underlying ESC (sgACC-DMN) and ISC (DLPFC-ACC) and that these changes in connectivity will correlate with reductions in ESC and ISC, respectively. MDD with current Major Depressive Episode will be defined according to DSM-5 criteria, and active SI will be defined by a baseline modified Scale for Suicide Ideation (M-SSI) score ≥ 9.

The primary objective is to determine if active versus sham SAINT aiTBS applied to the left dorsolateral prefrontal cortex (L-DLPFC)-subgenual anterior cingulate cortex (sgACC) is effective in modulating neural networks underlying explicit suicidal cognition (ESC) in psychiatric inpatients.

The secondary objective is to determine if active versus sham SAINT aiTBS applied to the L-DLPFC-sgACC is effective in modulating neural networks underlying implicit suicidal cognition (ISC) in psychiatric inpatients.

The tertiary objective is to determine if active versus sham SAINT aiTBS applied to the L-DLPFC-sgACC is effective in modulating neural networks underlying mediators of suicidal cognitions such as depression, hopelessness, and anhedonia.

The study will enroll approximately 100 participants and employ a two-arm design with 50 subjects per arm. The target population is adults of all genders and ethnicities who are between 18 and 75 years of age with a diagnosis of treatment-resistant MDD experiencing a current Major Depressive Episode, with active suicidal ideation, and who are otherwise in good general health. Participants must be without contraindications to Magnetic Resonance Imaging (MRI) or transcranial magnetic stimulation (TMS) and must be able to attend all study visits.

This study will deliver both active and sham SAINT via a MagPro X100 edition (MagVenture, Skovlunde, Denmark) TMS device equipped with a Cool-B65 A/P coil. The stimulation paradigm consists of 10 daily sessions (50 total over 5-days) of MNS with SAINT stimulation (3-pulse 50-Hz bursts at 5-Hz for 2-second trains, with trains every 10 seconds), delivered with 50-minute inter-session intervals (10-minute sessions, 50-minutes in between sessions). Stimulation will be delivered at 90% of the resting motor threshold (with depth correction to account for the distance between the scalp and cortex). An operator entered code (derived from the study EDC) will instruct the device to deliver active or sham magnetic stimulation.

Eligibility criteria: Inclusion Criteria:

1. Adults of all genders between the ages of 18 and 75 years at the time of screening.
2. Able to read, understand, and provide written, dated informed consent prior to screening.
3. Proficiency in English sufficient to complete questionnaires / follow instructions during fMRI assessments and aiTBS treatments. Stated willingness to comply with all study procedures, including availability for the duration of the study, and to communicate with study personnel about adverse events and other clinically important information.
4. Currently diagnosed with either Major Depressive Disorder (MDD) and meets criteria for a current Major Depressive Episode (MDE) according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5).
5. Medical records confirming a history of moderate to severe treatment-resistance as defined by a score of 7-14 on the Maudsley Staging Method (MSM).
6. Endorses clinically significant explicit suicidal cognitions (score ≥ 9 on the M-SSI and score ≥ 6 on the BSS self-report) at screening.
7. MADRS score of \>/=20 at screening (visit 1).
8. rTMS/iTBS naive.
9. Access to ongoing psychiatric care before and after completion of the study.
10. Access to clinical rTMS after hospital discharge.
11. In good general health, as evidenced by medical history.
12. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation.
13. Agreement to adhere to Lifestyle considerations:

    * Abstain from becoming pregnant from the screening visit (Visit 1) until after the final study visit (Visit 9).
    * Abstain from caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 3 hours before the start of each dosing session until after the final TMS session.
    * Abstain from alcohol for 24 hours before the start of each dosing session until after collection of the final MRI.
    * Participants who use tobacco products will be instructed that use of cigarettes will not be allowed during the trial.

Exclusion Criteria:

1. Females who are pregnant or planning to become pregnant during the course of the study or any female that is breastfeeding
2. The presence or diagnosis of prominent anxiety disorder, personality disorder, or dysthymia in which in the Investigator's opinion is predominant to MDD
3. Depressed mood/dysphoria as a result of an illness other than MDD (e.g. gender dysphoria)
4. Current severe insomnia (must sleep a minimum of 5 hours each night before stimulation)
5. Current mania or psychosis
6. Bipolar Affective Disorder I and primary psychotic disorders.
7. Autism Spectrum disorder or Intellectual Disability
8. A diagnosis of obsessive-compulsive disorder (OCD)
9. Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal.
10. Urine screening test positive for illicit substances.
11. Any history of ECT (greater than 8 sessions) without meeting responder criteria
12. No recent (during the current depressive episode) or concurrent use of a rapid acting antidepressant agent (i.e., ketamine or a course of ECT).
13. History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, brain tumor, unexpected seizure/epilepsy disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma.
14. Untreated or insufficiently treated endocrine disorder.
15. Contraindications to receiving rTMS (e.g., metal in head, history of seizure, known brain lesion)
16. Contraindications to MRI (ferromagnetic metal in their body).
17. Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with study results interpretation.
18. Treatment with another investigational drug or other intervention within the study period.
19. Depth-adjusted SAINT® treatment dose \> 65% maximum stimulator output (MSO)
20. Any other condition deemed by the PI to interfere with the study or increase risk to the participant.

Primary outcomes:
measure: Change in the neural network underlying Explicit Suicidal Cognition (ESC) as measured by resting state functional connectivity changes in subgenual anterior cingulate (sgACC) and the default mode network (DMN).
timeFrame: At baseline (day 0) and at post-inpatient treatment completion (day 2-7)
Secondary outcomes:
measure: Change in the neural network underlying Implicit Suicidal Cognition (ISC) as measured by resting state functional connectivity changes in dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC).
timeFrame: At baseline (day 0) and at post-inpatient treatment completion (day 2-7)
Other outcomes:
measure: Change in the neural networks underlying depression, hopelessness and anhedonia as measured by resting state functional connectivity changes of sgACC and medial orbitofrontal cortex (mOFC).
timeFrame: At baseline (day 0) and at post-inpatient treatment completion (day 2-7)
Locations:
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Manhattan
country: United States
facility: Weill Cornell Medicine
state: New York
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Austin
country: United States
facility: University of Texas, Austin
state: Texas
Study officials:
affiliation: Magnus Medical
name: Brandon Bentzley, MD
role: STUDY_DIRECTOR
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