Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04197765 |
| Other study ID # |
19-001320 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2020 |
| Est. completion date |
June 1, 2025 |
Study information
| Verified date |
May 2023 |
| Source |
University of California, Los Angeles |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This is a pilot study to analyze the benefit of accelerated continuous Transcranial magnetic
stimulation for inpatient subjects suffering with suicidal ideation. This study will enroll
40 inpatient subjects recruited from the Resnick Neuropsychiatric hospital. Subjects will be
blinded and randomized to active or sham TMS treatment and will receive up to 5 assigned
treatments per day. Subjects will also be asked to complete mood surveys throughout their
participation. Participation in this study will last 7-10 days depending on scheduling.
Description:
1.0 SPECIFIC AIMS
Suicide is a leading cause of death worldwide. In the United States, someone commits suicide
every 13 minutes. Few treatments exist apart from in-patient hospitalization, medication, and
psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is an efficacious
treatment for major depressive disorder (MDD), and may hold therapeutic potential for
suicidality, specifically. Novel treatment methods including accelerated theta-burst
stimulation (aTBS) allow compressed treatment times and courses, making aTBS ideally suited
to an inpatient environment.
In the accelerated continuous theta-burst stimulation for suicidal inpatients (ACT-SI) pilot
study, our objective is to examine the feasibility and therapeutic benefit of adding
accelerated cTBS to the right orbitofrontal cortex (R-OFC) to standard inpatient treatment in
a proof-of-concept, open-label feasibility study. The hypothesis for this study is that
active acTBS will be well-tolerated, and lead to a decrease in suicidal ideation over four
treatment days.
2.0 RATIONALE
Suicide is a leading cause of death worldwide. Completed suicide significantly, and
negatively, affects the individual's family unit, community, and society. Research examining
risk factors suggest access to lethal means, accompanied by a specific intent and plan remain
significant indicators of acute risk, while a history of suicidal and parasuicidal behaviors,
mental health diagnosis (in particular depression), male gender, and history of abuse are
common static risk indicators. Psychiatric and legal interventions, including inpatient
admission, typically focuses on limiting access to lethal means, and blunting the effect of
life stressors, to the greatest extent possible.
Acutely suicidal patients may remain involuntarily on an inpatient unit to receive
psychiatric treatment. Nonetheless, little is known about the best methods to treat
suicidality. Clinicians may combine psychotherapy with medication to treat depressive and
other underlying psychiatric disorders, but treatment can be lengthy, often obviating full
treatment courses in the inpatient setting. Acceptable, efficacious, and efficient
interventions, suited to brief inpatient stays are sorely needed.
Repetitive transcranial magnetic stimulation (rTMS) is one form of non-invasive brain
stimulation (NIBS) that has demonstrated efficacy in the treatment of depression and some
evidence of efficacy for suicidality. FDA approved treatment for major depressive disorder
(MDD) typically involves a single session of high frequency (10 Hz) stimulation delivered to
the left dorsolateral prefrontal cortex (L-DLPFC), lasting 37.5 min a day over several weeks.
Research suggests that longer treatment courses may be associated with improved response,
remission, and time to relapse. More recently, the FDA approved theta-burst stimulation
(TBS), a novel approach requiring 1-3 minutes of treatment per day. Evidence suggests TBS and
conventional high-frequency treatment are equivalent in efficacy5. TBS could therefore
abbreviate treatment time, enhancing the capacity of an overburdened healthcare system.
Some investigators have also examined the efficacy of rTMS and TBS delivered in an
"accelerated" fashion. In this approach a patient receives several sessions (ranging from
2-5) a day with the aim of compressing overall treatment length. Preliminary evidence
suggests accelerated TBS (aTBS) may improve suicidal ideation4,8,9 apart from its
antidepressive effects8.
TBS is arguably uniquely suited to acceleration, as briefer stimulation sessions allow
additional sessions per day, without significantly increasing burden of care. TBS may also
have a more favourable safety profile than conventional rTMS10. Moreover, TBS studies in the
motor cortex demonstrate a more robust post-stimulation effect on cortical excitability than
conventional rTMS. Whether these effects translate into greater therapeutic gains, however,
remains undetermined. It was shown that accelerated intermittent TBS (aiTBS) produced an
antisuicidal effect in medication-free, treatment resistant depressed outpatients. In their
study, there was no separation from sham control, however, the study sample was small, and
lack of statistical power along with a high placebo response rate could account for the lack
difference observed.
Although most accelerated protocols target the L-DLPFC using excitatory stimulation (i.e.
high-frequency, or intermittent theta-burst stimulation [iTBS]), some literature suggests
inhibitory rTMS (1 Hz) delivered to the right orbitofrontal cortex (R-OFC) can improve
depressive symptoms in those who failed to respond to standard rTMS approaches. Continuous
TBS (cTBS) is known to have inhibitory properties15 but unlike standard 1 Hz protocols, can
be delivered in under 1 minute. Given its inhibitory properties, and brief administration
time, it may be possible to increase stimulation intensity beyond 120% motor threshold,
potentially enhancing therapeutic effect, without decreasing tolerability.
To date, the has not been a study that has examined the feasibility and clinical effects of
daily R-OFC accelerated cTBS (acTBS) on suicidal ideation in the inpatient setting. This is a
proof-of-concept, randomised, sham-controlled pilot study to examine the feasibility
(recruitment, retention, tolerability) and clinical effects of acTBS on suicidal thinking in
adults admitted to the inpatient unit for suicidality.
3.0 METHODOLOGY
Study Design. The aims to recruit and randomize 40 inpatients (18-65y) with "suicidality" as
a reason for admission at the Resnick Neuropsychiatric Hospital to receive: a) active acTBS
of the R-OFC or b) sham acTBS of the R-OFC as an add-on intervention to standard inpatient
treatment.
Study Specific Endpoints.
Subjects will be involuntarily withdrawn if they experience worsening depression, defined as
an increase in IDS-Self Report from baseline of more than 25% during two consecutive
assessments, or worsening active suicidal intent, defined as an increase in Suicidal Ideation
Attributes Scale of 25% or more over two consecutive assessments, or attempted suicide. In
addition, missing more than 10% of treatment sessions consecutively (i.e. 2 sessions in a
row) or 20% (i.e. 4 sessions) over the study period will also result in study
discontinuation. Subjects will also be withdrawn if they are not compliant with
study-specific requirements or if they experience a TMS-induced seizure.
Recruitment. Uo to 40 subjects will be recruited from the psychiatric inpatient unit at the
Resnick Neuropsychiatric Hospital. Inpatient psychiatrists will refer patients with MDD and
suicidality for a 1-hour consultation with Neuromodulation division staff to determine
eligibility. If suitable, staff will offer patients an opportunity to participate, and
initiate the consent process.
The inpatient team treating the potential study participant will initiate the recruitment
process, however, they will not obtain consent. Treating team members may provide potential
Subjects with a study brochure to provide them more information. They may identify potential
research subjects and obtain verbal permission from these potential subjects for a member of
the research team to approach them. Research team members will contact potential subjects
interested in hearing more about the study to initiate the informed consent process.
Research team members will offer all eligible inpatients the option to participate.
Participation will be voluntary, and based on informed, capable consent. The decision to
participate will not affect an inpatients' receipt of treatment or clinical services at the
Resnick Neuropsychiatric Hospital. Research team members will inform subjects that they may
terminate their participation at any time, without consequence.
Randomization. Subjects will be assigned to a group (sham versus active) randomly by a
computer-generated, block-permutation scheme managed by a study team member not directly
involved in study assessments or treatment. This person will inform the study technician of a
unique participant code that, when entered into the Magventure stimulator using its research
interface, will direct the technician to use one side or another of the coil - thereby
determining whether the patient receives sham or active treatment - without the technician
knowing which side corresponds to which treatment arm.
Blinding. Only the study team member responsible for randomization will know each
participant's group assignment (sham versus active) for the duration of the trial. Subjects,
psychiatrists and technicians delivering acTBS will not know which treatment subjects
receive. At the end of all treatments, the study team will ask subjects if they believe they
received active or sham treatment. The study team members will also write down whether they
believe study subjects received sham or active treatment.
Motor Threshold (MT).
On the first day of stimulation, the study psychiatrist will explain the process of motor
threshold determination, provide a single test pulse to the patient's forearm to demonstrate
the sensation of TMS, and proceed to determine each patient's unique motor threshold using
single-pulse TMS. Starting with the magnetic coil tangential to the scalp, at 45 degrees to
the midsagittal line, the psychiatrist will deliver suprathreshold single pulses to the motor
cortical area corresponding to the abductor polllicis brevis (APB) to initiate visible thumb
deflections. The MT is the percentage of stimulator output necessary to cause a thumb
deflection in 5 out of 10 trials. This process typically takes approximately 10-15 min and
serves to titrate stimulation intensity for the whole of the treatment course.
Stimulation Procedure.
The Magventure Therapy System will be used to administer treatment. The Magventure Therapy
System (Model r30) is FDA-approved for Major Depressive Disorder and peripheral stimulation.
Subjects will receive up to five sessions of acTBS daily, on consecutive weekdays. Subjects
will be escorted from the inpatient unit to the TMS suite where a technician will greet them,
and set up the stimulation sessions. Subjects will sit comfortably in a semi-reclined chair
for the duration of each session. A Magpro X100 will be used for all study-related TMS
procedures, coupled with a CoolB60 A/P treatment coil which allows administrators to deliver
both active and sham treatment depending on the orientation of the coil.
Sham stimulation mimics both the auditory (a clicking noise) and somatosensory experiences
(i.e. tingling sensation on scalp through electrodes that deliver suprathreshold stimulation
with each TMS train) associated with receiving active TMS. Prior research suggests that
treatment-naïve subjects (and at times study personnel who have received true TMS in the
past) are unable to distinguish sham from active TMS using this arrangement.
Accelerated Continuous Theta-Burst Stimulation (acTBS). Between 20-30 treatment sessions will
be administered over the course of the study. The study technician will place the coil over
the Fp2 electrode of a 10-20 International EEG system hair net, to approximate stimulation of
the R-OFC). For the first three treatments, the study psychiatrist will set treatment
intensity to 90% MT, and gradually increase intensity to 120% MT over 20 seconds to maximize
tolerability. Subsequent treatment sessions (treatment 4 and onward) will begin, and remain,
at 120% MT.
Treatment will occur 4-5 times a day, separated by an at least 45-min interval between
sessions on consecutive weekdays. It is estimated that all study-related treatments will be
complete in 5-6 weekdays.
Justification for acTBS versus the standard of care for MDD
Though standard rTMS treatment consists of daily sessions of 75 cycles of 4 seconds of 10Hz
stimulation followed by 26 seconds of rest over 4-6 weeks, this approach is impractical for
typical lengths of stay of 5-10 days. By contrast, our experimental acTBS approach will
enable us to compress 20-30 treatments into 4-6 days, enabling inpatients to receive a full
course of rTMS add-on therapy without lengthening conventional inpatient stays. Accelerated
protocols documented in the literature are well-tolerated.
This experimental approach will differ from published accelerated approaches in that it will
use acTBS rather than high-frequency or iTBS treatment. This choice could theoretically
enhance tolerability and safety as acTBS is generally thought to be inhibitory in nature, as
opposed to both high-frequency and iTBS paradigms. Should this approach prove beneficial in
mitigating symptoms of suicidal ideation as indexed by the SIDAS, it may result in the
identification of a tolerable, and efficacious augmentation strategy to standard inpatient
care.
Potential Side Effects. During the consent process, the study psychiatrist will review common
side effects and potential adverse events associated with receiving single-pulse and
repetitive-TMS.
Subjects who receive TMS using the Magventure Therapy System are subject to the same risks as
FDA-approved Clinical TMS treatment. Generally, TMS is considered safe and well-tolerated.
However, it can cause some side effects. They may include headaches, scalp discomfort at the
site of stimulation, tingling, spasms or twitching of facial muscles or lightheadedness.
Unlike electroconvulsive therapy (ECT), TMS is unassociated with any cognitive impairment. On
the contrary, people receiving TMS generally demonstrate improved clarity of thought and
memory on post-stimulation cognitive tests. Serious side effects are rare and may include
seizures, mania particularly in people with bipolar disorder or hearing loss if there is
inadequate ear protection during treatment.
Subjects who receive single pulse TMS using our research or clinical device may experience
discomfort from the individual or paired pulses and/or a minor muscle twitch during the
pulse. There is no risk of seizure with single pulse TMS.
Risks. Individuals studied in this project will be, by definition, experiencing suicidal
thoughts and/or have acted on these thoughts prior to admission In the event that the study
team grows concerned about worsening suicidal ideation (as defined in study endpoints), the
inpatient treatment team will be notified and study participation terminated.
Subjects may experience psychological discomfort by completing questionnaires about their
mental health and suicidal ideation.
Participation in this research may also expose patients to potential breaches in
confidentiality and privacy. Every effort will be utilized to guard patient information
within the limits of the law. By assigning a research ID that is assigned to study-related
data, the code to which will be kept in a locked cabinet, in a locked office, to which only
study personnel have access.
The primary risk of this treatment protocol is the potential for lack of clinical
improvement. Subjects may suffer some fluctuation or worsening of symptoms during treatment.
As a safety precaution, participant's symptoms will be monitored during their treatment.
Seizure Risks:
Generalized seizures have been reported with the use of rTMS in the clinical trial
literature. The estimated risk of seizure under ordinary clinical use is approximately 1 in
30,000 treatments (0.003% of treatments) or 1 in 1000 patients (0.001% of patients).
Suicide Individuals with the conditions being studied in this project will, by definition, be
at risk for suicidal thoughts or actions. In the event that they tell the research staff that
they are thinking about killing themselves or answer 'yes' to a question about having
thoughts of suicide, the investigator will ask them additional questions about these
thoughts. Depending on how intense these thoughts are or how much they feel like harming
themselves or others, the research staff may contact their inpatient physician to discuss
these thoughts of self-harm. The investigator will proceed with the Suicide protocol by also
reporting to the IRB and all other necessary entities.
Benefits Individual. Individuals participating in the study will receive all acTBS treatments
gratis, and may experience improved mood and suicidality as a result.
Society. The results obtained may identify a more efficient and effective TMS treatment for
MDD, particularly for those hospitalized for suicidal ideation and actions.
