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Unable to enroll the planned number of participants.
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Bipolar Disorder is a common condition that is characterized by periods of mood elevation however periods of chronic and recurring depressive episodes are more common and can be severely disabling. Effective treatments exist, however a significant portion of bipolar depressed patients do not respond to, or have difficulty tolerating many of these interventions. Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuromodulatory technique that is effective in major depression and there is evidence for its efficacy in bipolar depression which needs to be assessed in larger randomized controlled trials. This study is a randomised, double-blind, sham-controlled trial over four weeks. The primary objective is to assess improvement in depressive symptoms in acute bipolar depressed patients on treatment with intermittent Theta-Burst Stimulation (iTBS) in comparison to sham-rTMS.
rTMS is a treatment that involves stimulating a certain area of the brain with magnetic field pulses. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression. The device used in this study has been approved by Health Canada for therapeutic use since 2002. Participants will complete a screen visit to determine eligibility based on the inclusion/exclusion criteria. If the participants are not eligible, no further study procedures will be conducted. Eligible subjects will be randomized to receive either active iTBS-rTMS or sham rTMS treatment (scalp stimulation with no magnetic pulse) daily for four weeks (20 sessions) to the left dorsolateral prefrontal cortex (DLPFC). All participants will complete a MRI (to target the left DLPFC region of the brain and functional activity), EEG & fNIRS, lab work, and neurocognitive testing prior to the commencement and post rTMS treatment. Efficacy, safety and tolerability will be evaluated at screen visit, during daily rTMS treatments, clinic visits and post rTMS treatment. All participants will have a phone interview two weeks post rTMS treatment.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active iTBS rTMS | Active Comparator | The active arm involves magnetic stimulation of the brain to the left dorsolateral prefrontal cortex (DLPFC) daily for four weeks. The active arm will be receiving intermittent Theta-Burst (iTBS) repetitive Transcranial Magnetic Stimulation (rTMS) to deliver magnetic pulses. |
|
| Sham rTMS | Sham Comparator | sham rTMS treatment involves scalp stimulation with no magnetic pulse daily for four weeks (20 sessions). Sham rTMS involves only the click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| iTBS repetitive Transcranial Magnetic Stimulation (rTMS) | Device | rTMS is a non-invasive procedure in which cerebral electrical activity is influenced by a rapidly changing magnetic field. The magnetic field is created by a plastic-encased coil which is placed over the patient's scalp. The magnetic field can be directed onto specific areas of the brain. rTMS can modulate cerebral activity by low or high frequencies. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression. |
| Measure | Description | Time Frame |
|---|---|---|
| Montgomery Asberg Depression Rating Scale (MADRS) Scale Score | The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. A higher score means a worse outcome. Min value is 0, Max value is 60 | Baseline, Week 2, Week 4 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Clinical Response | Response rates are defined as patients showing ≥50% reduction in MADRS scores. | Baseline to Week 4 (assessed at Week 2 and Week 4, Week 4 reported) |
| Number of Participants Meeting Criteria for Clinical Remission |
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Inclusion Criteria:
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lakshmi Yatham, MBBS,FRCPsy | Regional Head and Program Medical Director, | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dr. Alexander McGirr | Calgary | Alberta | T2N 4Z6 | Canada | ||
| Djavad Mowfaghian Centre for Brain Heath |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36924413 | Derived | Torres IJ, Ge R, McGirr A, Vila-Rodriguez F, Ahn S, Basivireddy J, Walji N, Frangou S, Lam RW, Yatham LN. Effects of intermittent theta-burst transcranial magnetic stimulation on cognition and hippocampal volumes in bipolar depression. Dialogues Clin Neurosci. 2023 Dec;25(1):24-32. doi: 10.1080/19585969.2023.2186189. | |
| 33710288 | Derived |
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Of the 71 assessed for eligibility 37 were randomized.
Participants were recruited by referral, as well as online and community advertisements 2 Canadian centers (University of British Columbia [UBC], British Columbia, Canada; and University of Calgary [UC], Alberta, Canada) between October 2016 and March 2020 .
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| ID | Title | Description |
|---|---|---|
| FG000 | Active iTBS rTMS | The active arm involves magnetic stimulation of the brain to the left dorsolateral prefrontal cortex (DLPFC) daily for four weeks. The active arm will be receiving intermittent Theta-Burst (iTBS) repetitive Transcranial Magnetic Stimulation (rTMS) to deliver magnetic pulses. iTBS repetitive Transcranial Magnetic Stimulation (rTMS): rTMS is a non-invasive procedure in which cerebral electrical activity is influenced by a rapidly changing magnetic field. The magnetic field is created by a plastic-encased coil which is placed over the patient's scalp. The magnetic field can be directed onto specific areas of the brain. rTMS can modulate cerebral activity by low or high frequencies. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression. |
| FG001 | Sham rTMS | sham rTMS treatment involves scalp stimulation with no magnetic pulse daily for four weeks (20 sessions). Sham rTMS involves only the click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. Sham rTMS: Sham rTMS involves a click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Active iTBS rTMS | The active arm involves magnetic stimulation of the brain to the left dorsolateral prefrontal cortex (DLPFC) daily for four weeks. The active arm will be receiving intermittent Theta-Burst (iTBS) repetitive Transcranial Magnetic Stimulation (rTMS) to deliver magnetic pulses. iTBS repetitive Transcranial Magnetic Stimulation (rTMS): rTMS is a non-invasive procedure in which cerebral electrical activity is influenced by a rapidly changing magnetic field. The magnetic field is created by a plastic-encased coil which is placed over the patient's scalp. The magnetic field can be directed onto specific areas of the brain. rTMS can modulate cerebral activity by low or high frequencies. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Montgomery Asberg Depression Rating Scale (MADRS) Scale Score | The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. A higher score means a worse outcome. Min value is 0, Max value is 60 | Diagnosis of BD type I or type II by Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria, experiencing a major depressive episode (MDE). | Posted | Mean | Standard Deviation | score on a scale | Baseline, Week 2, Week 4 |
|
Baseline to 4 weeks
Systematic collection of Non-Serious Adverse events occurred only at the DMCBH site in Vancouver.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active iTBS rTMS | The active arm involves magnetic stimulation of the brain to the left dorsolateral prefrontal cortex (DLPFC) daily for four weeks. The active arm will be receiving intermittent Theta-Burst (iTBS) repetitive Transcranial Magnetic Stimulation (rTMS) to deliver magnetic pulses. iTBS repetitive Transcranial Magnetic Stimulation (rTMS): rTMS is a non-invasive procedure in which cerebral electrical activity is influenced by a rapidly changing magnetic field. The magnetic field is created by a plastic-encased coil which is placed over the patient's scalp. The magnetic field can be directed onto specific areas of the brain. rTMS can modulate cerebral activity by low or high frequencies. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pain and discomfort at treatment site | Nervous system disorders | Systematic Assessment |
This study is limited by a modest sample size; however, this is the direct consequence of premature termination after interim analyses indicated futility.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Lakshmi Yatham | University Of British Columbia | 604-822-7310 | l.yatham@ubc.ca |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 4, 2019 | Oct 21, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001714 | Bipolar Disorder |
| D003863 | Depression |
| ID | Term |
|---|---|
| D000068105 | Bipolar and Related Disorders |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D001526 | Behavioral Symptoms |
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| Sham rTMS | Device | Sham rTMS involves a click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. |
|
|
Clinical Remission is defined as a MADRS score ≤12 |
| Baseline to Week 4 (assessed at Week 2 and Week 4, Week 4 reported) |
| Overall Well Being | The visual analog scale (VAS) is a self report measure that captures the over all well being. Min 0-worse health to Max 100- best health. | Baseline to 4 weeks |
| Brief Illness Perception Questionnaire | Brief Illness Perception Questionnaire measures participant's perception of illness. Min = 0 Max = 80. Higher score means worse outcome. | Baseline to 4 weeks |
| Sheehan Disability Scale (SDS) | The Sheehan Disability Scale is a five-item, self-rated questionnaire designed to measure the extent to which a patient's disability due to an illness interferes with work/school, social life/leisure activities, and family life/home responsibilities. Each subscale score (a work disability, a social life disability, a family life disability) is combined into a single total score (sum of the non missing responses for items 1-3) representing a global impairment rating, ranging from 0 to 30, with higher scores indicative of significant functional impairment. | Baseline to 4 weeks |
| Quality of Life Questionnaire | The Quality of Life in Bipolar Disorder scale is a 56 item scale which assesses 12 core and 2 optional (work and study) domains, each containing four self-report items (1: strongly disagree to 5: strongly agree). An overall score (range: 48-240) may be calculated by summing responses to the 48 items of the core 12 domains. Higher scores reflect greater satisfaction with a person's quality of life. | Baseline to 4 weeks |
| Patient Global Impression Rating Scale: Severity | Patient Global Impression Rating Scale: Severity rates how depressed the participant is at the current time. 1-4 (1 is normal and 4 is severe) | Baseline to 4 weeks |
| Patient Global Impression Rating Scale- Improvement | Rates current depression compared to baseline. Min =1 Max =7 Higher scores mean worse outcome. | Week 4 |
| Vancouver |
| British Columbia |
| V6T 1Z3 |
| Canada |
| McGirr A, Vila-Rodriguez F, Cole J, Torres IJ, Arumugham SS, Keramatian K, Saraf G, Lam RW, Chakrabarty T, Yatham LN. Efficacy of Active vs Sham Intermittent Theta Burst Transcranial Magnetic Stimulation for Patients With Bipolar Depression: A Randomized Clinical Trial. JAMA Netw Open. 2021 Mar 1;4(3):e210963. doi: 10.1001/jamanetworkopen.2021.0963. |
| BG001 | Sham rTMS | sham rTMS treatment involves scalp stimulation with no magnetic pulse daily for four weeks (20 sessions). Sham rTMS involves only the click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. Sham rTMS: Sham rTMS involves a click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Primary Diagnosis | Count of Participants | Participants |
|
| OG001 | Sham rTMS | sham rTMS treatment involves scalp stimulation with no magnetic pulse daily for four weeks (20 sessions). Sham rTMS involves only the click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. Sham rTMS: Sham rTMS involves a click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. |
|
|
| Secondary | Number of Participants With Clinical Response | Response rates are defined as patients showing ≥50% reduction in MADRS scores. | Posted | Count of Participants | Participants | Baseline to Week 4 (assessed at Week 2 and Week 4, Week 4 reported) |
|
|
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| Secondary | Number of Participants Meeting Criteria for Clinical Remission | Clinical Remission is defined as a MADRS score ≤12 | Posted | Count of Participants | Participants | Baseline to Week 4 (assessed at Week 2 and Week 4, Week 4 reported) |
|
|
|
| Secondary | Overall Well Being | The visual analog scale (VAS) is a self report measure that captures the over all well being. Min 0-worse health to Max 100- best health. | Posted | Mean | Standard Deviation | score on a scale | Baseline to 4 weeks |
|
|
|
| Secondary | Brief Illness Perception Questionnaire | Brief Illness Perception Questionnaire measures participant's perception of illness. Min = 0 Max = 80. Higher score means worse outcome. | Not all participants completed the questionnaire. | Posted | Mean | Standard Deviation | score on a scale | Baseline to 4 weeks |
|
|
|
| Secondary | Sheehan Disability Scale (SDS) | The Sheehan Disability Scale is a five-item, self-rated questionnaire designed to measure the extent to which a patient's disability due to an illness interferes with work/school, social life/leisure activities, and family life/home responsibilities. Each subscale score (a work disability, a social life disability, a family life disability) is combined into a single total score (sum of the non missing responses for items 1-3) representing a global impairment rating, ranging from 0 to 30, with higher scores indicative of significant functional impairment. | Posted | Mean | Standard Deviation | score on a scale | Baseline to 4 weeks |
|
|
|
| Secondary | Quality of Life Questionnaire | The Quality of Life in Bipolar Disorder scale is a 56 item scale which assesses 12 core and 2 optional (work and study) domains, each containing four self-report items (1: strongly disagree to 5: strongly agree). An overall score (range: 48-240) may be calculated by summing responses to the 48 items of the core 12 domains. Higher scores reflect greater satisfaction with a person's quality of life. | Not all participants completed the questionnaire. | Posted | Mean | Standard Deviation | score on a scale | Baseline to 4 weeks |
|
|
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| Secondary | Patient Global Impression Rating Scale: Severity | Patient Global Impression Rating Scale: Severity rates how depressed the participant is at the current time. 1-4 (1 is normal and 4 is severe) | Not all participants completed the scale at Week 4. | Posted | Mean | Standard Deviation | score on a scale | Baseline to 4 weeks |
|
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| Secondary | Patient Global Impression Rating Scale- Improvement | Rates current depression compared to baseline. Min =1 Max =7 Higher scores mean worse outcome. | Not all participants completed the scale. | Posted | Mean | Standard Deviation | score on a scale | Week 4 |
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|
| 0 |
| 18 |
| 0 |
| 18 |
| 7 |
| 7 |
| EG001 | Sham rTMS | sham rTMS treatment involves scalp stimulation with no magnetic pulse daily for four weeks (20 sessions). Sham rTMS involves only the click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. Sham rTMS: Sham rTMS involves a click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. | 0 | 19 | 0 | 19 | 9 | 9 |
| Nausea/Vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Anxiety | Psychiatric disorders | Systematic Assessment |
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| Fatigue | General disorders | Systematic Assessment |
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| Stomach Cramp/ Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
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| D001519 |
| Behavior |
| Week 4 |
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| Week 4 |
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| Week 4 |
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