The Effectiveness of rTMS in Depressed VA Patients

• ClinicalTrials.gov Identifier: NCT01191333
• Recruitment Status: Completed
• First Posted: August 30, 2010
• Results First Posted: February 7, 2018
• Last Update Posted: March 9, 2018
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Tracking Information

• First Submitted Date: August 26, 2010
• First Posted Date: August 30, 2010
• Results First Submitted Date: January 10, 2018
• Results First Posted Date: February 7, 2018
• Last Update Posted Date: March 9, 2018
• Actual Study Start Date: July 2, 2012
• Actual Primary Completion Date: February 15, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2018)

The Proportion of Participants Achieving Remission From Depression as Assessed by Hamilton Rating Scale for Depression [ Time Frame: End of acute treatment 4-6 weeks ]

The primary outcome is a proportion of participants achieving remission from depression based on the HRSD24 less than or equal to 10 at the end of the acute treatment phase. 24 item Instrument with overall score range from 0 - 76. High values represent a worse outcome.

• Original Primary Outcome Measures (submitted: August 27, 2010): Hamilton Rating Scale for Depression [ Time Frame: 6 Months ]

Current Secondary Outcome Measures (submitted: February 8, 2018)

• Mean Suicidal Ideation Score as Assessed by Beck Scale for Suicide Ideation (BSS) [ Time Frame: End of acute treatment 4-6 weeks, then end of F/U 6 months ]
  To help clinicians screen psychiatric patients for suicidal ideation, the Beck Scale for Suicide Ideation was developed, and is herein referred to as the BSS. This self-report measure consists of 21 items with overall score range from 0 - 38, with the last two items not counted in scoring. A high score represents a worse outcome.
• Mean Depression Score as Assessed by Beck Depression Inventory (BDI) [ Time Frame: Baseline - end of acute treatment 4-6 weeks, then end of F/U 6 months ]
  This measure is a 21-item self-report test presented in a multiple choice format which measures presence and extent of depression with overall score range from 0 - 63. A higher score represents a worse outcome. Each of the 21 items addresses a specific symptom or attitude that pertains to depressed patients, and which are consistent with descriptions of the depression within the peer-reviewed literature. While generally deemed less reliable than scales score by a trained rater (for example, the HRSD), the Beck scale is easy to administer, and provides convenient means by which patients can effectively communicate their own perception of their mood state.
• Mean Mental Component Score as Assessed by VR-36 Mental Component Summary (MCS) [ Time Frame: End of acute treatment 4-6 weeks, then end of F/U 6 months ]
  The VR-36 is a self-administered survey that measures eight dimensions of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these eight health domains, and two summary measures of physical and mental health: the Physical Component Summary (PCS) and Mental Component Summary (MCS). MCS is analyzed in this section. Standardized scoring ranging from 0-100. A higher score represents a better outcome.
• Mean Physical Component Score as Assessed by VR-36 Physical Component Summary (PCS) [ Time Frame: End of acute treatment 4-6 weeks, then end of F/U 6 months ]
  The VR-36 is a self-administered survey that measures eight dimensions of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these eight health domains, and two summary measures of physical and mental health: the Physical Component Summary (PCS) and Mental Component Summary (MCS). PCS is analyzed in this section. Standardized scoring ranging from 0-100. A higher score represents a better outcome.
• Mean Depression Score as Assessed by the Montgomery Asberg Depression Rating Scale (MADRS) [ Time Frame: End of acute treatment 4-6 weeks, then end of F/U 6 months ]
  As another measure of depression, the Montgomery-Asberg Depression Rating Scale (MADRS) has been used with increasing frequency in recent years to measure outcome in antidepressant efficacy trials. It offers an alternative view of depressive illness, and may be sensitive to depressive symptoms that are not easily captured in the context of the HRSD, such as hypersomnia, increased appetite, and concentration/indecision. The MADRS is a 10-item clinician rating of depressive symptoms. Each item is scored on a 7-point scale (0 to 6) (range 0-60). A high score represents a worse outcome.

Original Secondary Outcome Measures (submitted: August 27, 2010)

• Beck Scale for Suicide Ideation (BSI) [ Time Frame: Baseline - end of active treatment 4-6 weeks, then end of F/U 6 months ]
• Beck Depression Inventory (BDI) [ Time Frame: Baseline - end of active treatment 4-6 weeks, then end of F/U 6 months ]
• VR-36 [ Time Frame: Baseline - end of active treatment 4-6 weeks, then end of F/U 6 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Effectiveness of rTMS in Depressed VA Patients
• Official Title: CSP #556 - The Effectiveness of rTMS in Depressed VA Patients
• Brief Summary: The purpose of this multi-site trial is to determine if repetitive Transcranial Magnetic Stimulation (rTMS) helps people with depression who have not been helped by medications or who have not been helped enough by medications.

Detailed Description

Major depression occurs in about 10% of American outpatients every year and of those, approximately 20% respond incompletely or not at all to trials of antidepressants, mood stabilizers, or psychotherapy (Kaplan and Sadock, 1996; Keller et al 1992; Thase, 2004). Treatment as usual for these cases of treatment resistant major depression (TRMD) frequently involves increased risks and increased side effects, such as those seen in monoamine oxidase inhibitors (MAOIs) and electroconvulsive therapy (ECT). New TRMD treatments are needed, preferably without major safety concerns or side effects as seen with aggressive polypharmacy or ECT.

Repetitive transcranial magnetic stimulation (rTMS) is a method of delivering brain stimulation without the seizures or risks associated with ECT, nor the potential side effects and risks of MAOI therapy. Systematic review and meta-analysis of the studies to date, which are typically of a small scale, appear to show a positive effect in TRMD (Martin et al. 2003). With a minimal side effect profile, and the rarity of untoward events and side-effects (Pascual-Leone et al. 1993; Wassermann 1997), safety concerns regarding the use of rTMS are considerably less than with ECT. Given this, rTMS has the potential to be a significant advance in care, if it were shown to be effective in TRMD in VA patients.

The trials of rTMS performed to date have not included participants with comorbid disorders, such as substance abuse and post-traumatic stress disorder (PTSD), thus the generalizability of their findings to a VA population is not clear. Further research including Veterans with possible comorbid disorders is necessary, given the high rates of co-occurring substance abuse and PTSD that is present in the Veteran population.

The present study is a randomized, controlled trial that compares active rTMS to a sham condition in Veterans with treatment resistant major depression and possible comorbid post-traumatic stress disorder (PTSD) and / or a history of substance abuse. Veterans will remain under the care of their VA primary mental health provider throughout the project. Participants will be assessed at pre-, mid- and several post-treatment time points. This is a multisite trial that will be conducted at 9 VA Medical Centers around the country.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Major Depressive Disorder

Intervention

• Device: rTMS
  Repetitive Transcranial Magnetic Stimulation
• Device: Sham Device
  Placebo Device that simulates active rTMS treatment

Study Arms

• Experimental: Active rTMS
  Those receiving experimental treatment will receive 20 to 30 sessions of rTMS in blocks of 5 sessions. The treatment will be delivered by trained medical personnel.
  Intervention: Device: rTMS
• Placebo Comparator: Sham rTMS
  Those receiving the sham rTMS will receive 20 to 30 sessions of sham rTMS in blocks of 5 sessions. The treatment will be delivered by trained medical personnel.
  Intervention: Device: Sham Device

Publications *

• Mi Z, Biswas K, Fairchild JK, Davis-Karim A, Phibbs CS, Forman SD, Thase M, Georgette G, Beale T, Pittman D, McNerney MW, Rosen A, Huang GD, George M, Noda A, Yesavage JA. Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression (TRMD) Veteran patients: study protocol for a randomized controlled trial. Trials. 2017 Sep 2;18(1):409. doi: 10.1186/s13063-017-2125-y.
• Yesavage JA, Fairchild JK, Mi Z, Biswas K, Davis-Karim A, Phibbs CS, Forman SD, Thase M, Williams LM, Etkin A, O'Hara R, Georgette G, Beale T, Huang GD, Noda A, George MS; VA Cooperative Studies Program Study Team. Effect of Repetitive Transcranial Magnetic Stimulation on Treatment-Resistant Major Depression in US Veterans: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Sep 1;75(9):884-893. doi: 10.1001/jamapsychiatry.2018.1483.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 13, 2016): 164
• Original Estimated Enrollment (submitted: August 27, 2010): 1012011
• Actual Study Completion Date: March 31, 2017
• Actual Primary Completion Date: February 15, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Between 18 and 80 years of age
• Using the Structured Clinical Interview for Diagnostic and Statistical Manual (DSM) Disorders (SCID) for DSM-IV-TR (First et al. 2002) patients will be diagnosed Major Depressive Disorder (MDD).
• Have a Hamilton Rating Scale for Depression (HRSD-24) score greater or equal to 20 no more than 7 days prior to randomization.
• Exhibit moderate level of resistance to antidepressant treatment defined, using the Antidepressant Treatment History Form (ATHF) (Sackeim et al. 1990), as failure of at least two adequate medication trials.
• Duration of current episode of less than or equal to 10 years.
• Ability to obtain a Motor Threshold (MT) (should be determined at the end of the screening process).
• Currently under the care of a VA psychiatrist.
• If on a psychotropic medication regimen, that regimen will be stable for at least 4 weeks prior to randomization and patient will be willing to remain on a stable regimen during the acute treatment phase.
• Has an adequately stable condition and environment to enable attendance at scheduled clinic visits.

• For female participants, agrees to use one of the following acceptable methods of birth control

  • Complete abstinence (not having sexual intercourse with anyone)
  • An oral contraceptive (birth control pills)
  • Norplant
  • Depo-Provera
  • A condom with spermicide
  • A cervical cap with spermicide
  • A diaphragm with spermicide
  • An Intrauterine device
  • Surgical sterilization (having tubes tied)
• Able to read, verbalize understanding and voluntarily sign the Informed Consent Form prior to performance of any study-specific procedures or assessments.

Exclusion Criteria:

• Pregnant or lactating female (This is an FDA-required exclusion. In the future, if rTMS becomes a proven treatment for major depression, its safety in the context of pregnancy should be studied separately (Nahas et al. 1999).
• Unable to be safely withdrawn, at least two-weeks prior to treatment commencement, from medications that substantially increase the risk of having seizures. For the purpose of this study, those medications are listed in Appendix G (for example, theophylline).
• Have a cardiac pacemaker.
• Have an implanted device (deep brain stimulation) or metal in the brain.
• Have a cochlear implant.
• Have a mass lesion, cerebral infarct, increased intracranial pressure, or other active central nervous system (CNS) disease, including a seizure disorder.
• Known current psychosis as determined by DSM-IV or SCID (axis I, psychotic disorder, schizophrenia) or a history of a non-mood psychotic disorder.
• Known current Bipolar I disorder as determined by SCID or a History of Bipolar I disorder.
• Current amnestic disorders, dementia, Blessed Orientation-Memory-Concentration (BOMC) greater than 10, delirium, or other cognitive disorders.
• Current substance abuse (not including caffeine or nicotine) as determined by positive toxicology screen, or by history via SCID, within 3 months prior to screening.
• Patients with an elevated risk of seizure due to traumatic brain injury (TBI).
• Participation in another concurrent clinical trial.
• Patients with prior exposure to rTMS.
• Active current suicidal intent or plan as evidenced by a score of 4 or 5 on the suicidal ideation portion of the Columbia Suicide Severity Rating Scale (C-SSRS) or the endorsement of an actual attempt, interrupted attempt, or an aborted attempt in the past 6 months. All patients will be required to establish a written safety plan involving their primary psychiatrist and the treatment team before entering the clinical trial (See Section X.B.8).
• Unstable cardiac disease or recent (< 3 months previous) myocardial infarction.
• Patient refuses to sign consent for participation in the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01191333
• Other Study ID Numbers: 556
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: VA Office of Research and Development
• Study Sponsor: VA Office of Research and Development
• Collaborators: Not Provided

Investigators

• Study Chair: Jerome A. Yesavage, MD; VA Palo Alto Health Care System, Palo Alto, CA

• PRS Account: VA Office of Research and Development
• Verification Date: February 2018