Ignite Creation Date:
2024-05-05 @ 5:12 PM
Last Modification Date:
2024-10-26 @ 9:29 AM
Study NCT ID:
NCT00402220
Status:
COMPLETED
Last Update Posted:
2020-10-19
First Post:
2006-11-18
Brief Title:
A Double-blind Sham Controlled Trial of rTMS in Treatment Resistant Major Depression
Sponsor:
Bayside Health
Organization:
Bayside Health
Study Overview
Official Title:
A Double-blind Sham Controlled Trial of rTMS in Treatment Resistant Major Depression
Status:
COMPLETED
Status Verified Date:
2020-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The main treatment option for Treatment Resistant Depression is electroconvulsive therapy ECT which is often effective but complicated by cognitive side effects need for anaesthesia and considerable stigma
In recent years considerable efforts have been made to increase public awareness about depression and increase access to services However the increasing number of patients accessing treatment for depression in clinical services is also likely to be accompanied by a sizeable increase in the number of patients with TRD Despite the demand relatively few treatment options are available to such patients One of the only substantially new treatments developed for TRD in recent years has been the advent of repetitive transcranial magnetic stimulation rTMS Repetitive TMS has been evaluated in over 20 trials conducted over the last 10 years Previous research indicates that rTMS has antidepressant activity however the proportion of patients who respond to rTMS and the degree of treatment response demonstrated in trials to date is limited The limitations of these studies include relatively small samples and limited duration of treatment ie 2 weeks as well as a lack of long term follow-up As rTMS is gradually entering use in routine clinical practice for example recent regulation of its use in Canada research is urgently required to establish ways to enhance treatment response both in regards to the extent of response within individuals and the proportion of individuals in whom rTMS has effects
Stimulation site is another important treatment factor thus far almost all of the trials of rTMS in TRD conducted have evaluated the utility of high frequency left prefrontal cortex PFC rTMS HFL-TMS In addition several studies have evaluated the treatment efficacy of low frequency rTMS to right PFC LFR-TMS In a previously published study we have demonstrated that these two approaches have similar therapeutic benefit and both were superior to sham stimulation
A promising new approach to enhance efficacy involves combining LFR-TMS and HFL-TMS in a sequential manner We describe this as sequential bilateral rTMS SB-rTMS We have recently published the results of the first substantial evaluation of SB-rTMS showing not only a superiority to placebo in TRD but also a therapeutic response that is substantially superior to response rates in most of the published studies of unilateral rTMS 50 of patients achieving standard criteria for clinical response compared to usually 30 in most studies In this proposed research study we will directly test the hypothesis that SB-rTMS produces a greater therapeutic response than HFL-TMS and compare both of these forms of stimulation to placebo ie sham stimulation
In recent years considerable efforts have been made to increase public awareness about depression and increase access to services However the increasing number of patients accessing treatment for depression in clinical services is also likely to be accompanied by a sizeable increase in the number of patients with TRD Despite the demand relatively few treatment options are available to such patients One of the only substantially new treatments developed for TRD in recent years has been the advent of repetitive transcranial magnetic stimulation rTMS Repetitive TMS has been evaluated in over 20 trials conducted over the last 10 years Previous research indicates that rTMS has antidepressant activity however the proportion of patients who respond to rTMS and the degree of treatment response demonstrated in trials to date is limited The limitations of these studies include relatively small samples and limited duration of treatment ie 2 weeks as well as a lack of long term follow-up As rTMS is gradually entering use in routine clinical practice for example recent regulation of its use in Canada research is urgently required to establish ways to enhance treatment response both in regards to the extent of response within individuals and the proportion of individuals in whom rTMS has effects
Stimulation site is another important treatment factor thus far almost all of the trials of rTMS in TRD conducted have evaluated the utility of high frequency left prefrontal cortex PFC rTMS HFL-TMS In addition several studies have evaluated the treatment efficacy of low frequency rTMS to right PFC LFR-TMS In a previously published study we have demonstrated that these two approaches have similar therapeutic benefit and both were superior to sham stimulation
A promising new approach to enhance efficacy involves combining LFR-TMS and HFL-TMS in a sequential manner We describe this as sequential bilateral rTMS SB-rTMS We have recently published the results of the first substantial evaluation of SB-rTMS showing not only a superiority to placebo in TRD but also a therapeutic response that is substantially superior to response rates in most of the published studies of unilateral rTMS 50 of patients achieving standard criteria for clinical response compared to usually 30 in most studies In this proposed research study we will directly test the hypothesis that SB-rTMS produces a greater therapeutic response than HFL-TMS and compare both of these forms of stimulation to placebo ie sham stimulation
Detailed Description:
Justification for project
TRD is clearly a major health issue - depression is common results in marked morbidity and mortality and a large percentage of patients do not respond to or cannot tolerate standard treatment The development of new treatments for this condition is undoubtedly required International efforts are underway to try and establish the efficacy of HFL-TMS to the point where the technique may be approved by regulatory authorities and clinically introduced However clearly the response rate to HFL-TMS is suboptimal for its widespread use
The overall goal of this research program is to develop rTMS methods to the point at which they are highly relevant and applicable to clinical practice None of the substantial international studies is focusing on novel applications such as SBrTMS As an outcome we expect positive results to change the focus of rTMS application and practice nationally and internationally If we can follow our well received initial study of this technique with a substantial comparative trail as planned here it will provide enough evidence for the more widespread adoption and testing of SBrTMS as a viable alternative to HFL-TMS Ultimately this or a modification of it may become the rTMS administration method of choice
Additionally we will have a sufficient sample size to start to explore meaningful predictors of clinical response including biological psychosocialpersonality variable predictors
Hypotheses Research Questions
Primary Hypothesis
Hypothesis 1 Treatment with left sided and SBrTMS will both result in a greater reduction in HAMD and MADRS scores than sham rTMS
Hypothesis 2 Treatment with SBrTMS will result in a greater reduction in HAMD and MADRS scores than left sided rTMS applied alone
Secondary Hypotheses
Greater than 50 of treatment responders to rTMS will continue to experience clinical benefits from rTMS as indexed by persistently low HAMD and MADRS scores at 6 months post acute treatment
Methodology including project design and sequence of procedures
Experimental Design
The study will involve a 2 phases of treatment an acute treatment phase of 3-9 weeks duration and a maintenance treatment phase lasting 52 weeks In the initial 3 weeks of the acute treatment phase the study will be randomised double blind and sham-controlled with three arms
1 SBrTMS
2 Unilateral left rTMS
3 Sham rTMS
Prior to randomization participants will undergo an EEG and MRI see below for more detail The EEG and MRI will be repeated once during the active treatment phase
Randomization will occur via the generation of a single computer number sequence Subjects will be randomised immediately prior to the commencement of the first treatment session after the measurement of bilateral resting motor thresholds with standard means 30
Acute treatment will be administered daily 5 days per week initially for three weeks ie 15 treatments Following 3 weeks of treatment response will be assessed and the blind broken At this point non responders ie HAM-D score 10 who have been receiving active treatment will be offered an additional 3 weeks of treatment at the same treatment parameters Responders who have been receiving active treatment will enter the maintenance phase At week 6 treatment response will again be assessed and non responders will be offered a final 3 weeks of active treatment while responders will enter the maintenance phase At week 9 response will again be assessed and non responders will cease their participation in the trial while responders will continue onto the maintenance phase With regard to the sham treatment arm subjects who respond to treatment and received sham treatment will be discontinued from the study at week 3 Those subjects who are classified as non responders and were in the sham treatment arm will be randomised to one of the two active treatment arms and receive an additional 3 weeks of active treatment
The maintenance phase will be open labeled and consist of weekly treatments at the same parameters to which patients initially responded for a total of 8 weeks Maintenance treatment will then be further reduced to fortnightly treatments for 44 weeks Patients will be evaluated clinically every 2 weeks Should patients relapse ie a HAM-D score of 15 for 2 consecutive weeks they will be offered active treatment only ie no sham treatment for up to six weeks at the same stimulus parameters to which they previously experienced a response
Subjects
Inclusion Criteria Patients will be included if they
1 Have a DSM-IV diagnosis of a major depressive episode SCID 11
2 Aged 18-85
3 Have treatment resistant depression at Stage II of the Thase and Rush classification 31 e have failed to achieve a clinical response or did not tolerate at least two separate antidepressant trials of sufficient dose for at least 6 weeks
4 Have a Hamilton Depression Rating Scale Score of 20 moderate - severe depression Including only a severely ill group of subjects limits the placebo response rate 32 Moreover this will allow us to address the application of rTMS methods in the most clinically relevant subgroup of patients in addition helping to constrain group heterogeneity a major issue in depression research
5 Have had no increase or initiation of new antidepressant or other psychoactive therapy in the 4 weeks prior to screening
Additional Exclusion Criteria
1 Patients who have an unstable medical condition neurological disorder or any history of a seizure disorder or are currently pregnant or lactating
2 In the opinion of the investigator are a sufficient suicidal risk to require immediate electro-convulsive therapy
3 Have a current DSM IV diagnosis of substance abuse or dependence disorder a diagnosis of a personality disorder SCID II or another axis 1 disorder
Please note several of these criteria eg inclusion criteria 1 2 exclusion criteria 3 have been selected to explicitly constrain the heterogeneity of the sample to increase the likely power of the study to detect differences between the groups given the potentially subtle difference between the treatment methods
Sample Size Calculations We aim to recruit 40 patients into each group total n120 The sample size calculation for the study was conducted based on the within group standard deviation of 129 this was the standard deviation for baseline to final study visit in our SBrTMS study and between group difference of 50 points With an alpha of 005 the study will have a power of 087 to detect a difference in end scores between the 3 groups calculation in PASS 80
Clinical Measures Demographic variables and potential co-variates will be recorded at baseline following a clinical interview These will include the duration of the current episode years from first diagnosis number of previous episodes type and dose of current and previous treatment and family history of mood disorder
Clinical measures will be performed at randomization at 3 and 6 weeks and 9 weeks in the patients in the extension phase as well as at the follow up assessments A trained rater who is blind to treatment type will administer all measures Raters will be required to maintain 90 reliability on the primary outcome assessments on ratings with 6 monthly assessments based on videotaped interviews
To ensure comparability with previous studies the primary outcome variable will be the 17-item Hamilton Rating Scale for Depression HAMD Other outcome measures will include the Montgomery-Asberg Depression Rating Scale MADRS Beck Depression Questionnaire BDI Brief Psychiatric Rating Scale BPRS and an interview to record the subjective experiences of TMS and any adverse events Final response and remission rates will be measured using standard rating scale score criteria but the patients will need to achieve these scores at the study end and at the 2 week follow up assessment
Assessments made at baseline to explore potential predictors of clinical response will include the CORE rating of melancholia 33 the Measure of Parental Styles 34 the Depressive Personality Inventory 35 and the Costello and Comrey trait anxiety measure 36
A battery of cognitive tests will be administered prior to commencement and at 3 6 and 9 weeks in the active treatment phase with a specific focus on attention and memory
HVLT Controlled oral word association Trail making AB Digit Span The inclusion of these measures in the will assess the potential beneficial effects of TMS on frontally mediated cognitive functions as well as act as a safety check
TMS Treatment TMS will be administered with a Medtronic Magpro30 magnetic stimulator using a 70mm figure of 8 coil Prior to the commencement of treatment TMS single pulse TMS will be used to measure the resting motor thresholds RMT for the abductor pollicis brevis APB bilaterally in all subjects using standard published methods 30
Stimulation parameters rTMS will be administered on a daily basis 5 days per week for all subjects
Bilateral
Left 10Hz 100 RMT 30 Trains 5 second duration 25 second inter-train interval Right 1 Hz 100 RMT 1 Train of 600 pulses
Left Unilateral
Left 10Hz 100 RMT 30 Trains 5 second duration 25 second inter-train interval Right as above BUT applied with a Medtronic sham coil Sham the following applied with a sham coil Left 10Hz 100 RMT 30 Trains 5 second duration 25 second inter-train interval Right 1 Hz 100 RMT 1 Train of 600 pulses Missed sessions will be made up by an extension of the treatment duration but only one missed session will be allowed weekly and only one missed session in a row
Stimulation localisation This will follow standard procedures Firstly the site for the optimal activation of the abductor pollicis brevis muscle in the contralateral hand will be located whilst stimulating the relevant motor cortical region at supra-threshold intensity This site will be marked on the scalp We will then measure 6 cm anteriorly on the scalp surface and mark it with ink This point will be then used as the site of stimulation The majority of rTMS studies have measured 5 cm anteriorly However this has been shown to result consistently in localisation that is posterior to the dorsolateral PFC 37 The measurement described here should result in more consistent treatment of dorsolateral PFC but still provide considerable stimulation overlap with the established 5 cm site
Imaging MRI imaging will be conducted before the commencement of treatment all subjects and at the end of the active treatment phase where possible Each subject will undergo a 3D sagittally orientated T1 weighted structural MR scan on the 15 Tesla MRI scanner at the Alfred 128 slices Analysis of scalp to cortex distance in prefrontal cortex and at the site of stimulation will be conducted using previously published methods This will allow the post hoc analysis of the relationship between scalp to cortex distance and treatment response In addition where possible subjects will undergo additional measures of white matter tract integrity diffusion tensor imaging and activation None of the scanning procedures will involve the administration of contrast
Electroencephalography EEG EEG before and after the acute phase of treatment will be used to examine mean absolute spectral power within 5 frequency bands The mean absolute power in squared microvolts per hertz will then be computed within the following 5 frequency bands delta 05-35 Hz theta 35-75 Hz alpha 75-125 Hz beta 1 125-205 Hz and beta 2 205-325 Hz EEG activation spectral power will be assessed at rest eyes open and closed and during cognitive engagement in several tasks
TRD is clearly a major health issue - depression is common results in marked morbidity and mortality and a large percentage of patients do not respond to or cannot tolerate standard treatment The development of new treatments for this condition is undoubtedly required International efforts are underway to try and establish the efficacy of HFL-TMS to the point where the technique may be approved by regulatory authorities and clinically introduced However clearly the response rate to HFL-TMS is suboptimal for its widespread use
The overall goal of this research program is to develop rTMS methods to the point at which they are highly relevant and applicable to clinical practice None of the substantial international studies is focusing on novel applications such as SBrTMS As an outcome we expect positive results to change the focus of rTMS application and practice nationally and internationally If we can follow our well received initial study of this technique with a substantial comparative trail as planned here it will provide enough evidence for the more widespread adoption and testing of SBrTMS as a viable alternative to HFL-TMS Ultimately this or a modification of it may become the rTMS administration method of choice
Additionally we will have a sufficient sample size to start to explore meaningful predictors of clinical response including biological psychosocialpersonality variable predictors
Hypotheses Research Questions
Primary Hypothesis
Hypothesis 1 Treatment with left sided and SBrTMS will both result in a greater reduction in HAMD and MADRS scores than sham rTMS
Hypothesis 2 Treatment with SBrTMS will result in a greater reduction in HAMD and MADRS scores than left sided rTMS applied alone
Secondary Hypotheses
Greater than 50 of treatment responders to rTMS will continue to experience clinical benefits from rTMS as indexed by persistently low HAMD and MADRS scores at 6 months post acute treatment
Methodology including project design and sequence of procedures
Experimental Design
The study will involve a 2 phases of treatment an acute treatment phase of 3-9 weeks duration and a maintenance treatment phase lasting 52 weeks In the initial 3 weeks of the acute treatment phase the study will be randomised double blind and sham-controlled with three arms
1 SBrTMS
2 Unilateral left rTMS
3 Sham rTMS
Prior to randomization participants will undergo an EEG and MRI see below for more detail The EEG and MRI will be repeated once during the active treatment phase
Randomization will occur via the generation of a single computer number sequence Subjects will be randomised immediately prior to the commencement of the first treatment session after the measurement of bilateral resting motor thresholds with standard means 30
Acute treatment will be administered daily 5 days per week initially for three weeks ie 15 treatments Following 3 weeks of treatment response will be assessed and the blind broken At this point non responders ie HAM-D score 10 who have been receiving active treatment will be offered an additional 3 weeks of treatment at the same treatment parameters Responders who have been receiving active treatment will enter the maintenance phase At week 6 treatment response will again be assessed and non responders will be offered a final 3 weeks of active treatment while responders will enter the maintenance phase At week 9 response will again be assessed and non responders will cease their participation in the trial while responders will continue onto the maintenance phase With regard to the sham treatment arm subjects who respond to treatment and received sham treatment will be discontinued from the study at week 3 Those subjects who are classified as non responders and were in the sham treatment arm will be randomised to one of the two active treatment arms and receive an additional 3 weeks of active treatment
The maintenance phase will be open labeled and consist of weekly treatments at the same parameters to which patients initially responded for a total of 8 weeks Maintenance treatment will then be further reduced to fortnightly treatments for 44 weeks Patients will be evaluated clinically every 2 weeks Should patients relapse ie a HAM-D score of 15 for 2 consecutive weeks they will be offered active treatment only ie no sham treatment for up to six weeks at the same stimulus parameters to which they previously experienced a response
Subjects
Inclusion Criteria Patients will be included if they
1 Have a DSM-IV diagnosis of a major depressive episode SCID 11
2 Aged 18-85
3 Have treatment resistant depression at Stage II of the Thase and Rush classification 31 e have failed to achieve a clinical response or did not tolerate at least two separate antidepressant trials of sufficient dose for at least 6 weeks
4 Have a Hamilton Depression Rating Scale Score of 20 moderate - severe depression Including only a severely ill group of subjects limits the placebo response rate 32 Moreover this will allow us to address the application of rTMS methods in the most clinically relevant subgroup of patients in addition helping to constrain group heterogeneity a major issue in depression research
5 Have had no increase or initiation of new antidepressant or other psychoactive therapy in the 4 weeks prior to screening
Additional Exclusion Criteria
1 Patients who have an unstable medical condition neurological disorder or any history of a seizure disorder or are currently pregnant or lactating
2 In the opinion of the investigator are a sufficient suicidal risk to require immediate electro-convulsive therapy
3 Have a current DSM IV diagnosis of substance abuse or dependence disorder a diagnosis of a personality disorder SCID II or another axis 1 disorder
Please note several of these criteria eg inclusion criteria 1 2 exclusion criteria 3 have been selected to explicitly constrain the heterogeneity of the sample to increase the likely power of the study to detect differences between the groups given the potentially subtle difference between the treatment methods
Sample Size Calculations We aim to recruit 40 patients into each group total n120 The sample size calculation for the study was conducted based on the within group standard deviation of 129 this was the standard deviation for baseline to final study visit in our SBrTMS study and between group difference of 50 points With an alpha of 005 the study will have a power of 087 to detect a difference in end scores between the 3 groups calculation in PASS 80
Clinical Measures Demographic variables and potential co-variates will be recorded at baseline following a clinical interview These will include the duration of the current episode years from first diagnosis number of previous episodes type and dose of current and previous treatment and family history of mood disorder
Clinical measures will be performed at randomization at 3 and 6 weeks and 9 weeks in the patients in the extension phase as well as at the follow up assessments A trained rater who is blind to treatment type will administer all measures Raters will be required to maintain 90 reliability on the primary outcome assessments on ratings with 6 monthly assessments based on videotaped interviews
To ensure comparability with previous studies the primary outcome variable will be the 17-item Hamilton Rating Scale for Depression HAMD Other outcome measures will include the Montgomery-Asberg Depression Rating Scale MADRS Beck Depression Questionnaire BDI Brief Psychiatric Rating Scale BPRS and an interview to record the subjective experiences of TMS and any adverse events Final response and remission rates will be measured using standard rating scale score criteria but the patients will need to achieve these scores at the study end and at the 2 week follow up assessment
Assessments made at baseline to explore potential predictors of clinical response will include the CORE rating of melancholia 33 the Measure of Parental Styles 34 the Depressive Personality Inventory 35 and the Costello and Comrey trait anxiety measure 36
A battery of cognitive tests will be administered prior to commencement and at 3 6 and 9 weeks in the active treatment phase with a specific focus on attention and memory
HVLT Controlled oral word association Trail making AB Digit Span The inclusion of these measures in the will assess the potential beneficial effects of TMS on frontally mediated cognitive functions as well as act as a safety check
TMS Treatment TMS will be administered with a Medtronic Magpro30 magnetic stimulator using a 70mm figure of 8 coil Prior to the commencement of treatment TMS single pulse TMS will be used to measure the resting motor thresholds RMT for the abductor pollicis brevis APB bilaterally in all subjects using standard published methods 30
Stimulation parameters rTMS will be administered on a daily basis 5 days per week for all subjects
Bilateral
Left 10Hz 100 RMT 30 Trains 5 second duration 25 second inter-train interval Right 1 Hz 100 RMT 1 Train of 600 pulses
Left Unilateral
Left 10Hz 100 RMT 30 Trains 5 second duration 25 second inter-train interval Right as above BUT applied with a Medtronic sham coil Sham the following applied with a sham coil Left 10Hz 100 RMT 30 Trains 5 second duration 25 second inter-train interval Right 1 Hz 100 RMT 1 Train of 600 pulses Missed sessions will be made up by an extension of the treatment duration but only one missed session will be allowed weekly and only one missed session in a row
Stimulation localisation This will follow standard procedures Firstly the site for the optimal activation of the abductor pollicis brevis muscle in the contralateral hand will be located whilst stimulating the relevant motor cortical region at supra-threshold intensity This site will be marked on the scalp We will then measure 6 cm anteriorly on the scalp surface and mark it with ink This point will be then used as the site of stimulation The majority of rTMS studies have measured 5 cm anteriorly However this has been shown to result consistently in localisation that is posterior to the dorsolateral PFC 37 The measurement described here should result in more consistent treatment of dorsolateral PFC but still provide considerable stimulation overlap with the established 5 cm site
Imaging MRI imaging will be conducted before the commencement of treatment all subjects and at the end of the active treatment phase where possible Each subject will undergo a 3D sagittally orientated T1 weighted structural MR scan on the 15 Tesla MRI scanner at the Alfred 128 slices Analysis of scalp to cortex distance in prefrontal cortex and at the site of stimulation will be conducted using previously published methods This will allow the post hoc analysis of the relationship between scalp to cortex distance and treatment response In addition where possible subjects will undergo additional measures of white matter tract integrity diffusion tensor imaging and activation None of the scanning procedures will involve the administration of contrast
Electroencephalography EEG EEG before and after the acute phase of treatment will be used to examine mean absolute spectral power within 5 frequency bands The mean absolute power in squared microvolts per hertz will then be computed within the following 5 frequency bands delta 05-35 Hz theta 35-75 Hz alpha 75-125 Hz beta 1 125-205 Hz and beta 2 205-325 Hz EEG activation spectral power will be assessed at rest eyes open and closed and during cognitive engagement in several tasks
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None