Ignite Creation Date:
2024-05-06 @ 11:33 AM
Last Modification Date:
2024-10-26 @ 12:46 PM
Study NCT ID:
NCT03541707
Status:
UNKNOWN
Last Update Posted:
2018-05-30
First Post:
2018-04-16
Brief Title:
Evaluation of the H1-Coil TMS- Double Blind Placebo Controlled Study in Adolescent Patients Suffering From Major Depression
Sponsor:
Shalvata Mental Health Center
Organization:
Shalvata Mental Health Center
Study Overview
Official Title:
Evaluation of the H1-Coil TMS- Double Blind Placebo Controlled Study in Adolescent Patients Suffering From Major Depression
Status:
UNKNOWN
Status Verified Date:
2018-05
Last Known Status:
NOT_YET_RECRUITING
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:
This study is a randomized double blind placebo controlled EEG monitored study of deep rTMS treatment to treat adolescent depression
The present study is the first well controlled study to examine the possible clinical utility of deep TMS to treat a severe and life threatening disorder- depression among adolescents
Patients will be allocated based on chance to receive active therapy or a as if stimulation with no knowledge of patient or therapist who receives the active therapy In addition a simple and feasible monitoring of brain waves EEG will be conducted This addition will enable us to evaluate the possibility to use biological markers to predict the course of therapy
Our hypothesis is that 1 patients receiving the active therapy will improve significantly more than those who received the as if treatment 2 There will be no significant side effects 3 The brain waves as measured by the EEG will predict treatment response
The present study is the first well controlled study to examine the possible clinical utility of deep TMS to treat a severe and life threatening disorder- depression among adolescents
Patients will be allocated based on chance to receive active therapy or a as if stimulation with no knowledge of patient or therapist who receives the active therapy In addition a simple and feasible monitoring of brain waves EEG will be conducted This addition will enable us to evaluate the possibility to use biological markers to predict the course of therapy
Our hypothesis is that 1 patients receiving the active therapy will improve significantly more than those who received the as if treatment 2 There will be no significant side effects 3 The brain waves as measured by the EEG will predict treatment response
Detailed Description:
Adolescent depression is a severe disorder affecting 5-8 of adolescents It is a major risk factor for adolescent suicide-one of the 3 most common reasons for death in this age group It carries with it a heavy burden of harsh comorbidities such as substance abuse and behavioral problems1 2
The first line treatment of moderate or severe illness includes pharmacotherapy with serotonin reuptake inhibitors SSRIs such as fluoxetine in combination with psychotherapy However more than 30 of the patients do not achieve remission defined as minimal or no symptoms despite treatment with a combined intervention 3 In adolescents there is some evidence that as a second line switching to another SSRI combined with cognitive behavioral therapy CBT can be useful 4 There is no evidence to what should be the third line in therapy Early intervention in the course of a disease is expected to protect from the grave long term sequelae9 but in treating adolescent depression our therapeutic tools are extremely limited10
There is a necessity to advance our evidence based interventions to treat treatments resistant adolescent depression
Hypoactivity in the left dorsolateral prefrontal cortex DLPC is a key finding in brain imaging of depression11 Repetitive transcranial magnetic stimulation rTMS is a therapeutic procedure in which a magnetic coil that generates recurrent pulsatile magnetic fields from a rapidly oscillating electrical current is placed on the scalp to induce recurrent electrical currents in the brain High frequency rTMS causes activation of the affected brain regions and networks This is the suggested mechanism of the antidepressant effect of high frequency rTMS to the left DLPC in depression12 Recent advances in custom coil technology led to the development of H coils that support stimulation of deeper limbic structures13 Due to the accumulating knowledge on safety and efficacy in adult depression both the custom rTMS and the deep H coil TMS are approved FDA and Israeli ministry of health for clinical not just research use 12 14-16 In a large multicenter study of the H1 coil to treat adult depression there were minimal side effects and a large effect size of 078 was reported strengthening the promise of this mode of therapy 5
The field of brain stimulation and specifically TMS is based on the concept of neuroplasticity the ability of repeated stimulations to cause a longer lasting neuronal change In this respect the adolescent developing brain is a period of opportunity for such changes17 18 To date there are no randomized placebo controlled studies on rTMS to treat adolescents suffering from depression although reports support the safety of rTMS in treating adolescents Recently there was a report of a self-limited convulsion in an adolescent treated with deep rTMS at 120 motor threshold-strengthening the necessity for well-structured studies in the field23
Studying biomarkers holds the promise for translating neuroscientific understandings to the clinical practice of adolescent depression24 In order to be useful a biomarker has to be discriminative between responder vs non responder for example to reflect a pathophysiological process but last and not least it is important that it will be accessible for use25 26 This explains the evolving interest in using electroencephalography EEG findings to study depression and monitor the course of therapy27 28 Imaging and electrophysiological studies support the importance of the interplay between the attentional and default networks as a marker of the disease course29 30 In a recent study our group cooperated in a study of a new simple EEG technique that by using repeated simple attentional EEG measures was able to predict treatment response in a heterogeneous group of adult depressed patients31 These safe and simple markers were never studied in adolescent depression
The present research is a randomized double blind placebo controlled EEG monitored study of deep rTMS treatment to treat adolescent depression
Research goals and expected significance
1 To study the efficacy and safety of deep rTMS to treat treatments resistant adolescent depression As there are no well controlled studies of rTMS to treat adolescent depression the possibility to evaluate a new therapeutic tool for this severe life threatening disease has immense clinical value Since this technique is based on evolving neuroscientific understandings it holds promise for advancing our understanding of adolescent depression
2 To evaluate a potential pragmatic EEG measure to predict and monitor therapeutic outcome Since the effect of deep rTMS on the developing brain of the depressed adolescent has a potential for both therapy and side effects early prediction of the effect is crucial The potential of having biomarkers to complement clinical and subjective evaluations is of paramount importance for personalizing objectively monitoring therapy to treat adolescent depression
Methods
Subjects Fifty-two adolescents age 14-18y suffering from treatment resistant depression will be recruited from Shalvata mental health center in patient ward and outpatient facilities Sample size calculation was based on the effect size of 078 found in the adult depression study5 The Shalvata Mental Health Center serves a large catchment area and the investigators are experienced in recruiting depressed adolescent patients to rTMS studies 20 21 33 Participation will be based on the following criteria
Devices
Deep TMS Brainsways H coil and deep TMS are registered in Israel for clinical use to treat depression in adults Our center has gained years of experience in studies with this system5 16 32 37 Deep TMS treatments will be carried out by a technician trained and approved by the manufacturer that will remain in the treatment room during the entire procedure In addition a physician will be available on-call within the hospital grounds
At the beginning of the trial individual motor threshold MT will be measured by placing the assigned coil above the hand area of the motor cortex Patients will receive stimulations over the prefrontal cortex 6 cms anterior to the hot spot for stimulation of the abductor policies brevis in the hand area Each deep TMS treatment will be conducted as follows Before starting each treatment patients will be instructed to insert earplugs to lessen any possible adverse effect on hearing Twice a week the MT will be measured by delivering single stimulations to the motor cortex The MT is measured by gradually increasing the intensity This is done by using the single pulse mode and applying one pulse every 5 secs ie 02 Hertz The electrical activity in abductor pollicis brevis is then recorded using surface electrodes Threshold is defined as the lowest intensity of stimulation able to produce motor evoked potentials of at least 50µV in 5 of 10 trials After defining the motor threshold the same intensity will be used in following treatments until the next threshold examination The coil will be positioned 6 cm anterior to the hot spot according to clinical judgment of the physician in charge The reference point could move 5 anterior to the hot spot and an dTMS session will be performed at 100 of the motor threshold for safety the investigatores lowered the 120 threshold used with adult depressed subjects
During the treatment trial period all subjects will receive the following dose of TMS 18 Hz at 100 RMT 2 sec pulse train 20 second inter-train interval 80 trains for a total of 57600 pulses over the complete treatment course In the placebo group a state of the art sham procedure will be used- the coil is programed to produce the noise and local sensation but with no activation38
MindWave of NeuroSky LTD This is an simple and approved EEG system that enables us to produce off line with the technology of Brain marc a valuable marker related to attention39 The recording will be performed by a trained technician and carries no danger and minimal inconvenience Recording is done with and without an acoustic oddball trigger in order to have both resting state and event related recordings The evaluation takes approximately 5 minutes The data are transported as anonymous signals to a secured cloud Our group has had fruitful experience with working with this system with depressed patients31
Cognitive assessment
Computerized Neuropsychological Battery Penn CNP In studying innovative treatments for adolescent depression cognitive and affective assessments are extremely important Depression has state and trait effects on cognitive abilities including attention and working memory40 41 Since possible effect on memory is a central concern with the use of electroconvulsive therapy considered by some the prototype of brain stimulation techniques monitoring cognitive functions especially in an adolescent brain stimulation TMS study is crucial42 43 The web-based Computerized Neuropsychological Battery Penn CNP of the Brain Behavior Laboratory at the University of Pennsylvania offers a range of probes of human neuropsychological functioning www penncnpmedupennedu It was designed for neuropsychological measurement of major cognitive domains PennCNP has granted us permission to use the WenCNP battery after assurance that our study is held in research institutions with IRB support under the direction of accredited research faculty members or students The WebCNP is administered using clickable icons on desktop or laptop computers in a fixed order An Applescript routine is used to collect participant IDs and basic demographic information and to present the tests in a prescribed order The test administrator reads instructions for each test and observes as the participant performs the tests Administrating the tests in a standard fashion fostering optimal performance without aiding the participant is required The test administrator provides a status code and comments regarding the validity of collected data The results are uploaded to a data repository using an automated script and scored using a program written in the Python programming language For each domain accuracy number of correct responses and speed response time for correct answers are computed Full battery completion takes approximately 1 hour Each test begins with a practice module to assure understanding of the instructions The tasks in the battery include the following Motor Praxis Test The Penn Face Memory Test Short Visual Object Learning Test Short Penn continuous performance task CPT Short Letter N-Back Task Penn Facial Memory Test- Delayed Memory Short Visual Object Learning Test - Delay Penn Emotion Recognition Faces 40 The Penn Conditional Exclusion Test The Penn Word Memory Test Penn Emotion Discrimination Task Short Penn Computerized Tapping Task Penn Matrix Analysis Test Penn Facial Age discrimination Variable Short Penn Line Orientation Test 34
Clinical Questionnaires
The development and well-being assessment DAWBA Is a commonly used structured interview intended to improve diagnostic reliability 34
CGI - Clinical Global Impression CGI is a commonly used tool for assessing the severity of the patients depression It uses 7 levels ranging from normal to severely ill36 It is important to note that this is a course but extremely relevant measure used in some of the most influential studies on treating adolescent depression3
Child depression rating scale CDRS Is a well validated structured assessment of adolescent depression using questions relevant to this age group35
Quick Inventory of Depressive Symptomatology QIDS-SR This is self-report commonly used in studying and monitoring depression in different age groups44
Suicidal ideation questionnaire SIQ This evaluation tool has shown reliability and validity in assessing and monitoring the severity of suicidal ideation45
The screen for child anxiety and related emotional disorders SCARED This is a brief and well established questionnaire that helps evaluate anxiety highly relevant measure in depressed adolescents46
Experimental design
After a brief presentation and screen eligible patients and their guardians will be invited to complete the informed consent process
Visit 1-pretreatment evaluation
Will include a physical and psychiatric evaluation completed with the DAWBA34 interview the CDRS35 to evaluate depression severity the suicidal ideation questionnaire SIQ45 and the CGI36 Patients will complete a demographic questionnaire QIDS 44 the screen for child anxiety and related emotional disorders SCARED46 In addition patients will go through a cognitive evaluation using the Penn Web-Based Computerized Neurocognitive Battery WebCNP47 On this visit the first EEG evaluation will be performed31
After the pretreatment visit patients will be blindly randomized to active or sham procedure
Visit 2-21 On visit 2 treatment threshold will be determined For the next 4 weeks patients will have a daily treatment sham or active session on each working day 5 days a week Before and after each treatment patients will be asked about their general condition mood suicidal thoughts and side effects from the treatment Before each therapy day an EEG monitoring will be performed
On visits 2 7 12 17 and 21 the first visit of every week and the last session patients will complete the clinical evaluation using the questionnaires detailed in the screen and repeat the EEG assessment after therapy
Follow up visits visits 22-24
After a week visit 22 a month visit 23 and two months visit 24 patients will repeat the more detailed evaluation as on the weekly visits On visit 22 the cognitive evaluation done in the screen will be repeated
Study Duration The anticipated enrollment rate is 2-3 per month Therefore approximately 20 months will be required to enroll 52 subjects The protocol duration for each subject is 4 weeks followed by 8 weeks for the 2 follow-up visits therefore the total study duration including data processing is expected to be approximately 24 months After an ethical consultation it has been decided that patients who were in the sham group at the end of the blinding will be able to receive active therapy
Monitoring of Subjects and Criteria for Withdrawal During the entire study the subjects will be under the direct monitoring of the principal investigator Any adverse effect or subjective disturbance will be immediately recorded and responded to If subjects are not cooperative they may be withdrawn by the investigators Subjects or parents wishing to withdraw at any time would be able to do so without prejudice Subjects whose condition is deteriorating as expressed by a 15 rise or more in the clinical questionnaires during the study period with no known emotional trigger such as a family or romantic crisis will discontinue therapy
Subject that completed 16 treatments or more within 6 weeks will be considered as a subject who completed the study trail
The first line treatment of moderate or severe illness includes pharmacotherapy with serotonin reuptake inhibitors SSRIs such as fluoxetine in combination with psychotherapy However more than 30 of the patients do not achieve remission defined as minimal or no symptoms despite treatment with a combined intervention 3 In adolescents there is some evidence that as a second line switching to another SSRI combined with cognitive behavioral therapy CBT can be useful 4 There is no evidence to what should be the third line in therapy Early intervention in the course of a disease is expected to protect from the grave long term sequelae9 but in treating adolescent depression our therapeutic tools are extremely limited10
There is a necessity to advance our evidence based interventions to treat treatments resistant adolescent depression
Hypoactivity in the left dorsolateral prefrontal cortex DLPC is a key finding in brain imaging of depression11 Repetitive transcranial magnetic stimulation rTMS is a therapeutic procedure in which a magnetic coil that generates recurrent pulsatile magnetic fields from a rapidly oscillating electrical current is placed on the scalp to induce recurrent electrical currents in the brain High frequency rTMS causes activation of the affected brain regions and networks This is the suggested mechanism of the antidepressant effect of high frequency rTMS to the left DLPC in depression12 Recent advances in custom coil technology led to the development of H coils that support stimulation of deeper limbic structures13 Due to the accumulating knowledge on safety and efficacy in adult depression both the custom rTMS and the deep H coil TMS are approved FDA and Israeli ministry of health for clinical not just research use 12 14-16 In a large multicenter study of the H1 coil to treat adult depression there were minimal side effects and a large effect size of 078 was reported strengthening the promise of this mode of therapy 5
The field of brain stimulation and specifically TMS is based on the concept of neuroplasticity the ability of repeated stimulations to cause a longer lasting neuronal change In this respect the adolescent developing brain is a period of opportunity for such changes17 18 To date there are no randomized placebo controlled studies on rTMS to treat adolescents suffering from depression although reports support the safety of rTMS in treating adolescents Recently there was a report of a self-limited convulsion in an adolescent treated with deep rTMS at 120 motor threshold-strengthening the necessity for well-structured studies in the field23
Studying biomarkers holds the promise for translating neuroscientific understandings to the clinical practice of adolescent depression24 In order to be useful a biomarker has to be discriminative between responder vs non responder for example to reflect a pathophysiological process but last and not least it is important that it will be accessible for use25 26 This explains the evolving interest in using electroencephalography EEG findings to study depression and monitor the course of therapy27 28 Imaging and electrophysiological studies support the importance of the interplay between the attentional and default networks as a marker of the disease course29 30 In a recent study our group cooperated in a study of a new simple EEG technique that by using repeated simple attentional EEG measures was able to predict treatment response in a heterogeneous group of adult depressed patients31 These safe and simple markers were never studied in adolescent depression
The present research is a randomized double blind placebo controlled EEG monitored study of deep rTMS treatment to treat adolescent depression
Research goals and expected significance
1 To study the efficacy and safety of deep rTMS to treat treatments resistant adolescent depression As there are no well controlled studies of rTMS to treat adolescent depression the possibility to evaluate a new therapeutic tool for this severe life threatening disease has immense clinical value Since this technique is based on evolving neuroscientific understandings it holds promise for advancing our understanding of adolescent depression
2 To evaluate a potential pragmatic EEG measure to predict and monitor therapeutic outcome Since the effect of deep rTMS on the developing brain of the depressed adolescent has a potential for both therapy and side effects early prediction of the effect is crucial The potential of having biomarkers to complement clinical and subjective evaluations is of paramount importance for personalizing objectively monitoring therapy to treat adolescent depression
Methods
Subjects Fifty-two adolescents age 14-18y suffering from treatment resistant depression will be recruited from Shalvata mental health center in patient ward and outpatient facilities Sample size calculation was based on the effect size of 078 found in the adult depression study5 The Shalvata Mental Health Center serves a large catchment area and the investigators are experienced in recruiting depressed adolescent patients to rTMS studies 20 21 33 Participation will be based on the following criteria
Devices
Deep TMS Brainsways H coil and deep TMS are registered in Israel for clinical use to treat depression in adults Our center has gained years of experience in studies with this system5 16 32 37 Deep TMS treatments will be carried out by a technician trained and approved by the manufacturer that will remain in the treatment room during the entire procedure In addition a physician will be available on-call within the hospital grounds
At the beginning of the trial individual motor threshold MT will be measured by placing the assigned coil above the hand area of the motor cortex Patients will receive stimulations over the prefrontal cortex 6 cms anterior to the hot spot for stimulation of the abductor policies brevis in the hand area Each deep TMS treatment will be conducted as follows Before starting each treatment patients will be instructed to insert earplugs to lessen any possible adverse effect on hearing Twice a week the MT will be measured by delivering single stimulations to the motor cortex The MT is measured by gradually increasing the intensity This is done by using the single pulse mode and applying one pulse every 5 secs ie 02 Hertz The electrical activity in abductor pollicis brevis is then recorded using surface electrodes Threshold is defined as the lowest intensity of stimulation able to produce motor evoked potentials of at least 50µV in 5 of 10 trials After defining the motor threshold the same intensity will be used in following treatments until the next threshold examination The coil will be positioned 6 cm anterior to the hot spot according to clinical judgment of the physician in charge The reference point could move 5 anterior to the hot spot and an dTMS session will be performed at 100 of the motor threshold for safety the investigatores lowered the 120 threshold used with adult depressed subjects
During the treatment trial period all subjects will receive the following dose of TMS 18 Hz at 100 RMT 2 sec pulse train 20 second inter-train interval 80 trains for a total of 57600 pulses over the complete treatment course In the placebo group a state of the art sham procedure will be used- the coil is programed to produce the noise and local sensation but with no activation38
MindWave of NeuroSky LTD This is an simple and approved EEG system that enables us to produce off line with the technology of Brain marc a valuable marker related to attention39 The recording will be performed by a trained technician and carries no danger and minimal inconvenience Recording is done with and without an acoustic oddball trigger in order to have both resting state and event related recordings The evaluation takes approximately 5 minutes The data are transported as anonymous signals to a secured cloud Our group has had fruitful experience with working with this system with depressed patients31
Cognitive assessment
Computerized Neuropsychological Battery Penn CNP In studying innovative treatments for adolescent depression cognitive and affective assessments are extremely important Depression has state and trait effects on cognitive abilities including attention and working memory40 41 Since possible effect on memory is a central concern with the use of electroconvulsive therapy considered by some the prototype of brain stimulation techniques monitoring cognitive functions especially in an adolescent brain stimulation TMS study is crucial42 43 The web-based Computerized Neuropsychological Battery Penn CNP of the Brain Behavior Laboratory at the University of Pennsylvania offers a range of probes of human neuropsychological functioning www penncnpmedupennedu It was designed for neuropsychological measurement of major cognitive domains PennCNP has granted us permission to use the WenCNP battery after assurance that our study is held in research institutions with IRB support under the direction of accredited research faculty members or students The WebCNP is administered using clickable icons on desktop or laptop computers in a fixed order An Applescript routine is used to collect participant IDs and basic demographic information and to present the tests in a prescribed order The test administrator reads instructions for each test and observes as the participant performs the tests Administrating the tests in a standard fashion fostering optimal performance without aiding the participant is required The test administrator provides a status code and comments regarding the validity of collected data The results are uploaded to a data repository using an automated script and scored using a program written in the Python programming language For each domain accuracy number of correct responses and speed response time for correct answers are computed Full battery completion takes approximately 1 hour Each test begins with a practice module to assure understanding of the instructions The tasks in the battery include the following Motor Praxis Test The Penn Face Memory Test Short Visual Object Learning Test Short Penn continuous performance task CPT Short Letter N-Back Task Penn Facial Memory Test- Delayed Memory Short Visual Object Learning Test - Delay Penn Emotion Recognition Faces 40 The Penn Conditional Exclusion Test The Penn Word Memory Test Penn Emotion Discrimination Task Short Penn Computerized Tapping Task Penn Matrix Analysis Test Penn Facial Age discrimination Variable Short Penn Line Orientation Test 34
Clinical Questionnaires
The development and well-being assessment DAWBA Is a commonly used structured interview intended to improve diagnostic reliability 34
CGI - Clinical Global Impression CGI is a commonly used tool for assessing the severity of the patients depression It uses 7 levels ranging from normal to severely ill36 It is important to note that this is a course but extremely relevant measure used in some of the most influential studies on treating adolescent depression3
Child depression rating scale CDRS Is a well validated structured assessment of adolescent depression using questions relevant to this age group35
Quick Inventory of Depressive Symptomatology QIDS-SR This is self-report commonly used in studying and monitoring depression in different age groups44
Suicidal ideation questionnaire SIQ This evaluation tool has shown reliability and validity in assessing and monitoring the severity of suicidal ideation45
The screen for child anxiety and related emotional disorders SCARED This is a brief and well established questionnaire that helps evaluate anxiety highly relevant measure in depressed adolescents46
Experimental design
After a brief presentation and screen eligible patients and their guardians will be invited to complete the informed consent process
Visit 1-pretreatment evaluation
Will include a physical and psychiatric evaluation completed with the DAWBA34 interview the CDRS35 to evaluate depression severity the suicidal ideation questionnaire SIQ45 and the CGI36 Patients will complete a demographic questionnaire QIDS 44 the screen for child anxiety and related emotional disorders SCARED46 In addition patients will go through a cognitive evaluation using the Penn Web-Based Computerized Neurocognitive Battery WebCNP47 On this visit the first EEG evaluation will be performed31
After the pretreatment visit patients will be blindly randomized to active or sham procedure
Visit 2-21 On visit 2 treatment threshold will be determined For the next 4 weeks patients will have a daily treatment sham or active session on each working day 5 days a week Before and after each treatment patients will be asked about their general condition mood suicidal thoughts and side effects from the treatment Before each therapy day an EEG monitoring will be performed
On visits 2 7 12 17 and 21 the first visit of every week and the last session patients will complete the clinical evaluation using the questionnaires detailed in the screen and repeat the EEG assessment after therapy
Follow up visits visits 22-24
After a week visit 22 a month visit 23 and two months visit 24 patients will repeat the more detailed evaluation as on the weekly visits On visit 22 the cognitive evaluation done in the screen will be repeated
Study Duration The anticipated enrollment rate is 2-3 per month Therefore approximately 20 months will be required to enroll 52 subjects The protocol duration for each subject is 4 weeks followed by 8 weeks for the 2 follow-up visits therefore the total study duration including data processing is expected to be approximately 24 months After an ethical consultation it has been decided that patients who were in the sham group at the end of the blinding will be able to receive active therapy
Monitoring of Subjects and Criteria for Withdrawal During the entire study the subjects will be under the direct monitoring of the principal investigator Any adverse effect or subjective disturbance will be immediately recorded and responded to If subjects are not cooperative they may be withdrawn by the investigators Subjects or parents wishing to withdraw at any time would be able to do so without prejudice Subjects whose condition is deteriorating as expressed by a 15 rise or more in the clinical questionnaires during the study period with no known emotional trigger such as a family or romantic crisis will discontinue therapy
Subject that completed 16 treatments or more within 6 weeks will be considered as a subject who completed the study trail
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None