Ignite Creation Date:
2024-10-25 @ 8:05 PM
Last Modification Date:
2024-10-26 @ 3:39 PM
Study NCT ID:
NCT06590025
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-09-06
Brief Title:
Study the Efficacy and Safety of the INtegral Cognitive REMediation Program INCREM for Depression
Sponsor:
None
Organization:
None
Study Overview
Official Title:
A Phase III Randomized Active Comparator-controlled Clinical Trial to Study the Efficacy and Safety of the INtegral Cognitive REMediation Program INCREM in Patients with Depression
Status:
RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
INCREM
Brief Summary:
Feeling sad about negative or stressful events has nothing to do with the diagnosis of depression as this is a very prevalent mental illness among the population with devastating consequences for the person suffering from it Symptoms range from mood swings extreme sadness apathy inability to feel pleasure to sleep problems eating disorders physical problems and more Other very common but little-known symptoms are those that affect memory concentration and the ability to organize and solve problems
Recent scientific findings have shown that these symptoms called cognitive symptoms are the most interfering with day-to-day life even when other mental symptoms begin to improve or have resolved Cognitive symptoms are associated with work difficulties especially in terms of productivity or a decrease in social relationships to the point of isolation thus interfering with the full recovery from depression Studies have estimated that the economic and social costs not related to the health costs of depression can be more than 90 million euros per year The fact that cognitive symptoms are not explored during clinical interviews means that they are not treated adequately and professionals usually wait for cognitive difficulties to be resolved with the available antidepressant treatments But more than 30 of people with depression are unable to return to work and up to 45 of patients are on sick leave a year later although mood symptoms have often been ameliorated
This opens a new line of research worldwide that aims to find effective treatments for the cognitive symptoms of depression Some drugs have been developed and cognitive training programs designed for patients with dementia or neurological conditions have been tested but the results are not convincing enough because there is no transfer of cognitive improvements into peopleampampampampamp39s lives The research team of this proposal designed a comprehensive rehabilitation program for cognition and daily functioning for depression taking into account the specific cognitive symptoms and the real difficulties that patients face Thus was born INCREM INtegral Cognitive REMediation for Depression which includes cognitive training and therapy sessions focused on the rehabilitation of daily functioning The first results in very selected samples have shown an objective improvement in day-to-day functioning not only after the intervention but up to 6 months later The aim of this proposal is to demonstrate the effectiveness and benefits of INCREM for depression in a larger and more diverse sample of patients as well as finding out the effects of INCREM on the brain The ultimate goal is to implement this type of therapy in mental health care centers in order to treat patientsampampampampamp39 cognitive symptoms and get them back to their personal work and social lives
Recent scientific findings have shown that these symptoms called cognitive symptoms are the most interfering with day-to-day life even when other mental symptoms begin to improve or have resolved Cognitive symptoms are associated with work difficulties especially in terms of productivity or a decrease in social relationships to the point of isolation thus interfering with the full recovery from depression Studies have estimated that the economic and social costs not related to the health costs of depression can be more than 90 million euros per year The fact that cognitive symptoms are not explored during clinical interviews means that they are not treated adequately and professionals usually wait for cognitive difficulties to be resolved with the available antidepressant treatments But more than 30 of people with depression are unable to return to work and up to 45 of patients are on sick leave a year later although mood symptoms have often been ameliorated
This opens a new line of research worldwide that aims to find effective treatments for the cognitive symptoms of depression Some drugs have been developed and cognitive training programs designed for patients with dementia or neurological conditions have been tested but the results are not convincing enough because there is no transfer of cognitive improvements into peopleampampampampamp39s lives The research team of this proposal designed a comprehensive rehabilitation program for cognition and daily functioning for depression taking into account the specific cognitive symptoms and the real difficulties that patients face Thus was born INCREM INtegral Cognitive REMediation for Depression which includes cognitive training and therapy sessions focused on the rehabilitation of daily functioning The first results in very selected samples have shown an objective improvement in day-to-day functioning not only after the intervention but up to 6 months later The aim of this proposal is to demonstrate the effectiveness and benefits of INCREM for depression in a larger and more diverse sample of patients as well as finding out the effects of INCREM on the brain The ultimate goal is to implement this type of therapy in mental health care centers in order to treat patientsampampampampamp39 cognitive symptoms and get them back to their personal work and social lives
Detailed Description:
BACKGROUND Major Depressive Disorder MDD is a mood disorder that places substantial clinical social and economic burden onpatients as well as on their families and wider society The total cost of MDD is estimated at 170000 million euros per year wwweurowhoint where more than a half are indirect costs such as loss of productivity in the workplace sick leave and early retirement In Spain it is estimated that depression causes complete functional disability of 47 days per year on average and partial functional disability of 60 days per year 1 Particularly in Catalonia depression had a direct health cost of 155 million which rose to 735 million when lost productivity was included temporary disability 27 permanent 48 in the last decade 2 The authors concluded that the cost of mental illness has a considerable impact from asocietal perspective as direct costs in the public health system or indirect costs related to productivity losses are only part of total costs of depression 3 Some studies confirm that severity of depressive symptoms predicts the functional deterioration of patients beyond losing a job or spending public health resources More recent studies add that cognitive symptoms ie alterations in executive functions attention memory and processing speed are even more important independent predictors of such psychosocial dysfunction in subsequent depressive episodes 4 Therefore cognitive symptoms could explain the low full recovery rates and the functional disability of patients with MDD 56 Although cognitive symptoms are nowadays recognized and partially incorporated as a criterion for the diagnosis of an episode of MDD DSM-5 until recently no treatment addressed these symptoms There is increasing evidence that patients with MDD show heterogeneity in cognitive difficulties presenting different cognitive profiles in the first depressive episode as demonstrated in project PI1301057 IP Maria J Portella and in the different stages of the disease 7 Up to 45 of patients with treated MDD have permanent cognitive deficits 8 which significantly interfere with work and daily functioning 9
Some evidence has acknowledged the poor efficacy of most pharmacological treatments in the improvement of cognitive symptoms 10 Although new antidepressants with other mechanisms of action seem to have different effects on the cognitive function these still show low or moderate efficacy Regarding non-pharmacological treatments cognitive remediation CR has been investigated as a possible treatment of cognitive dysfunction of depressive disorders in the last decade But the results are not fully satisfactory and efficacy is in its infancy Different reasons have been suggested to explain the low impact of cognitive rehabilitation programs for MDD among which the use of neurological models in the design of these programs instead of using compensatory techniques more effective in psychiatric disorders 11 or the fact of not taking into account the episodic nature and tendency to chronicity of MDD which implies very different profiles of cognitive involvement among patients 7 Therefore a critical aspect of remediation programs for MDD is to adapt them to the cognitive profile of each patient
In an attempt to improve previous results using poorly structured programs computerized cognitive training CCT had proven to be more beneficial than available CR programs in patients with MDD 12 This type of training was based on mental tasks repetition which ended up having an effect on patients difficulties Subsequently several studies have shown that CCT is perhaps the best method of administration for MDD as tasks are adjusted to the needs of each individual In a meta-analysis including the 9 randomized studies that existed of CCT in MDD 13 it was observed how CCT was associated with a slight improvement of depressive symptoms but scarcely of daily functioning In this regard it should be noted that only two of the nine studies investigated the impact of treatment on global functioning specifically Regarding cognitive benefits the results depended on cognitive domains seeing a notable improvement in working memory and attention while executive functions and verbal memory remained altered These benefits were not easily transferred to new tasks or only when they required the same processing requirements as trained tasks Thus one of the biggest problems of these computerized programs was the transfer of trained skills to daily life tasks including work capacity Another recent approach is the Goal Management Training GMT a strategy-based CR intervention The findings comparing GMT with drill-and-practice CCT has shown long-term mental health following GMT while improvements in everyday life might require additional treatment or maintenance to sustain 14 Sample sizes of previous works are extremely limited nampampampamplt30 casting doubt on the representativeness of findings and thus impeding their generalization or implementation to real-world clinical settings The study on Functional Remediation FR with the largest sample was carried out by the group of MartÃnez-Aran for patients with bipolar disorders in a multicentre clinical trial which showed efficacy of FR compared to treatment as usual TAU or psychosocial functioning 15 However these programs did not include any tailored cognitive intervention at the individual level such as CCT and therefore the transfer of cognitive improvement to daily functioning was not achieved
The mechanism of action of cognitive remediation interventions is still unknown Very few studies have investigated biomarkers associated to CR response apart from a unique study 11 There is mounting evidence that neurotrophic factors immune markers and oxidative stress play a key role in cognitive dysfunction 16-20 regardless of underlying psychiatric pathology Research of peripheral biomarkers and treatment response have described fairly consistent findings in which neuroimmune alterations back to normal levels 1617 Magnetic resonance imaging MRI evidence suggests a possible link between structuralfunctional anomalies in the brain and on one hand a decrease of growth factors and on the other an increase of circulating inflammation and oxidative markers Several of these studies have been carried out by the PI as well as other members of the consortium see references Mostly neuroimaging studies have reported alterations in brain regions involving fronto-temporal and cortico-limbic circuits 21 also related with pharmacological treatment response and prediction of recurrence 22 in the areas mentioned above where smaller brain volumes typically estimate poorer treatment response whereas larger brain volumes correlate with good response and remission Less consensus has been achieved with white matter alterations investigated with diffusion tensor imaging DTI where some studies report lower white matter fractional anisotropy FA in good response to treatment while others show the opposite 23 Other inconsistencies are found in functional MRI fMRI in treatment response especially in task-based fMRI but also in resting-state functional connectivity RSFC partially due to a considerable variability in study designs 24 One of the recent MRI technical advances is to study microstructural changes in both grey and white matter more expectable to be detected in usually normal-appearing brains ie without atrophy o severe detectable white matter hyperintensities One limitation of previous studies was the application of gross neuroimaging techniques that may not capture subtle cortical changes driving cognitive and behavioural outcomes DTI has now been proposed to measure both cortical grey matter and subcortical white matter changes using mean diffusivity MD metrics overcoming former technical difficulties for the study of cortical microstructure Cortical MD is a measure of cortical microstructure integrity and has proven to be a sensitive tool for subtle cortical changes in early stages of neurodegenerative diseases 24
However most of the randomized controlled trials of CR or CCT effects in psychiatric and neurologic conditions use clinical endpoints that may be soaked in subjectivity or surrogate endpoints based on psychometric tools Blood and neuroimaging biomarkers may therefore represent a clinically applicable alternative surrogate endpoints that would be cost-effective and minimally invasive so as to provide the neurobiological underpinnings of functional and cognitive remediation response
STATE-OF-THE-ART Based on the evidence of unfavourable findings in 2017 a project was granted for the development of INtegral Cognitive REMediation for Major Depression INCREM PI1700056 IP Maria J Portella This comprehensive functional remediation program includes a traditional CR component with a specialized therapist based on the compensation model and a CCT component adapted to the difficulties of each patient The inclusion of both aspects allows adapting the intervention to the present difficulties by forming new strategies with compensation techniques and promoting translation to everyday life Therefore the intervention aims at improving cognitive functioning beyond a mere training so as to facilitate the improvement and maintenance of psychosocial functioning for patients with MDD The details of INCREM program have been published as a protocol 25
The proof-of-concept revealed very promising findings Preliminary data was acquired through a randomized clinical trial which included 3 treatment arms INCREM active arm a psychoeducation program active comparator arm and usual treatment TAU non-active arm Such a change in the methodology made it impossible to demonstrate the efficacy of the program but the pilot study has served to demonstrate the feasibility of INCREM The results showed that INCREM significantly improved psychosocial functioning in remitted depressed patients soon after the end of the intervention and six months after 26 More than 65 of patients achieved functional recovery There was also an enhancement of general cognition providing evidence of the necessity to combine compensatory and drill-and-practice strategies The acceptability of the interventions explored through open question to all participants varies from good to very good More importantly this previous study demonstrates the feasibility safety and benefits of INCREM The efficacy of the INCREM program with respect to the psychoeducation intervention is now being analysed through a multicentre randomized clinical trial which was funded by the ISCIII call PI2000270 IP Maria J Portella and covers different sociodemographic areas Preliminary findings point towards the confirmation of significant improvement of long-term psychosocial functioning as well as enhancement of cognitive functioning and of overall patients well-being The inclusion of comprehensive data other than clinical outcomes should be part of future studies The integration of clinical neuroimmuno-oxidative factors and fine neuroimaging markers will improve the study of INCREM outcomes and therefore the accuracy and sensitivity of the prediction for this particular treatment response
The present call offers an exceptional opportunity to continue this innovative and promising line of research started by the PI in which most of the members of the research team have been involved This Phase III clinical trial will involve a much larger group of patients and will focus on determining whether INCREM would be safe and effective for a wide variety of patients with depressive disorders This should confirm and expand the efficacy of INCREM and more importantly should help depressed patients with cognitive symptoms achieving full recovery which in turn should represent significant decrements of public health and social-personal costs associated to depression
HYPOTHESES
1 Patients in the INCREM arm will improve their functional and cognitive functioning showing
an improvement in psychosocial functioning on the FAST scale main variable
a mid-term improvement in pragmatic psychosocial variables reduction in the number of sick leaves increment of self efficacy measures related with work and social activities
an improvement in cognitive performance both in objective cognitive tests and subjective appraisal
2 Patients in the INCREM arm will achieve full recovery ie global clinical functional and cognitive symptoms amelioration
3 INCREM will reduce the number of relapses and improve subsyndromic symptoms
4 functioning and cognitive improvements will be associated with neuroimmune-oxidative markers Specifically
increments of neurotrophic markers will be associated with decrements of psychosocial and cognitive dysfunction
decrements of oxidative stress markers will be associated with decrements of psychosocial and cognitive dysfunction
decrements of pro-inflammatory markers will be associated with decrements of psychosocial and cognitive dysfunction
microstructural grey and white matter changes will be associated with percentage change in psychosocial and cognitive scales
OBJECTIVES Main
1 To demonstrate the efficacy of INCREM program through a randomized clinical trial with an active comparator psychoeducation in a representative sample of patients with depressive disorders
2 To improve the global functioning through aiming full recovery of patients with depressive disorders
3 To determine the mechanism of action on INCREM by using neurobiological biomarkers that may serve as surrogate clinical endpoints of the efficacy of INCREM
Secondary
1 To use individual cognitive profiles of patients with MDD to personalize the content of CCT so as to achieve full recovery
2 To increase the effect size of the results of INCREM with respect to previous phases which were run in limited samples
by using a larger sample from different geographical settings and in a wider spectrum of depression
by including compensatory and drill-and-practice strategies
by combining traditional groups sessions individualized cognitive training
3 To study the specific clinical sociodemographic factors ie psychosocial and self-efficacy and biomarkers that mediate the potential clinical and functional improvement
STUDY DESIGN Randomized multicentre blind evaluator controlled with active comparator clinical trial Phase III stratified by biological sex age and level of studies to assess the efficacy of the INCREM program functional rehabilitation and computerized cognitive training The main variable will be the improvement in global psychosocial functioning -average change in the FAST Functioning Assessment Short Test score between baseline T0 post-treatment T1 and follow-up 6 mo after the end of intervention T2
Some evidence has acknowledged the poor efficacy of most pharmacological treatments in the improvement of cognitive symptoms 10 Although new antidepressants with other mechanisms of action seem to have different effects on the cognitive function these still show low or moderate efficacy Regarding non-pharmacological treatments cognitive remediation CR has been investigated as a possible treatment of cognitive dysfunction of depressive disorders in the last decade But the results are not fully satisfactory and efficacy is in its infancy Different reasons have been suggested to explain the low impact of cognitive rehabilitation programs for MDD among which the use of neurological models in the design of these programs instead of using compensatory techniques more effective in psychiatric disorders 11 or the fact of not taking into account the episodic nature and tendency to chronicity of MDD which implies very different profiles of cognitive involvement among patients 7 Therefore a critical aspect of remediation programs for MDD is to adapt them to the cognitive profile of each patient
In an attempt to improve previous results using poorly structured programs computerized cognitive training CCT had proven to be more beneficial than available CR programs in patients with MDD 12 This type of training was based on mental tasks repetition which ended up having an effect on patients difficulties Subsequently several studies have shown that CCT is perhaps the best method of administration for MDD as tasks are adjusted to the needs of each individual In a meta-analysis including the 9 randomized studies that existed of CCT in MDD 13 it was observed how CCT was associated with a slight improvement of depressive symptoms but scarcely of daily functioning In this regard it should be noted that only two of the nine studies investigated the impact of treatment on global functioning specifically Regarding cognitive benefits the results depended on cognitive domains seeing a notable improvement in working memory and attention while executive functions and verbal memory remained altered These benefits were not easily transferred to new tasks or only when they required the same processing requirements as trained tasks Thus one of the biggest problems of these computerized programs was the transfer of trained skills to daily life tasks including work capacity Another recent approach is the Goal Management Training GMT a strategy-based CR intervention The findings comparing GMT with drill-and-practice CCT has shown long-term mental health following GMT while improvements in everyday life might require additional treatment or maintenance to sustain 14 Sample sizes of previous works are extremely limited nampampampamplt30 casting doubt on the representativeness of findings and thus impeding their generalization or implementation to real-world clinical settings The study on Functional Remediation FR with the largest sample was carried out by the group of MartÃnez-Aran for patients with bipolar disorders in a multicentre clinical trial which showed efficacy of FR compared to treatment as usual TAU or psychosocial functioning 15 However these programs did not include any tailored cognitive intervention at the individual level such as CCT and therefore the transfer of cognitive improvement to daily functioning was not achieved
The mechanism of action of cognitive remediation interventions is still unknown Very few studies have investigated biomarkers associated to CR response apart from a unique study 11 There is mounting evidence that neurotrophic factors immune markers and oxidative stress play a key role in cognitive dysfunction 16-20 regardless of underlying psychiatric pathology Research of peripheral biomarkers and treatment response have described fairly consistent findings in which neuroimmune alterations back to normal levels 1617 Magnetic resonance imaging MRI evidence suggests a possible link between structuralfunctional anomalies in the brain and on one hand a decrease of growth factors and on the other an increase of circulating inflammation and oxidative markers Several of these studies have been carried out by the PI as well as other members of the consortium see references Mostly neuroimaging studies have reported alterations in brain regions involving fronto-temporal and cortico-limbic circuits 21 also related with pharmacological treatment response and prediction of recurrence 22 in the areas mentioned above where smaller brain volumes typically estimate poorer treatment response whereas larger brain volumes correlate with good response and remission Less consensus has been achieved with white matter alterations investigated with diffusion tensor imaging DTI where some studies report lower white matter fractional anisotropy FA in good response to treatment while others show the opposite 23 Other inconsistencies are found in functional MRI fMRI in treatment response especially in task-based fMRI but also in resting-state functional connectivity RSFC partially due to a considerable variability in study designs 24 One of the recent MRI technical advances is to study microstructural changes in both grey and white matter more expectable to be detected in usually normal-appearing brains ie without atrophy o severe detectable white matter hyperintensities One limitation of previous studies was the application of gross neuroimaging techniques that may not capture subtle cortical changes driving cognitive and behavioural outcomes DTI has now been proposed to measure both cortical grey matter and subcortical white matter changes using mean diffusivity MD metrics overcoming former technical difficulties for the study of cortical microstructure Cortical MD is a measure of cortical microstructure integrity and has proven to be a sensitive tool for subtle cortical changes in early stages of neurodegenerative diseases 24
However most of the randomized controlled trials of CR or CCT effects in psychiatric and neurologic conditions use clinical endpoints that may be soaked in subjectivity or surrogate endpoints based on psychometric tools Blood and neuroimaging biomarkers may therefore represent a clinically applicable alternative surrogate endpoints that would be cost-effective and minimally invasive so as to provide the neurobiological underpinnings of functional and cognitive remediation response
STATE-OF-THE-ART Based on the evidence of unfavourable findings in 2017 a project was granted for the development of INtegral Cognitive REMediation for Major Depression INCREM PI1700056 IP Maria J Portella This comprehensive functional remediation program includes a traditional CR component with a specialized therapist based on the compensation model and a CCT component adapted to the difficulties of each patient The inclusion of both aspects allows adapting the intervention to the present difficulties by forming new strategies with compensation techniques and promoting translation to everyday life Therefore the intervention aims at improving cognitive functioning beyond a mere training so as to facilitate the improvement and maintenance of psychosocial functioning for patients with MDD The details of INCREM program have been published as a protocol 25
The proof-of-concept revealed very promising findings Preliminary data was acquired through a randomized clinical trial which included 3 treatment arms INCREM active arm a psychoeducation program active comparator arm and usual treatment TAU non-active arm Such a change in the methodology made it impossible to demonstrate the efficacy of the program but the pilot study has served to demonstrate the feasibility of INCREM The results showed that INCREM significantly improved psychosocial functioning in remitted depressed patients soon after the end of the intervention and six months after 26 More than 65 of patients achieved functional recovery There was also an enhancement of general cognition providing evidence of the necessity to combine compensatory and drill-and-practice strategies The acceptability of the interventions explored through open question to all participants varies from good to very good More importantly this previous study demonstrates the feasibility safety and benefits of INCREM The efficacy of the INCREM program with respect to the psychoeducation intervention is now being analysed through a multicentre randomized clinical trial which was funded by the ISCIII call PI2000270 IP Maria J Portella and covers different sociodemographic areas Preliminary findings point towards the confirmation of significant improvement of long-term psychosocial functioning as well as enhancement of cognitive functioning and of overall patients well-being The inclusion of comprehensive data other than clinical outcomes should be part of future studies The integration of clinical neuroimmuno-oxidative factors and fine neuroimaging markers will improve the study of INCREM outcomes and therefore the accuracy and sensitivity of the prediction for this particular treatment response
The present call offers an exceptional opportunity to continue this innovative and promising line of research started by the PI in which most of the members of the research team have been involved This Phase III clinical trial will involve a much larger group of patients and will focus on determining whether INCREM would be safe and effective for a wide variety of patients with depressive disorders This should confirm and expand the efficacy of INCREM and more importantly should help depressed patients with cognitive symptoms achieving full recovery which in turn should represent significant decrements of public health and social-personal costs associated to depression
HYPOTHESES
1 Patients in the INCREM arm will improve their functional and cognitive functioning showing
an improvement in psychosocial functioning on the FAST scale main variable
a mid-term improvement in pragmatic psychosocial variables reduction in the number of sick leaves increment of self efficacy measures related with work and social activities
an improvement in cognitive performance both in objective cognitive tests and subjective appraisal
2 Patients in the INCREM arm will achieve full recovery ie global clinical functional and cognitive symptoms amelioration
3 INCREM will reduce the number of relapses and improve subsyndromic symptoms
4 functioning and cognitive improvements will be associated with neuroimmune-oxidative markers Specifically
increments of neurotrophic markers will be associated with decrements of psychosocial and cognitive dysfunction
decrements of oxidative stress markers will be associated with decrements of psychosocial and cognitive dysfunction
decrements of pro-inflammatory markers will be associated with decrements of psychosocial and cognitive dysfunction
microstructural grey and white matter changes will be associated with percentage change in psychosocial and cognitive scales
OBJECTIVES Main
1 To demonstrate the efficacy of INCREM program through a randomized clinical trial with an active comparator psychoeducation in a representative sample of patients with depressive disorders
2 To improve the global functioning through aiming full recovery of patients with depressive disorders
3 To determine the mechanism of action on INCREM by using neurobiological biomarkers that may serve as surrogate clinical endpoints of the efficacy of INCREM
Secondary
1 To use individual cognitive profiles of patients with MDD to personalize the content of CCT so as to achieve full recovery
2 To increase the effect size of the results of INCREM with respect to previous phases which were run in limited samples
by using a larger sample from different geographical settings and in a wider spectrum of depression
by including compensatory and drill-and-practice strategies
by combining traditional groups sessions individualized cognitive training
3 To study the specific clinical sociodemographic factors ie psychosocial and self-efficacy and biomarkers that mediate the potential clinical and functional improvement
STUDY DESIGN Randomized multicentre blind evaluator controlled with active comparator clinical trial Phase III stratified by biological sex age and level of studies to assess the efficacy of the INCREM program functional rehabilitation and computerized cognitive training The main variable will be the improvement in global psychosocial functioning -average change in the FAST Functioning Assessment Short Test score between baseline T0 post-treatment T1 and follow-up 6 mo after the end of intervention T2
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