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Neurobiological Analyses Within the FORESEE III Study

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ClinicalTrials.gov Identifier: NCT04021823
Recruitment Status : Recruiting
First Posted : July 16, 2019
Last Update Posted : August 15, 2019
Sponsor:
Collaborators:
German Center for Neurodegenerative Diseases (DZNE)
University Medical Center Freiburg
University Hospital, Bonn
Information provided by (Responsible Party):
Thomas E. Schlaepfer, Prof. Dr., University Hospital Freiburg

Brief Summary:
In this observational, non-invasive clinical study different neurobiological analyses will be performed in a group of patients with severe treatment resistant major depression participating in an efficacy study of deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB) - FORESEE III.

Condition or disease
Treatment Resistant Depression

Detailed Description:

This study is a sub-project of the FORESEE III study (Controlled Randomized Clinical Trial to assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients with Treatment Resistant Major Depression). The FORESEE III study itself is a randomized, sham-controlled, double blind (patient and observer blinded) clinical trial to assess the antidepressant effect of DBS compared to sham.

The aim of this sub-project is to analyze the time-course of biological correlates of treatment resistant major depression as well as neurobiological markers of treatment response to treatment with DBS in a well-characterized patient population during 12 month of DBS.

Specific neurobiological analyses include testing of

  1. epigenetic markers (DNA methylation in candidate genes of depression and epigenome-wide association studies, EWAS) and
  2. markers of neuroinflammation (cytokines, neuropeptides and other immune factors),
  3. micro RNAs and transcriptome signatures as well as
  4. markers of neurodegeneration (neurofilament light protein). All markers will be tested in plasma samples before neurosurgery as well as at several time points during DBS and sham condition intervals. Additionally
  5. hemodynamic parameters will be analysed at test stimulation of the slMFB during neurosurgery.

The results will be correlated with clinical and other biological response parameters of the FORESEE III study and are hypothesized to indicate treatment response as well as allowing prediction of response to DBS. All neurobiological analyses will be linked in a tightly integrated and comprehensive translational approach.


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Study Type : Observational
Estimated Enrollment : 29 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Neurobiological Analyses Within the FORESEE III Study
Actual Study Start Date : August 1, 2019
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine





Primary Outcome Measures :
  1. Plasma levels of Neurofilament light protein [ Time Frame: At baseline (up to 10 weeks before surgical device implantation), 2 days before implantation, at week 5, week 17, week 21 and week 33 after implantation as well as at end of study, i.e. after 12 month of DBS ]
    Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays.

  2. DNA methylation patterns in plasma [ Time Frame: At baseline (up to 10 weeks before surgical device implantation), at week 5, week 17, week 21 and week 33 after implantation as well as at end of study, i.e. after 12 month of DBS ]

    Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes.

    DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression.


  3. Neuroinflammatory and neuropeptide patterns in plasma [ Time Frame: At baseline (up to 10 weeks before surgical device implantation), at week 5, week 17, week 21 and week 33 after implantation as well as at end of study, i.e. after 12 month of DBS ]
    A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors.

  4. Exosomal Micro-RNA (miR) expression levels and transcriptome profiles in plasma [ Time Frame: At baseline (up to 10 weeks before surgical device implantation), at week 5, week 17, week 21 and week 33 after implantation as well as at end of study, i.e. after 12 month of DBS ]
    A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles.

  5. Non-invasive blood pressure (mmHG) [ Time Frame: At test stimulation of the slMFB during neurosurgery ]
    Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring).

  6. Cardiac stroke volume (ml) [ Time Frame: At test stimulation of the slMFB during neurosurgery ]
    Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring).

  7. Cardiac stroke volume variation (%) [ Time Frame: At teststimulation of the slMFB during neurosurgery ]
    Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring)

  8. Systemic vascular resistance (mmHg⋅min⋅mL-1) [ Time Frame: At test stimulation of the slMFB during neurosurgery ]
    Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring).



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Ages Eligible for Study:   20 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Eligible participants are patients who participate in the FORESEE III study (NCT03653858) and have provided written informed consent to take part in this additional observational study.

All patients suffering from severe, treatment-resistant depression, i.e. patients who have not sufficiently improved under established antidepressant therapies (such as psychotherapy, antidepressant drug therapy, and electroconvulsive therapy).

Criteria

Inclusion Criteria:

  • All enrolled subjects of the Controlled Randomized Clinical Trial to assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients with Treatment Resistant Major Depression (FORESEE III) may participate in this study.

Exclusion Criteria:

  • Non-Caucasian (because of requirements for genetic/epigenetic analyses)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04021823


Contacts
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Contact: Susanne Spanier ‭+49 761 270 69800‬ susanne.spanier@uniklinik-freiburg.de
Contact: Thomas E. Schläpfer, Prof. Dr. 0049 761 270 68820 thomas.schlaepfer@uniklinik-freiburg.de

Locations
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Germany
University Hospital Freiburg Recruiting
Freiburg, Baden Württemberg, Germany, 79106
Contact: Susanne Spanier    0049 761 270 69800    susanne.spanier@uniklinik-freiburg.de   
Contact: Thomas E. Schläpfer, Prof. Dr.    0049 761 270 68820    thomas.schlaepfer@uniklinik-freiburg.de   
Sponsors and Collaborators
University Hospital Freiburg
German Center for Neurodegenerative Diseases (DZNE)
University Medical Center Freiburg
University Hospital, Bonn
Investigators
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Principal Investigator: Thomas E. Schläpfer, Prof. Dr. University of Freiburg

Publications:
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Responsible Party: Thomas E. Schlaepfer, Prof. Dr., Professor Dr. Thomas E. Schläpfer, University Hospital Freiburg
ClinicalTrials.gov Identifier: NCT04021823     History of Changes
Other Study ID Numbers: 40418
First Posted: July 16, 2019    Key Record Dates
Last Update Posted: August 15, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Thomas E. Schlaepfer, Prof. Dr., University Hospital Freiburg:
Treatment Resistant Depression
Neurobiological correlates of treatment resistant depression
Predictors of treatment response in DBS
Additional relevant MeSH terms:
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Depression
Depressive Disorder, Treatment-Resistant
Behavioral Symptoms
Depressive Disorder
Mood Disorders
Mental Disorders