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Refractory DepressionNCT04202770

Focused Ultrasound and Exosomes to Treat Depression, Anxiety, and Dementias

A study testing Exosomes in people with Refractory Depression and Anxiety Disorders, run by Neurological Associates of West Los Angeles at 1 site in United States.

Suspended

Paused. Enrolment is on hold for now and may resume.

Official record
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Trial summary

This study is designed to evaluate the safety and efficacy of exosome deployment with concurrent transcranial ultrasound in patients with refractory, treatment resistant depression, anxiety, and neurodegenerative dementia. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Exosomes
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
300 participants
Where
1 siteUnited States
Study dates
1 Dec 2019to Dec 2024
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • In order for a subject to be considered for the depression application of this study, the following criteria are required:
  • Diagnosis of Major Depressive Disorder
  • Score greater than 13 on the Beck Depression Inventory
  • Failure to remit with 3 antidepressants
  • At least 18 years of age
  • In order for a subject to be considered for the anxiety application of this study, the following criteria are required:
Show all 14Show fewer
  • Diagnosis of Generalized or Acute Anxiety Disorder
  • Score greater than 22 on the Beck Anxiety Inventory
  • Failure to remit with 3 anxiolytics
  • At least 18 years of age
  • In order for a subject to be considered for the neurodegenerative application of this study, the following criteria are required:
  • Cognitive decline with mild cognitive impairment (Clinical Dementia Rating stage 0.5) through moderate dementia (CDR stage 2)
  • Lumbar puncture for Abeta 42 and Tau proteins evincing clinical correlation of neurodegenerative disease pathology
  • Advanced MRI of the brain including volume measurement of the hippocampus, BOLD, and ASL perfusion scans. On entry, patients will have CDR stage of at least 0.5 and at least one abnormal imaging biomarker. CSF studies have demonstrated good sensitivity and specificity for MCI and dementia of the Alzheimer's type (Tapiola et al., 2009). Additionally, MRI volumetrics and perfusion scans have shown to be useful in differentiating subgroups of AD, PDD/DLB, and FTLD; these values are also responsive to change as patients progress form MCI to dementia (Targosz-Gajniak et al., 2013).

Who cannot join

  • Cognitive decline clearly related to an acute illness
  • Subjects unable to give informed consent
  • Subjects who would not be able to lay down without excessive movement in a calm environment sufficiently long enough to be able to achieve sleep
  • Recent surgery or dental work within 3 months of the scheduled procedure.
  • Pregnancy, women who may become pregnant or are breastfeeding
  • Advanced terminal illness
Show all 16Show fewer
  • Any active cancer or chemotherapy
  • Bone marrow disorder
  • Myeloproliferative disorder
  • Sickle cell disease
  • Primary pulmonary hypertension
  • Immunocompromising conditions and/or immunosuppressive therapies
  • Any other neoplastic illness or illness characterized by neovascularity
  • Macular degeneration
  • Subjects with scalp rash or open wounds on the scalp (for example from treatment of squamous cell cancer)
  • Advanced kidney, pulmonary, cardiac or liver failure

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Neurological Associates of West Los Angeles

    Santa Monica, California, 90403

Other trials in United States

About this study

Official title: Focused Ultrasound Delivery of Exosomes for Treatment of Refractory Depression, Anxiety, and Neurodegenerative Dementias

This study is designed to evaluate the safety and efficacy of exosome deployment with concurrent transcranial ultrasound in patients with refractory, treatment resistant depression, anxiety, and neurodegenerative dementia.

Read the detailed description

The present study is designed to enhance the delivery of growth factors and anti-inflammatory agents to localized targets (determined by specific condition) by using focused transcranial ultrasound prior to intravenous infusion of exosomes. Exosomes, which are ubiquitous in blood, body fluids, and tissues are thought to play a normal physiological role in intercellular signaling. Exosomes delivered intravenously can be demonstrated to cross the blood brain barrier naturally. Exosomes and mesenchymal signaling cells (MSC's) demonstrate anti-inflammatory and pro-growth effects in preclinical models and clinical cases reports and have been used intravenously and with intracerebral and intrathecal injection. Various clinical trials have claimed safety and clinical efficacy.

Focused ultrasound has been demonstrated to enhance local blood flow and has been proposed as a non-invasive means of targeting delivery of therapeutic agents. The present paper was designed to use focused ultrasound as a means of enhancing delivery of intravenous exosomes to the subgenual target for patients with refractory depression, the amygdala for patients with anxiety, and the hippocampus for patients with cognitive impairment due to neurodegenerative disease.

Being tested
Exosomes
Medical subject headings
Depressive Disorder, Treatment-Resistant, Anxiety Disorders, Neurodegenerative Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ExosomesOther

    Focused ultrasound delivery of intravenously-infused exosomes

Study groups in NCT04202770
Study groupRoleWhat they receive
TreatmentExperimentalPatients deemed potentially appropriate candidates for exosome and focused ultrasound therapy for either treatment refractory depression (trMDD), anxiety, or neurodegenerative dementia will be treated with exosomes derived from healthy, full-term Cesarean section amniotic fluid. Up to one hour of transcranial focused ultrasound will be administered immediately prior to exosome treatment in an attempt to facilitate enhanced deployment to the subgenual cingulate for trMDD, the amygdala for anxiety, or the hippocampus for dementia. Target location will be determined by the physician upon enrollment depending on the patient's specific syndrome. Patients will be given 15cc of unconcentrated solution allogenic exosomes (equivalent to 21 million stem cells, Kimera Corporation) intravenously in 200 ccs of normal saline dripped over thirty minutes to one hour.
Receives: Other: Exosomes

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. [trMDD] Beck Depression Inventory (BDI-II)

    The BDI-II is a 21-question multiple-choice self-report inventory. Each question involves four possible responses, ranging in intensity from "0" (this item does not apply) to "3" (this item applies severely). The test is scored as the sum of all of the response values; this number is used to determine the severity of depressive symptoms. A score of 0 to 3 is possible for each question with a maximum total score of 63 points. The standard cutoff scores are as follows: 0-13 total points = minimal depression; 14-19 total points = mild depression; 20-28 total points = moderate depression; and 29-63 total points = severe depression. A reduction in the total score by at least 30% is considered to be clinically significant.

    Measured: 8 weeks from baseline

  2. [Anxiety] Beck Anxiety Inventory (BAI)

    The BAI is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety symptoms. Each of the 21 items asks whether the patient has experienced various anxiety symptoms in the last two weeks, and if so, how severely. Each question/answer is scored on a scale value of "0" (not at all) to "3" (severely). Higher total scores indicate more severe anxiety symptoms. The maximum total score possible is 63 points. The standard cutoff scores are: 0-7 = minimal anxiety; 8-15 = mild anxiety; 16-25 = moderate anxiety; 26-63 = severe anxiety. A reduction in score by at least 30% is considered clinically meaningful.

    Measured: 8 weeks from baseline

  3. [Dementia] Quick Dementia Rating Scale (QDRS)

    The Quick Dementia Rating Scale (QDRS) is an interview-based tool administered by study officials to participants' caregivers used to obtain observations from a consistent source. The QDRS form consists of 10 categorical questions (5 cognitive, 5 functional), each with 5 detailed options depicting the level of impairment as either 0 (normal), 0.5 (mild/inconsistent impairment), 1 (mild/consistent impairment), 2 (moderate impairment), or 3 (severe impairment). Based on the conversion table outlined in Dr. James Galvin's research (2015), total QDRS scores were converted to Clinical Dementia Rating (CDR) scale levels ranging from 0 (normal aging), 0.5 (mild cognitive impairment), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia).

    Measured: 8 weeks from baseline

  4. [ALL] Global Rating of Change (GRC)

    The GRC consists of a single likert-scale ranging from "-5" (very much worse) to "0" (neutral/no change) to "5" (very much better). The GRC is obtained in an interview format to assess a patient's perceived change in status following a treatment. A score that is at least 2 or greater is considered to indicate clinically significant change.

    Measured: 8 weeks from baseline

Secondary outcomes (5)

  1. [trMDD] Patient Depression Questionnaire (PDQ-9)

    The PDQ-9 is a 9-item, self-report questionnaire to evaluate for depressive symptoms. Each question asks the patient if they have experienced a particular depressive symptom over the past two weeks. Answers may range from "0" (not at all), "1" (several days/week), "2" (more than half of the days), and "3" (nearly every day). Maximum total score is 27 points. A higher score indicates more severe depressive symptoms. A reduction in total score by at least 30% is considered clinically meaningful.

    Measured: 8 weeks from baseline

  2. [trMDD] Hamilton Depression Rating Scale (HAM-D)

    The HAM-D is a 17-item, interview style questionnaire. A trained staff member administers this form to a patient and scores the patients' responses on a scale of "0" (symptom absent) to "4" (most severe option per symptom). A higher total score indicates a more severe level of depression. The maximum possible score is 50 points. A change in score of at least 30% is considered clinically meaningful.

    Measured: 8 weeks from baseline

  3. [Anxiety] Hamilton Anxiety Rating Scale (HAM-A)

    The HAM-A is an observer/rater scale consisting of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.

    Measured: 8 weeks from baseline

  4. [Dementia] Repeatable Battery Assessment of Neuropsychological Status (RBANS) versions A-D

    RBANS assesses immediate memory, visuospatial skill, language, attention, and delayed memory. Patient performance on each subscale immediate memory, language, attention, visuospatial, and delayed memory are scored relative to validated norms for same-aged peers. A change of 8+ points in the Total Scale score, 11+ points in the Immediate Memory score, 9+ points in the Language score, 4+ points on the Attention score, 14+ points is considered significant for the Visuospatial score, and 10+ points for the Delayed Memory score are considered significant.

    Measured: 8 weeks from baseline

  5. [Dementia] Montreal Cognitive Assessment (MoCA) versions 7.1-7.3

    The MoCA evaluates frontal-executive functions (e.g., verbal abstraction and mental calculation), language (e.g., confrontation naming, phonemic fluency), orientation (e.g., person, place, date, day of the week, and time), visuospatial construction (e.g., simple figure copy), divided visual attention, and immediate and delayed memory of unstructured information. MoCA scores range from 0-30 possible points; 26 or greater is considered to reflect normal cognitive status.

    Measured: 8 weeks from baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Dec 2019
  2. Study start1 Dec 2019
  3. Primary completionDec 2023 (estimated)
  4. Study completionDec 2024 (estimated)

Why it stopped: Pending COVID-19 pandemic; pending status of product development

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
The present study is being undertaken as an open-label study to evaluate the safety and feasibility of exosomes and concurrent focused ultrasound as an intervention for patients with refractory depression, anxiety, and cognitive impairment due to a neurodegenerative disease (e.g., Alzheimer's).
Masking
None (open label)
Enrolment
300 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04202770
Sponsor's protocol ID
ICSS-2018-018
Status last verified
Sep 2022
First submitted
16 Dec 2019
Last updated
28 Sep 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: Data from this study will not be made publicly available due to ethical and privacy concerns. Anonymized data will be available upon reasonable request from any qualified investigator.

Publications

  • Bandelow B, Michaelis S. Epidemiology of anxiety disorders in the 21st century. Dialogues Clin Neurosci. 2015 Sep;17(3):327-35. doi: 10.31887/DCNS.2015.17.3/bbandelow.

    PubMed 26487813

  • Coupe P, Manjon JV, Lanuza E, Catheline G. Lifespan Changes of the Human Brain In Alzheimer's Disease. Sci Rep. 2019 Mar 8;9(1):3998. doi: 10.1038/s41598-019-39809-8.

    PubMed 30850617

  • Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ, Vos T, Whiteford HA. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013 Nov;10(11):e1001547. doi: 10.1371/journal.pmed.1001547. Epub 2013 Nov 5.

    PubMed 24223526

  • Hebron ML, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson's disease models. Hum Mol Genet. 2013 Aug 15;22(16):3315-28. doi: 10.1093/hmg/ddt192. Epub 2013 May 10.

    PubMed 23666528

  • Pagan, F., Valadez, E., Torres-Yaghi, Y., Falconer, R., Mills, R., Rogers, S., Wilmarth, B., Hebron, M., & Moussa, C. (2016) Effects of nilotinib on safety in open-label phase I clinical trial in Parkinson's disease with dementia and Lewy body dementia. Movement Disorders, 31(2).

  • Montgomery SA, Baldwin DS, Riley A. Antidepressant medications: a review of the evidence for drug-induced sexual dysfunction. J Affect Disord. 2002 May;69(1-3):119-40. doi: 10.1016/s0165-0327(01)00313-5.

    PubMed 12103459

  • Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905.

    PubMed 17074942

  • Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009 Feb 28;373(9665):746-58. doi: 10.1016/S0140-6736(09)60046-5.

    PubMed 19185342

  • Setiawan E, Attwells S, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Xu C, Sharma S, Kish S, Houle S, Meyer JH. Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study. Lancet Psychiatry. 2018 Apr;5(4):339-347. doi: 10.1016/S2215-0366(18)30048-8. Epub 2018 Feb 26.

    PubMed 29496589

  • Drevets WC, Savitz J, Trimble M. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 2008 Aug;13(8):663-81. doi: 10.1017/s1092852900013754.

    PubMed 18704022

  • Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008 Sep 15;64(6):461-7. doi: 10.1016/j.biopsych.2008.05.034. Epub 2008 Jul 18.

    PubMed 18639234

  • Jalbrzikowski M, Larsen B, Hallquist MN, Foran W, Calabro F, Luna B. Development of White Matter Microstructure and Intrinsic Functional Connectivity Between the Amygdala and Ventromedial Prefrontal Cortex: Associations With Anxiety and Depression. Biol Psychiatry. 2017 Oct 1;82(7):511-521. doi: 10.1016/j.biopsych.2017.01.008. Epub 2017 Jan 17.

    PubMed 28274468

  • Mayberg H. Depression, II: localization of pathophysiology. Am J Psychiatry. 2002 Dec;159(12):1979. doi: 10.1176/appi.ajp.159.12.1979. No abstract available.

    PubMed 12450943

  • Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997 Summer;9(3):471-81. doi: 10.1176/jnp.9.3.471.

    PubMed 9276848

  • Mayberg HS. Modulating limbic-cortical circuits in depression: targets of antidepressant treatments. Semin Clin Neuropsychiatry. 2002 Oct;7(4):255-68. doi: 10.1053/scnp.2002.35223.

    PubMed 12382208

Questions about this trial

What is this clinical trial studying?

A study testing Exosomes in people with Refractory Depression and Anxiety Disorders, run by Neurological Associates of West Los Angeles at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: paused, as of the sponsor's last update on 28 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

[trMDD] Beck Depression Inventory (BDI-II) (time frame: 8 weeks from baseline). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04202770, which also lists 38 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2022.

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