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Intranasal Inhalations of Bioactive Factors Produced by M2 Macrophages in Patients With Organic Brain Syndrome

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ClinicalTrials.gov Identifier: NCT02957123
Recruitment Status : Completed
First Posted : November 6, 2016
Results First Posted : February 18, 2021
Last Update Posted : February 18, 2021
Information provided by (Responsible Party):
Alexander A Ostanin, Russian Academy of Medical Sciences

Brief Summary:
The investigators have designed an innovative proof-of-concept trial designed to provide data as to whether the treatment/rehabilitation efficacy and functional outcome of patients with organic brain syndrome are improved with intranasal inhalations of bioactive factors (BF), produced by autologous M2 macrophages (auto-M2-BFs). The rationale for this approach is the ability of central nervous system to repair and the important role of macrophages in the regulation of this process. It was found that type 2 macrophages have anti-inflammatory and reparative potential, whereas M1 cells possess pro-inflammatory and neurotoxic effects. Action of M2 macrophages is largely realized through the production a wide variety of bioactive factors (cytokines, chemokines, growth factors, neuropeptides, microvesicles etc) that inhibit inflammation, protect neurons from apoptosis, stimulate neurogenesis, the growth and remyelination of axons, the formation of new synapses and activate angiogenesis. This study uses auto-M2-BFs, as therapeutic agents and intranasal administration focusing on nose to brain transport, as a mode of delivery. Expected clinical effects in treated subjects: improvement of cognitive functions (memory, language, attention); correction of focal neurological deficit (paresis, spasticity, sensory disorders); reduction vestibular/ataxic disorders (vertigo, unsteadiness when walking); reduction of headaches; reduction of asthenia (weakness, fatigue); correction of emotional disorders (anxiety, depression).

Condition or disease Intervention/treatment Phase
Organic Brain Syndrome, Nonpsychotic Neurocognitive Disorders Mental Disorder, Organic Delirium, Dementia, Amnestic, Cognitive Disorders Nonpsychotic Organic Brain Syndrome Organic Mental Disorder Encephalopathy, Post-Traumatic, Chronic Encephalopathy, Ischemic Brain Ischemia Drug: Intranasal auto-M2-BFs Phase 1 Phase 2

Detailed Description:

Following injury to the central nervous system (CNS), immune-mediated inflammation profoundly affects the ability of neural cells to survive and to regenerate. The role of inflammation comprises mostly of macrophages, is controversial, since macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages may be conditioned by their functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in CNS repair. Using low serum conditions the investigators have generated M2-like macrophages and evaluated their phenotypic and functional features [1, 2]. Our data indicate that M2 macrophages, in contrast to pro-inflammatory M1 cells, produced significantly lower levels of pro-inflammatory cytokines (IL-1β, tumor necrosis factor-α, IL-6, IL-18, IL-12), chemokines (IL-8, monocyte chemoattractant protein 1-1) and Th1/Th2-cytokines (interferon-γ, IL-2, IL-4) coupled with a higher IL-10 level. M2 macrophages were capable of producing neurotrophic- (brain-derived neurotrophic factor,insulin-like growth factor-1), angiogenic- (vascular endothelial growth factor), and other growth factors (erythropoietin, granulocyte-colony stimulating factor , basic fibroblast growth factor, epidermal growth factor) with neuroprotective and regenerative activity.

Our pilot clinical trials have demonstrated the safety and clinical efficacy of intrathecal administration of M2 macrophages in children with severe cerebral palsy [3] and in non-acute stroke patients [4].

Since cell-free culture medium of M2 macrophages contains a wide variety of neurotrophic, immunoregulatory and pro-angiogenic factors, the investigators expect that intranasal administration of these auto-M2-BFs will improve the treatment/rehabilitation efficacy and functional outcome of patients with organic brain syndrome. Of note, intranasal administration of M2-macrophage soluble factors allow to delivery bioactive agents to brain through the olfactory and trigeminal ways across brain-blood barrier.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety/Efficacy of Intranasally-Administered Bioactive Factors Produced by Autologous M2 Macrophages in Patients With Organic Brain Syndrome
Actual Study Start Date : March 2016
Actual Primary Completion Date : September 2020
Actual Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Intranasal auto-M2-BFs

Intranasally-Administered Bioactive Factors, Produced by Autologous M2 Macrophage (auto-M2-BFs). M2 macrophages were generated in vitro from peripheral blood of patients during 7 days.Cell-free culture medium, containing auto-M2-BFs, was collected and aliquots of 2 mL/vial were cryopreserved.

30 patients with organic brain syndrome will receive auto-M2-BFs with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.

Drug: Intranasal auto-M2-BFs
Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Other Name: Bioactive Factors, Produced by M2 Macrophage

Primary Outcome Measures :
  1. The Number of Patients With Severe Adverse Events and Adverse Reactions [ Time Frame: up to 6 months after treatment ]
    Occurrence of severe adverse events and adverse reactions (allergic, toxic, inflammatory reactions; neurological deterioration, convulsive syndrome)

Secondary Outcome Measures :
  1. Change in Subjective Assessment of Clinical Symptoms (SACS) [ Time Frame: Baseline and 6 months after treatment ]
    Subjective Assessment of Clinical Symptoms (SACS) is a 5-point rating scale with standardized criteria (0 - no; 1 - mild; 2 - moderate; 3 - severe; 4 - intensive) subjective assessment of the severity of fifteen clinical symptoms most characteristic of neurological disorders (headache, dizziness, gait disturbance, speech, visual impairment, tremor et al). Minimum SACS "total" score is 0, and maximum SACS "total" score is 60. Neurological improvements are assessed by SACS "total" score as > 6 points' reduction from baseline.

  2. Change in Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Baseline and 6 months after treatment ]
    Hospital Anxiety and Depression Scale (HADS) is used to diagnose anxiety/depression symptoms (absence - 0~7 points; subclinical form - 8~10 points; clinical form - 11 points or more). Minimum HADS "total" score (anxiety + depression subscale) is 0, and maximum HADS "total" score is 42. Improvements in patients with anxiety/depression symptoms are assessed by HADS "total" score as > 4 points reduction from baseline.

  3. Change in Functional Mobility Assessment (FMA) Scale [ Time Frame: Baseline and 6 months after treatment ]

    Functional Mobility Assessment (FMA) iscale is designed to evaluate parameters characterizing stability (0~24 points) and gait (0~16 points).

    The maximum FMA "total" score on stability and gait subscales is 39-40 and corresponds to the norm, minimum FMA "total" score is 0 and corresponds to the gross impairment. The degree of impairment of "total" score is divided into significant (0~20 points), moderate (21~33 points), and light (34~38 points), whereas 39~40 points indicate no impairments. Improved mobility is assessed as FMA "total" score enhancement > 4 points from baseline.

  4. Change in Montreal Cognitive Assessment (МоСА) [ Time Frame: Baseline and 6 months after treatment ]
    Montreal Cognitive Assessment (MoCa) is used to assess cognitive functions. The maximum MoCa "total" score is 26-30 points and corresponds to the norm, 19-25 points - mild cognitive disorder; 11-21 points - dementia. Improvements in patients with cognitive disorder are assessed as MoCA "total" score increase > 3 points from baseline.

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Adults: age 18 - 80
  • Persistent neurological deficits (cognitive, mental, motor, vestibular/ataxic disorders as a result of trauma, cardiovascular, neurodegenerative and others cerebral injuries), confirmed clinically and by CT or MRI
  • A written informed consent of the patient or close relatives

Exclusion Criteria:

  • Psychiatric disorders
  • Seizures
  • Severe dementia
  • Hepatic or renal dysfunctions
  • Hemodynamic or respiratory instability
  • HIV or uncontrolled bacterial, fungal, or viral infections
  • Pregnancy
  • Malignancy
  • Intolerance to gentamicin and / or multiple drug allergies
  • Participation in other clinical trials

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): NCT02957123

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Russian Federation
Institute of Fundamental and Clinical Immunology
Novosibirsk, Russian Federation, 630099
Sponsors and Collaborators
Russian Academy of Medical Sciences
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Study Chair: Elena R Chernykh, MD, PhD Institute of Fundamental and Clinical Immunology
Principal Investigator: Alexander A Ostanin, MD, PhD Institute of Fundamental and Clinical Immunology
  Study Documents (Full-Text)

Documents provided by Alexander A Ostanin, Russian Academy of Medical Sciences:
Study Protocol  [PDF] October 11, 2015
Informed Consent Form  [PDF] October 11, 2015
Statistical Analysis Plan  [PDF] October 11, 2015

Additional Information:
Publications of Results:
Shevela EY., Davydova MN, Starostina NM, Yankovskaya AA, Ostanin AA, Chernykh ER. Intranasal delivery of M2 macrophage-derived soluble products reduces neurological deficit in patients with cerebrovascular disease: A Pilot Study. Journal of Neurorestoratology, 2019; 7: 89-100 doi:10.26599/JNR.2019.9040010

Other Publications:
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Responsible Party: Alexander A Ostanin, Head of Clinical Department, Russian Academy of Medical Sciences
ClinicalTrials.gov Identifier: NCT02957123    
Other Study ID Numbers: IFCI-25/05/2015
First Posted: November 6, 2016    Key Record Dates
Results First Posted: February 18, 2021
Last Update Posted: February 18, 2021
Last Verified: February 2021
Keywords provided by Alexander A Ostanin, Russian Academy of Medical Sciences:
macrophages M2 type
intranasal administration
organic brain syndrome
neurocognitive disorders
Additional relevant MeSH terms:
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Brain Diseases
Brain Ischemia
Chronic Traumatic Encephalopathy
Mental Disorders
Psychotic Disorders
Neurocognitive Disorders
Cognition Disorders
Pathologic Processes
Central Nervous System Diseases
Nervous System Diseases
Schizophrenia Spectrum and Other Psychotic Disorders
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Brain Injuries, Traumatic
Brain Injuries
Brain Injury, Chronic
Neurodegenerative Diseases
Craniocerebral Trauma
Trauma, Nervous System
Wounds and Injuries